Podcasts about ldls

What if everything we thought we knew about cholesterol and heart disease risk… doesn't apply to everyone?In this episode, world-renowned cardiologist Dr. Matthew Budoff unpacks the results of a landmark one-year study tracking 100 lean, metabolically healthy individuals on a ketogenic diet with extremely elevated LDL levels.Dr. Budoff is the Program Director, Director of Cardiac CT, and the endowed chair of preventive cardiology at The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center.In this interview, Dr. Scher and Dr. Budoff further break down the results of his new publication, which used advanced imaging to demonstrate that LDL cholesterol and ApoB levels are not associated with plaque progression in Lean-Mass Hyper Responders following a ketogenic diet.

Today, I am excited to share the first class in a series of lipid masterclasses with the amazing Dr. Thomas Dayspring! Dr. Dayspring is certified in internal medicine and clinical epidemiology and is a fellow of the American College of Physicians and the National Lipid Association. He was previously the Educational Director of a nonprofit organization and has served as the Chief Academic Advisor for two major cardiovascular labs.  Due to the in-depth nature of my discussions with Dr. Dayspring over several sessions, each lasting nearly six hours, it seemed logical to present these masterclasses in segmented chunks to make them easier to understand. In our first class today, we dive into the fundamentals, exploring what lipids are and how lipids and fatty acids are classified. We cover the physiology and transportation of cholesterol and the role of apoptosis, apo-proteins, and apo-lipoproteins, unravel the differences between HDL, LDL, IDL, and VLDL, and explain how to calculate LDLs and triglycerides for assessing metabolic health. Dr. Dayspring also shares his preferences regarding lab values and the indicators that provide information to help him determine the early risk of cardiovascular disease. We get into some detailed aspects of physical chemistry in this episode, so I highlight the main clinical points throughout our conversation to make it more understandable. Be sure to join Dr. Dayspring and me for our next episode in the lipid masterclass series. IN THIS EPISODE YOU WILL LEARN: What are lipids, and why are they important? Dr. Dayspring explains what triglycerides are. How lipids get absorbed and transported throughout the body What lipoproteins are, and how they get classified How cholesterols get calculated The impact of triglycerides on cholesterol levels and cardiovascular health How high triglyceride levels can indicate early insulin resistance or increased ASCVD risk What is the role of HDL particles? How metabolic syndrome impacts cardiovascular health Bio: Thomas Dayspring MD is a Fellow of both the American College of Physicians and the National Lipid Association and is certified in internal medicine and clinical lipidology. After practicing in New Jersey for 37 years, in 2012, he moved to Virginia. He served as an educational director for a nonprofit cardiovascular foundation and until mid-2019 as a Chief Academic Advisor for two major CV laboratories. Since then, he has served as a virtual cardiovascular / lipidology educator. Career-wise he has given over 4000 domestic (in all 50 states) and several international lectures, including over 600 CME programs on atherothrombosis, lipids/lipoproteins (and their treatment), vascular biology, biomarker testing, and women's cardiovascular issues. He has authored several manuscripts and lipid textbook chapters and performed several podcasts. For several years he was an Associate Editor of the Journal of Clinical Lipidology. He was the recipient of the 2011 National Lipid Association's Presidents Award for services to clinical lipidology and the 2023 Foundation of NLA Clinician/Educator Award. He has over 34K followers on his educational Twitter (X) feed (@Drlipid). He has Gold Heart Member status as a professional member of the American Heart Association and serves as a Social Media Ambassador for the European Atherosclerosis Society and the National Lipid Association. Connect with Cynthia Thurlow Follow on Twitter, Instagram & LinkedIn Check out Cynthia's website Submit your questions to support@cynthiathurlow.com Connect with Dr. Thomas Dayspring Twitter (@DrLipid) LinkedIn

Welcome back, Mayhem Mommas!! This week, hear Mel share her recent misadventures driving back from Ohio in the midst of Hurricane Debby, aka Debby Downer! Next, Miranda discusses a corny, yet beneficial topic in the world of parenting... family meetings! What are they, why should you have them, and what should you talk about to make sure your fam is all on the same page when the calendars and the chaos collide. Lastly, Mel delves into a medical mystery we hear a lot about, but may not fully understand-- cholesterol! After this episode, you'll be able to rattle off the nuances between HDLs and LDLs, and maybe even triglycerides! Grab yourself a heart-healthy snack (like oatmeal with some almonds) and let's dive in to learn more! #cholesterol #hearthealth #familymeetings #parenting #motherhoodSpotlight: The American Heart Association www.heart.org From humble beginnings, the AHA has grown into the nation's oldest and largest voluntary organization dedicated to fighting heart disease and stroke. A shared focus on cardiovascular health unites our more than 35 million volunteers and supporters as well as our more than 2,900 employees.Sources: Mel-https://www.heart.org/en/health-topics/cholesterol/about-cholesterolhttps://my.clevelandclinic.org/health/articles/23922-what-is-cholesterolMiranda-https://centerforparentingeducation.org/library-of-articles/healthy-communication/family-meetings-power-working-together/https://www.healthychildren.org/English/family-life/family-dynamics/Pages/How-to-Have-a-Family-Meeting.aspx Hosted on Acast. See acast.com/privacy for more information.

Pradeep is a brilliant geneticist and Director of Preventive Cardiology, holds the Paul & Phyllis Fireman Endowed Chair in Vascular Medicine at Mass General Hospital and on faculty at Harvard Medical School and the Broad Institute. His prolific research has been illuminating for the field of improving our approach to reduce the risk of heart disease. That's especially important because heart disease is the global (and US) #1 killer and is on the increase. We didn't get into lifestyle factors here since there was so much ground to cover on new tests. drugs, and strategies.A video snippet of our conversation on ApoB. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to key publications and audioEric Topol (00:06):Well, welcome to Ground Truths. I'm Eric Topol and with me is Pradeep Natarajan from Harvard. He's Director of Preventative Cardiology at the Mass General Brigham Health System and he has been lighting it up on the field of cardiovascular. We're going to get to lots of different parts of that story and so, Pradeep welcome.Pradeep Natarajan (00:31):Thanks Eric, really delighted and honored to be with you and have this discussion.Eric Topol (00:36):Well, for years I've been admiring your work and it's just accelerating and so there's so many things to get to. I thought maybe what we'd start off with is you recently wrote a New England Journal piece about two trials, two different drugs that could change the landscape of cardiovascular prevention in the future. I mean, that's one of the themes we're going to get to today is all these different markers and drugs that will change cardiology as we know it now. So maybe you could just give us a skinny on that New England Journal piece.Two New Lipid Targets With RNA DrugsPradeep Natarajan (01:16):Yeah, yeah, so these two agents, the trials were published at the same time. These phase two clinical trials for plozasiran, which is an siRNA against APOC3 and zodasiran, which is an siRNA against ANGPTL3. The reason why we have medicines against those targets are based on human genetics observations, that individuals with loss of function mutations and either of those genes have reduced lipids. For APOC3, it's reduced triglycerides for ANGPTL3 reduced LDL cholesterol and reduced triglycerides and also individuals that have those loss of function mutations also have lower risk for coronary artery disease. Now that's a very similar parallel to PCSK9. We have successful medicines that treat that target because people have found that carriers of loss of function mutations in PCSK9 lead to lower LDL cholesterol and lower coronary artery disease.(02:11):Now that suggests that therapeutic manipulation without significant side effects from the agents themselves for APOC3 and ANGPTL3 would be anticipated to also lower coronary artery disease risk potentially in complementary pathways to PCSK9. The interesting thing with those observations is that they all came from rare loss of function mutations that are enriched in populations of individuals. However, at least for PCSK9, has been demonstrated to have efficacy in large groups of individuals across different communities. So the theme of that piece was really just the need to study diverse populations because those insights are not always predictable about which communities are going to have those loss of function mutations and when you find them, they often have profound insights across much larger groups of individuals.Eric Topol (03:02):Well, there's a lot there that we can unpack a bit of it. One of them is the use of small interfering RNAs (siRNA) as drugs. We saw in the field of PCSK9, as you mentioned. First there were monoclonal antibodies directed against this target and then more recently, there's inclisiran which isn't an RNA play if you will, where you only have to take it twice a year and supposedly it's less expensive and I'm still having trouble in my practice getting patients covered on their insurance even though it's cheaper and much more convenient. But nonetheless, now we're seeing these RNA drugs and maybe you could comment about that part and then also the surprise that perhaps is unexplained is the glucose elevation.Pradeep Natarajan (03:53):Yeah, so for medicines and targets that have been discovered through human genetics, those I think are attractive for genetic-based therapies and longer interval dosing for the therapies, which is what siRNAs allow you to do because the individuals that have these perturbations, basically the naturally occurring loss of function mutations, they have these lifelong, so basically have had a one-time therapy and have lived, and so far, at least for these targets, have not had untoward side effects or untoward phenotypic consequences and only reduce lipids and reduce coronary artery disease. And so, instead of taking a pill daily, if we have conviction that that long amount of suppression may be beneficial, then longer interval dosing and not worrying about the pill burden is very attractive specifically for those specific therapeutics. And as you know, people continue to innovate on further prolonging as it relates to PCSK9.(04:57):Separately, some folks are also developing pills because many people do feel that there's still a market and comfort for daily pills. Now interestingly for the siRNA for zodasiran at the highest dose, actually for both of them at the highest doses, but particularly for zodasiran, there was an increase in insulin resistance parameters actually as it relates to hyperglycemia and less so as it relates to insulin resistance, that is not predicted based on the human genetics. Individuals with loss of function mutations do not have increased risks in hyperglycemia or type 2 diabetes, so that isolates it related to that specific platform or that specific technology. Now inclisiran, as you'd mentioned, Eric is out there. That's an siRNA against PCSK9 that's made by a different manufacturer. So far, the clinical trials have not shown hyperglycemia or type 2 diabetes as it relates inclisiran, so it may be related to the specific siRNAs that are used for those targets. That does merit further consideration. Now, the doses that the manufacturers do plan to use in the phase three clinical trials are at lower doses where there was not an increase in hyperglycemia, but that does merit further investigation to really understand why that's the case. Is that an expected generalized effect for siRNAs? Is it related to siRNAs for this specific target or is it just related to the platform used for these two agents which are made by the same manufacturer?Eric Topol (06:27):Right, and I think the fact that it's a mystery is intriguing at the least, and it may not come up at the doses that are used in the trials, but the fact that it did crop up at high doses is unexpected. Now that is part of a much bigger story is that up until now our armamentarium has been statins and ezetimibe to treat lipids, but it's rapidly expanding Lp(a), which for decades as a cardiologist we had nothing to offer. There may even be drugs to be able to lower people who are at high risk with high Lp(a). Maybe you could discuss that.What About Lp(a)?Pradeep Natarajan (07:13):Yeah, I mean, Eric, as you know, Lp(a) has been described as a cardiovascular disease risk factors for quite so many years and there are assays to detect lipoprotein(a) elevation and have been in widespread clinical practice increasing widespread clinical practice, but we don't yet have approved therapies. However, there is an abundance of literature preclinical data that suggests that it likely is a causal factor, meaning that if you lower lipoprotein(a) when elevated, you would reduce the risk related to lipoprotein(a). And a lot of this comes from similar human genetic studies. The major challenge of just relating a biomarker to an outcome is there are many different reasons why a biomarker might be elevated, and so if you detect a signal that correlates a biomarker, a concentration to a clinical outcome, it could be related to that biomarker, but it could be to the other reasons that the biomarker is elevated and sometimes it relates to the outcome itself.(08:10):Now human genetics is very attractive because if you find alleles that strongly relate to that exposure, you can test those alleles themselves with the clinical outcome. Now the allele assignment is established at birth. No other factor is going to change that assignment after conception, and so that provides a robust, strong causal test for that potential exposure in clinical outcome. Now, lipoprotein(a) is unique in that it is highly heritable and so there are lots of different alleles that relate to lipoprotein(a) and so in a well powered analysis can actually test the lipoprotein(a) SNPs with the clinical outcomes and similar to how there is a biomarker association with incident myocardial infarction and incident stroke, the SNPs related to lipoprotein(a) show the same. That is among the evidence that strongly supports that this might be causal. Now, fast forward to many years later, we have at least three phase three randomized clinical trials testing agents that have been shown to be very potent at lowering lipoprotein(a) that in the coming years we will know if that hypothesis is true. Importantly, we will have to understand what are the potential side effects of these medicines. There are antisense oligonucleotides and siRNAs that are primarily in investigation. Again, this is an example where there's a strong genetic observation, and so these genetic based longer interval dosing therapies may be attractive, but side effects will be a key thing as well too. Those things hard to anticipate really can anticipate based on the human genetics for off target effects, for example.(09:52):It's clearly a risk signal and hopefully in the near future we're going to have specific therapies.Eric Topol (09:57):Yeah, you did a great job of explaining Mendelian randomization and the fact the power of genetics, which we're going to get into deeper shortly, but the other point is that do you expect now that there's these multiple drugs that lower Lp(a) efficiently, would that be enough to get approval or will it have to be trials to demonstrate improved cardiovascular outcomes?Pradeep Natarajan (10:24):There is a great regulatory path at FDA for approval just for LDL cholesterol lowering and inclisiran is on the market and the phase three outcomes data has not yet been reported because there is a wide appreciation that LDL cholesterol lowering is a pretty good surrogate for cardiovascular disease risk lowering. The label will be restricted to LDL cholesterol lowering and then if demonstrated to have clinical outcomes, the label could be expanded. For other biomarkers including lipoprotein(a), even though we have strong conviction that it is likely a causal factor there hasn't met the bar yet to get approval just based on lipoprotein(a) lowering, and so we would need to see the outcomes effects and then we would also need to understand side effects. There is a body of literature of side effects for other therapies that have targeted using antisense oligonucleotides. We talked about potential side effects from some siRNA platforms and sometimes those effects could overtake potential benefits, so that really needs to be assessed and there is a literature and other examples.(11:31):The other thing I do want to note related to lipoprotein(a) is that the human genetics are modeled based on lifelong perturbations, really hard to understand what the effects are, how great of an effect there might be in different contexts, particularly when introduced in middle age. There's a lot of discussion about how high lipoprotein(a) should be to deliver these therapies because the conventional teaching is that one in five individuals has high lipoprotein(a), and that's basically greater than 75 nanomoles per liter. However, some studies some human genetic studies to say if you want to get an effect that is similar to the LDL cholesterol lowering medicines on the market, you need to start with actually higher lipoprotein(a) because you need larger amounts of lipoprotein(a) lowering. Those are studies and approaches that haven't been well validated. We don't know if that's a valid approach because that's modeling based on this sort of lifelong effect. So I'm very curious to see what the overall effect will be because to get approval, I think you need to demonstrate safety and efficacy, but most importantly, these manufacturers and we as clinicians are trying to find viable therapies in the market that it won't be hard for us to get approval because hopefully the clinical trial will have said this is the context where it works. It works really well and it works really well on top of the existing therapies, so there are multiple hurdles to actually getting it directly to our patients.How Low Do You Go with LDL Cholesterol?Eric Topol (13:02):Yeah, no question about that. I'm glad you've emphasized that. Just as you've emphasized the incredible lessons from the genetics of people that have helped guide this renaissance to better drugs to prevent cardiovascular disease. LDL, which is perhaps the most impressive surrogate in medicine, a lab test that you already touched on, one of the biggest questions is how low do you go? That is Eugene Braunwald, who we all know and love. They're in Boston. The last time I got together with him, he was getting his LDL down to close to zero with various tactics that might be extreme. But before we leave these markers, you're running preventive cardiology at man's greatest hospital. Could you tell us what is your recipe for how aggressive do you go with LDL?Pradeep Natarajan (14:04):Yeah, so when I talk to patients where we're newly getting lipid lowering therapies on, especially because many people don't have a readout of abnormal LDL cholesterol when we're prescribing these medicines, it's just giving them a sense of what we think an optimal LDL cholesterol might be. And a lot of this is based on just empirical observations. So one, the average LDL cholesterol in the modern human is about 100 to 110 mg/dL. However, if you look at contemporary hunter gatherers and non-human primates, their average LDL is about 40 to 50 and newborn babies have an LDL cholesterol of about 30. And the reason why people keep making LDL cholesterol lowering medicines because as you stack on therapies, cardiovascular disease events continue to reduce including down to these very low LDL cholesterol values. So the population mean for LDL cholesterol is high and everybody likely has hypercholesterolemia, and that's because over the last 10,000 years how we live our lives is so dramatically different and there has not been substantial evolution over that time to change many of these features related to metabolism.(15:16):And so, to achieve those really low LDL cholesterol values in today's society is almost impossible without pharmacotherapies. You could say, okay, maybe everybody should be on pharmacotherapies, and I think if you did that, you probably would reduce a lot of events. You'll also be treating a lot of individuals who likely would not get events. Cardiovascular disease is the leading killer, but there are many things that people suffer from and most of the times it still is not cardiovascular disease. So our practice is still rooted in better identifying the individuals who are at risk for cardiovascular disease. And so, far we target our therapies primarily in those who have already developed cardiovascular disease. Maybe we'll talk about better identifying those at risk, but for those individuals it makes lots of sense to get it as low as possible. And the field has continued to move to lower targets.(16:07):One, because we've all recognized, at least based on these empirical observations that lower is better. But now increasingly we have a lot of therapies to actually get there, and my hope is that with more and more options and the market forces that influence that the cost perspective will make sense as we continue to develop more. As an aside, related aside is if you look at the last cholesterol guidelines, this is 2018 in the US this is the first time PCSK9 inhibitors were introduced in the guidelines and all throughout that there was discussions of cost. There are a lot of concerns from the field that PCSK9 inhibitors would bankrupt the system because so many people were on statins. And you look at the prior one that was in 2013 and cost was mentioned once it's just the cost effectiveness of statins. So I think the field has that overall concern.(17:01):However, over time we've gotten comfortable with lower targets, there are more medicines and I think some of this competition hopefully will drive down some of the costs, but also the overall appreciation of the science related to LDL. So long-winded way of saying this is kind of the things that we discussed just to give reassurance that we can go to low LDL cholesterol values and that it's safe and then we think also very effective. Nobody knows what the lower limit is, whether zero is appropriate or not. We know that glucose can get too low. We know that blood pressure can be too low. We don't know yet that limit for LDL cholesterol. I mean increasingly with these trials we'll see it going down really low and then we'll better appreciate and understand, so we'll see 40 is probably the right range.Eric Topol (17:49):40, you said? Yeah, okay, I'll buy that. Of course, the other thing that we do know is that if you push to the highest dose statins to get there, you might in some people start to see the hyperglycemia issue, which is still not fully understood and whether that is, I mean it's not desirable, but whether or not it is an issue, I guess it's still out there dangling. Now the other thing that since we're on LDL, we covered Lp(a), PCSK9, the siRNA, is ApoB. Do you measure ApoB in all your patients? Should that be the norm?Measuring ApoBPradeep Natarajan (18:32):Yeah, so ApoB is another blood test. In the standard lipid panel, you get four things. What's measured is cholesterol and triglycerides, they're the lipids insoluble in blood to get to the different tissues that get packaged in lipoprotein molecules which will have the cholesterol, triglycerides and some other lipids and proteins. And so, they all have different names as you know, right? Low density lipoprotein, high density lipoprotein and some others. But also in the lipid panel you get the HDL cholesterol, the amount of cholesterol in an HDL particle, and then most labs will calculate LDL cholesterol and LDL cholesterol has a nice relationship with cardiovascular disease. You lower it with statins and others. Lower risk for cardiovascular disease, turns out a unifying feature of all of these atherogenic lipoproteins, all these lipoproteins that are measured and unmeasured that relate to cardiovascular disease, including lipoprotein(a), they all have an additional protein called ApoB. And ApoB, at least as it relates to LDL is a pretty good surrogate of the number of LDL particles.(19:37):Turns out that that is a bit better at the population level at predicting cardiovascular disease beyond LDL cholesterol itself. And where it can be particularly helpful is that there are some patients out there that have an unexpected ratio between ApoB and LDL. In general, the ratio between LDL cholesterol and ApoB is about 1.1 and most people will have that rough ratio. I verify that that is the expected, and then if that is the expected, then really there is no role to follow ApoB. However, primarily the patients that have features related to insulin resistance have obesity. They may often have adequate looking LDL cholesterols, but their ApoB is higher. They have more circulating LDL particles relative to the total amount of LDL cholesterol, so smaller particles themselves. However, the total number of particles may actually be too high for them.(20:34):And so, even if the LDL cholesterol is at target, if the ApoB is higher, then you need to reduce. So usually the times that I just kind of verify that I'm at appropriate target is I check the LDL cholesterol, if that looks good, verify with the ApoB because of this ratio, the ApoB target should be about 10% lower. So if we're aiming for about 40, that's like 36, so relatively similar, and if it's there, I'm good. If it's not and it's higher, then obviously increase the LDL cholesterol lowering medicines because lower the ApoB and then follow the ApoB with the lipids going forward. The European Society of Cardiology has more emphasis on measuring ApoB, that is not as strong in the US guidelines, but there are many folks in the field, preventive cardiologists and others that are advocating for the increasing use of ApoB because I think there are many folks that are not getting to the appropriate targets because we are not measuring ApoB.Why Aren't We Measuring and Treating Inflammation?Eric Topol (21:37):Yeah, I think you reviewed it so well. The problem here is it could be part of the standard lipid panel, it would make this easy, but what you've done is a prudent way of selecting out people who it becomes more important to measure and moderate subsequently. Now this gets us to the fact that we're lipid centric and we don't pay homage to inflammation. So I wrote a recent Substack on the big miss on inflammation, and here you get into things like the monoclonal antibody to interleukin-6, the trial that CANTOS that showed significant reduction in cardiovascular events and fatal cancers by the way. And then you get into these colchicine trials two pretty good size randomized trials, and here the entry was coronary disease with a high C-reactive protein. Now somehow or other we abandon measuring CRP or other inflammatory markers, and both of us have had patients who have low LDLs but have heart attacks or significant coronary disease. So why don't we embrace inflammation? Why don't we measure it? Why don't we have better markers? Why is this just sitting there where we could do so much better? Even agents that are basically cost pennies like colchicine at low doses, not having to use a proprietary version could be helpful. What are your thoughts about us upgrading our prevention with inflammation markers?Pradeep Natarajan (23:22):Yeah, I mean, Eric, there is an urgent need to address these other pathways. I say urgent need because heart disease has the dubious distinction of being the leading killer in the US and then over the last 20 years, the leading killer in the world as it takes over non-communicable diseases. And really since the early 1900s, there has been a focus on developing pharmacotherapies and approaches to address the traditional modifiable cardiovascular disease risk factors. That has done tremendous good, but still the curves are largely flattening out. But in the US and in many parts of the world, the deaths attributable to cardiovascular disease are starting to tick up, and that means there are many additional pathways, many of them that we have well recognized including inflammation. More recently, Lp(a) that are likely important for cardiovascular disease, for inflammation, as you have highlighted, has been validated in randomized controlled trials.(24:18):Really the key trial that has been more most specific is one on Canakinumab in the CANTOS trial IL-1β monoclonal antibody secondary prevention, so cardiovascular disease plus high C-reactive protein, about a 15% reduction in cardiovascular disease and also improvement in cancer related outcomes. Major issues, a couple of issues. One was increased risk for severe infections, and the other one is almost pragmatic or practical is that that medicine was on the market at a very high price point for rare autoinflammatory conditions. It still is. And so, to have for a broader indication like cardiovascular disease prevention would not make sense at that price point. And the manufacturer tried to go to the FDA and focus on the group that only had C-reactive protein lowering, but that's obviously like a backwards endpoint. How would you know that before you release the medicine? So that never made it to a broader indication.(25:14):However, that stuck a flag in the broader validation of that specific pathway in cardiovascular disease. That pathway has direct relevance to C-reactive protein. C-reactive protein is kind of a readout of that pathway that starts from the NLRP3 inflammasome, which then activates IL-1β and IL-6. C-reactive protein we think is just a non causal readout, but is a reliable test of many of these features and that's debatable. There may be other things like measuring IL-6, for example. So given that there is actually substantial ongoing drug development in that pathway, there are a handful of companies with NLRP3 inflammasome inhibitors, but small molecules that you can take as pills. There is a monoclonal antibody against IL-6 that's in development ziltivekimab that's directed at patients with chronic kidney disease who have lots of cardiovascular disease events despite addressing modifiable risk factors where inflammatory markers are through the roof.(26:16):But then you would also highlighted one anti-inflammatory that's out there that's pennies on the dollar, that's colchicine. Colchicine is believed to influence cardiovascular disease by inhibiting NLRP3, I say believed to. It does a lot of things. It is an old medicine, but empirically has been shown in at least two randomized controlled trials patients with coronary artery disease, actually they didn't measure C-reactive protein in the inclusion for these, but in those populations we did reduce major adverse cardiovascular disease events. The one thing that does give me pause with colchicine is that there is this odd signal for increased non-cardiovascular death. Nobody understands if that's real, if that's a fluke. The FDA just approved last year low dose colchicine, colchicine at 0.5 milligrams for secondary prevention given the overwhelming efficacy. Hasn't yet made it into prevention guidelines, but I think that's one part that does give me a little bit pause. I do really think about it particularly for patients who have had recurrent events. The people who market the medicine and do research do remind us that C-reactive protein was not required in the inclusion, but nobody has done that secondary assessment to see if measuring C-reactive protein would be helpful in identifying the beneficial patients. But I think there still could be more work done on better identifying who would benefit from colchicine because it's an available and cheap medicine. But I'm excited that there is a lot of development in this inflammation area.Eric Topol (27:48):Yeah, well, the development sounds great. It's probably some years away. Do you use colchicine in your practice?Pradeep Natarajan (27:56):I do. Again, for those folks who have had recurrent events, even though C-reactive protein isn't there, it does make me feel like I'm treating inflammation. If C-reactive protein is elevated and then I use it for those patients, if it's not elevated, it's a much harder sell from my standpoint, from the patient standpoint. At the lower dose for colchicine, people generally are okay as far as side effects. The manufacturer has it at 0.5 milligrams, which is technically not pennies on the dollar. That's not generic. The 0.6 milligrams is generic and they claim that there is less side effects at the 0.5 milligrams. So technically 0.6 milligrams is off label. So it is what it is.CHIP and Defining High Risk People for CV DiseaseEric Topol (28:40):It's a lot more practical, that's for sure. Now, before I leave that, I just want to mention when I reviewed the IL-1β trial, you mentioned the CANTOS trial and also the colchicine data. The numbers of absolute increases for infection with the antibody or the cancers with the colchicine are really small. So I mean the benefit was overriding, but I certainly agree with your concern that there's some things we don't understand there that need to be probed more. Now, one of the other themes, well before one other marker that before we get to polygenic risk scores, which is center stage here, defining high risk people. We've talked a lot about the conventional things and some of the newer ways, but you've been one of the leaders of study of clonal hematopoiesis of indeterminate potential known as CHIP. CHIP, not the chips set in your computer, but CHIP. And basically this is stem cell mutations that increase in people as we age and become exceptionally common with different mutations that account in these clones. So maybe you can tell us about CHIP and what I don't understand is that it has tremendous correlation association with cardiovascular outcomes adverse as well as other system outcomes, and we don't measure it and we could measure it. So please take us through what the hell is wrong there.Pradeep Natarajan (30:14):Yeah, I mean this is really exciting. I mean I'm a little bit biased, but this is observations that have been made only really over the last decade, but accelerating research. And this has been enabled by advances in genomic technologies. So about 10 years or plus ago, really getting into the early days of population-based next generation sequencing, primarily whole exome sequencing. And most of the DNA that we collect to do these population-based analyses come from the blood, red blood cells are anucleate, so they're coming from white blood cells. And so, at that time, primarily interrogating what is the germline genetic basis for coronary artery disease and early onset myocardial infarction. At the same time, colleagues at the Broad Institute were noticing that there are many additional features that you can get from the blood-based DNA that was being processed by the whole exome data. And there were actually three different groups that converged on that all in Boston that converged on the same observation that many well-established cancer causing mutations.(31:19):So mutations that are observed in cancers that have been described to drive the cancers themselves were being observed in these large population-based data sets that we were all generating to understand the relationship between loss of function mutations in cardiovascular disease. That's basically the intention of those data sets for being generated for other things. Strong correlation with age, but it was very common among individuals greater than 70; 10% of them would have these mutations and is very common because blood cancer is extremely, it's still pretty rare in the population. So to say 10% of people had cancer causing driver mutations but didn't have cancer, was much higher than anyone would've otherwise expected. In 2014, there were basically three main papers that described that, and they also observed that there is a greater risk of death. You'd say, okay, this is a precancerous lesion, so they're probably dying of cancer.(32:17):But as I said, the absolute incidence rate for blood cancer is really low and there's a relative increase for about tenfold, but pretty small as it relates to what could be related to death. And in one of the studies we did some exploratory analysis that suggested maybe it's actually the most common cause of death and that was cardiovascular disease. And so, a few years later we published a study that really in depth really looked at a bunch of different data sets that were ascertained to really understand the relationship between these mutations, these cancer causing mutations in cardiovascular disease, so observed it in enrichment and older individuals that had these mutations, CHIP mutations, younger individuals who had early onset MI as well too, and then also look prospectively and showed that it related to incident coronary artery disease. Now the major challenge for this kind of analysis as it relates to the germline genetic analysis is prevalence changes over time.(33:15):There are many things that could influence the presence of clonal hematopoiesis. Age is a key enriching factor and age is the best predictor for cardiovascular disease. So really important. So then we modeled it in mice. It was actually a parallel effort at Boston University (BU) that was doing the same thing really based on the 2014 studies. And so, at the same time we also observed when you modeled this in mice, you basically perturb introduce loss of function mutations in the bone marrow for these mice to recapitulate these driver mutations and those mice also have a greater burden of atherosclerosis. And Eric, you highlighted inflammation because basically the phenotype of these cells are hyper inflamed cells. Interestingly, C-reactive protein is only modestly elevated. So C-reactive protein is not fully capturing this, but many of the cytokines IL-1β, IL-6, they're all upregulated in mice and in humans when measured as well.(34:11):Now there've been a few key studies that have been really exciting about using anti-inflammatories in this pathway to address CHIP associated cardiovascular disease. So one that effort that I said in BU because they saw these cytokines increased, we already know that these cytokines have relationship with atherosclerosis. So they gave an NLRP3 inflammasome inhibitor to the mice and they showed that the mice with or without CHIP had a reduction in atherosclerosis, but there was a substantial delta among the mice that are modeled as having CHIP. Now, the investigators in CANTOS, the manufacturers, they actually went back and they survey where they had DNA in the CANTOS trial. They measured CHIP and particularly TET2 CHIP, which is the one that has the strongest signal for atherosclerosis. As I said, overall about 15% reduction in the primary outcome in CANTOS. Among the individuals who had TET2 CHIP, it was a 64% reduction in event.(35:08):I mean you don't see those in atherosclerosis related trials. Now this has the caveat of it being secondary post hoc exploratory, the two levels of evidence. And so, then we took a Mendelian randomization approach. Serendipitously, just so happens there is a coding mutation in the IL-6 receptor, a missense mutation that in 2012 was described that if you had this mutation, about 40% of people have it, you have a 5%, but statistically significant reduction in coronary artery disease. So we very simply said, if the pathway of this NLRP3 inflammasome, which includes IL-6, if you have decreased signaling in that pathway, might you have an even greater benefit from having that mutation if you had CHIP versus those who didn't have CHIP. So we looked in the UK Biobank, those who didn't have CHIP 5% reduction, who had that IL-6 receptor mutation, and then those who did have CHIP, if they had that mutation, it was about a 60% reduction in cardiovascular disease.(36:12):Again, three different lines of evidence that really show that this pathway has relevance in the general population, but the people who actually might benefit the most are those with CHIP. And I think as we get more and more data sets, we find that not all of the CHIP mutations are the same as it relates to cardiovascular disease risk. It does hone in on these key subsets like TET2 and JAK2, but this is pretty cool as a preventive cardiologist, new potential modifiable risk factor, but now it's almost like an oncologic paradigm that is being applied to coronary artery disease where we have specific driver mutations and then we're tailoring our therapies to those specific biological drivers for coronary artery disease. Hopefully, I did that justice. There's a lot there.Why Don't We Measure CHIP?Eric Topol (36:57):Well, actually, it's phenomenal how you've explained that, but I do want to review for our listeners or readers that prior to this point in our conversation, we were talking about germline mutations, the ones you're born with. With CHIP, we're talking about acquired somatic mutations, and these are our blood stem cells. And what is befuddling to me is that with all the data that you and others, you especially have been publishing and how easy it would be to measure this. I mean, we've seen that you can get it from sequencing no less other means. Why we don't measure this? I mean, why are we turning a blind eye to CHIP? I just don't get it. And we keep calling it of indeterminate potential, not indeterminate. It's definite potential.Pradeep Natarajan (37:51):Yeah, no, I think these are just overly cautious terms from the scientists. Lots of people have CHIP, a lot of people don't have clinical outcomes. And so, I think from the lens of a practicing hematologists that provide some reassurance on the spectrum for acquired mutation all the way over to leukemia, that is where it comes from. I don't love the acronym as well because every subfield in biomedicine has its own CHIP, so there's obviously lots of confusion there. CH or clinical hematopoiesis is often what I go, but I think continuing to be specific on these mutations. Now the question is why measure? Why aren't we measuring it? So there are some clinical assays out there. Now when patients get evaluated for cytopenias [low cell counts], there are next generation sequencing tests that look for these mutations in the process for evaluation. Now, technically by definition, CHIP means the presence of these driver mutations that have expanded because it's detectable by these assays, not a one-off cell because it can only be detected if it's in a number of cells.(38:55):So there has been some expansion, but there are no CBC abnormalities. Now, if there's a CBC abnormality and you see a CHIP mutation that's technically considered CCUS or clonal cytopenia of unknown significance, sometimes what is detected is myelodysplastic syndrome. In those scenarios still there is a cardiovascular disease signal, and so many of our patients who are seen in the cancer center who are being evaluated for these CBC abnormalities will be detected to have these mutations. They will have undergone some risk stratification to see what the malignancy potential is. Still pretty low for many of those individuals. And so, the major driver of health outcomes for this finding may be cardiovascular. So those patients then get referred to our program. Dana-Farber also has a similar program, and then my colleague Peter Libby at the Brigham often sees those patients as well. Now for prospective screening, so far, an insurance basically is who's going to pay for it.(39:51):So an insurance provider is not deemed that appropriate yet. You do need the prospective clinical trials because the medicines that we're talking about may have side effects as well too. And what is the yield? What is the diagnostic yield? Will there actually be a large effect estimate? But there has been more and more innovation, at least on the assay and the cost part of the assay because these initial studies, we've been using whole exome sequencing, which is continuing to come down, but is not a widely routine clinical test yet. And also because as you highlighted, these are acquired mutations. A single test is not necessarily one and done. This may be something that does require surveillance for particular high risk individuals. And we've described some risk factors for the prevalence of CHIP. So surveillance may be required, but because there are about 10 genes that are primarily implicated in CHIP, that can substantially decrease the cost of it. The cost for DNA extraction is going down, and so there are research tests that are kind of in the $10 to $20 range right now for CHIP. And if flipped over to the clinical side will also be reasonably low cost. And so, for the paradigm for clinical implementation, that cost part is necessary.Eric Topol (41:10):I don't know the $10 or $20 ones. Are there any I could order on patients that I'm worried about?Pradeep Natarajan (41:17):Not yet clinical. However, there is a company that makes the reagents for at least the cores that are developing this. They are commercializing that test so that many other cores, research cores can develop it. I think it's in short order that clinical labs will adopt it as well too.Eric Topol (41:36):That's great.Pradeep Natarajan (41:37):I will keep you apprised.What About Polygenic Risk Scores?Eric Topol (41:39):I think that's really good news because like I said, we're so darn lipid centric and we have to start to respect the body of data, the knowledge that you and others have built about CHIP. Now speaking of another one that drives me nuts is polygenic risk score (PRS) for about a decade, I've been saying we have coronary disease for most people is a polygenic trait. It's not just a familial hypercholesterolemia. And we progressively have gotten better and better of the hundreds of single variants that collectively without a parental history will be and independently predict who is at double, triple or whatever risk of getting heart disease, whereby you could then guide your statins at higher aggressive or pick a statin, use one or even go beyond that as we've been talking about. But we don't use that in practice, which is just incredible because it's can be done cheap.(42:45):You can get it through whether it's 23andMe or now many other entities. We have an app, MyGeneRank where we can process that Scripss does for free. And only recently, Mass General was the first to implement that in your patient population, and I'm sure you were a driver of that. What is the reluctance about using this as an orthogonal, if you will, separate way to assess a person's risk for heart disease? And we know validated very solidly about being aggressive about lipid lowering when you know this person's in the highest 5% polygenic risk score. Are we just deadheads in this field or what?Pradeep Natarajan (43:30):Yeah, I mean Eric, as you know, lots of inertia in medicine, but this one I think has a potential to make a large impact. Like CHIP mutations, I said news is about 10% in individuals greater than 70. The prospect here is to identify the risk much earlier in life because I think there is a very good argument that we're undertreating high risk individuals early on because we don't know how to identify them. As you highlighted, Dr. Braunwald about LDL cholesterol. The other part of that paradigm is LDL cholesterol lowering and the duration. And as we said, everybody would benefit from really low LDL cholesterol, but again, you might overtreat that if you just give that to everybody. But if you can better identify the folks very early in life, there is a low cost, low risk therapy, at least related to statins that you could have a profound benefit from the ones who have a greater conviction will have future risk for cardiovascular disease.(44:21):You highlighted the family history, and the family history has given the field of clues that genetics play a role. But as the genome-wide association studies have gotten larger, the polygenic risk scores have gotten better. We know that family history is imperfect. There are many reasons why a family member who is at risk may or may not have developed cardiovascular disease. A polygenic risk score will give a single number that will estimate the contribution of genetics to cardiovascular disease. And the thing that is really fascinating to me, which is I think some of a clinical implementation challenge is that the alleles for an individual are fixed. The genotyping is very cheap. That continues to be extremely cheap to do this test. But the weights and the interpretation of what the effects should be for each of the SNPs are continually being refined over time.(45:18):And so, given the exact same SNPs in the population, the ability to better predict cardiovascular diseases getting better. And so, you have things that get reported in the literature, but literally three years later that gets outdated and those hypotheses need to be reassessed. Today, I'll say we have a great relative to other things, but we have a great polygenic risk score was just reported last year that if you compare it to familial hypercholesterolemia, which has a diagnostic yield of about 1 in 300 individuals, but readily detectable by severe hypercholesterolemia that has about threefold risk for cardiovascular disease. By polygenic risk score, you can find 1 in 5 individuals with that same risk. Obviously you go higher than that, it'll be even higher risk related to that. And that is noble information very early in life. And most people develop risk factors later in life. It is happening earlier, but generally not in the 30s, 40s where there's an opportunity to make a substantial impact on the curve related to cardiovascular disease.(46:25):But there is a lot of momentum there. Lots of interest from NIH and others. The major challenge is though the US healthcare system is really not well set up to prevention, as you know, we practice healthcare after patient's developed disease and prevent the complications related to progression. The stakeholder incentives beyond the patient themselves are less well aligned. We've talked a lot here today about payers, but we don't have a single payer healthcare system. And patients at different times of their lives will have different insurers. They'll start early in life with their parents, their first employer, they'll move on to the next job and then ultimately Medicare. There's no entity beyond yourself that really cares about your longevity basically from the beginning and your overall wellness. That tension has been a major challenge in just driving the incentives and the push towards polygenic risk scores. But there are some innovative approaches like MassMutual Life Insurance actually did a pilot on polygenic risk scoring.(47:33):They're in the business of better understanding longevity. They get that this is important data. Major challenges, there are federal protections against non-discrimination in the workplace, health insurance, not necessarily life insurance. So I think that there are lots of things that have to be worked out. Everybody recognizes that this is important, but we really have to have all the incentives aligned for this to happen at a system-wide level in the US. So there's actually lots of investment in countries that have more nationalized healthcare systems, lots of development in clinical trials in the UK, for example. So it's possible that we in the US will not be the lead in that kind of evidence generation, but maybe we'll get there.The GLP-1 DrugsEric Topol (48:16):Yeah, it's frustrating though, Pradeep, because this has been incubating for some time and now we have multi ancestry, polygenic risk scores, particularly for heart disease and we're not using it, and it's not in my view, in the patient's best interest just because of these obstacles that you're mentioning, particularly here in the US. Well, the other thing I want to just get at with you today is the drugs that we were using for diabetes now blossoming for lots of other indications, particularly the glucagon-like peptide 1 (GLP-1) drugs. This has come onto the scene in recent years, not just obviously for obesity, but it's anti-inflammatory effects as we're learning, mediated not just through the brain but also T cells and having extraordinary impact in heart disease for people with obesity and also with those who have heart failure, about half of heart failure for preserved ejection fraction. So recently you and your colleagues recently published a paper with this signal of optic neuropathy. It was almost seven eightfold increase in a population. First, I wanted to get your sense about GLP-1. We're also going to get into the SGLT2 for a moment as well, but how do you use GLP-1? What's your prognosis for this drug class going forward?Pradeep Natarajan (49:55):As it relates to the paper, I can't claim credit as one of my former students who is now Mass Eye and Ear resident who participated, but we can talk about that. There's obviously some challenges for mining real world data, but this was related to anecdotes that they were observing at Mass Eye and Ear and then studied and observed an enrichment. In general though, I feel like every week I'm reading a new clinical trial about a new clinical outcome benefit as it relates to GLP-1 receptor agonists. This is kind of one thing that stands out that could be interrogated in these other clinical trials. So I would have that caveat before being cautious about ocular complications. But the data has been overwhelmingly beneficial, I think, because at minimum, obesity and inflammation are relayed to myriad of consequences, and I'm really excited that we have therapies that can address obesity that are safe.(50:52):There's a legacy of unsafe medicines for obesity, especially related to cardiovascular disease. So the fact that we have medicines that are safe and effective for lowering weight that also have real strong effects on clinical outcomes is tremendous. We in cardiology are increasingly using a range of diabetes medicines, including GLP-1 receptor agonists and SGLT2 inhibitors. I think that is also the secular changes of what influences cardiovascular disease over time. I talked about over the last 10 years or so with this increase in deaths attributable to cardiovascular disease. If you look at the influences of traditional clinical risk factors today, many of them have decreased in importance because when abnormal, we recognize them, in general we modify them when recognized. And so, many of the things that are unaddressed, especially the features related to insulin resistance, obesity, they start rising in importance. And so, there is a dramatic potential for these kinds of therapies in reducing the residual risks that we see related to cardiovascular disease. So I'm enthusiastic and excited. I think a lot more biology that needs to be understood of how much of this is being influenced specifically through this pathway versus a very effective weight loss medicine. But also interesting to see the insights on how the effect centrally on appetite suppression has profound influences on weight loss as well too. And hopefully that will lead to more innovations in weight management.The SGLT-2 DrugsEric Topol (52:25):And likewise, perhaps not getting near as much play, but when it came on the cardiovascular scene that an anti-diabetic drug SGLT2 was improving survival, that was big, and we still don't know why. I mean, there's some ideas that it might be a senolytic drug unknowingly, but this has become a big part of practice of cardiology in patients with diabetes or with preserved ejection fraction heart failure. Is that a fair summary for that drug?Pradeep Natarajan (53:00):Yeah, I totally agree. I mean, as there has been increased recognition for heart failure preserved ejection fraction, it has been almost disheartening over the last several years that we have not had very specific effective therapies to treat that condition. Now, it is a tremendous boon that we do have medicines interestingly focused on metabolism that are very helpful in that condition for heart failure with preserved ejection fraction. But there is still much more to be understood as far as that condition. I mean, the major challenge with heart failure, as you know, especially with heart failure preserved ejection fraction, it likely is a mix of a wide variety of different etiologies. So in parallel with developing effective therapies that get at some aspect is really understanding what are the individual drivers and then targeting those specific individual drivers. That requires a lot of unbiased discovery work and further profiling to be done. So lot more innovation, but relative to heart failure itself, it is not had widespread recognition as heart failure reduced ejection fraction. So much more to innovate on, for sure.Eric Topol (54:07):Right, right. Yeah, I am stunned by the recent progress in cardiovascular medicine. You have been center stage with a lot of it, and we've had a chance to review so much. And speaking of genetics, I wanted to just get a little insight because I recently came across the fact that your mother here at the City of Hope in Southern California is another famous researcher. And is that, I don't know what chromosome that is on regarding parental transmission of leading research. Maybe you can tell me about that.Pradeep Natarajan (54:41):Yeah, I mean, I guess it is a heritable trait when a parent has one profession that there is a higher likelihood that the offspring will have something similar. So both of my parents are PhDs, nonphysicians. There is a diabetes department at the City of Hope, so she's the chair of that department. So very active. We do overlap in some circles because she does investigate both vascular complications and renal complications. And then sometimes will ask my advice on some visualization. But she herself has just had a science translational medicine paper, for example, just a couple of months ago. So it's fun to talk about these things. To be honest, because my parents are researchers, I was not totally sure that I would be a researcher and kind of wanted to do something different in medicine. But many of my early observations and just how common cardiovascular disease is around me and in my community and wanting to do something useful is what got me specifically into cardiology.(55:45):But obviously there are numerous outstanding, important questions. And as I went through my career, really focused on more basic investigations of atherosclerosis and lipids. What got me excited sort of after my clinical training was the ability to ask many of these questions now in human populations with many new biological data sets, at least first centered on genetics. And the capabilities continue to expand, so now I teach first year Harvard medical students in their genetics curriculum. And when I talk to them just about my career arc, I do remind them they're all doing millions of things and they're exploring lots of things, but when they get to my shoes, the capabilities will be tremendously different. And so, I really advise them to take the different experiences, mainly in an exercise for asking questions, thoughtfully addressing questions, connecting it back to important clinical problems. And then once they start to understand that with a few different approaches, then they'll totally take off with what the opportunities are down the road.Eric Topol (56:51):No, it's great. I mean, how lucky somebody could be in the first year of med school with you as their teacher and model. Wow. Pradeep, we've really gone deep on this and it's been fun. I mean, if there's one person I'm going to talk to you about cardiovascular risk factors and the things that we've been into today, you would be the one. So thank you for taking the time and running through a lot of material here today, and all your work with great interest.Pradeep Natarajan (57:24):Thanks, Eric. I really appreciate it. It's tremendous honor. I'm a big fan, so I would be glad to talk about any of these things and more anytime.***************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

Send us a Text Message.What if you could unlock the secrets of optimal nutrition and harness the power of macronutrients to transform your health and fitness journey? In this enlightening episode of Health and Fitness Redefined, we break down the essentials of nutrition, focusing on the critical roles of protein, carbohydrates, and fats in our bodies. You'll discover how each macronutrient contributes uniquely to your muscle and tissue building, energy supply, and brain development. We also demystify the concept of calories, offering a clear explanation of how proteins, carbs, fats, and even alcohol convert into caloric energy, shaping your daily dietary needs.Maintaining a balanced diet is key to sustaining muscle and energy levels, and this episode provides actionable insights to help you achieve just that. Learn about the importance of adequate protein intake, with a recommended one gram per pound of body weight to ensure muscle preservation. Understand how carbohydrates aid in energy provision and protein breakdown, and why focusing on net carbs and opting for whole foods over processed options can significantly benefit your health. We also highlight the significance of healthy fats in digesting fat-soluble vitamins and suggest practical dietary swaps like choosing smoothies over juices to maximize fiber intake.Navigating the world of fats can be confusing, but our episode promises to clarify everything you need to know. Discover the differences between saturated and unsaturated fats, and their impacts on cholesterol and blood pressure. We explain the roles of LDLs and HDLs, shedding light on how genetics can influence cholesterol levels. With tips on understanding your Basal Metabolic Rate (BMR) and the caloric deficit required for weight loss, we empower you with the knowledge to overcome weight loss plateaus and appreciate the role of fat in burning calories even at rest. Don't miss our wrap-up, where we encourage listener feedback and future topic suggestions at healthfitnessredefinedpodcast@gmail.com. Tune in and redefine your approach to nutrition and fitness today!Support the Show.

Simon is dog tired from baking too much bread, and Lee is in the midst of a work load that is barely sustainable: enter Grover from Sesame Street.Some other details from the episode: Enjoying making processes efficient; sourdough and allergens; Lee figuring out the rhythm of his job; being surrounded by kindness; a packet of crisps and a sandwich; cheese and Simon's LDLs; sheese (vegan cream cheese); everybody say tofu; tofurkey time; two-thirty and tooth-hurty; the life-cycle of bad jokes; Grover's near and far; the rule of three in comedy; Simon breathes differently when he is Duck Duck Going; public floggings for academics; finding the toddler; Clifford Geertz (anthropologist, died in 2006); Clifford the Big Red Dog; the difference between a twitch and a wink; Kevin Kelley (and other Kevins); The Girl from Ipanema; Kevin Keegan; Princess Leia; IDEO design laboratory; John Galliano; what Lee wears when he cooks; innovation; first past the post voting systems; Godwin's Law.--- Related links (and necessary corrections): Grover's near and far: https://www.youtube.com/watch?v=E9IuXEwpU7UKevin Kelley "Excellent Advice For Living: Wisdom I Wish I'd Known Earlier": https://www.amazon.co.uk/Excellent-Advice-Living-Wisdom-Earlier/dp/0593654528IDEO: https://www.ideo.com/Godwin's Law: https://en.wikipedia.org/wiki/Godwin%27s_lawGet in touch with Lee and Simon at info@midlifing.net. ---The Midlifing logo is adapted from an original image by H.L.I.T: https://www.flickr.com/photos/29311691@N05/8571921679 (CC BY 2.0)

Today, I am excited to share the first class in a series of lipid masterclasses with the amazing Dr. Thomas Dayspring! Dr. Dayspring is certified in internal medicine and clinical epidemiology and is a fellow of the American College of Physicians and the National Lipid Association. He was previously the Educational Director of a nonprofit organization and has served as the Chief Academic Advisor for two major cardiovascular labs.  Due to the in-depth nature of my discussions with Dr. Dayspring over several sessions, each lasting nearly six hours, it seemed logical to present these masterclasses in segmented chunks to make them easier to understand. In our first class today, we dive into the fundamentals, exploring what lipids are and how lipids and fatty acids are classified. We cover the physiology and transportation of cholesterol and the role of apoptosis, apo-proteins, and apo-lipoproteins, unravel the differences between HDL, LDL, IDL, and VLDL, and explain how to calculate LDLs and triglycerides for assessing metabolic health. Dr. Dayspring also shares his preferences regarding lab values and the indicators that provide information to help him determine the early risk of cardiovascular disease. We get into some detailed aspects of physical chemistry in this episode, so I highlight the main clinical points throughout our conversation to make it more understandable. Be sure to join Dr. Dayspring and me for our next episode in the lipid masterclass series. IN THIS EPISODE YOU WILL LEARN: What are lipids, and why are they important? Dr. Dayspring explains what triglycerides are. How lipids get absorbed and transported throughout the body What lipoproteins are, and how they get classified How cholesterols get calculated The impact of triglycerides on cholesterol levels and cardiovascular health How high triglyceride levels can indicate early insulin resistance or increased ASCVD risk What is the role of HDL particles? How metabolic syndrome impacts cardiovascular health Bio: Thomas Dayspring MD is a Fellow of both the American College of Physicians and the National Lipid Association and is certified in internal medicine and clinical lipidology. After practicing in New Jersey for 37 years, in 2012, he moved to Virginia. He served as an educational director for a nonprofit cardiovascular foundation and until mid-2019 as a Chief Academic Advisor for two major CV laboratories. Since then, he has served as a virtual cardiovascular / lipidology educator. Career-wise he has given over 4000 domestic (in all 50 states) and several international lectures, including over 600 CME programs on atherothrombosis, lipids/lipoproteins (and their treatment), vascular biology, biomarker testing, and women's cardiovascular issues. He has authored several manuscripts and lipid textbook chapters and performed several podcasts. For several years he was an Associate Editor of the Journal of Clinical Lipidology. He was the recipient of the 2011 National Lipid Association's Presidents Award for services to clinical lipidology and the 2023 Foundation of NLA Clinician/Educator Award. He has over 34K followers on his educational Twitter (X) feed (@Drlipid). He has Gold Heart Member status as a professional member of the American Heart Association and serves as a Social Media Ambassador for the European Atherosclerosis Society and the National Lipid Association. Connect with Cynthia Thurlow Follow on Twitter, Instagram & LinkedIn Check out Cynthia's website Submit your questions to support@cynthiathurlow.com Connect with Dr. Thomas Dayspring Twitter (@DrLipid) LinkedIn Books written by Gary Taubes

Simon comes in hot with some "content" about margarine and he and Lee discuss health stuff (again), before transitioning into body fat content and (unrelated) a discussion about making ciabatta.Some other details from the episode: Apologising at the beginning of something, attribution and circulation of ideas in dance, saying 'fuck' in multiple languages, margarine trigger warnings, Lee reminisces on learning how to bake, Simon's LDLs and a low saturated fat diet, the difference between statins and stents, Lee's gallbladder (and gallbladders in general), peanut butter being good for you, Lee's body signals as a guide to modifying his diet, Simon really liking butter, brussells sprouts recipes, foul-smelling green smoothies, Michael Fassbender and yoga, The Killer (film), Ben Affleck in The Accountant, George Clooney in The American, skinfolds and fatfolds, being too thin, Lee's Madonna phase, Apple's 'memories' feature, making ciabatta, and how everything on Amazon has 4.5 stars, and enshittification (Cory Doctorow).Related links (and necessary corrections):How statins work: https://www.healthline.com/health/high-cholesterol/how-do-statins-workHealth benefits of red wine: https://www.medicalnewstoday.com/articles/265635#benefitsMeasuring body fat with underwater weighing: https://www.verywellfit.com/what-is-hydrostatic-underwater-weighing-3120276Enshittification: https://en.wikipedia.org/wiki/EnshittificationGet in touch with Lee and Simon at info@midlifing.net. ---The Midlifing logo is adapted from an original image by H.L.I.T: https://www.flickr.com/photos/29311691@N05/8571921679 (CC BY 2.0)

Simon and Lee discuss some health concerns, eating butter, the unrelenting depressing feeling of watching Fleishman is in Trouble, Taylor Swift's Eras film, and the trouble with boys and men.Some other details from the episode: Follow up on Simon's PSA test, some stuff about lipids, heart disease, LDLs, a TV update (Slow Horses, Reacher, Fleishman is in Trouble, Taylor Swift's Eras film, Saltburn, The Creator), ferries vs fairies, woman vs women, spoilers for a concert film, video mapping, the end of Simon's days as a swifty, grave fucking, pearl clutching and class in the UK, CJ Cregg, John David Washington, Denzel Washington turning 70 in 2024, Of Boys and Men by Richard Reeves, Lee's knee jerk shouting, Lee being gobbed at for being queer, performing versions of masculinity, being loved by one's father, feminism and masculinity, empowerment of men and women not being a zero-sum game, and some audio feedback from a listener's child immitating Lee's German accent. Get in touch with Lee and Simon at info@midlifing.net. ---The Midlifing logo is adapted from an original image by H.L.I.T: https://www.flickr.com/photos/29311691@N05/8571921679 (CC BY 2.0)

Unlock the hidden mysteries of advanced lipid profiles with our insightful guest, Al Lopez, DO a respected internist with a special interest in lipids. Journey with us as we explore the sophisticated world of lipid profiles, dig into the data sets impacting heart and vascular disease, and reveal unseen risk factors that could be lurking in your health journey. Get an in-depth look at the intriguing bond between Geri Garcia and advanced lipid profiles, and learn about the vital role of the ApoB protein. Discover the silent dyslipidemias hiding among those who are overweight, diabetic, or resistant.We take it up a notch as we steer our conversation towards oxidized LDL and its profound health implications. With 20 years of experience in measuring oxidized LDLs under his belt, Dr. Lopez, DO enlightens us on their potential peril in the vascular bed and the formation of plaque. Gain exclusive knowledge on where these LDLs may be embedding themselves and the impact of lipoprotein A on our overall wellbeing. This episode is indeed a goldmine for all those keen to enhance their understanding of advanced lipid profiles and their bearing on our health.Be a part of advancing science by participating in clinical researchShare with a friend. Rate, Review, and Subscribe to the MedEvidence! podcast to be notified when new episodes are released.Follow us on Social Media:FacebookInstagramTwitterLinkedIn Powered by ENCORE Research GroupMusic: Storyblocks - Corporate InspiredThank you for listening!

This week, please join authors Marc Sabatine and Prakriti Gaba, as well as Associate Editor Amit Khera, as they discuss the article "Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE." Dr Greg Hundley: Welcome listeners, to this April 18th issue of Circulation on the Run and I am Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Peder Myhre: And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo. Dr Greg Hundley: Peder, today's feature discussion, very interesting. We're going to evaluate the association between what's achieved with LDL cholesterol lowering, and then also long-term cardiovascular and safety outcomes. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first? Dr Peder Myhre: Yes, Greg. I would love to. And the first paper is from the World of Preclinical Science and it comes to us from corresponding author, Jan Magnus Aronsen from University of Oslo in Norway. And perhaps, as you know, Greg, cardiomyocyte contraction and relaxation depend on the activity of the sarcoplasmic reticulum CA+2 ATPase 2, abbreviated SERCA2, and lowered levels or reduced activity of SERCA2, as seen in chronic heart failure, weakens contractile force and delays relaxation and no available therapy involves direct manipulation of the SERCA2 activity. And Greg, phosphodiesterase 3A is proposed to be present in the SERCA2 interactome limit SERCA2 activity and disruption of phosphodiesterase 3A from SERCA2 might thus be a strategy to develop SERCA2 activators. And in this study, the authors investigated and mapped SERCA2 and phosphodiesterase 3A and assessed this in experiments assessing the binding between these two in cardiomyocytes and in vesicles. Dr Greg Hundley: Wow Peder, sounds very interesting. So what did they find and how about the clinical implications of the findings? Dr Peder Myhre: So Greg phosphodiesterase 3A bounded directly to SERCA2 in the cardiomyocyte. So that's the first finding. Second, they demonstrated that SERCA2 phosphodiesterase 3A disruption increased SERCA2 activity independently of the catalytic activity of phosphodiesterase 3A in both normal and failing cardiomyocytes. And third, SERCA2 activity by the optimized SERCA2 phosphodiesterase 3A disruptor peptide OPT F reduced mortality and improved contractility after aortic binding in mice. So the clinical implication is that direct targeting of phosphodiesterase 3A binding to SERCA2 could be a novel approach to increase SERCA2 activity and thus cardiac contractility in patients with heart failure. Dr Greg Hundley: Very nice Peder. What a great new finding in the world of preclinical science. Well my paper is going to delve into the world of clinical science and involves patients with stroke. So Peder in this study led by corresponding author, Dr. Dileep Yavagal from University of Miami Miller School of Medicine performed a survey in 75 countries through the Mission Thrombectomy 2020+ Global Network between November of 2020 and February of 2021 to determine the availability of mechanical thrombectomy for large vessel occlusion in patients with stroke. Now Peder, the primary endpoints were the current annual mechanical thrombectomy availability, the mechanical thrombectomy operator availability and the mechanical thrombectomy center availability. All of these availabilities were defined as the proportion of estimated large vessel occlusion for patients receiving mechanical thrombectomy in a given region annually. Dr Peder Myhre: Okay, Greg, so this is really an access question. So in essence, what is the availability of mechanical thrombectomy worldwide? So what did they find? Dr Greg Hundley: Right, great Peder. So what they found, the authors received 887 responses from 67 countries and low-income countries had 88% lower mechanical thrombectomy availability compared to high-income countries. The global mechanical thrombectomy operator availability was 16.5% of optimal, and the mechanical thrombectomy center availability was only 20.8% optimal. And with these results, the authors indicate that global cooperation and targeted region-specific public health interventions, including all stakeholders involved in stroke care delivery, are really needed to rapidly increase access to this brain-saving and disability-sparing treatment with mechanical thrombectomy really worldwide. Dr Peder Myhre: Oh wow. What a beautiful summary, Greg. Thank you so much. And we also have some other interesting papers in the mailbag today. We have an exchange of letters between Dr. Yang and Dr. O'Donoghue regarding the article “Long Term evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease.” Dr Greg Hundley: Great Peder, and also Professor Perera has a Frontiers article entitled “Unloading the Left Ventricle in Venoarterial ECMO in Who, When and How?” and then finally there's a Research Letter from Professor Verma entitled “Prevalence of Diabetes and Cardiovascular Risk in the Middle East and Africa: The Primary results of the PACT-MEA Study.” Well Peder, how about we jump to that feature discussion? Dr Peder Myhre: Can't wait. Dr Greg Hundley: Welcome listeners to this feature discussion on April 18th and we have with us today Prakriti Gaba and Marc Sabatine from Brigham and Women's Hospital and our own associate editor, Dr. Amit Khera. Welcome everyone. Well Marc, we'll start with you. Can you describe for us some of the background information that really helps constitute the preparation of your study and what was the hypothesis that you wanted to address? Dr. Marc Sabatine: Yeah, thanks Greg and thanks for having us. So we've seen in a variety of epidemiologic cohorts the association between LDL cholesterol and the risk of adverse cardiovascular events like in Framingham Heart Study and UK Biobank. But in those cohorts, in these industrial societies, we don't have the benefit of lots of data in individuals with very low levels of LDL cholesterol and so we had the opportunity with the FOURIER study that was the randomized comparison of evolocumab PCSK9 inhibitor versus placebo to get patients down to extremely low levels of LDL cholesterol and evolocumab. We were able to get individuals down to about 30 mg/dL. And so in addition to all the studies we've done showing the comparison of evolocumab to placebo, we also then had the chance to use FOURIER, and as you'll hear from PK, FOURIER-OLE, the open-label extension, as a cohort to then examine patients' new baseline, if you will, their new achieved LDL cholesterol and then it's association not only with cardiovascular events but safety events. And so the hypothesis is that there would be a relationship with the lower the LDL cholesterol, the lower the risk of cardiovascular events and we wanted to explore how far down that went. And then the second one for safety would be that there wouldn't be any association between low levels of LDL cholesterol and a variety of safety outcomes that rightly or wrongly people have ascribed to low levels of LDL cholesterol. Dr Greg Hundley: Thanks so much, Marc. Well listeners, now we're going to turn to PK, the first author, on this very interesting paper and PK, Marc mentioned to us the FOURIER-OLE study. Maybe describe for us here your study design and then what specifically was your study population? Dr. Prakriti Gaba (PK): Yeah, definitely. Thanks so much for the introduction. So the study population included 27,564 patients with stable atherosclerotic cardiovascular disease and LDL cholesterol levels that were greater than or equal to 70 mg/dL or non-HDL cholesterol greater than or equal to a 100 mg/dL on statin therapy. The patients who then went on to the FOURIER-OLE or the open-label extension part of the trial consisted of about 6,635 patients. And so in this study we essentially evaluated the combination of those populations in 2 separate analyses. We then categorized patients according to 6 pre-specified bins based on their achieved LDL cholesterol levels at designated time points and those ranged from LDL levels of less than 20 mg/dL all the way up to 100 mg/dL. And then we looked at their baseline characteristics and evaluated the cardiovascular and safety outcomes that Dr. Sabatine mentioned earlier. Dr Greg Hundley: Very nice PK. Well we've got a great listening audience today and they're anxious to hear your study results, so can you share those with us please? Dr. Prakriti Gaba (PK): Definitely. So over the course of more than 77,000 patient years of follow-up, we found that there was a monotonic relationship between achieving lower LDL cholesterol levels down to very low levels of less than 20 mg/dL and a lower annualized risk of the primary efficacy endpoint, which was a composite of 5 individual endpoints. We also found that there was a similar relationship observed between lower LDL achieved, LDL cholesterol levels and a lower annualized risk of the secondary efficacy endpoint, and then when we looked at safety, there were actually no clear monotonic trends between lower achieved LDL levels and the risk of any of the 8 adverse events and these included things like serious adverse events, hemorrhagic stroke or muscle related events. Dr Greg Hundley: Very nice PK and I'm sure our listeners are wanting to know, did you find any discrepancy in your results based on either age or gender? Dr. Prakriti Gaba (PK): That's an excellent question, and we did look at age and gender throughout. I think across the board the results were pretty consistent, but additional subanalyses will further address this question. Dr Greg Hundley: Very good. Well listeners now we're going to turn to one of our associate editors, Dr. Amit Khera, who has helped move this article through the process of evaluation with the editorial team. Amit, you have many papers come across your desk, what attracted you to this paper and then how do we put this study's results really in the context of other studies that have sought to dramatically lower LDL cholesterol? Dr. Amit Khera: Well first thanks a lot Greg for allowing me to participate today. I want to congratulate Drs. Gaba and Sabatine on a fantastic paper and the minute I saw it, and you know can tell when you've done this for a while what's a great paper, and this one certainly is and we work closely with them to try to make it better and enhance the analyses and as a group, I think we achieved that. I was fortunate to write an accompanying editorial that you'll see. So I got to take a pretty deep dive in this paper and I want to just talk about sort of what's important here, why is this important, and I think as Dr. Gaba mentioned, there's two sides to this. There's the efficacy side where you talk about LDL lowering and getting to very low levels. Now mind you, they got to, what I call, ultra low levels, even explored for a down to a median of 7 mg/dL, so really, really low. And first I think what our listeners need to know when we look at guidelines, these numbers of 70 or 55, these are completely arbitrary and they're based on what was observed in clinical trials, what was achieved in high intensity versus moderate intensity statins in IMPROVE-IT. There's no biology behind that, and I think what this study does is reminds us there is no biology behind how low we need to go. This group previously published their shorter-term data approximately 2 years with this construct of lower is better and I think that's fine, but people worry, particularly on the safety side about extension, and we'll get to that in a minute, so where this fits is it gives us even more reassurance that lower is better, reminds us there's no biologic basis of that even down to very low levels. And so what does that mean? I think that comes back to guidelines. We have some discrepancy between European, ACC, Multisociety Guidelines that are around 55 and so from a guideline perspective, I think we'll see a little bit more enthusiasm about lower cut points or lower thresholds. And from a clinical standpoint, as a clinician it reminds me that when I see someone that's very high risk, there's no magic to achieving a number that if the risk is high, we need to be quite intensive and get their LDL down as low as possible and as safely as possible. I do want to also acknowledge, there's not, to your point about context, the IMPROVE-IT study also showed very low levels show additional efficacy and there's also a lot of other data, genetics and ecologic data supporting this. So this is... we look at Bayesian analysis that this is consistent that we're seeing across different platforms. I do want to talk about safety too, Greg. That's really important because honestly this is when it comes to patient level, the safety part of it. We as clinicians may have comfort with very low levels, but the safety is important. I also want to, just from a steady design, this is post-hoc, so those that achieve very low levels are different. You can see that in their table 1, but these investigators did lots of things. They did pretty extensive multi-variable analysis, they looked at time-dependent LDLs, they looked at it multiple different ways, but as mentioned, there really did not seem to be a safety signal. And this is where time matters. Safety in two years, interesting, but safety 5 to 8 years really offers us much more reassurance. So I think that's where this really comes in about that safety piece with the extended analysis. So again, I think from a guideline perspective, from a clinical perspective, there's so many implications from this paper and I really hope people take the time to take a deep dive and also put it in context, like you said, to the other literature where this is not standalone, but it's corroborating what we're seeing. Dr Greg Hundley: Very nice, amit. Marc, I want to come back to you, just two quick questions thinking about the preparation of your study. One, did you sample cognition? One thing we hear about frequently in dramatic lowering of LDL cholesterol are questions around cognition, particularly in the elderly? Dr. Marc Sabatine: Yeah, it's a great question Greg. So first of all, in the FOURIER study itself, there was an embedded study called EBBINGHAUS that Bob Giugliano from our group led that actually did formal neurocognitive testing in individuals using basically a iPad-like test. We also collected the usual neurocognitive adverse events as part of safety collecting. So 2 ways, the general asking about any adverse events and then the specific neurocognitive testing. We had previously reported out the results of EBBINGHAUS that there wasn't any relationship between evolocumab and the low LDL cholesterol and the risk of any neurocognitive AEs. We just were able to recently do this OLE analysis over time for the major adverse cardiovascular events and for the general safety events including cognition, so all that looked good. As PK indicated, we're now digging into the EBBINGHAUS formal neurocognitive testing, which was also extended out. So stay tuned for those results. Dr Greg Hundley: Very nice. And then eligibility, maybe just walk us through that really quickly. Patients that are going to be randomized to this form of therapy, were they already on high-dose statins? Who exactly did we randomize in this trial? Dr. Marc Sabatine: Yeah, so at the get-go, as PK indicated, these are patients with atherosclerotic cardiovascular disease, so they had a prior MI, prior stroke, symptomatic PAD. They were to be on an optimized lipid-lowering regimen, optimized statin therapy, so for close to 70%, that was a high-intensity statin. We had a small percentage on ezetimibe, but that's because we hadn't yet published the results of the IMPROVE-IT trial that Amit mentioned when we were enrolling in FOURIER, but it was a well-treated population on statin therapy. So these results would apply to your typical patient with ASCVD who's on a good statin regimen. Dr Greg Hundley: Very nice. Well, listeners now we're going to go back to both of our authors and investigators, as well as Dr. Khera. PK we'll start with you. What do you see as the next study to really be performed in this sphere of research? Dr. Prakriti Gaba (PK): I think that's an excellent question. I think with the data presented here now we know that the lower the LDL, the lower the risk of adverse cardiovascular events and that having a low LDL is safe in the long term. I think moving forward, as Dr. Khera mentioned, there needs to be a shift of these recommendations into the guidelines. So I think additional studies confirming these findings is what we need, but we do have the evidence available. Dr Greg Hundley: Very nice. And Marc? Dr. Marc Sabatine: Yeah, and I agree with PK of course. I think there's a couple things that we want to look at. We had looked in the parent FOURIER trial and found some groups who were higher risk, who seemed to have a bigger benefit early on, and those by and large were people who had a lot of athero. But as Amit indicated that the parent FOURIER trial was relatively short at about in two and a quarter years median follow up, and so now we have the benefit of an additional half decade of follow up in a subset of people and so now we're starting to look through and see the subgroups where we saw some differential benefit and this was a paper we published in circulation soon after we published the primary results of FOURIER. Now we have the ability to go through and look at those same subgroups and see what happens now with an additional 5 years. And so that'll be quite interesting, I think, to see how those groups play out now over time. I think as Amit indicated, time is critical. We know the benefit of lipid lowering really tends to grow with time. We saw that in FOURIER, we saw that in FOURIER-OLE and then as Amit indicated, I think for safety also it's now very reassuring, being able to go out to not two and a half years, but 5, 6, 7, 8 years of safety follow up. Dr Greg Hundley: Very nice. Well, listeners we're next going to turn to Dr. Khera. I'm going to put him on the spot a little bit. I don't know if many of you know he's a cardiologist with expertise in primary prevention. So here we've really focused today, I think, on a very unique set of results in secondary prevention. Amit, as you think about studies to be performed in the future, is there a role for really lowering LDL cholesterol as a primary prevention target? Dr. Amit Khera: The short answer is absolutely. I think, to be fair, you can't necessarily directly extrapolate these results 'cause it's a secondary prevention population, but I think if we step back for a second, is there any reason I think this wouldn't work in primary prevention, there's not, and I think there's tons of genetic data, tons of other long-term data that suggests that lower is better than primary prevention. I think the challenge, as you know, is just from primary prevention is it's just about the number that you need to treat and primary prevention is pretty profound in terms of to lower events. So this is where the trade-off comes. I think even in their study, we do have to appreciate while lower is better, when you have very low levels and you're going to even lower, let's say when you go from in secondary prevention from 50 to 40, as much as that sounds valuable, that delta's pretty small and then the absolute risk reduction is still going to be pretty small for those individuals and that's only magnified in primary prevention. So the short answer is I have no reason to believe that lower is better is not applicable in primary prevention, but I do know that the cost and what entails to get there, you don't get as much return on investment. I do want to say one last thing though. We're talking about lower is better, and I know these investigators know this well, but it's not only just how low but how long and I think that's where primary prevention about to go to clinic and I play the long game for primary prevention that we know we've magnified these benefits over the long term and even a little bit early in life can pay off long dividends. So that's how I look at it. Dr Greg Hundley: Very nice. Well, listeners we want to thank Dr. Prakriti Gaba, Dr. Marc Sabatine, both from Brigham and Women's Hospital and also our own associate editor, Dr. Amit Khera from University of Texas Southwestern Medical Center for bringing us this study involving patients with arteriosclerotic cardiovascular disease indicating that long-term achievement of lower LDL cholesterol levels down to values less than 20 mg/dL was associated with a lower risk of cardiovascular outcomes and not and not an increase in the risk of significant safety related events. Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Lipoproteins are a transport system for fats in the body. Certain classes of them have been implicated in atherosclerosis. We'll cover an overview on lipoproteins as they are commonly discussed in the medical world and also answer certain basic questions such as where small dense LDLs come from and what is oxidized in OxLDL?For more information visit http://www.VyvyaneLohMD.com

Today's guest grew up, like so many of us, on the Standard American Diet. But after watching the seminal documentary, Forks Over Knives, Dr. Steven Lome charted a new course in his life, both personally and professionally, by adopting a vegan diet, losing 100 pounds, and spreading the message about the healing power of plants. Dr. Lome is a board certified cardiologist, the founder of the Plant Based Nutrition Movement, and a member of the Physicians Committee for Responsible Medicine, where he fights to improve America's diet at a legislative level. And, you may have heard about him in the news recently for his heroics at the Monterey Bay Half Marathon.  We're super excited to have him here today to share his passion for plant-based eating, and discuss the benefits it has on cardiovascular health. “Maybe 20 percent of being healthy is exercise, but 80 percent of it is diet. Predominantly diet related. And I've been a cardiologist in practice for almost thirteen years now. I've seen at least a dozen or more ironman triathletes, marathon runners, elite cyclists, end up having significant heart disease, coronary artery disease, despite how much they exercise. If you're not focusing on eating a very healthy diet that keeps your cholesterol numbers low, protects your endothelium from damage and inflammation, it doesn't matter how much you exercise.” - Dr. Steven Lome What we discuss in this episode: How a plant-based diet transformed Dr. Lome's health. How to overcome the challenges of getting children to eat plant based. Saturated fats, LDLs and heart disease. The myths of olive oil consumption and health. How processed foods inflame and damage arteries. How to keep your endothelium healthy. His work with the Plant Based Nutrition Movement. How plant-based eating affects artery blockage. Resources: Steven's practice: Steven Lome | Monterey, CA Watching "Forks Over Knives" Changed This Doctor's Life—and Career PBNM: Steven Lome - Plant Based Nutrition Movement Instagram: Steve Lome (@stevenlome) • Instagram photos and videos Dairy-Free Swaps Guide: Easy Anti-Inflammatory Meals, Recipes, and Tips https://switch4good.org/dairy-free-swaps-guide SUPPORT SWITCH4GOOD https://switch4good.org/support-us/ ★☆★ JOIN OUR PRIVATE FACEBOOK GROUP ★☆★  https://www.facebook.com/groups/podcastchat ★☆★ SWITCH4GOOD WEBSITE ★☆★ https://switch4good.org/ ★☆★ ONLINE STORE ★☆★ https://shop.switch4good.org/shop/ ★☆★ FOLLOW US ON INSTAGRAM ★☆★ https://www.instagram.com/Switch4Good/ ★☆★ LIKE US ON FACEBOOK ★☆★ https://www.facebook.com/Switch4Good/ ★☆★ FOLLOW US ON TWITTER ★☆★ https://mobile.twitter.com/Switch4GoodNFT ★☆★ DOWNLOAD THE ABILLION APP ★☆★ https://app.abillion.com/users/switch4good  

Today's episode is sponsored by Paleovalley Apple Cider Vinegar Complex. One of my favorite, whole food supplements to support digestion, blood sugar stabilization, and cravings. Did you know that poor digestion can lead to nutrient deficiencies which can cause bloating, gas, weight gain, poor skin and nail health, and more? Paleovalley's Apple Cider Vinegar complex is the solution to a happy and healthy gut. You can get 15% off today by heading over to paleovalley.com/jockers and entering the code "JOCKERS" at checkout! Today's episode is also proudly sponsored by Lifeboost Coffee. They provide premium, low-acid, healthy coffee that is easy on your gut and 3rd party tested for mycotoxins, molds, heavy metals, plus 450+ toxins. It's a staple in my household. Hurry and grab your first order for 50% off here: www.LifeboostDeal.com.  Why do low-carbers need so much sodium? When insulin levels drop, so does the production of the hormone aldosterone. This triggers a process that makes you LOSE sodium at a rapid rate, causing headaches, low energy, muscle cramps, and insomnia. LMNT Recharge's low-carb energy drink powders fix the problem so you feel your best!   Welcome to another Q&A episode with Melissa and Dr. Jockers. Today, they'll talk about issues around oxidative stress, anemia, mold exposure, and eliminating mycotoxins after the successful colonization of molds. They also answer prevalent questions about cholesterol and food recommendations for those who are dealing with anxiety and depression. Learn the steps you can take to heal naturally and the tests that can help you isolate the specific conditions you might be going through with your health.   “Somebody that's insulin resistant and more inflamed has higher inflammatory markers. They have these small dense LDL particles. Whereas the large, fluffy LDL particles have more fat-soluble antioxidants like Vitamins E and A which helps them have less oxidative stress." -Dr. David Jockers   Subscribe to the podcast on: Apple Podcast Stitcher Spotify PodBean TuneIn Radio   In This Episode:   - How you'd like your triglyceride levels to range after a fasting blood test and the type of diet that can help bring your triglycerides down   - What we discovered that disproved the belief of modern medicine that all LDLs are bad   - Understand how, from a functional perspective, low ferritin doesn't necessarily mean anemia   - 3 big things we need to ask to properly identify a case of anemia   - Learn how molds drive up inflammation throughout the body   - Natural strategies and tips for clearing out mycotoxins   - Discover the human equivalent of rusting or browning and what causes it     Resources: - ACV Complex - Use Code JOCKERS for 15% off - Lifeboost Coffee – Click the link for 50% off - LMNT Recharge – https://drinklmnt.com/   Connect with Melissa Nohr:   -Website -https://drjockers.lpages.co/nutrition-coaching-melissa/     Connect with Dr. Jockers:   - Instagram – https://www.instagram.com/drjockers/   - Facebook – https://www.facebook.com/DrDavidJockers   - YouTube – https://www.youtube.com/user/djockers   - Website – https://drjockers.com/   - If you are interested in being a guest on the show, we would love to hear from you! Please contact us here! - https://drjockers.com/join-us-dr-jockers-functional-nutrition-podcast/

In today's episode we are joined by Dr. David G. Harper and his co-author and wife Dale Harper to explore the August 2022 paper, “Statin therapy is not warranted for a person with high LDL-cholesterol on a low-carbohydrate diet”. We share with you Dale's personal journey, what it means to have high total cholesterol and high LDLs, especially when following a low carbohydrate or ketogenic diet, statin drugs and their side effects, the coronary artery calcium score and so much more. While the paradigm continues to shift, we are here until the dogma around cholesterol finally ends. Head to https://www.stephlowe.com/podcasts/398 for show notes, episode transcripts and more.

PEDS are a reality of the sport of bodybuilding and they can have a very negative impact on your "good" HDL cholesterol as well as increase your "bad" LDL cholesterol. Here are some ways that @glamgirlbikini coaches @chrisnicole_ifbbpro and @amyehinger share to help increase your HDLs and decrease your LDLs: 1. Limit unhealthy fats 2. Get your omega-3s 3. Eat more fiber 4. Cut back on added sugars. 5. Limit alcohol 6. Quit smoking 7. Exercise on most days 8. Develop healthy sleep habits 9. Drink more water You can find us on IG @preplifepodcast You can apply for the team here: https://www.glamgirlbikini.com/get-started/ 

Cholesterol is often misinterpreted as a scary thing in the medical world. It's deemed as a danger to our health but what if we told you that it's actually helpful? High cholesterol actually isn't even a disease, it's often actually a symptom of another issue.  In this episode, we're discussing cholesterol. There are a lot of misconceptions about cholesterol and the vital role it plays in our body and organs' functions. Dr. Carling is explaining why you don't want to get your cholesterol too low, the myths about HDLs and LDLs, and what is actually a bigger concern than cholesterol when it comes to your health.  What's in this episode: Why cholesterol is a protective mechanism of your body What cholesterol actually is and what it means if its “normal” Why triglyceride levels are more concerning than cholesterol The functions that need cholesterol to run in your body What you need to know about HDLs and LDLs Drugs that are used for lowering cholesterol Advice for people taking cholesterol-lowering drugs The dangers of low cholesterol For full show notes, resources and links head to: https://vitalhealthcda.com/podcasts/ The Vital Health for You Podcast is for everyone. Subscribe and stick around to hear doctor recommendations and insight into why you're having health challenges in the first place (and what to do about it!) You have more power to change your health than you realize. Get to know us more by connecting with us on our website (www.vitalhealthcda.com) or on Facebook at (https://www.facebook.com/vitalhealthcda). *Disclaimer: The statements made in this episode about specific products have not been evaluated by the U.S. Food & Drug Administration and are not intended to diagnose, treat, cure or prevent disease. All information provided is for informational purposes only and is not intended as a substitute for advice from your physician or other healthcare professional.

Do you worry about your clothing size or whether your butt looks too big or not big enough? (hello everchanging and unrealistic beauty standards). Let's take a look at some of the numbers that REALLY matter. On this episode, Dr Sarah explains what your insulin, glucose and cholesterol levels should be. Come for the juicy science, stay for the nickname Sarah once gave her liver in Med School. The information in this podcast is for general use, always consult your doctor or physiotherapist before undertaking a new exercise program. Contact us:womenlikeyoupodcast@gmail.com WLY resources and recommendations: AusDRisk calculator https://www.health.gov.au/resources/apps-and-tools/the-australian-type-2-diabetes-risk-assessment-tool-ausdrisk Aerobic exercise and lipids and lipoproteins in women: a meta-analysis of randomized controlled trialshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447858/pdf/nihms34518.pdf WLY newsletter subscription  The Women Like You podcast is recorded on the lands of the Gadigal people of the Eora nation. We pay our respects to elders past, present and emerging. We acknowledge Aboriginal and Torres Strait Islander peoples as the First Australians and Traditional Custodians of the land where we live, work, and exercise. See omnystudio.com/listener for privacy information.

In episode 350 we are joined by Dr. David Harper, author of BioDiet, to continue to explore the great cholesterol debate. We take you back in time to recap where it all started, to explore where our dietary guidelines surrounding saturated fat went so wrong. We look at heart disease, the role of sugar and insulin resistance, LDLs and take a deeper dive into the ongoing scientific debate, and why term the term ‘cholesterol denialism' is being used, even in the presence of strong scientific evidence to the contrary. Let's dive in. Head to https://www.stephlowe.com/podcasts/350 for show notes, episode transcripts and more.

Watch those LDLs.

For more information on this topic or to schedule a consultation please visit us at http://WhatIsHashimotos.com Today we are talking about thyroid and low libido, and this goes for females as well as males. Frankly, I don't treat a lot of males, but almost everyone that comes in here has a low libido. It's a pretty straight forward shot as far as why that occurs. If we go back to the thyroid, we go back to Hashimoto's most of the time it's hypo thyroid that has been caused by an immune attack on the thyroid. Hypo thyroid means everything slows down. Your thyroid hormones have receptor sites in other words, where they hook into the cells in every single one of the trillions of cells that we have in our body. Now, if you came to me and again, it's mostly females but if a female came to me and said, you know, I have all kinds of menstrual problems, I have periods that are off. I have periods that are gone, that shouldn't be gone. I have heavy bleeding, low bleeding, cramping, no cramping. Oh, and by the way, I also have a dry vagina, and I have no libido. That's usually how it works. People don't usually come in here specifically for no libido and if somebody, or if a guy said this it's a little different, but the bottom line is with either one of them, you would be looking to see why their testosterone in a guy, or why their estrogen in a woman isn't working. In a woman, it's usually gut problems, It's usually liver problems, It's usually gallbladder problems because estrogen needs to be used whether it's made by your body or whether you're taking a hormone replacement therapy, it needs to be used. It needs to be effective. Then the kind of the residue needs to go through the liver, gallbladder, through the intestines and into the toilet. That doesn't happen, you're going to have high estrogen and believe it or not high estrogen causes the same problems as low estrogen. Without me getting into that whole thing, at this point in time, it's about the estrogen. It's also about blood sugar. It's also about stress. It's also about essential fatty acids, all of these work together to make your brain tell your adrenal glands or tell your ovaries to make the estrogen that you need and then process it properly and get it into the toilet and, you know, detox you and get it into the toilet. If you have a hypo thyroid, that's not going to happen. Now, thyroid does have kind of a straight shot relationship to progesterone as far as prolactin and as far as, so having a baby and fertility and stuff like that. But in the end, all of those things I just talked about are going to slow down. Your liver is going to start slowing down and you're not gonna be able to get the estrogen through it as much. You can tell by looking on your labs, whether your liver enzymes are up or not, a lot of the times you can look at that. You can look on your labs and if you're the one who has the high cholesterol, and you have the high LDLs, and you have low, good, HDLs, low, good fat then people go, well, you need a statin drug. You need to stop eating, you know, junk and everything. You go, like I'm on the autoimmune paleo diet. I don't need any of that stuff. How could that be? http://powerhealthtalk.com Martin P. Rutherford, DC 1175 Harvard Way Reno, NV 89502 775 329-4402 http://powerhealthreno.com https://goo.gl/maps/P73T34mNB4xcZXXBA

In order to interpret your cholesterol tests, we need to understand lipoproteins. If fats and oils are released into the bloodstream, they would cause major damage if not for lipoproteins. Fats and oils would coalesce into large "bubbles" or emboli. These emboli would cause damage like heart attack if not controlled. Lipoproteins keep the fats and oils from forming large, or embolic, particles.  LDL (low-density lipoprotein) and HDL (high-density lipoprotein) are mostly the same except for the portion of protein. HDL has 50% or more protein. LDL has 25% or less protein. HDL is, therefore, like an empty dump truck, able to carry LDL away from the artery wall. LDL is like a full dump truck, spilling and leaving LDL in the lining of the arteries. That LDL deposition is plaque formation.  Other particles (lipoprotein) get larger and are carry even more fats and oils. These are called IDL (intermediate density lipoprotein) and VLDL (very low density lipoprotein) all have more fats and oils (cholesterol and triglycerides). The particles that are the most likely to get caught in the artery wall have mostly fat (LDLs), but they are small & dense enough to slip between cracks in the intima. They're called sdLDL, which stands for small, dense LDL. For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources: PrevMed's article on cardiovascular inflammationPrevMed's websitePrevMed's YouTube channelPrevMed's Facebook page

For more information on this topic or to schedule a consultation please visit us at http://WhatIsHashimotos.com Hashimoto's and high cholesterol. The reason I am taking this question and doing it is because it's something I see all the time. And it's like people come in and they have high cholesterol and they have high LDLs, low density lipids. And they go, "Oh my God, my doctor told me I got to go on a statin drug, my cholesterol is too high." That's another whole thing as for what actually constitutes high cholesterol. You can look at some of our other videos on powerhealthtalk.com on that. But they're like, "Man, I think I eat pretty good and I feel like I exercise," and all that type of stuff. So two things that can cause high cholesterol, which most doctors aren't taking into consideration, one is actually insulin resistance. One is actually pre-diabetes. I won't get into the physiology of it, but prediabetes causes insulin resistance and insulin resistance causes high cholesterol. It's kind of like the basis of all the research for keto stuff. But thyroid, hypo-thyroid and 90... We'll use Mayo Clinic's numbers. In 85 to 95% of the people out there with hypo thyroid likely have Hashimoto's. And Hashimoto's is frequently called Hashimoto's Hypothyroid Disease. So the hypo-thyroid aspect of it is what creates the condition. So basically the thyroid has receptor sites all over the body. And when you get hypo-thyroid, everything starts slowing down for two reasons. One, it affects the vagus nerve coming off of your brainstem. And your vagus nerve is what controls your stomach. It controls your gallbladder. It controls your pancreas. It helps to control... It controls the movement of your bowels. It's the number one cause of constipation is when that guy's not working. It controls your liver. So everything slows down. Cholesterol is made and stored in the liver. And so what happens is when you get hypo-thyroidism, things start to slow down. The liver can't clear as well as it should. And the next thing you know, you start making... High density lipids, they're the good cholesterol. Low density are the bad cholesterol. And cholesterol is cholesterol. Okay, so high density lipids, the good guys, usually go down because those are guys that are going out to your arteries and bringing back the bad cholesterol. And the bad cholesterol is the bad cholesterol because it's going into your arteries and staying there. And cholesterol is just cholesterol. When everything slows down, the low density lipids, the bad cholesterol starts not mobilizing as well as it should. When everything slows down, the overall cholesterol guys don't get out of the out of liver the way that they should. And you start to get this picture of a high cholesterol and high low density lipids. And that's the point in time when people start saying, "Oh, let's give you a statin drug." Or even in the alternative world, let's give you something for that. http://powerhealthtalk.com http://powerhealthreno.com Martin P. Rutherford, DC 1175 Harvard Way Reno, NV 89502 775 329-4402 https://goo.gl/maps/P73T34mNB4xcZXXBA

Presented by various Local Dharma Leaders   This recording was edited and prepared for publication by volunteer Aruna Bala.

See all series | See all talksTeacher: Susan AlotricoDate: 2020-12-20 SundaySeriesSunday Morning Meditation & Dhamma 2020-08-02 Aravind Moorthy, Lauren Wilson, Lyndal Johnson, Sooz Appel, Susan Alotrico, Tuere Sala Presented by various Local Dharma Leaders This recording was edited and prepared for publication by volunteer Aruna Bala.

het daeThis episode is a deep dive into the rise of cardiovascular conditions and the impact on you as a Health and Fitness Professional. Stay tuned as we focus on Hypertension and Hypercholesterolemia, which are the two biggest silent cardio killers. In this episode, you’ll discover: the rise of cardiovascular conditions why clients are at a higher risk with undiagnosed cardiovascular conditions the importance of screening and assessing client readiness to exercise Read the show notes for S4E2: The Silent Cardio Killers: A Rise of cardiovascular conditions https://parallelcoaching.co.uk/the-silent-cardio-killers-a-rise-of-cardiovascular-conditions Timestamps: 0:30 Welcome to S4E2 of FitpRo Sessions Podcast: The rise of cardiovascular conditions 2:00 The Silent Cardio Killers causing heart attacks and strokes 5:00 Asymptomatic cardiovascular conditions require screening and measurement 11:00 What is hypertension? and what is normal blood pressure? 13:00 Blood Pressure increases during exercise 22:40 Side effects and co-morbidities of medication for cardiovascular conditions 24:00 Prevalence of hypertension in the UK: 12.5 million diagnosed 27:00 What is hypercholesterolemia – and how many are diagnosed with raised cholesterol levels 29:30 The hereditary line of hypercholesterolemia 31:00 What is the difference between HDLs and LDLs: are they really good and bad? 37:00 Activity and lifestyle changes versus medication 40:00 The snowball effect of a sedentary lifestyle 43:00 Putting the HEALTH back into health and fitness professionals 46:00 What is your big takeaway, Message us … m.me/ParallelCoaching Or Comment Below Join our Parallel Coaching Inner Circle with other fitness professionals like you https://www.facebook.com/groups/parallelcoachinginnercircle/ Want to help more clients and become a specialist exercise referral instructor? Discover How 1000+ Fitpros Have closed the knowledge gap of common clinical conditions and expanded their client base. Our Level 3 Diploma in Exercise Referral teaches how to liaise with other health and medical professionals to build a referral network. As well as the ins and outs of all 14 common clinical conditions so you know how to successfully coach a client to manage existing conditions and prevent the onset of further comorbidities. “EVERYTHING You Need To Step Up As a Specialist Trainer” https://revision.parallelcoaching.co.uk/level-3-exercise-referral-qualification Dedicated to More Hayley “Cardiovascular Conditions” Bergman Parallel Coaching P.S. You can also find us on the following platforms: Instagram: https://www.instagram.com/parallelcoaching Facebook: https://www.facebook.com/ParallelCoaching Twitter: https://twitter.com/ParallelCoach YouTube: http://bit.ly/2F1Z1bs Download all FitPro Session Shownotes: HERE Listen on Itunes: http://bit.ly/itunes-fitpro-sessions Download on Spotify: http://bit.ly/spotify-fitpro-sessions --- Send in a voice message: https://anchor.fm/fitpro-sessions/message

Neuropathy@CoreHealthStatins are so good for you they belong in the water supply! Who would ever say such a thing? Probably a lobbyist for Big Pharma, you know those magnanimous people you provide an annuity for with your health. They count on you needing their pills by the handful to keep their profits rolling in. When one or two pills are not enough they magically provide a self-sponsored study showing you really need to stack another pill onto the same one you are already taking to be even more healthy. Then all you have to do is eat Honey Nut Oat Cheerios to keep your cholesterol in check. What if I told you that your body needs cholesterol to function properly? I know what the commercials say, somehow if you take cholesterol-lowering medication without proper dieting and exercise it is implied that you are healthy. Do you honestly believe that you can have an unhealthy lifestyle and still be healthy? Dream on. Cholesterol is needed to make vitamin D, hormones (including testosterone and estrogen), and fat-dissolving bile acids. In fact, cholesterol production is so important that your liver and intestines make about 80% of the cholesterol you need to stay healthy. Only about 20% comes from the foods you eat. Although we usually think of cholesterol as some sort of evil being in our body, it is important to your health. Cholesterol, a waxy, fatty substance carried through the bloodstream by two different particles—low-density lipoproteins (LDL) and high-density lipoproteins (HDL)—is essential for building cell membranes, producing hormones, and helping your metabolism work efficiently. LDL is considered the “bad” cholesterol because it deposits plaque within the arteries, while HDL, or the “good” cholesterol, transports excess cholesterol out of the arteries and to the liver, where it can be broken down. In other words, a high level of HDLs may reduce the risk of a heart attack, while a high level of LDLs may raise your risk of a heart attack. Shouldn't the focus be on raising the levels of HDL's? helps your body make cell membranes, many hormones, and vitamin D. The cholesterol in your blood comes from two sources: the foods you eat and your liver. Cholesterol medicines alter enzymes in your liver, one would conclude that this is a good thing. In some cases, it is but if you are overweight, don't exercise, eat poorly, smoke cigarettes what good is a good cholesterol number? Here is something I want you to think about when it comes to cholesterol. Your brain requires Myelin. It is an insulating layer or sheath that forms around nerves, including those in the brain and spinal cord. It is made up of protein and fatty substances. This myelin sheath allows electrical impulses to transmit quickly and efficiently along the nerve cells. Your body needs cholesterol to produce myelin. When the myelin sheath is damaged, nerves do not conduct electrical impulses normally. Sometimes the nerve fibers are also damaged. If the sheath is able to repair and regenerate itself, normal nerve function may return. However, if the sheath is severely damaged, the underlying nerve fiber can die. This has serious implications for people with peripheral neuropathy. While we are on topic what does a lack of good cholesterol mean for aging brains that are being wracked with dementia? I doubt Big Pharma will do a study on dementia and the use of statins they would be afraid of losing a cash cow with no end in sight. It's your health and your decision to take statins, be informed, watch your diet, exercise, stay healthy.Educational Neuropathy Video Peripheral neuropathy affects chemotherapy patients and diabetics primarily.Neuropathy@CoreHealth is Fairfield County's leading provider of natural

Proper mold/mycotoxin testing, Fasted BJJ, Statins vs PSK9 inhibitors for high LDLs, Best Conventional Meat Cut, Keto and breastfeeding Make your health an act of rebellion. Join The Healthy Rebellion Please Subscribe and Review: Apple Podcasts | RSS  Submit your questions for the podcast here   Show Notes: ---- News topic du jour: Original UN tweet I talked about seems to be deleted/removed: https://www.stockjournal.com.au/story/6855807/un-told-to-stick-to-knitting-after-urging-people-to-eat-less-meat/ https://www.beefcentral.com/news/un-removes-meat-worse-than-oil-tweet/ ---- 1. Proper mold/mycotoxin testing [17:20] Scott says: Hello Robb and Nicki, I've been struggling with mycotoxins/Lyme.  I read Toxic by Dr. Nathan last October when my doctor diagnosed.  I am wondering can you recommend a company that can test for ERMI and do the plate testing.  I live in a 1 bedroom apartment.  I had testing done in October but was not as informed at that time and it was a company that did the basic air quality although even that did have some positives as well as my 1st GPL urine test and most recent one this month.  I live in Oak Park, IL which is a suburb of Chicago.  Thank you in advance for your time and information. With gratitude, Scott Davis 2. Fasted BJJ [19:43] Eric says: Hi Robb and Nicki, First, thanks for all that both of you do. I’m a listener since episode one of The Paleo Solution Podcast and continue to refer my personal training clients to all of your content, new and old. Ok, context first. I’ve been a time restricted eater for about a year and half and have had great results. Monday-Saturday I run an 18:6 protocol and Sunday’s are 16:8. Whether it’s 6am or towards the end of the TRE window, I feel good and perform well when I have a strength or sprint workout. Next week I start no gi BJJ from 11:30-1pm Tues/Thurs. I typically end my TRE around 12:30 or so but am wondering how BJJ workouts will play out. Should I supplement with quality sea salt and/or other electrolytes since they have little or no impact on most types of fasting (per Dr. Rhonda Patrick)? Of course I’m going to give it a whirl and see how it goes but just curious in case I end up needing something. Again, thanks and keep up the great work! 3. Statins vs PSK9 inhibitors for high LDLs [24:42] Dr. Mandal says: Hey Robb and Nicki. I shot this question off to the Peter Atia podcast also cause I'd be genuinely intrigued how someone with your biochemistry background would approach this problem, I know you can't give medical advice, but just wondering what ideas you'd have about treating someone like myself with an elevated LDL particle count who has an APOE3/E4 genotype. The LDL particle count did improve with a 3 times a week dosing with Lipitor 10mg. However, since statins work by diminishing the output of total cholesterol by inhibiting HMG-CoA reductase would long term use of a statin eventually be detrimental to someone who is more prone to Alzheimer's dementia with an APOE3/E4 genotype? Would a PSK9 inhibitor be a better choice since it works by removing LDL particles? Additionally, total cholesterol, triglyceride, HDL levels, and inflammatory markers are excellent and are controlled with a targeted keto-ish diet (

The September episode of 3 Minute 3rs, brought to you by the NC3Rs (www.nc3rs.org.uk), the North American 3Rs Collaborative (www.na3rsc.org), and Lab Animal (www.nature.com/laban) Papers behind the pod: 1. http://jpet.aspetjournals.org/content/371/1/15.long 2. https://www.sciencedirect.com/science/article/pii/S001216061830006X 3. https://www.nature.com/articles/s41467-019-11259-w [NC3Rs] Accurate measurements of drug and metabolite concentrations in the blood are vital to estimate exposure to the target in humans and animals during drug development. Zebrafish larvae are increasingly used for pharmacological research, but measurements of blood drug concentrations in these small animals have been technically challenging. A team at Leiden University have developed a method for nanoscale blood sampling from the posterior cardinal vein of zebrafish larvae at five days post fertilisation. A median volume of 1.12 nL of blood can be collected from each embryo and samples pooled to form a single replicate, which can be analysed by Liquid chromatography–mass spectrometry. While drug and metabolites could be successfully measured in the pooled samples, the authors suggest improvements to the sensitivity of the technique, which could reduce the number of embryos needed for each replicate. In addition, using microfluidic embryo handling techniques, blood sampling could be further automated and yield improved while reducing the amount of drug required. Further development of this microsampling technique has the potential to increase the use of the zebrafish embryo model to define drug pharmacokinetic properties. [NA3RsC] Josephine Morris and her colleagues at Bristol University used transgenic lines of zebrafish to study mechanisms of collagen formation and repair. This work was published in the journal Developmental Biology, Vol 441. They crossed transgenic zebrafish lines which integrated green fluorescent protein, expressed in the epidermis and mCherry collagen which is specifically expressed in the basal epidermis which allowed them to understand the dynamic nature of collagen 1 fibril deposition. The authors used Transmission Electron microscopy to demonstrate the intricate pattern integration of the fluorescent proteins in embryonic development. In other studies, a wound was created with a 30 g needle on the flank of 4 day old larvae and collagen repair was documented pictorially. By using the GFP collagen and mCherry collagen lines together, they were able to exploit the unique live imaging in larval fish to probe the process of collagen deposition and wound remodeling specifically in the basal epidermis and deeper layers. It is hoped that these transgenic lines will enable live imaging of collagen deposition and remodeling in various other organs and diseases. [LA] And finally, say hello to LipoGlo, a new reporter system for keeping track of lipoproteins in vivo. These proteins ferry fats throughout the body – you may be familiar with HDLs and LDLs, the latter of which can contribute to cardiovascular disease in people. A particular particle, Apolipoprotein B-containing lipoprotein, is particularly problematic and while it has been studied in mammals, such animals don't lend themselves to the large numbers needed for high-throughput drug discovery work. Enter the larval zebrafish. In order to visualize APoB-lipoproteins across the whole translucent organism, the research team took advantage of a glowing enzyme called NanoLuc, which they attached to APoB in the larvae. This bioluminescent reporter is highly sensitive and quite bright, allowing the team to follow the distribution and concentrations of the lipoprotein as it traversed the vascular system of the tiny little zebrafish. Additional details about the new tool can be found in the journal Nature Communications. See acast.com/privacy for privacy and opt-out information.

In Episode 144 of Keto Talk, Jimmy and Dr. Will Cole dig into the subject of Functional Medicine and Dr. Cole explains to us exactly what tests every keto dieter should be running and what they mean to you. “It's rarely one thing that is the magic bullet. Normally it's a confluence of different factors. These labs allow us to find the pieces of the puzzle.” – Dr. Will Cole “You can take a shotgun approach with labs and do everything, or use them to really fine tune your health.” – Jimmy Moore The specific tests we talk about in this episode and the ranges you should be looking for: C-reactive protein Inflammation is one primary way disease genes get turned on, and it is generally destructive all over the body. C-reactive protein is an inflammatory protein that, while it is essential for cleaning up bad bacteria, in excess it can lead to accelerated aging, chronic disease, and damage to the telomeres. Optimal Range: < 0.5 mg/L Small dense LDL particles What you thought was “bad cholesterol” (LDL) isn’t all bad, and labelling it so is a simplistic and inaccurate view of cholesterol. LDL particles are proteins that carry cholesterol around in your body. Some of these particles are big and buoyant, while others are small and dense. It’s the small dense LDL particles that can cause damage, while the larger fluffier particles are essentially benign. Knowing your level of small dense LDL particles is much more instructive that simply knowing your total cholesterol, because it is the small dense LDLs – not the cholesterol itself – that indicate a riskfor heart attack and stroke (and thereby put you at risk for an earlier death). Optimal Range: < 200 nmol/L Homocysteine This protein in excess (especially when coupled with a B vitamin deficiency) has been linked to cognitive decline, which can drastically reduce quality as well as length of life. Optimal Range: < 7 Umol/L Hgb A1C This test tells you what your blood sugar has been, on average, for the past two to three months. When it is high, it can indicate pre-diabetes or diabetes, and an elevated A1C has been linked with higher rates of all-cause mortality in patients with diabetes. Optimal Range: < 5.3% Vitamin D This nutrient is responsible for hundreds of different genetic pathways in the body but because most people spend most of their day indoors and get little sun exposure, vitamin D deficiency is rampant. That’s too bad because this deficiency is linked to chronic disease, and optimal levels are linked to an actual preservation of telomeres, meaning you live longer and stay healthier! If that’s not a reason to get a little sunshine, I don’t know what is. Note that vitamin D should be paired with other fat soluble vitamins, like vitamin A and K2, for maximum absorption. Optimal Range: 50-60 ng/mL Fasting insulin When your body breaks down carbohydrates, and to a lesser extent, proteins into glucose, your blood sugar goes up. In response, your pancreas secretes insulin to send your blood sugar into your cells (for energy) and bring down the level in your blood. However, if insulin gets activated too often at too high levels, this has been linked to accelerated aging and telomere shortening. Optimal Range: < 3 ulU/mL C-peptide: Optimal Range: 0.8 to 3.1 ng/mL Fasting blood sugar: Optimal Range: 75 to 90 mg/dL Triglycerides: Optimal Range: < 100 mg/dL HDL: Optimal Range: 59 to 100 mg/dL Hormone testing: Urine and Saliva Other Nutrients: Selenium, Mg, Iron, MMA, Microbiome labs: We look to assess gut health, where around 80 percent of our immune system resides. Intestinal permeability lab: This blood test looks for antibodies against the proteins that govern your gut lining (occludin and zonulin), as well as bacterial toxins that can cause inflammation throughout the body, called lipopolysaccharides (LPS). Multiple autoimmune reactivity labs: This array shows us if your immune system is creating antibodies against many different parts of the body, such as the brain, thyroid, gut, and adrenal glands. The labs are not meant to diagnose an autoimmune disease, but to look for possible evidence of abnormal autoimmune-inflammation activity. Cross reactivity labs: Helpful for people who are gluten-sensitive and who have gone gluten-free and eat a clean diet, but still experience symptoms like digestive problems, fatigue, and neurological symptoms. In these cases, relatively healthy food proteins—such as gluten-free grains, eggs, dairy, chocolate, coffee, soy, and potatoes—may be mistaken by the immune system as gluten, triggering inflammation. To their immune system, it’s as if they have never gone gluten-free. 1. AHCY: This enzyme is responsible for breaking down the amino methionine by converting S-adenosylhomocysteinase into pro-inflammatory homocysteine. Mood disorders are common for those with a double mutation but typically do well with SAMe supplementation. 2. BHMT: The BHMT gene directs the enzyme responsible for the amino acid methionine, the building block in the choline oxidation process for optimal brain function. Changes in this gene are associated with ADHD. 3. CBS No, not the television network! It actually stands for the enzyme that makes the amino acid cystathionine. A mutation of this gene will lead a person to produce more sulfur end products and as a result will need to limit sulfur-rich foods such as legumes and dairy. These foods can increase ammonia levels and contribute to existing health problems. NOS and SUOX are two other genes that can increase sulfur and are linked to immune disorders like asthma. 4. COMT: This gene is responsible for creating a healthy balance of neurotransmitters and, in turn, a healthy brain. A double COMT gene change is associated with increased risk for anxiety, OCD, bipolar disorder, and ADHD. 5. MAO: The main role of the MAO gene is to clear out excess neurotransmitters like serotonin. When changes to this gene occur it can create an imbalance in neurotransmitters leading to increased rates of anxiety and depression. Those with an MAO mutation, as well as the MTHFR gene mutation, can have a higher rate of histamine intolerance. Because of this even healthy foods such as fermented foods, bone broth, and vinegar can increase inflammation. 6. MTHFR: This is not an acronym for a swear word guys, get your mind out of the gutter. The biggest thing I use DNA testing for is to assess methylation, a biochemical superhighway that help your gut, brain, hormones, and detox pathways function properly. This process happens a billion times every single second so if methylation isn’t functioning well, neither are you. Since I often deal with a variety of gut, brain, and hormonal problems in my clinic it is important to see if my patients methylation is working well. The MTHFR enzyme is responsible for converting folic acid into folate which acts as fuel to the methylation process. A1298C and C677T are the two main MTHFR mutation. When A1298C is altered it can lead to mood disorders due to its important role in neurotransmitter function. C677T changes can cause higher levels of inflammatory homocysteine. Both of these are linked to autism and autoimmune conditions like autoimmune thyroid issues. 7. MTR/MTRR: These are necessary for B12 production, another methyl donor. Those who have this mutation need higher intake of B12 because their body uses it faster than it produces it. Oftentimes people who have this genetic change can also be low in lithium which is needed for mood regulation. We can easily check lithium levels through testing blood and hair. 8. VDR VDR stands for vitamin D receptor. Every single cell in your body uses vitamin D. Other than your thyroid hormone, no other nutrient or hormone can claim that importance. It is responsible for over 200 different pathways in the body. Mutations in this gene make it really difficult to absorb vitamin D. It’s important to know if this is the case for you in order to supplement higher doses on a consistent basis to make sure you are getting enough of this vital nutrient. 9. Detox genes I also look for changes in your detox genes such as CYP1A2, also known as your caffeine gene. This can show just how well you can tolerate caffeine and whether or not it can be harmful or beneficial to your health.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 In today's feature discussion, we will be doing a deep dive into the LEADER trial results, looking at new results of liraglutide and its effects in patients with type two diabetes, with or without a history of myocardial infarction or stroke. All of that coming right up after these summaries.                                                 In today's issue, five groups of investigators in two original basic research articles and three research letters tackled the same biological question, and all reached the same conclusion that cells in the heart expressing the SCA-1 cell surface antigen do not become cardiomyocytes to any meaningful degree, and instead become endothelial cells. Among the original basic papers, first author Dr Vagnozzi, corresponding author Dr Molkentin from Howard Hughes Medical Institute and Cincinnati Children's Hospital Medical Center, and their colleagues use the inducible recombinase method and generated a constitutive recombinase at the SCA-1 locus. They found that cardiac resident SCA-1 positive cells were not significant contributors to cardiomyocyte renewal in vivo. Instead, SCA-1 positive cells generated cardiac vasculature throughout development, during aging, and following injury with trivial contribution to the cardiomyocyte population.                                                 In the second paper from co-first authors, Drs Zhang and Sultana, with corresponding author Dr Cai from Indiana University School of Medicine and colleagues, these authors engineered a series of genetically altered mice to identify and track SCA-1 positive cells in the heart, and found that SCA-1 positive cells were purely of the endothelial lineage. Together with three research letters, these five papers add to the growing body of evidence that in adult mammals, our new cardiomyocytes arise from preexisting cardiomyocytes and rarely, if at all, from adult cardiac stem cells.                                                 Could metformin be cardioprotective in patients with type one diabetes? Co-first authors Drs Bjornstad and Schafer, corresponding author Dr Nadeau from University of Colorado School of Medicine, and their colleagues hypothesized that adolescents with type one diabetes have impaired vascular function, and that metformin may improve insulin resistance and vascular dysfunction.                                                 To test this hypothesis, they studied 48 adolescents with type one diabetes and 24 non-diabetic controls using MRI of the ascending and descending aorta, as well as assessment of carotid intima-medial thickness by ultrasound, brachial distance ability by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic euglycemic clamp. The adolescents with type one diabetes were randomized one as to one to three months of 2000 milligrams metformin or placebo daily, after which the baseline measures were repeated.                                                 The authors detected early signs of cardiovascular disease with MRI in these adolescents with type one diabetes compared to controls. They further found that three months of metformin therapy improved insulin sensitivity as assessed by gold standard hyperinsulinemic euglycemic clamp, both in normal weight and obese adolescents with type one diabetes. Moreover, metformin improved carotid intima-medial thickness and aortic wall shear stress and stiffness. Thus, metformin may hold promise as a cardioprotective intervention in type one diabetes.                                                 What are the clinical genetic and environmental determinants of varicose vein formation? Co-first authors Drs Fukaya and Flores, corresponding author Dr Leeper from Stanford University, and colleagues applied machine learning to agnostically search for risk factors of varicose veins in nearly half a million individuals in the UK bio bank. They found that greater height appeared as a novel predictor of varicose vein disease in machine learning analyses, and was independently associated in multi-variable adjusted Cox regression. Using Mendelian randomization, they demonstrated that greater height had a causal role in varicose vein development. A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development, and skeletal/limb biology, and discovering a strong genetic correlation between varicose veins and deep vein thrombosis. The knowledge greatly expands our understanding of disease pathophysiology, and may help future improvements in the management of varicose veins and their associated complications.                                                 The final original paper describes the effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events, and all-cause mortality in patients with type two diabetes and chronic kidney disease. First and corresponding author Dr Mann from Friedrich Alexander University of Erlangen in Germany and their colleagues performed a post hoc analysis of the LEADER trial comparing the liraglutide's treatment effects in patients with and without kidney disease.                                                 As a reminder, LEADER was designed to recruit a subgroup of at least 660 patients with an estimated glomerular filtration rate, or eGFR, less than 60, approximately 220 patients with severe renal impairment, eGFR less than 30, and at least 440 patients with moderate renal impairment with an eGFR of 30 to 60. The authors found that the liraglutide reduced the risk of major adverse cardiovascular events, and all-cause mortality compared with placebo in patients with chronic kidney disease defined as an eGFR less than 60, and also in patients with albuminuria defined as a urinary albumin to creatinine ratio above 30.                                                 The overall risk of adverse events did not differ between the liraglutide and placebo treated patients either with or without chronic kidney disease in the LEADER trial. In summary, these results show that liraglutide added to standard of care reduced the risk of major cardiovascular events and all-cause mortality in patients with type two diabetes and chronic kidney disease. Furthermore, these results appear to apply across the chronic kidney disease spectrum that was enrolled.                                                 And that brings us to the end of our summaries. Now for this week's feature discussion.                                                 Cardiovascular outcome trials have transformed the world of treating patients with diabetes. And for our feature discussion today, we're going to be talking about a new analysis from a very important trial, the LEADER trial of GLP-1 receptor agonists, and that's the liraglutide. I'm very proud to have the corresponding author of this paper with us, Dr Subodh Verma, and he's from St Michael's Hospital and University of Toronto, and our senior associate editor, Dr Gabriel Steg, from University of Paris. Actually, Gabriel, I'm actually going to start with you for once because I recall perhaps something you may have written about cardiovascular outcome trials. Dr Gabriel Steg:                Yeah, it's really funny. I'll try to take it graciously. You know, I wrote a frame of reference in Circulation a few years ago, wondering whether we were doing good by doing all these large outcome trials for safety with new anti-diabetic drugs, because there had been not one but two, three, four, five, six trials that were essentially neutral, enrolling more than 107 patients and participants at the expense of millions of dollars, and not much came out of it. And this was published in circulation. I was very happy until the next trial comes up, and this is EMPA-REG. And the next one is LEADER. And we have two trials that literally transform our vision of anti-diabetic agents as major agents for cardiovascular prevention. The trial we're going to discuss today, which you wrote about, is one of these trials. And I think I have to revisit my own writings and probably eat my hat. Dr Carolyn Lam:                So indeed, that's a great segue. Thank you, Gabriel. And Subodh, tell us then, what did you look at this time in LEADER? And maybe start by saying a little bit about LEADER, and the rationale for doing this particular sub analysis. Dr Subodh Verma:           Right. So, as Dr Steg mentioned, these were FDA-mandated studies to look at safety and potential efficacy of newer antihyperglycemic agents. The entire premise was that cardiologists and cardiovascular specialists were not really getting that excited about antihyperglycemic therapies in people with diabetes, because there was no data that they did much. And as Dr Steg mentioned, even the data leading up to some of these trials were disappointing, suggesting that they're safe, but they neither reduce nor increase events.                                                 So, I think EMPA-REG and LEADER really changed the calculus in many ways of how we look at cardiovascular risk reduction with antihyperglycemic agents. LEADER was a trial that was 9,340 patients. These are patients that were at high cardiovascular risk, but unlike EMPA-REG that only enrolled people with prior to ischemic cardiovascular events ICAD, PAD, and CVD, LEADER took a position of enriching the population with this spectrum of patients with cardiovascular disease and risk factors.                                                 So, some were in so-called high risk primary prevention who had not had established ASCVD, but had multiple risk factors such as uncontrolled hypertension or chronic kidney disease. Some had evidence of ASCVD, but had not had a prior myocardial infarction. And some, in fact, had had a prior MI stroke or PAD. So, it was a broad population of patients that was enrolled. And the primary result, again, for the primary outcome of MACE, demonstrated a significant reduction in favor of liraglutide versus placebo. And then for the individual components of that primary outcome, they were all statistically significant, or at least went in the right direction. Importantly, CV death was reduced by 22% with liraglutide versus placebo.                                                 I would like to emphasize that in this day and age, and Dr Steg has nicely set the stage, we have started thinking about how do we think about cardiovascular phenotypes of patients. You know, is a drug more likely to reduce heart failure? More likely to reduce ischemic events? And with LEADER, we found that in fact the trial actually reduced mostly ischemic events, and was really not that beneficial on heart failure related outcomes.                                                 So, that was the broad positive outcome from LEADER. They've led to guideline changes worldwide that patients with diabetes should be prioritized to receive an agent that has shown benefit, particularly if they have cardiovascular disease. And one of those agents was empagliflozin. The other was liraglutide. But, secondary prevention is a pretty crowded space, and not everybody can get everything, and not everybody should get everything, and not everybody can afford everything. So, I think leaders like the two of you here are often thinking about, how do you risk-stratify these populations, and how do we start thinking about people who are at greater risk, people who can actually derive benefit? And I think that's the smart and thoughtful way of doing this. And is there a certain threshold at which point the therapy loses its ability to reduce cardiovascular events, at least in the short term?                                                 So, in that theme, in that vein, what we looked at here was an analysis of people in LEADER who truly had a prior ischemic event. And the work that Dr Steg and others have done in REACH registries, etc. clearly establish that that's a population of patients, type two diabetes and a prior ischemic event. You don't really need many more calculators beyond that. That's the highest risk population. And then, the next level is really type two diabetes with a ASCVD. And we know that from REACH as well, that that's the next level of risk. And then, what about people who have type two diabetes just by itself? Which certainly are much higher risk than people who don't have diabetes, but we didn't have a non-diabetic group to compare to.                                                 And what we find is that the higher the baseline risk defined by this, the greater is the absolute risk reduction. The P value is consistent for ... You know, this is non-significant for heterogeneity. but specifically, people with a prior ischemic event derive benefit. People without a prior ischemic event who've had ASCVD derive significant benefit. But, in fact, we found that the curves were almost superimposable for people who did not have prior ASCVD. And that's not to say the GLP-1 receptor agonists should not be used in diabetes in the absence of cardiovascular disease, because they're great glucose lowering agents. They cause hypoglycemia, they cause weight loss. And potentially, within longer exposure times, cardiovascular benefit may actually emerge. And we've heard data from Dr Gerstein's study called Rewind that is positive, that will be presented next year. Harmony Outcomes was a study that was presented recently that also showed a benefit. So, whether in the primary prevention group we see a benefit in the future remains to be seen. Dr Carolyn Lam:                Oh, that's a great, great summary. But Subodh, you know, it's become a bit of what do we define as a primary and secondary prevention anymore, you know? And the patient that already got type two diabetes. Now, in this paper, it's very nice. As you said, has a history of myocardial infarction and stroke. And maybe I could just clarify to the audience, you couldn't just pick up the primary paper and see that because the way the inclusion exclusion criteria were designed in LEADER, you can't just pick up the sub-groups. So, this specific analysis, so carefully and wonderfully done, was absolutely needed. But then you know, what do you think? What's primary and what's secondary prevention anymore? Dr Gabriel Steg:                Well, I want to commend the authors for doing the careful stratification of diabetic patients they've done in the paper, and particularly for pointing out that it's one thing to have had an event where you actually ruptured a plaque and had a traumatic event. And it's very different from merely having plaque in one of your carotids or your arteries, and which is, of course, in turn very different from the majority of diabetic patients who have neither an event, nor diagnosed plaque or established plaque. And when we think about preventing cardiovascular and diabetes, we have to remember that the outer circle, the broader circle of diabetic patients who haven't had disease is the largest component. Dr Subodh Verma:           True. Dr Gabriel Steg:                And these are the patients whom we treat every day with the hope of eventually keeping them from harm, safe from harm, or with therapies that are new and potentially beneficial. And I think your research very clearly shows that there's a gradient of benefit. The sicker the patient, the greater the benefit in preventing MACE. And as long as you get to more healthier phenotypes of diabetes, then there is less of a benefit. Which doesn't mean that we shouldn't use these agents. As you point out, they're very convenient and effective agents for glucose control. But then, their cardiovascular benefits are more uncertain. And I think this is the key message from this analysis, and it's a great analysis. Dr Subodh Verma:           Thank you. I appreciate that. I totally agree that for the doctor in the trenches, particularly the cardiologist who's just trying to get their feet wet with antihyperglycemic therapy, you know? Cardiologists will embrace PCSK9 inhibitors and rivaroxaban at low dose, and maybe a new way of doing surgery or putting an LVAD. But it's very hard to get their attention when it comes to antihyperglycemic therapy. So, defining for them the population that matters the most, where the greatest risk and risk reduction can be achieved, I think is quite important from a clinical standpoint. And I think most cardiologists will agree that type two diabetes and a prior ischemic event is a high-risk population. Type two diabetes in a prior ASCVD is a high-risk population, and the magnitude of CV death reduction here is something meaningful for them to pay attention to. Dr Carolyn Lam:                Yeah, indeed. That's what I love best about this paper. It's actually asking the question the way a cardiologist would, exactly like you had both put. So, what do you think is the next step now? Do you think we need to look at this primary prevention type two diabetics with no established cardiovascular disease? Do we really need to? Is it that we need a method analysis, which you can talk about? Or, is it that we need longer follow up? Or, what next? Dr Subodh Verma:           I think that first of all, we have to get rid of the terminology, and maybe as a heart surgeon, I can be a little bit provocative and just say it. I wrote an editorial to the Declare Study that was just published yesterday in The Lancet called "Pumps, Pipes, and Filter: Do SGLT2 inhibitors cover it all?" Then I made a strong statement there that this nomenclature of primary and secondary really is artificial because it only captures ischemic risk, and does not capture risk of heart failure or renal disease. So, in a patient, as you've asked, Carolyn, who has type two diabetes, whose renal function is 54 or GFR is 55, who's not had a prior MI ... Is that patient primary prevention? Maybe from an ischemic standpoint, but he's clearly secondary prevention from a renal standpoint. Dr Subodh Verma:           So, I think we need to just think about all disease as a spectrum, and not as an artificial cutoff that, if you've had an ischemic event, suddenly the world changes for you there. Because, that gradient I think is probably what we need to somehow appreciate as to where that risk lies. The patient who's 40 who's had no risk factors, you know? The Rashami paper from the New England Journal that looks at risk factor control and diabetes make a very compelling story that if you control your five risk factors, you actually don't have an excess risk of cardiovascular events in diabetes, at least from MACE. The story is whether anybody can have those five risk factors controlled. But, early on in diabetes, with diabetes duration not being that significant, with risk factors not being that significant, I think maybe that's not the population to go after. But certainly, waiting for ASCVD to develop and then start therapy is also not the right way of doing it, so ... Dr Carolyn Lam:                Interesting. I really wonder what new guidelines are gonna show. Gabriel, any other perspective? Dr Gabriel Steg:                Well, first of all, I love the editorial. I thought the title was fantastic, and you summarize here what we need to think about when we think about diabetes; not solely the pipes. As an interventional cardiologist, I'm very interested in the pipes. Dr Subodh Verma:           Me, too. Dr Gabriel Steg:                Not solely the pump, but also the filter. And there's more than the heart and vessels in the complications of diabetes. So I thought it was a great, great title. My view is that we still need to remember that if we take the lifetime perspective, a healthy youngster with type one diabetes, a relatively healthy patient in his fifties with type two diabetes, their probability of dying from cardiovascular disease is enormous. Even though risk calculators will give them a relatively low probability over the 5 year or 10 year term, eventually that's what's gonna get them. And therefore, we still have progress to make. We are fortunate to have lived an incredible period in the past few years where we've had emergence of new risk preventive therapies in diabetes. That's incredible. It's an epiphany. But, it's not over. We need more information, more trials in other populations. We need to look at renal function and heart failure. So, it's a great time to be doing clinical trials in diabetes. Dr Subodh Verma:           Right. Dr Carolyn Lam:                And indeed, a great time to be publishing in circulation. We've been really doing a lot of publications in the cardiovascular outcome trials in diabetes here. Dr Subodh Verma:           And it's being noticed. There's no doubt about it. Dr Carolyn Lam:                I hope so. And, maybe a time for a new frame of reference, because what you just said was diametrically sort of in contrast. Dr Subodh Verma:           I would emphasize one more point, and that is, you know in atherosclerosis, the dominant mechanism has been LDL, right? And Dr Steg here is changing the landscape of that with Odyssey Outcomes and many other strategies. But again, in Circulation, Dr Bhatt, and I, along with the LEADER investigators, recently presented and published a paper showing that liraglutide's benefit is seen independent of LDL cholesterol, and all the way down to people with LDLs of below .5. So, the point is that this mechanism of benefit of GLP-1 seems to be complimentary to LDL lowering. And therefore, I think it offers great hope that you can actually reduce the ischemic burden in diabetes, not just by ultra-low LDL, but by potentially additional mechanisms as well. Dr Carolyn Lam:                Absolutely. And then now, because I have to have the last word here on this show, let's not forget heart failure outcomes in diabetes. I think it's underestimated. I think it's really important. Okay, and with that, thank you gentlemen for joining me today.                                                 You've been listening to Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association, 2018.  

In this podcast episode, we talk about cardiovascular labs with naturopathic cardiology expert, Daniel Chong, ND. Chong discusses the use of cholesterol panels and other tests he uses in practice. He dispels some common myths about how to interpret different lab results.   About the Expert Daniel Chong, ND, has been a licensed naturopathic physician, practicing in Portland, Oregon, since 2000 and focusing on risk assessment, prevention, and drug-free treatment strategies for cardiovascular disease and diabetes, as well as general healthy aging, and acute and chronic musculoskeletal injuries. Chong has also completed certificate training in cardio-metabolic medicine from the American Academy of Anti-Aging Medicine and is an active member of the Society for Heart Attack Prevention and Eradication (SHAPE). In addition to his clinical work, Chong serves as a clinical consultant for Boston Heart Diagnostics Lab. Tina Kaczor, ND, FABNO: Hello I'm Tina Kaczor editor-in-chief at the Natural Medicine Journal. I'm speaking today with my friend and colleague Dr. Daniel Chong a naturopathic physician and specialist in cardiology specifically. Dr. Chong is a founder and lead consultant at healthyheartacademy.com as well as a consultant for the cardiology industry. Dan, thanks for joining me today. Daniel Chong, ND: Hello Dr. Kaczor, it's nice to be here. Kaczor: We have talked informally, and I thought this would be a great opportunity to talk specifically for our audience, about the use of cholesterol panels, and we'll go into specifically some breakdown of the usefulness of common cholesterol panels, and then break that out into more particular cardiology panels. There's a lot out there right now about whether cholesterol is or isn't even linked to heart disease, so let's just start at the beginning. Can you give us a little bit about the roots of the cholesterol theory? We'll branch off from there. Chong: I can try. It definitely is a relatively long-standing theory now. As I understand it, the first thoughts as to whether or not cholesterol had anything to do with cardiovascular disease came in the early 1900s on animal research with rabbits, but at that point it was dismissed because people were still not clear whether or not you could make any correlations between findings in rabbits and extrapolate out to humans. The major real focus on the connection between cholesterol and heart disease started more in the mid-1900s almost simultaneously in a way with Ancel Keys and the Framingham study, so they started around the same time. Ancel Keys was one of the first people to really make a point of saying, "We should really research this because we repeatedly are seeing this potential connection," and so he was one of the first people to really start trying to splice it out. Then, the Framingham study started simultaneously. They don't come out with any of their more definitive conclusions until a little later than him with that. That's where it all began as far as I understand it. Kaczor: In the Framingham study specifically I know that there has been ... The broad interpretation in the professional world has been high cholesterol equals risk of heart disease, LDL being the "bad cholesterol," in general. Is there particular subpopulations that this is more true for? In other words, can we say if you are a 40 or 50 something-year-old male this is more true than if you're a 80-year-old male, or a female? Is there any way to delineate that with just looking at broad generic cholesterol levels, nothing too specific yet? Chong: Hopefully, it will be answering your question by saying this, but to me one of the most fascinating pieces of information I heard come out of the Framingham study in particular is that over the course of however many years ... this was a statistic we heard about maybe five or so years ago. The Framingham study had been active for well over 50 years and they had well over 50 years of data on how many thousands of people, and the statement was made by the former director of the Framingham study, so it was certainly legitimate. Essentially what they said was, one of the key pieces of information that they saw in terms of the relationship between at least total cholesterol and cardiovascular disease was that it appeared as though if a person's total cholesterol was at or below 150 naturally, so throughout their lives without necessarily an intervention with a drug or whatever, just the people in the study who had naturally low cholesterol did not get heart disease period. Of course, you can't then take that and make any truly definitive statements, but there is, in terms of a general viewpoint that was one of the things that came out. In other words, nobody with cholesterol under 150 naturally got a heart attack in their study. Again, there would still need to be more done to splice that out and figure out what exactly is going on there and why that is, but there's definitely something to be said. You can see the same exact type of finding if you look at epidemiological research on different cultures of people in history who did not get heart disease or got very little heart disease, all of those people regardless of where they were on the planet, what types of specific foods they were eating, even to some extent what their lifestyle was some of these people smoked, et cetera, the cultures of people who were known and found not to get cardiovascular disease all had cholesterol at or below 150. Kaczor: You're talking about total cholesterol? Chong: Correct. Kaczor: Let's move over to talking about the bad cholesterol. LDL- Chong: Can I pause you for one quick second? Kaczor: Yeah. Chong: Just to say one other thing about that. There's a lot of questions that would be immediately raised from those statements that I just made. One other way that I look at things is, and I know we'll get into it more, but cholesterol in of itself, I will say right from the beginning, has to be involved. It is not a worthless thing to measure, it is not something to just disregard and only focus on information. Time and again it has to be involved, technically it has to be involved. You can't make plaque without it, but it's just an important way to think about it. It's just whether or not it's the primary causative factor and we'll get into that. Kaczor: Yeah, that's an important point. I don't see many people with total cholesterol below 150, but we'll put that aside. It's pretty uncommon. I don't know about other people. Let's break it down- Chong: In modern times it absolutely it is. Kaczor: Let's talk about LDL specifically and just start out with there's a lot of more specific labs that are looking at LDL particle size rather than total LDL. Just a brief primer, if you would, on the difference between LDL- Chong: I like your emphasis on brief. Kaczor: Yeah. Chong: Sorry, go ahead. Kaczor: On LDL calculated as it is in a common cholesterol panel and the particle size as it is measured by several different labs now. Chong: I'll do two separate simple ways that I look at it. One is technically LDLC or "LDL cholesterol" measurements that are most commonly done in the average physicians' offices et cetera is technically measuring the mass or total amount of cholesterol being carried around on LDL molecules. Just as a reminder to people, these LDL molecules are protein-based particles that are essentially like cargo ships carrying around different substances, one of the main ones being cholesterol. When you are getting an LDLC you are getting an estimate of the mass of the total amount of cholesterol being a carried around by all of the LDL particles in the system whereas, an LDLP is specifically getting a count of the LDL particles floating around in any one measurement of blood. From an analogy perspective it's like you're counting either the cargo that's being ... The Pacific Ocean has a certain amount of cargo ships out in it carrying cargo and LDLC is like, "Okay, what's the estimate of total cargo being carried around by all of those ships?" Whereas an LDLP would be like, "Okay, we're going to go into the ocean, we're going to count each one of those ships and see how many there are." Depending on some different factors this is why you could theoretically ... Let's say a cargo ship could technically carry 100 pounds of cargo, you could technically have two ships carrying 200 total pounds of cargo or you could have 20 ships carrying 10 pounds of cargo each. In both cases the LDLC would be the same and yet one, there's 20 ships and the other there's two ships, if that makes sense. The reason why that's so important to make the distinction is that what we know now is that risk specifically goes up with ship count or particle count—not necessarily total mass or total cargo. If you have a way of identifying, "Aha, there is actually only two ships in this ocean versus 20," that can significantly impact risk level. Kaczor: Looking at the LDLC, which is the calculated one, it may or may not correlate with cardiovascular disease is what I'm hearing you say, and LDLP we can use as a more specific correlation with cardiovascular disease. Chong: Right, that is correct. In the grand scheme of things when we're also potentially considering other factors like inflammation, and oxidative stress, et cetera, it's still relative ... we're just talking about cholesterol-related markers and their impact on risk, so there are obviously ... I don't want to discount the fact there are other factors involved here, but when we're just talking about the cholesterol and its impact on future risk or not the particle count is what trumps everything. Again, just in the realm of the cholesterol markers. Just for an example, there's a research study I've seen where they looked at 16-year survival, from year 0 to 16 and measured LDLP and LDLC in each person. This is a very large study, and what they saw is a distinct difference between particle count and future event risk for cardiovascular disease. In other words, you had a distinct increase or higher rate of survival in people who have low particle counts regardless of what their LDLC or mass was. Whereas the people with worse outcomes all had high particles even though some of them technically had low LDLCs or low amount of total mass or cargo. Kaczor: It's been- Chong: It's been clearly seen that there's a distinct difference. It's also important to mention here, it is unfortunately true that there are some people out there who are still saying, "If I have large puffy LDL (i.e., my LDL particles are loaded with a lot of cargo per particle) and yet not necessarily ..." If you have a high LDLC, but all of your LDLs are large and puffy, and you also have a high LDL particle count you will still have an increased risk. There are some people out there who are under the misconception that if LDL particles are large and fluffy or large and puffy enough they can't cause problems, that's totally inaccurate. Bottom line, when we're talking about LDL, particle count trumps everything. Kaczor: Let's move on to HDL. That's really good points on the LDL because I do know that the size and the type, the fluffy or the dense, that idea is very much part of the verbiage that patients use when they come through the door- Chong: I'm sorry, I will say one other thing quickly about that. I don't mean to say that it's worthless to check LDL particle size because it's still true that LDL particle size, the smaller the particles the higher the potential is for future risk, but it's not just because of the mechanism itself. It's like just because there is a strong relation between what causes LDL particle sizes small and what causes cardiovascular disease. As an example, typically people with poor insulin sensitivity, or insulin resistance, diabetes, et cetera tend to have smaller particles, so it's still important to look at particle size because it does add to the predictive value of the test you're running. I don't mean to say that it's worthless or anything like that, you just can't say, "If my particles are large and puffy, I don't care how many there are." Kaczor: Got you. Okay. Let's go back and just come back to HDL, the high density lipoproteins. This we don't harp on as much, the drugs aren't targeted towards it as much. We tend to know that higher is better. How do you use HDL in your interpretations? Chong: One of the reasons why the drugs aren't targeted as much is because they keep trying and failing. Pretty much every study that's ever been done on a drug that it raises HDL shows that they clearly work and then oftentimes the people die sooner, so they have to stop. The bottom line is it's not a cut and dry direct simple relationship where the higher the HDL the better necessarily. Especially if you make a change in somebody, so like diet, lifestyle, et cetera, and their HDL goes up it is absolutely not a guarantee that they are getting better or that they are more cardio protected than they were beforehand. It might be the case, but it's not a certainty. From that perspective, at least personally, when I'm looking at HDL I'm always looking at the whole picture. If I see a relatively low HDL and yet this person might happen to be one of these lifelong naturally low in total cholesterol, naturally low in LDL people I'm not as concerned about that low HDL as I am in somebody who has really high LDL, really high total cholesterol, insulin resistance, et cetera, and they have low HDL. There's a definite difference. Those two people might both have the same HDL number, but one is way more concerning than the other one, and it just has to do with the role of these particles, these molecules, and what are they doing for us? If you really simplify it down HDL does a lot of complicated things, we still don't even know everything that it does, but definitely one of its main job is reverse cholesterol transport where it's helping to remove excessive cholesterol deposited in the periphery so to speak. I like to look at it as a garbage truck or a garbage collector. It is very true that if you do have a lot of "garbage" in the system, you have a high total cholesterol, a high LDL there's lots of cargo, or garbage, or whatever you want to call it being shipped outward you would hope to see the body responding to that by increasing garbage truck count to pick up the extras. You commonly see that on people who go onto low-carbohydrate, high-fat diets. Oftentimes you will see, hopefully, an elevation in HDL as the body is literally just adapting to the additional load on the system that you're putting on it. It does not, however ... Unfortunately, you can't take that response and then conclude that the low-carbohydrate diets are cardioprotective because they cause HDL to go up. It's not that cut and dry, it's more just that the body is responding and having to increase its HDL to adapt and make up for the extra amount of cholesterol in the system, if that makes sense. It's quite complicated. You do see HDL go up for that reason. The other thing is sometimes you'll see high HDL in somebody who's got disease, especially if they're inflamed or they have chronic inflammation. In those situations, in all likelihood, what's going on is that inflammation is known to hinder HDL function. The body always trying to adapt, always doing the best that it can to deal with the cards it's being dealt, if it has poorly functioning HDL it's going to spit out more of them in an effort to continue doing the job that needs to be done. If the HDL are dysfunctional as a result of oxidative stress, inflammation, et cetera in the system if the person has the capability you may sometimes see HDL production go up or HDL number go up on the person's lab because each one is not working as well as it should. Kaczor: That's an interesting idea, that it's a reaction. Chong: Absolutely. It's a fluid, functional system. Again, people just think, "Oh, HDL went up, that's good," or whatever. It's not like that. You have to think about why is the body doing that? What is the response going on? The body's always trying to maintain homeostasis, which would include not having cholesterol collect in the walls of the arteries. Kaczor: That's awesome. I appreciate that perspective. I think it's really helpful for us because we want the quickest most linear path to a conclusion, so it's good to remember to step back once in a while. Chong: For sure. Kaczor: We don't have time to go into labs, other labs in great detail, but what other laboratory parameters would you consider must haves? I'm going to give you a typical case, a patient comes to your office, they themselves have no history of cardiovascular disease. They have both sides lots of cardiovascular risk, so they believe that maybe there might be something going on there. What's your bare minimum of labs? What would you do? Chong: Especially in today's world where we're not necessarily billing insurance or whatever personally, for me, if I'm trying to get the most bang for my patient's buck in the realm of cholesterol I'm going to measure an apo A1, or apolipoprotein A1, I'm going to measure an apolipoprotein B, which for those people that aren't fully aware it's essentially like getting more precise HDL and LDL. Apo A1 is like getting a bit more precise HDL count and apo B is like getting a more precise particle count. Again, that's the name of the game, especially looking at the ratio between those two. I'm also going to measure a lipoprotein a, which has its own independent impact on things and is not necessarily going to be responsive to medications or dietary changes that do impact these other markers. It's a very important marker to assess and you can never really predict whether or not somebody's going to have high levels of that or not, but definitely the potential goes up with a strong family history. Then, beyond that in the realm of inflammation I'm at least going to want to see an HSCRP, I'm at least going to want to do some fundamental blood sugar metabolism related markers. I personally like to check a fasting insulin, and then potentially a hemoglobin A1c as well, although that sometimes has some questionable value depending on each patient. Beyond that, it starts getting a little bit more spliced out and potentially, depending on each patient, what you might go from there. I do check vitamin Ds pretty often, I check ferritin, and iron binding capacity pretty often at least screening that once to make sure there's no hemochromatosis going on. Those are probably the main ones I'm going to want to see. I will definitely do a CBC as well. Kaczor: The one I didn't hear you say, and I'm curious if you do, is homocysteine. Chong: Sorry, thank you Dr. Kaczor. Yes, absolutely homocysteine as well. Again, whenever I have the opportunity especially if there is a strong history and there's good reason to want to delve more deeply than average there are definitely some other markers I would typically run with people, but those would be a great starting point. I don't know if we're going to talk later about going outside of blood tests, but just long story short I don't consider an assessment truly complete without some type of imaging at least on the high risk population. Kaczor: By that, you mean? Chong: Sorry, carotid ultrasound, IMT, or a coronary calcium score. Kaczor: I can vouch for that. I've had several patients with cholesterols that didn't look too impressive, but their coronary calcium scores came back very, very good, and so they didn't have any [inaudible 00:24:42]. Chong: I will say one pearl type of information about that, the value of coronary calcium scores specifically goes up with age. The value of risk assessment using that test goes up with age. In other words, occasionally if a person is still relatively young, typically under about 55, you may have a situation where that person has a decent amount of soft plaque that has not been calcified yet and it will make their calcium score looks pretty good, but then if you check a carotid ultrasound it doesn't look so good. I have seen some mismatches in that regard with some of the slightly younger people, so my tendency is to measure carotid ultrasound, IMT tests with the understanding, obviously, that you're not checking the coronary arteries, but there's an over 90% correlation between the two. To me, a carotid ultrasound is a little pickier, a little more fine-tuned than the other one, but absolutely the high calcium score is a very powerful risk predictor. It's just whether or not you're going to catch everybody that way. Kaczor: Great. Dr. Chong, thank you so much for joining me today, I appreciate your expertise, taking the time. I think this is a to be continued type of thing because we didn't talk about what to do. Chong: I would love to keep talking, yes because I feel like we just started scratching the surface. Happy to delve more into some of these other details because there's a lot of other things to consider. Kaczor: We'll talk about treatments and we can talk a little bit more about imaging techniques next time. Thanks again. Chong: Super, yeah. Thank you.

Dr Carolyn Lam:                (Music playing)...Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and his editors I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore. Today is one of my favorite podcasts as always because it is the fellows in training podcast.                                                 This is where the center stage and we're so pleased to have two brilliant fellows with us today. Dr. Tom Ford from University of Glasgow and Dr. Kevin Shah from UCLA and of course joining us today as well is our editor for digital strategies, Dr. Amit Khera. Hi everyone. Dr Kevin Shah:                   Hi Carolyn. Dr Carolyn Lam:                Hey Kevin. Since you're there in wonderful bright and sunny California and going to talk about one of my favorite topics HFpEF. Could you please tell yourself and then please tell us also about the paper you chose? Dr Kevin Shah:                   I am a third-year general cardiology fellow at UCLA. I have a career interest in advanced heart failure and transplant cardiology. I'm going to be doing a one-year fellowship in that next year at Cedars Sinai in Los Angeles.                                                 The article that I picked to discuss was the Reduced LAP Heart Failure I Trial and it was specifically testing a novel device in a small cohort of patients to see if the creation of intraatrial septal connection in patients with HFpEF can improve their filling pressures as well as their symptoms with exercise. Dr Carolyn Lam:                Yeah so Kevin what about this paper stood out to you? Dr Kevin Shah:                   The two biggest things that were impressive to me and that really stood out were 1) this concept that keeps coming up more frequently in contemporary research, which is the idea of using a sham trial. Specifically, in this study they did perform a one-to-one randomized trial. With one of the arms, if they did not receive the actual device, they underwent a complete sham undertaking including headphones in music and blind folding the patient who were not sure if they received the device or not.                                                 I think it's an important concept because it does speak to the placebo aspect of procedures. It tries to really control for that when a patient doesn't know if they received a novel device, and we can still test them and see how they feel after-the-fact. I think that's an important strategy in modern trials. Dr Carolyn Lam:                Kevin, that is such a good point and really quite novel too. So we've discussed this paper before but not quite the aspect that you point out and I couldn't agree more. The REDUCED LAP follows its pilot study results, which was open label single arm right published in the Lancet. So this is a very reassuring results since knowledge sham controlled.                                                 I suppose the lesson comes from other device trials that were sham controlled and then gave maybe slightly different results), right when we're talking about the renal innervation trials before. But you said that there were two points that stood out to you so what was the second? Dr Kevin Shah:                   The other will also be endpoints and what they chose to target. It was a small trial but I think it's important in a disease state such as HFpEF to select specific endpoint that really reflect the physiology and pathophysiology and the authors should be commended. I think for selecting primary and secondary endpoint that will primarily focus on hemodynamics as well as symptomatic relief.                                                 I know that they are working toward their stage 3 trial and I think in the vein selection of these type of endpoint. Probably more so than endpoints such as mortality are going to favor this disease state in terms of trying to carve out some sort of therapy that actually make patients feel better. Dr Carolyn Lam:                Great great points. For me to just knowing that a hemodynamic endpoint makes sense, because if we look at the Champion Trial and look at the HFpEF  subgroup of the champion trial it also seems to show that if people just treated patients with HFpEF  according to a hemodynamic guide and in the champion trial that was the pulmonary artery pressure reading. That actually appeared to keep patients out of hospital. And I have to agree with you that sometimes we forget that has HFpEF  is about pulmonary congestion and that the end of the day it is a hemodynamic disease. It is heart failure in other words.                                                 Kevin one last thing what do you think about using this sort of strategy in HFREF? Dr Kevin Shah:                   That's a good question I can't say I know at least this device has been studied in this trial like you mentioned in one prior trial that was not randomized. I'm sure it's been at least investigated. I can't say I've seen any literature on it. I like to think that it would make some sense from a physiological standpoint, but I don't know if anyone is actually gone to the task of seeing how the device performs in HFREF. Dr Carolyn Lam:                As I said I think at the end of the day I think they're all part of the same heart failure family. And left atrial hyper tension is kind of the final common pathway. So I agree with you that maybe it's worth considering in HFREF too, but then on the other hand of course and have friends HFREF you've got all this great medical therapy. Well Kevin I really, really appreciate your selection. May I now switch over to Tom? Tom would you like to tell us a little bit about yourself ,and which paper you chose. Dr Tom Ford:                      Sure thing my name is Tom Ford. I'm very interested in interventional cardiology, and my career path has been a bit unusual because I did my basic cardiology training in Sydney. And then from there I got a great opportunity to pursue a research degree, a PhD, which I'm currently halfway through. That's what Prof. Colin Berry and Prof. Keith Oldroyd here in Glasgow and that's a British Heart Foundation Fellowship so it's a great opportunity. I went out for recent WOSCOPS Trial from posthoc analysis. In this is a really interesting study a lot of the readers and listeners will be familiar with the original publication. It was actually published 22 years ago. Published in the New England Journal of Medicine.                                                 The WOSCOPS was a landmark trial that looked at statins for primary prevention. And this is the present analysis that looked at just over 2500 Mills with LDL-cholesterol above hundred and 190 mg/dL. So for those of you listeners in the UK 4.5 mmol per liter so quite the high LDL. They looked at these gentlemen without pre-existing vascular disease. There's guideline recommendation for this group but not much evidence. And what they showed was over a five-year period of follow-up that there was a reduction in cardiovascular death and all cause mortality with this treatment. That wasn't just for the period of the trial because of the study design we were able to get a legacy effect which was noted over 20 years of follow-up. So in summary a trial will show the benefits of  statins and primary prevention mortality benefit for people without very high LDL to start with. Dr Carolyn Lam:                Carolyn awesome Tom. I love that she began saying that your into interventional cardiology but you chose an article about medical therapy and the importance of it, the statins. I fully agree with you. Amit did you have some for Tom? Dr Amit Khera:                  Sure. First I want to commend you both I don't think you did this on purpose but Carolyn's heart failure HFpEF  expert. I'm sure she loved the other trial and I'm a preventative cardiologists. So we certainly love you choices this week. Tom, thanks for the summary. It's an important article and one that we did highlight on the previous podcasts. You know there's so many things to talk about but certainly remind you that we have great data sets around that can answer unique questions that maybe are unanswerable today and I think this is an example of that.                                                 Can you speak to this ideal of pulling an old 22-year-old child as you mentioned and how that provides insights and kind of as a PhD student ways to think about ways to be creative and research? Dr Tom Ford:                      One of the reasons I chose this child because it's close to my heart looking at a population in the west of Scotland. Sadly over here we've got too high prevalence of cardiovascular morbidity and mortality. So what this trial speaks to is the benefits of a really carefully planned procedure. I mean these were outstanding researchers that thought ahead of their time, and as a result of their analysis. Over two decades later they are still multiple publications and there's kind of open approach where there's different research groups that have used this data set for number of different outputs.                                                 I think a real outstanding example of what can be done with well-planned study. Dr Amit Khera:                  Sounds like were in agreement about how to use a fruitful database and continue to learn from it as time goes on. The thing about this as you pointed out is the LDL above 190 component and what the authors say this is sort of the first clinical trial evidence for treatment. In your view, does this change practices or guidelines? Was this already what we were doing? Does this support what we were already doing, or how does this impact clinical care and guidelines currently? Dr Tom Ford:                      I think it's a good point. People will say we were doing this anyways. I think now it's going to be helpful and practical inside the clinic. If you can say to a patient well actually look I know we're asking you to take this tablet you've not actually had an event but, ultimately we know the natural history of people in your position may well be unfortunately that they're high-risk, and that there is actually a mortality benefit to be had from these tablets that you don't necessarily want to take but definitely the benefit's there. Dr Amit Khera:                  The neat part as you pointed out also was dual components when they're looking at the on treatments during the trial. We see an improvement in events. What the WOSCOPS investigators have done so creatively over the years is this idea of a legacy affect.                                                 The long-term impact in preventive cardiology – certainly a space for where were going was just looking beyond the short-term. There's obviously problems there too because that was not pre specified people were necessarily on assigned therapies. Tell me when you look at this long-term legacy effect what does that mean to you? How does that add be it the way you counsel patients or how you think about this treatment in patients with high LDL? Dr Tom Ford:                      The effect of the statin assumes that all the patients are actually taking the drug. I think there has to be an analysis of these patients in this trial and obviously not everyone was compliant. So I think we can maybe extraopolate that for the that there might be in even bigger effect for those patients that were actually taking the drug. And I think if you were to take it for five year period. Obviously we don't know what happens after that. What we do know is the solid mortality data.                                                 What it speaks to me is that if you take the drug and you are at high risk to begin with then potentially it's plaque stabilization, the pleiotrophic effects of statins that we know are beneficial and the hard endpoints are definitely reduced. That persists over 20 years of follow-up. So I think that's really a great victory for preventive cardiology as you said. Dr Amit Khera:                  That's a great point about biasing towards the know when you have people crossing over and that this may be conservative of what was seeing in the long term. I think that's a really important point. One last question for you. The West of Scotland trial - generations have changed and back then obviously part of it was trial design but LDLs on average were higher. The median or mean in the group was around 192.                                                 If you look when they look above or below that 190. The people below were 178 or so - still pretty high LDL. So it does beg the question you know we have this paradigm of LDL above 190 should be treated regardless. You wonder if that should be 160 or whether the number should be lower. What are your thoughts about that? Dr Tom Ford:                      I agree with you. I think it's always a challenge to kinda pass off dichotomous endpoints when you've got continuous variable like LDL. It's just a continuum of risk and divided using the figure 190 in the study. In fact the patients with LDL less than 190 they couldn't show statistically significant reductions in all cause mortality. But I think it's again personalization of meds and we may have to discuss the risk with individual patient.                                                 Ultimately we do have to have a firm conclusion. I think in this study the data is quite clear that 190 does seem to be quite robust as the predictor who's gonna get the most benefit. Dr Amit Khera:                  Listen I think protection article that you pointed out was close to home and you certainly discuss it very well and provided lots of important insights. And again I think it was an excellent choice and one that was really highlighted in the media as well. I think there was a broad allure to this article. If we make change gears now little bit we've heard about the science part know we want to talk about what it means to be a fellow in training.                                                 I just want to say on behalf Circulation also speak for myself. It's so important for us to involve fellows in training into our activities and you're one of our major targets in terms of impact and goals for the journal. We're so delighted to do this twice a year and were always thinking about other ways we can get FITs involved. I mentioned just a couple of things the American Heart Association has of fellows in training program where people can sign up for free and get online access to the journal.                                                 So I hope all fellows are taking part in that. We're starting a new initiative called FAVES where just like you both submitted articles of interest of the fellows can do the same. On Fridays we'll post those on social media so these are a few ways that were getting FITS more involved and we really hope to continue that. Let me start by maybe asking Kevin to have a chat with you as much.                                                 Kevin in terms of journals there's some me now we're getting inundated with information. I think that's a good thing. How do you consume the medical literature? There's old print journals; there's the online journal; there's a table of contents your social media tell us a little bit about how you consume the medical literature. Dr Kevin Shah:                   I agree. We're kinda getting to a space where now the amount of information that's coming out is tremendous. I think that finding a strategy to help filter out what appeals to your clinical and research interest is becoming more challenging. For me I'll say print journals are slowly kind of falling off. I don't subscribe to too many of them but they still do come to my doorstep. The main way that I would say I'm getting access to or at least becoming aware of articles that are kinda relevant to where I am in my training and what I'm doing is the social media. Some primarily at least for me is Twitter.                                                 I'll say it's a helpful tool and that I can follow a group of individuals that have a similar professional interest as me and you can almost always rely on the fact that somebody will post an article that becomes relevant to a common interest. So between sharing on social media I think that's the primary way that I'm really catching my eyes to a major journal articles.                                                 Aside from that I still subscribe by email to a couple larger journals and see their weekly or biweekly updates about what's being published. And the last at least in my institution our division chief Dr. Gregg Fonarow; he goes out of his way to send to the fellows and faculty new articles that are kind of pertinent to clinical practice. Which is very helpful for us. Dr Amit Khera:                  That's so helpful and you know everyone has their own way of consuming the literature but I certainly appreciate your interest in social media. You know there are some luddites out there that think of it literally as just social and it really has a professional bent to it. Well rapidly you can figure out the most cutting-edge important articles in your field so I certainly appreciate your comments. Tom let me ask you now, at your stage of training. You've had an interesting training path as you said you sort of started as an interventional cardiologist and now you are doing a PhD. There so many different articles in Circulation. We have original research, state-of-the-art reviews. We have these opinion pieces and on my minds and different ones. Tell us a little bit about what articles appeal to you and which other novel formats maybe you'd be interested in seeing. Dr Tom Ford:                      I think that the original research articles are great if it's in your chosen field. Obviously this is where we're going to a great deal of detail on specific topics but outside of that I think that the review articles are great form if it's something that's a common clinical topic to kinda brush up on. Your On My Mind section I think is great because it gives you an opportunity to hear from key opinion leaders in the field. I think it was Morton Kern discussing invasive coronary physiological assessment.                                                 So I think there's different types of articles that can be quite helpful.  To start with the original research ones. I'll skim through the contents. I'll tend not to read the details if it's not in my chosen field. Dr Amit Khera:                  Yeah great point. Obviously they are topical depending on what your main interest area and we always say reading around your field to get a broader perspective in cardiovascular medicine. I think you hit on the point about on my mind ones. We really want people be able to free associate and original article are sometimes more stiff and linear. So we really like those pieces as well. Carolyn we'll give you second set ask a question or two to for today. Dr Carolyn Lam:                Actually Amit I just wanted to comment. Isn't it so encouraging to hear the variety of approaches and you know Circulation has enough that we're meeting various different needs. I really wanted to take the opportunity to thank you as editor of digital strategies for just doing so many of these initiatives for Circulation. I think it's just incredibly important for the Journal to keep up with the times in that sense. Amit, may I be cheeky ask you how do you consume the literature? Dr Amit Khera:                  Carefully. You know the neat part in being on the editorial board of Circulation and one of the associate editors we get to see so many amazing papers that come through and I think obviously I get to see, essentially and also my digital strategies role I essentially see every paper that comes through that we end up publishing.                                                 Obviously I get wide exposure to Circulation but obviously beyond that I get all the e-Table of Contents for almost every major cardiovascular Journal. Certainly looking at social media and I tend to find hotspots interventions and other areas and podcasts – let's not forget podcasts. So there's some great podcasts out there. I know of one. Dr Carolyn Lam:                Oh I love it. All right but just one last question for both Tom and Kevin from me. I honestly would love to know what do you think we could do better or what would you like to see more from Circulation? Dr Kevin Shah:                   I guess the question I have for Circulation is there any role or have fellows ever gotten involved in the review process for articles? Dr Amit Khera:                  Listen that's really important because you learn a lot from doing that and obviously in institutions similar to ours where if you asked to review a paper you have a fellow contribute. I think you might be asking something sort of more formal and systematic with Circulation. I will say that one of our Circulation journals I believe it's Circ Heart Failure or  Quality and Outcomes I'll check. It has a formal program where fellows essentially can be assistant editors if you will.                                                 We have our cardiology fellows here at UT Southwestern involved in that process. And I think part of that process is just an IT issue of how to maintain confidentiality of our papers for our authors but yet still let fellows contribute meaningfully. And also timing because you know papers have cycles where you decide if he should go out for review but it'll come back and you never know when that happens you have to make the next level decision.                                                 Then it goes potentially to a meeting and so being able to make sure that fellows can participate at every level, cause that's where the value comes in. We are certainly interested in learning from what our other Circulation of family journals is doing in that space and definitely an area that we've thought about some fellows contribute but need to do more. Dr Carolyn Lam:                And Tom how about you? Dr Tom Ford:                      Just picking up on your point on what the sister journals are doing you know I see the Outcomes Journal is looking at more visual abstracts and video abstracts. You know I think it's really important that we increase the efficiency of learning. What's your take on that? Dr Carolyn Lam:                That is the greatest suggestion. I like first of all your phrase of increasing the efficiency of learning. Amit, I'm going to turf it to you again. Dr Amit Khera:                  I'll tell you what's amazing you know when I started this role a bit ago. Both of you are obviously contributing to research and everyone on this call is and I think we forget that in the social media space we don't have a lot of data. Some things sound good or feel good. At Circulation my predecessor Carolyn Fox did a randomized trial called intention to tweet if you haven't read it. And there's a follow-up to that that was published. And essentially by randomizing articles to social media or not there was no increase in the views if you will of the article.                                                 There's always limitations to every study but the point is, as you think about novel offerings, something we struggle or something we've seen as an opportunity, what works we tried a few things we tried certain videos and we look at what's the uptake and interestingly some things we thought that would be widely of interest really weren't. Then other avenues we've tried have been.                                                   I love what you said, and as Carolyn also felt, the idea of efficiency of learning. I think we need to do frankly in the social media and journal spaces is to continue not just to innovate but to study and figure out what works and what doesn't to help different learners. Dr Carolyn Lam:                (Music playing)....Thank you very much audience for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and back-stage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Center and Duke National University of Singapore.                                                 What is the evidence we have for LDL-lowering therapy in primary prevention? For individuals with an LDL cholesterol above 190 mg/dL, well, you may think you know the answer, but today's featured discussion may surprise you like it did for me, and this is a must-listen in my opinion for those of us taking care of these patients. More soon right after these summaries.                                                 How can we enhance the survival and therapeutic potential of human pluripotent stem cell-derived endothelial cells? Well, the first paper in today's journal tells us how. The first author Dr. Lee, corresponding doctor Dr. Yoon, from Emory University School of Medicine in Atlanta, Georgia, developed a novel, fully-defined, cell culture system to generate endothelial cells from human pluripotent stem cells. They not only showed that these endothelial cells had pro-angiogenic activities and exerted favorable therapeutic effects in repairing limb ischemia, but also showed that encapsulation of these cells in a biocompatible peptide amphiphile nanomatrix gel improved long-term survival of these endothelial cells in an ischemic environment and improved vessel-forming properties. This novel cell culture system and gel-mediated transplantation may serve as a novel platform for cell-based therapy.                                                 The next study brings us one step closer to application of immunomodulatory therapies in pulmonary arterial hypertension. In the study, first author Dr. Saito, corresponding author Dr. Rabinovitch, and colleagues from Stanford University School of Medicine isolated lung immune complexes and pulmonary arterial hypertension target antigens from lung tissues from 16 patients with pulmonary arterial hypertension and 12 controls. SAM domain and HD1 domain-containing protein, which is an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from patients with pulmonary arterial hypertension. These immune complexes resulted from elevation in products of human endogenous retrovirus K. The human endogenous retrovirus K deoxyuridine triphosphate nucleotidohydrolase, or dUTPase, activated B cells, elevated cytokines and monocytes and pulmonary endothelial cells, and increased pulmonary arterial vulnerability to apoptosis, thus contributing to sustained inflammation, immune dysregulation, and progressive obliterative vascular remodeling. Furthermore, rats treated with the human endogenous retrovirus K dUTPase developed pulmonary hypertension. In summary, this study suggests that harnessing mechanisms that repress human endogenous retrovirus K expression and its sequelae could prevent and reverse pulmonary arterial hypertension.                                                 The next study looked at the association of timing of coronary angiography with ischemic outcomes of non-STEMI who are at high risk with a Gray score of more than 140 in the TAO Trial. In this report from first author Dr. Deharo, corresponding author Dr. Steg, and colleagues from L'Hopital Bichat from Paris, France showed that in these high risk, non-STEMI patients, a very early invasive strategy of coronary angiography within the first 12 hours was associated with a lower risk of death in MI at 180 days compared to an early strategy of between 12 to 24 hours or a delayed strategy of between 24 and 72 hours. The bleeding risk was not different between patients managed with the very early, early, or delayed strategy. These observations deserve prospective confirmation in a randomized trial.                                                 The next study provides contemporary mortality trends for STEMI and non-STEMI. In this paper from first author Dr. Puymirat, corresponding author Dr. Danchin, and colleagues from Hopital europeen Georges-Pompidou in Paris, France, the authors assess trends in the characteristics, treatments, and outcomes for EMI from five month-long registries conducted five years apart and spanning 1995 to 2015, including more than 14,000 patients admitted to cardiac intensive care units in metropolitan France. They observed major changes in the characteristics and management of both patients with STEMI and those with non-STEMI over the last 20 years. The mean age decreased in patients with STEMI and remained stable in patients with non-STEMI, whereas diabetes, obesity, and hypertension increased. At the acute stage, intended primary PCI increased from 12 to 76 percent in patients with STEMI. In patients with non-STEMI, PCI within 72 hours from admission increased from 9 to 60 percent. In parallel with these changes, six-month mortality consistently declined in patients with STEMI, whereas in patients with non-STEMI, six-month mortality reached a plateau after 2010. The authors concluded that future challenges will be to reduce pre-hospital mortality and to improve long-term survival after the acute myocardial infarction event.                                                 That wraps it up for your summaries. Now for our feature discussion!                                                 What evidence do we have from randomized trials supporting the benefit of LDL cholesterol lowering as primary prevention among patients with an LDL cholesterol above 190 mg/dL? You may be surprised to know that until today's journal, we had very little trial evidence supporting this. But I'm so pleased to have with us the corresponding author of our featured paper today, Dr. Kausik Ray from Imperial College, London, who's going tell us a bit more and discuss this very intriguing paper with our Editor for Digital Strategies, Dr. Amit Khera from UT Southwestern. Welcome, both. Dr. Kausik Ray:                  Hi. Dr. Amit Khera:                 Thanks for having us. Dr. Carolyn Lam:               Kaus, you are a familiar voice and so pleased to have you here. Please tell us, is this the first evidence we have from a randomized trial for primary prevention in those with LDL above 190? Tell us about it. Dr. Kausik Ray:                  Yeah, it is. It really came about because we were interested in familial hypercholesterolemia and we used the level of 190 to talk about either primary hypercholesterolemia, which may have a genetic basis, or not. I kept hearing that there is no trial evidence, so you're not going to be able to ethically do a trial today despite the fact there's not much evidence, because most of us think that it's a bad thing to leave people on placebo in patients above 190, so I thought the only way to do this was to go historically to the WOSCOPS Study, which is, as you remember, 6,500 people, elevated LDL cholesterol. Interestingly, you go to WOSCOPS, the median LDL in that population is very close to 190. So, that gives a good starting point, thinking that we'll have at least half the population.                                                 Now interestingly in WOSCOPS, although none of the patients had a history of myocardial infarction, a very small number of the 6,500, about 1,000 actually had evidence of some other vascular disease, so maybe a TIA, maybe angina, maybe some sort of ECG non-specific change of coronary disease. Today, you would say, well, actually, you've got to give these people a statin because there's evidence of vascular disease, PVD, et cetera. So we had to take those people out and that left us with 5,529. Once you break people down by LDLs above and below 190, you have 2,560. You could actually look at the randomized treatment effect of pravastatin, which was the statin chosen, over a five year period both above and below 190.                                                 But interestingly, this was the first study and what we showed was that in this population, even with as little as 23% reduction in LDL cholesterol, over a five year period, you saw a statistically significant 27% reduction in CHD and if you take the usual 3 point MACE of current clinical trials, there was a 25% reduction, already statistically significant. We also had the ability to link data over 20 years. Remember, after the five year randomized treatment period, it becomes observational in nature, but what it showed was that when you gave nearly 40% in each arm statins and you followed people up this legacy effect, over a 20 year period, the people with the LDL above 190, that translated into this 28% reduction in CHD death. It translated into a 25% reduction in CV death, and actually an 18% reduction in all-cause mortality, which you didn't see in the population with slightly lower LDL cholesterol.                                                 This is the best evidence we're ever going to get, really, and answer the question about what should we do in this patient population. Should we treat with lipid-lowering therapy? The answer, unequivocally, is yes, and the longer you treat, the more likely you are to see survival benefits. Dr. Carolyn Lam:               Oh, my goodness! I just love his paper. I have to humbly admit. I mean, it's in the guidelines already that we should treat these individuals with LDL above 190, and it really made me think how I'd taken for granted that there would be a whole body of evidence behind it from randomized trials, and you are right! This is the first, and likely going to be the last we're going to get, because we can't randomize them. So, congratulations. What you said just now, I can already hear myself playing this podcast to my patients. May I just ask, are there other remaining questions to answer, and then what do you also say to those that say, well what are the harms? How do you balance that with any potential harms? Dr. Kausik Ray:                  In this particular study, given there was overall safety data observed in the WOSCOPS Trial population and in their extended follow-up in the overall 6,500 person cohort, we didn't go on and look at that. There was no evidence of harm in the extended follow-up of 6.500 people, so we didn't see the potential added gain in specifically looking for that. The main question we wanted to answer, because people had always pulled primary and secondary prevention patients together, and in fact, your best evidence is actually from CTT, pooling of primary and secondary prevention patients where they break the data down by an upper limit of about 175. With patients above 175, they don't specifically answer that question. So, to answer your question, we didn't look at that in the overall WOSCOPS Trial population. There was no signal for harm that was noticed. Even things like glucose elevation, if you remember in WOSCOPS, tended to be a little bit lower. Dr. Amit Khera:                 Let me comment on a few things about this paper. First, I want to congratulate Dr. Ray and his colleagues. I was a history major and I think this is a great use of a historical tool. At this point, I think we can talk about WOSCOPS. It's 22 years old. It is part of the medical history and a very seminal article. I think they got creative because, as he mentioned. We have guidelines that support this treatment, but this is almost an unanswerable question, whether you say it's from ethics, or from equipoise, it was essentially unanswerable. So, they had to go back and take this historical study where practice patterns were different, to be able to look at this question. It was pointed out, there's pretty clear evidence in here and I think if you look at that during the five-year study period of the randomized period, pretty clear evidence that treating participants with LDLs above 190 without vascular disease certainly lowers cardiovascular disease events.                                                 One of the best things about working on the editorial board is being able to work closely with authors, and I have to also thank Dr. Ray and his colleagues for being so gracious in working with us closely in some modifications as this went along. We hope, and I hope he feels this way, too, that at the end of the day, the product ends up being even better than where we started. That's our goal is to really help and work with authors in that way and they were incredibly responsive. The two things I thought they did really well that were insightful to the US guidelines and beyond. One is they also restricted to the group without diabetes, without ASCVD less than 7.5%, and some other parameters to really hone down on what we have in the current US guidelines and still the finding was consistent that the statin therapy benefited that group.                                                 The other part was just acknowledging that the legacy part, the long-term effect, is really valuable. They published heavily in this area, but at that point, it becomes an observational component. It's not part of the randomized period. The reason that adds value, if you look at our guidelines above the age of 21, an LDL above 190 can be treated with a statin, there would be less controversy if your LDL was 200 and you're 55, but if you're 22 or 23, I think there may be more angst. That's where the long-term data is important, because we're not looking necessarily always at 10 years, but we're looking at 20 or 30 or 40 or 50 years. I think this does at least shed some light. I appreciate the study population was older, but a least it helps us look at maybe some of the long-term benefits.                                                 If I may, Carolyn, I would love to ask Dr. Ray a question. Kaus, when you guys did this, the group with the LDL less than 190 had essentially similar benefit. The p-interaction was no. I think we have to acknowledge that the LDLs were higher in that group than what would seem because the lowest level was 155. Is it above 190, or should it be above 160 where we treat patients with statins? Dr. Kausik Ray:                  Yes, and I really want to thank the editors, because there were certain things that you pushed us with analyses and I think that you could make the case that if you have a LDL cholesterol above 155, over a five-year randomized treatment period, there was a significant reduction in CHD and MACE as well. So, you could make that point that actually the cutoff should perhaps be pulled down even further to about 155. What's interesting is, these groups, when you broke them down, age was identical, BMI was identical, blood pressure, and everything else. The only thing that was different, really, was the LDL cholesterol, which impacted on total cholesterol. TGs, HDLs were absolutely identical. I think you could probably make the case.                                                 I think the one thing that we didn't see, although it's observational in those with slightly lower LDL cholesterols, is that over the 25 year period, they seem to get slightly less mortality benefits. Now, that could be a chance finding, because it's observational. We don't really know the implications of that, but I think over a five-year period, this is the best evidence you're going to get for primary prevention, right? Dr. Amit Khera:                 Agreed. The US guidelines do say above 160, it's a point of consideration. It can be a factor to consider as we think about treatment, so perhaps this helps bolster that point as well. Dr. Kausik Ray:                  It's not just the American guidelines. In the European guidelines, when they use score, if you look at LDL cholesterol levels, the European case fatality 10 year risk is 2.5%, which is equivalent roughly to 7.5% fatal and non-fatal MI in the pooled cohort equation. There they still have diet and lifestyle, but it says, "Consider pharmacological," and one of the things I thought was really interesting is if you did a 10 year risk calculation in this group, 67% of the population with an LDL above 190, you would have said the predicted 10-year risk was below 7.5%, but the 10-year observed risk was double that. It was 15%. If you did the same thing for the group between 155 and 190, your ten-year risk predicted would be in most of these people, you would have said about 90% actually are less than 7.5%, so you wouldn't have given them a statin. But, their observed event rates in the placebo group was about 11%.                                                 So, I think that it tells you if you have an isolated elevated cholesterol above 155, you're probably going to be underestimating risk if you're using global risk score, and perhaps a discussion with the patient about risks and benefits in the way that most of us try to do and citing data like this might encourage patients to actually start that therapy earlier, which most of us probably believe from genetic and legacy effect is probably beneficial. That's one of the other implications of this. Dr. Amit Khera:                 This is why one has to read not just the abstract, but all the details, because there are so many kernels of interesting findings in this paper beyond just the highlights that we hit upon. Dr. Carolyn Lam:               Thank you both for just a marvelous discussion of an incredible paper that is really, really going to be extremely clinically relevant. We're so proud to be publishing this in Circulation this week.                                                 Audience, you heard it right here. Don't forget to tune in again next week as well to Circulation on the Run for even more hot news.

Learn the latest in lipid lowering therapy in this extensive discussion with Dr. Paul S. Jellinger, MD, MACE, Professor of Medicine at the University of Miami and Chair of the writing committee for the American Association of Clinical Endocrinologists (AACE) 2017 Guidelines for the Management of Dyslipidemia and Prevention of Cardiovascular Disease (CVD). Topics include ezetimibe, PCSK9, FOURIER trial, statin myopathy, CoQ10, fish oil, fibrates and more. For a more basic discussion of dyslipidemia check out episode #10. Full show notes are available at http://thecurbsiders.com/podcast Join our newsletter mailing list. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com. Time Stamps 00:00 Intro 03:10 Rapid fire questions 08:15 Dyslipidemia defined 10:26 Classifying dyslipidemia 13:21 Diagnosing Familial Hypercholesterolemia 17:48 A difficult lipid case discussed 22:40 Lp (a), Apo B and LDL particle concentration 28:40 What labs to order 31:31 ACC/AHA versus other risk scores 38:21 IMPROVE-IT 41:35 Non-statin medications discussed 45:05 Hypertriglyceridemia fibrates and fish oil 48:25 How often to check the lipid panel 49:58 Statin Myopathy and CoQ10 54:17 FOURIER, PCSK9 and very low LDLs 59:43 Extreme risk category discussed 62:34 Is plaque regression possible? 64:12 Take home points 67:08 Outro Tags: assistant, care, cholesterol, doctor, education family, fish oil, foam, foamed, health, hospitalist, hospital, internal, internist, ldl, lipid, medicine, medical, myopathy, nurse, pcsk9, physician, practitioner, primary, statin, resident, student

Adam Zickerman discusses his 90-day journey of religiously dedicating himself to following a ketogenic diet here in Episode 25 of the InForm Fitness Podcast.  Adam reveals the challenges of sticking to the ketogenic diet along with some misconceptions and the dramatic results.Here is a link to the website Adam mentions in this episode:  http://eatingacademy.com/nutrition/ketosis-advantaged-or-misunderstood-state-part-i Don't forget Adam's Zickerman's book, Power of 10: The Once-a-Week Slow Motion Fitness Revolution.  You can buy it in Amazon by  clicking here: http://bit.ly/ThePowerofTenTo find an Inform Fitness location nearest you to give this workout a try, please visit www.InformFitness.com.  At the time of this recording we have locations in Manhattan, Port Washington, Denville, Burbank, Boulder, Leesburg and Reston.If you'd like to ask Adam, Mike or Sheila a question or have a comment regarding the Power of 10. Send us an email or record a voice memo on your phone and send it to podcast@informfitness.com. Join Inform Nation and call the show with a comment or question.  The number is 888-983-5020, Ext. 3. For information regarding the production of your own podcast just like The Inform Fitness Podcast, please email Tim Edwards at tim@InBoundPodcasting.comThe transcript to the entire episode is below: Adam: You know when you're wearing clothes, my lean muscular build, it's hard to know that I was getting a little bit of a spare tire underneath them, but I was getting a little bit of a spare tire, but besides that, there were two things. One, my chronic back problems which you covered last episode, and I wanted to do whatever I could to ameliorate these back issues. Consistent and safe back exercises are one of them, and the other thought I had was maybe my diet is affecting my back, because I was reading a lot about the typical American diet and it's inflammatory. I'm thinking I might have an inflammation issue going, my back keeps going into spasm, it's probably chronically inflamed. If I can not only exercise my back properly but maybe reduce my chronic inflammation, that might be my answer. Tim: InForm Nation, welcome to episode 25 of the InForm Fitness podcast. Twenty minutes with New York Times bestselling author, Adam Zickerman and friends. I'm Tim Edwards with the InBound Podcasting Network and a client of InForm Fitness. Joined as always by Sheila Melody, Mike Rogers, and of course Adam Zickerman. Okay team, at the time of this recording, spring has just sprung, summer is just a few months away, and I'm sure a good portion of InForm nation is already thinking about summer which means they're thinking about slimming down a little or in some cases a lot, so dieting is on their minds. We've all heard of, and I'm sure participated, in at least a few nutrition plans, like the paleo diet, the Atkin's diet, or the one that I really enjoyed a few years ago was the slow carb diet from Tim Ferris. Most recently I had tremendous success by just eating cleanly as you describe Adam in chapter three of your book, Power of Ten: The Slow Motion Fitness Revolution.So Adam, you visited LA. just a few months ago when we recorded the Adam in LaLa Land episode and frankly, you looked extremely fit. So in the last episode, you mentioned that we're going to talk about a diet that you've been on for the last X amount of days, and my question is why did you even consider going on a diet in the first place because you don't look like you need to go on one.Adam: I picked up a few lessons from my female friends and I know how to dress to hide it.Tim: You wear Spanx, that's what you're telling me?Mike: Spanx and New York black. Everyone in New York knows how to hide it.Adam: Hide our emotions.Tim: You don't hide your emotions in New York, come on.Adam: The people in L.A want to hide their emotions.Tim: We're the passive aggressive ones.Sheila: Oh no, we want to talk about our emotions.Tim: That's down in the south where they're passive aggressive, but anyway, we digress. You mentioned the diet, and here's a guy, the guru, the InForm Fitness and you're fit. So what prompted you to go on a diet?Adam: I'm so glad you asked me that question, because you know the other question I get asked in a similar vein is why do you work out Adam, you look great. Sheila: You say because I never want to look like you.Adam: That just reminded me of something Yogi Bear once said. Nobody goes to that restaurant anymore, it's always too crowded. So listen, why did I go on this diet. Well first of all, diets are not always about weight loss, fat loss. Diets are about health, or they should be. Now I know that anyone who goes on a diet, their number one concern is I want to lose body fat, which is a noble goal because being overweight has health problems associated with it. Now I did want to lose a little weight first of all, because I always said that I hide it well half-jokingly, because the other half, I did need to lose a couple of pounds and it is true that when you're wearing clothes, my lean muscular build, it's hard to know that I was getting a little bit of a spare tire underneath them, but I was getting a little bit of a spare tire, but besides that, there were two things. One, my chronic back problems which you covered last episode, and I wanted to do whatever I could to ameliorate these back issues. Consistent and safe back exercises are one of them, and the other thought I had was maybe my diet is affecting my back, because I was reading a lot about the typical American diet and it's inflammatory. I'm thinking I might have an inflammation issue going, my back keeps going into spasm, it's probably chronically inflamed. If I can not only exercise my back properly but maybe reduce my chronic inflammation, that might be my answer. So for years, I've been reading about the ketogenic diet, and for years I was poo-pooing it.Tim: Why?Adam: Because I had a vast misunderstanding about what a ketogenic diet was. Basically using ketones for fuel. I'll get into what a ketone is a little bit later, but my understanding of ketones was when your body is using ketones for fuel, or if you're producing a lot of ketones, I always understood that to be very dangerous. In my mind without realizing it, I was really thinking about what they call ketoacidosis, which is much different than nutritional ketosis, using ketones for fuel from a nutritional point of view, as opposed to something very dangerous called ketoacidosis. That was where the confusion comes in. Whenever you talk to a doctor or a nutritionist and say I want to go into ketosis, they say it's dangerous, and being in ketoacidosis is very dangerous but you cannot go into ketoacidosis just by eliminating carbohydrates or going to what they call nutritional ketosis. Ketoacidosis, let me explain what that it is. It usually afflicts people with Type I diabetes. Type I diabetics cannot produce insulin, and when you cannot produce insulin, when you eat carbohydrates, the sugar starts building up and building up, and what happens is the body can't utilize that sugar, because the insulin is not there to use that sugar and bring it into the fat cells and the muscle cells, or bring it into any cell that needs that for energy. So the body, if it can't get glucose for energy, it starts metabolizing fat for fuel. That's where it's going to get it's energy from, and it starts going crazy producing these ketones. You see ketones come from fat, the metabolism of fat. An alternative sense of energy for the body are ketones, fat gets broken down into ketones, carbohydrates get broken down into glucose and when the body breaks down carbohydrates for glucose and those glucose molecules can't be used, the body will say okay, let me go break down some body fat, get some ketones out of it, and utilize that for fuel. So it's another source of currency if you will, and if you're a Type I diabetic, your body goes crazy producing these ketones and you end up having so many ketones that you go into an acidic state, a dangerously acidic state where basically all functions of the body cannot produce and cannot function when you're in such a high acidic state. In other words, we have to have a pH level that's very, very stable, like about normal, about 7. Our pH is about 7, that's the normal functioning pH of the human body. When you start having all these ketones that start going through the roof — ketones are acidic by the way, and ketones that are not being checked or regulated, start going through the roof and you are in a very dangerous state. So a Type I diabetic can very often go into ketoacidosis and they have to go the hospital, they have to get the injections, and usually it's a diabetic that's not taking care of themselves. You cannot go into that acidic state being in what I have been in the last ninety days which is called nutritional ketosis. Nutritional ketosis is a state in where you body instead of using glucose for fuel, not because there's no insulin, but because you're not eating anything that's going to produce a lot of glucose, your body says well I need energy, so I'm going to start using fat for fuel. Every cell cannot use actual fat for energy, they have to break down the fat. Just like we have break down carbohydrates for glucose, we have to break down fat, and we're breaking them down into fat and these ketone bodies are being used for fuel. Well there's a lot of evidence right now that's showing that these ketogenic diets which are to break it down into macronutrients about 70-75% fat, about 10% protein, maybe 15% protein, and then the rest which is about 5% carbohydrates.Tim: Now immediately, red flags are flying all over when you say the diet is made up of 75%  fat. Now let's drill down on that a little bit more. We're not talking cheeseburgers.Adam: Well we're not talking cheeseburgers with the bread, but we are talking cheeseburgers. I will have red meat, I will have cheese. Red meat has to be grass fed, not this factory raised cow. So the quality of the foods that you're eating is also very important, so I eat grass fed beef and beef, the fat in the beef is very good for you. What you have to be careful of, this is what I realized and this is a very common mistake that people make on ketogenic diets, that they think it's a high fat, high protein diet, but it's not really high protein. Having too much protein can actually produce an insulin response or produce sugar, because protein can be converted into glucose, it's called gluconeogenesis, and it can be almost as bad as actually eating carbohydrates. A lot of people will eliminate their carbohydrates and they'll end up having tons of red meat, which is a lot of protein.Tim: That sounds like the Atkin's diet to me.Sheila: That's what I was just going to say.Adam: The Atkin's diet, in essence, a ketogenic diet and the misinterpretation of the Atkin's diet of a ketogenic diet is that the image is like a bunch of caveman sitting around gnawing on a dead animal or something like that and just eating fat and bacon and protein all day long. It's not like that, it's mostly vegetables that are saturated in fat like olive oil, or coconut oil or avocado oil. Salads that are doused in that kind of fat, so getting vegetables or other types of oils and avocados in general, grass fed meat, pasture raised chickens, eggs, and of course wild fish. That is my diet, and it's not like I'm eating tons of meat. I'm eating six ounces of a steak, I'm eating tons of brussel sprouts that have been roasted in coconut oil.Tim: All sounds good to me so far.Sheila: Probably 85% of the time I eat exactly what you just described.Adam: I committed to eating this way without exception for ninety days. I started at the beginning of this year.  Here we are. Tim: Where are you now at the time of this recording?Adam: It's a coincidence but I am literally, today, on my 90th day. It started January 3rd, which is a Tuesday. So I don't know if it's the 90th day, but I just finished my twelfth week starting January 3 and this is a Tuesday. So today is the last day of my twelfth week.Mike: I don't think 90 is divisible by seven.Tim: Well he's close.Mike: I've got my advocates in the corner there.Tim: So nonetheless, let's review.Adam: By the way, at the beginning I said why I did this. I thought it'd help my back, anti inflammatory. Ketogenic diets are well suspected to be anti-inflammatory. The second reason why I wanted to do this diet was because I had my annual checkup and I'm in my early 50s now, but 50s nonetheless, and my blood work is creeping the wrong way. They're starting to get on the high side of normal.Tim: Let me ask you, is that prior to going on the diet?Adam: Prior to going on the diet, I had my annual checkup and the results came in and he said to me hey, nothing to be alarmed about at this point but you're trending the wrong way. You're C-reactive protein is creeping which is an inflammatory marker, and he said your cholesterol is creeping up, it's not too high per se but it's on the higher side of normal. My A1C which is an indicator of your blood sugar was creeping up again on a high side of normal. I was like wow. These are all things that indicate that I'm going towards what many Americans go towards which is metabolic syndrome. It reminded me the same situation that Dr. Peter Attia, his story when he started his quest on ketogenic diets, and he was in the same situation. He worked out all the time, he thought he ate well most of the time. We think eating well is eating whole grain breads, and fruits, and occasionally what's so bad about having a beer here and there, and next thing you know, in a day you're still ingesting 250 grams of carbohydrates without even thinking about it. So he started taking control of it as well, and when I saw that my blood numbers were going up and then I read what Dr. Attia went through as well, I was like holy cow that's me. So that also prompted me, I wanted to see if going on a ketogenic diet would change these numbers. Well this is the 90th day so I'm about to get those numbers checked, so I'm going to report back on this but when I can talk about now is how I feel. Tim: Let's start with your back.Adam: And what has happened. First of all my back, in combination with what I've been doing with my lower back exercises and staying consistent with that, my back has never felt better. I can sit for hours in a car, or I can sit for hours at my desk, and get up sideways.Tim: And you're giving this ketogenic diet credit for assisting with that.Adam: First of all, I'm a sample size of one, so this is scientific at all, but I am giving it credit. That in conjunction with taking care of my back with the exercises. So I don't know where the cause and effect is because I've been doing a couple of things at once, but the big teller is going to be obviously the blood work that I get done soon. Besides that and besides the fact that my back feels better, I've lost fifteen pounds of weight that you didn't think that I needed to lose. So I look a lot better naked now, so I don't have to wear clothes anymore. I don't have to wear a T-Shirt to the pool anymore.Mike: You know when your body gets a little bit smaller, it gives the illusion that other things are bigger.Adam: You have that as well. Big thing that I noticed was my digestion. My digestion changed dramatically. I don't have upset stomach, my elimination if you know what I'm talking about has been undramatic, it's been beautiful.Sheila: It's a beautiful thing.Tim: Well your good friend Dr. Oz would be proud of that.Mike: Maybe this will get edited out, maybe it won't, but I'm just curious. What does beautiful mean? Tim: That actually is so it will not be edited out, so describe beautiful? You mean like one clean long — Adam: Exactly, tapered on both ends, perfect.Tim: Dr. Oz was his thing right?Adam: It's embarrassing, especially since you're talking about me.Mike: You don't sound like you're embarrassed.Adam: I am. You've got to remember that this is someone who is too shy to urinate in front of his wife. Mike: I'm going to remind you that you're the one who is talking about himself right now. Tim: So nonetheless there's a lot of fiber in this diet and it's really helping Adam a lot, so good.Sheila: That's really, really very interesting and I want to ask a question about is there a difference in how women react to this diet as opposed to how men react to this diet? Coming off that interview we had a few weeks ago with Dr. Sylvia Tera and The Secret Life of Fat, and how different men and womens' makeup is and how we process fat and everything. It sounds like something I'd like to try, and I feel like I've been kind of doing this for the most part.Tim: I think she's committing, I think she should jump on 90 days.Adam: I'm not sitting here saying everyone should jump on the ketogenic diet bandwagon first of all. I need to make that disclaimer. First of all, women are different and we're all different. I'm different from another man, and women certainly have their issues. When you talk about nutrient partitioning and that no matter what you eat, some of it is going to be partitioned to fat. Hormonal issues with women as they get older, all kinds of things. Genetics for men and women are different amongst ourselves and all these things play into it for sure, but having said that, sugar is bad. Sugar is bad, sugar is inflammatory. There is nothing good that comes out of sugar and excessive carbohydrates. I don't believe being in ketosis is dangerous anymore, and this idea of eating a lot of fat, even if it's saturated fat, especially if it's saturated fat, is not bad for you. It's been shown over and over again that dietary fat does not raise your cholesterol, so just check that box off. It's not true, it is just not true that eating egg yolks and eating red meat raises your cholesterol, that is not what is raising your cholesterol. The last ten, fifteen years have been really showing that. My blood work will show this, if I go to my blood work and my cholesterol is through the roof I'm going to have to eat my words. It might even be another cause of it, but the thing is if all my triglycerides are good and inflammatory makers are lowered and my cholesterol happens to stay on a higher side, and everything else is really, really good, I'm not going to worry about high cholesterol. High cholesterol, high LDLs are not a very good marker on heart disease.Mike: On its own.Adam: On its own. Now there's this other test that Dr. Attia actually told me to get which is an NMR, nuclear magnetic resonance test, to test for your LDLP. See when you go to the doctor and you get your cholesterol and blood work done, you're getting blood work for your LDLC. LDLC is how much cholesterol, low density cholesterol is in your blood, whereas the LDLP is showing you how many LDL proteins are in your blood. I'm getting technical right now, but it's a different marker and a much better marker and indicator of potential heart disease, this LDLP. So I'm going to get that done, and see if my LDLP is nice and low, and if that is, regardless of what my LDLC is or total cholesterol is, I'm not going to be worrying about it. Again, my A1C, my C reactive protein, these markers, if they stat going down after ninety days of eating, I'm not kidding you, 70% of my diet being fat, I'll be pretty convinced. At least for myself. Let me tell you about my experience psychologically.Tim: I'm curious how you managed this, because it seemed like a lot of drastic changes.Adam: This is why I'm not necessarily telling people to just go on this ketogenic diet. First of all, I'm not a nutritionist, I just play one on TV. So I'm a nutritionist, secondly, I'm not going to lie, it's not easy to adjust to this type of diet. If you're used to eating grains and carbohydrates — I'm essentially a vegetarian that is saturating their vegetables with saturated fat and all kinds of fats, and having small portions of animal protein, whether it be a chicken or a fish or a cow, all well raised, but they're small quantities. I'm not eating a lot. I'm also intermittent fasting. I'll go at least two or three times a week, I'll go anywhere from eighteen to twenty four hours without eating. I'll be drinking lots of liquids, I'll be drinking homemade beef broth or chicken broth, and that's it. So that's all I eat, one meal all day.Tim: So tell us your schedule Adam. So with this intermittent fasting, what time are you stopping eating at the end of the day?Adam: I'll eat dinner.Tim: At what time?Adam: Anywhere between five and seven most days. So let's say I finish eating seven. I won't eat again until at least two or three o'clock the next day. On some cases I won't eat again until dinner the next day.Mike: When you work as much as we do, I've got to be honest with you, time flies and you sometimes forget about food. I'm not as strict as Adam is, but I'm probably doing about 85% or 90% of what he is doing in regards to the ketogenic model, and the fasting model without even trying to.Adam: We work a lot and that speaks to one of the techniques that people recommend to help you through these intermittent fasts and that's distraction techniques. So when your mind keeps saying eat, eat, eat, distract yourself, pick up your guitar, write a letter, do something else. Distract yourself. A lot of this hunger by the way, is psychological, we're just not used to it mentally, but besides that, at the beginning, your body is physically wanting that food but once you start utilizing your fat for fuel and you become what they call keto-adapted where your body is primed to really use fat for fuel, and that takes a couple of weeks. Three weeks, four weeks sometimes. The first there or four weeks was the toughest because I was not adapted yet, so I was very hungry. Now, well it's 4:30 and I haven't eaten yet today. Last time I ate was dinner time around five yesterday.Mike: That's a lie, he had two celery sticks from me.Adam: That's true, it's two celery sticks so I broke my fast. Honestly I grabbed them because they were there, it was not because I was dying to eat something, and if I was dying to eat something, I certainly wouldn't have picked that.Sheila: When you say you're fasting, so you mentioned the broth though. So you have that when you're fasting, or you just have nothing, you have water.Adam: I have water mostly, but yeah, we serve bone broth here, we're making our own bone broth now. We can talk about that at a later date, but yeah, that doesn't count as cheating. It's 99.9% water, it just has the minerals and the amino acids in it. So I don't consider that really cheating, but come on. Even if I was to have a small meal, the gist of it is going long periods of time without eating, and that from my understanding is the real anti-inflammatory aspect. I mean sugar causes inflammation, and eating a lot also causes inflammation because you're breaking down all this stuff and getting all these free radicals and all this oxidative work going on, and that's what causes a lot of the inflammation. Now I'm reading and I'm learning that intermittent fasting forces the body to regenerate its cells at a lot faster of a rate. There's something to that.Sheila: I also read that an easier way to do the intermittent — well, for a sixteen hour fast that you can basically do is just stop eating at seven, and then don't eat again until eleven AM. That's sixteen hours.Adam: Basically skipping breakfast.Tim: A lot of people do that anyway.Adam: But this is the problem with intermittent fasting. When I go 24 hours, I'm hungry by then. A lot of people say they can go days without eating and these are people that are really and truly keto-adapted, maybe they've been doing it for a year or more. I don't know, but so far, I haven't been able to go more than seventeen hours without all of a sudden having all those hunger pains, and at that point I just deal with it for another few hours. At that point, when I do eat, this is the hard part. You have to eat a regular, small meal. Tim: No binging.Adam: It's so easy when you're famished like that and you've gone all day without eating, it's like you want to eat lunch, breakfast, dinner, and snacks all at one time in one sitting. You have to stop yourself from doing that.Mike: That's probably one of the differences to what was going on even before you did this 90-day thing. Our lifestyle really lent itself to — none of us eat that many carbohydrates ever. Adam hasn't for a while, but when you were, you probably — I'm just guessing because you're like me, I do these all day fasts also. If I don't have some snacks or prepare my food throughout the day as I did this week, I will come home and I will eat like seven pieces of chicken and I'm not proud of it afterwards. Unless you can control that voracious urge, you're not going to get what Adam is talking about here.Tim: So Adam, as we come to end of this episode, I really would love you to encourage you to get those tests done quickly, and if you don't mind, share some of them with our audience so that we can gauge your success. The question that I have for you right now as we put the wraps on this is okay, we're close to or at day 90. Are you going to continue and forge ahead with the exact same plan that you've had for the last three months or so, are you going to augment it a little bit, what are your plans?Adam: I'm going to continue, I'm going to stay on this. I might eat a little bit more often at this point, because I don't really need to lose anymore body fat. I've got the six pack going for the summer, that's all good.Tim: Look at you, he's in his 50s and he has a six pack, that's impressive.Sheila: Do you drink coffee, can I ask that?Adam: I drink coffee. Let me speak to something Mike just said. He was saying that we're generally very good about not eating carbs, and that's partially true, with me anyway. What I mean by that is I have two young kids and I grab the M&Ms. My wife buys five-pound bags of them so she can make pancakes for the kids. Don't get me started, my wife will not let me put my kids on a ketogenic diet.Mike: My wife is a nutritionist and she would never let it happen either.Adam: Because they're afraid of ketoacidosis, but anyway what I wanted to say was this. My diet before I started this, yes, I'd go three or four days really good, and then I'll eat a whole pizza. I would never really string along many consistent weeks or days. I'd eat well one day, not very much the other day, summers come, barbecue, hotdogs, hamburgers, I just went for it. I can get away with it. You said at the beginning of this piece, Adam you don't look like you need to lose weight, why'd you start this diet? I was creeping up, and even though it appears that I eat very well, and I obviously eat well most of the time. I certainly eat good foods but I also supplement them with not such good stuff. This last 90 days, I made a commitment not to deviate from that, to be really consistent with it. Yes it's higher fat than I would normally do when I did eat well. Less protein than I would normally — that's what I learned about a ketogenic diet, that most people make the primary mistake of eating too much protein on a ketogenic diet, and so this has been the first time in my life that I've been this disciplined in my eating. I'm older now, I can't get away with what I used to get away with. The other thing that I want to say before we wrap this up is about cravings. I always hear about how you go on these low carb diets and when your body starts getting used to and primed for utilizing fat for fuel, they say you eliminate all your cravings. Bullshit. To me anyway. Maybe the physical cravings aren't there and I told you I could go all day and not really be hungry, but the truth of the matter is, I'm craving the foods that I've been giving up nonstop. To this day, 90 days into it give or take, I still crave the pizza. I still see my kids eating the pizza, I still see the buns on the hamburgers and I want it, I want it bad. I say no, the cravings are there. Maybe the physical cravings aren't there as much.Tim: What do you mean by physical cravings, define that.Adam: My stomach growling and saying man you're hungry, you've got to eat. Or feeling a little lightheaded, or physically feeling the effects of hunger. Now that I'm keto-adapted I don't have those physical — when I'm 24 hours in I start to feel them, but eighteen hours fasts, it's a no-brainer for me, it's as easy as it could be. Even though those physical things aren't there, I pass a pizza place, I pass chicken wings at the Superbowl, hot dogs at the baseball game. Beer, alcohol, I want it all, those cravings have not subsidized. I don't look at them and say ew. I want it badly, but I don't do it.Sheila: It's easier to not do it.Adam: So going forward, I'm going to continue my strict ketogenic diet for at least another 30 days. I might eat a little bit more food, but not the foods I'm not supposed to be having on a ketogenic diet. The foods I can have, add a little bit to my portions, but that's the extent of it for the next thirty days. By that point, I'll have my blood work done and we'll talk about this some more.Mike: I just think before we wrap up, I think blood tests aside, that's data that we all need. It's great to get all that stuff, but the bottom line is you've taken an educated approach to selfexperimentation and troubleshooting your body to figure out how to improve it, and your back has felt better. Do we know it's because of the ketogenic diet, maybe it did, maybe it didn't, but regardless you're in a trend where you feel so much better. Your body feels better, your back feels better. You like the way you look, you feel, it's like I almost want to say — if the tests are completely negative or there's no improvement or any markers have been changed, who cares. Looking at someone who looks healthy also. They say that they feel great but they don't look healthy, but this is not the case.Adam: Like vegans. First of all, I want to say that this is not a ringing endorsement or a push for people to go ketogenic. I'm not going to be that bull at this point to say something like that. It's definitely a viable option, and before you go into something like this, check with your doctor and do a lot of research, because compared to the recommendations by the ADA, the American Diet Association, this is not what's recommended. I want to make this disclaimer. Look into it for sure, do your research. If it sounds like you, if I sounded like you, definitely look into it. Like Mike just said, I'm very well researched. I have a background in biochemistry, I know how to read these things. I'm a little bit different than your average bear when it comes to this type of thing. If you're not in that world, you should get advice when you do something like this.Sheila: Can you give us a starting point?Adam: Yeah, I do, I recommend the doctor that I mentioned earlier. Dr. Peter Attia, and his website is called the eating academy. Read everything this guy writes, and he also refers you to other things he reads so that is a great start. The eating academy by Dr. Peter Attia. So if you're interested in possibly doing this for yourself, well pay attention to our podcast, we're going to be reporting back on this in a little while when I get my blood work back and we'll take it from there. Good luck.Tim: Okay. So don't forget to check out the show notes for a link to the website that Adam referenced, spotlighting the research done by Dr. Peter Attia. That's eatingacademy.com. Looking forward to the results of Adam's blood work to gauge the success of his three-month ketogenic dietary journey, and we should have that for you coming up in the next few weeks. Also on the way, we have a couple of interviews that we're really excited about here at the InForm Fitness Podcast. In two weeks, we'll be speaking with happiness expert, Gretchen Rubin. Gretchen has authored several books and has sold more than two million copies in thirty different languages. She has been a client of InForm Fitness for many years, and she has a popular podcast of her own, titled Happier with Gretchen Rubin. So give it a listen and even subscribe to her podcast so you can become more familiar with Gretchen before she joins us here on the show, and in the process, pick up some valuable tips on being, well, happier. Next week, we'll be talking to Dr. Martin Gaballa, the author of the One Minute Workout. Adam and Dr. Gaballa will contrast and compare high-intensity strength training like we do here at InForm Fitness, and high-intensity interval training, as described in Dr. Gaballa's book, The One Minute Workout. If you'd like to find an InForm Fitness location nearest you so you can give this high-intensity strength training workout a try for yourself, please visit informfitness.com and at the time of this recording, we have locations in Manhattan, Port Washington, Danville, Burbank, Boulder, Leesburg, and in Restin. If you aren't near an InForm Fitness location, you can always pick up Adam's book via Amazon: Power of Ten, The Once a Week Slow Motion Fitness Revolution. Included in the book are several exercises that support this protocol that you canIf you aren't near an InForm Fitness location, you can always pick up Adam's book via Amazon: Power of Ten, The Once a Week Slow Motion Fitness Revolution. Included in the book are several exercises that support this protocol that you can actually perform on your own at a gym nearest you. We'll have a link to Adam's book in the show notes as well. Thanks again for listening, and for Sheila Melody, Mike Rogers, and Adam Zickerman of InForm Fitness, I'm Tim Edwards with the InBound Podcasting Network.Thanks again for listening, and for Sheila Melody, Mike Rogers, and Adam Zickerman of InForm Fitness, I'm Tim Edwards with the InBound Podcasting Network.

Jane and Dan chat to Dr Rochelle Gellatly, a clinical pharmacy specialist in critical care, an Australian Advanced Practice Pharmacist in Cardiology and a Board Certified Pharmacotherapy Specialist with added qualifications in Cardiology. She is currently working in Vancouver. We talk to Rochelle about: Recent changes in thinking about hyperlipidaemia, target LDLs and risk assessment How scores for cardiovascular risk are used in practice What we know (or don’t) about the optimal dose of a statin and the frequency of adverse events

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Today we will be discussing the pooled analysis results of the 10 ODYSSEY Trials with important implications for the reduction of lipids in major cardiovascular events. But first, here's your summary of this week's journal. The first paper provides experimental data on vascular disease that brings into focus the critical roles of transcription factors such as GATA2 in the maintenance of endothelial cell function, as well as the role of selected microRNAs as a novel player of vascular regulation. In this study by first author Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and colleagues, authors used GATA2 gain and loss of function experiments in human umbilical vein endothelial cells to identify a key role of GATA2 as a master regulator of multiple endothelial functions, and this via microRNA-dependent mechanisms. Global microRNA screening identified several GATA2-regulated microRNAs, including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities, whereas supplementation with miR-126 normalized vascular function. In a mouse model of carotid injury, GATA2 was reduced and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo. In summary, GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Thus, modulation of GATA2 and its targets miR-126 and miR-221 represents a promising therapeutic strategy for the treatment of vascular diseases. The next study is the first to show that current smokers from the general population have lower levels of circulating cardiac troponin I, a seemingly paradoxical observation given the known detrimental cardiovascular impact of cigarette smoking. First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues from the University of Oslo used data from the large population-based HUNT study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341 former smokers, and 2,550 current smokers. Current smokers had significantly lower levels of cardiac troponin I than never smokers and former smokers, an association that remains significant even after adjustment for potential confounders. The authors also found an association between increasing concentrations of troponin I and clinical endpoints, namely acute myocardial infarction, heart failure, and cardiovascular death in the total cohort. However, this association was attenuated in current smokers and was significantly weaker than in never or former smokers with a p for interaction of 0.003. The prognostic accuracy of troponin I as assessed by C-statistics was lower in current smokers than in never smokers. Troponin I provided no incremental prognostic information to the Framingham Cardiovascular Disease risk score in the current smokers. Together, these results suggest that mechanistic pathways other than those involving subclinical myocardial injury may be responsible for the cardiovascular risk associated with current smoking. Future studies are needed to determine whether a lower cardiac troponin I threshold should be considered for exclusion of myocardial infarction in smokers or whether prognostic tools other than measurement of cardiac troponins should be utilized when evaluating risk of future events in current smokers. The next study contributes to our understanding of cardiomyocyte signaling in response to ischemic injury. In the study by first author Dr. [Wool 00:05:04], corresponding author Dr. [Ju 00:05:04] from Tongji University School of Medicine in Shanghai, and colleagues, authors sought to understand the role of low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin signaling in the heart. They did this using conditional cardiomyocyte-specific knockout mice who had surgically induced myocardial infarction. They found that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac ischemic insults. Conversely, deficiency of beta-catenin, a downstream target, was beneficial in ischemic injury. Interestingly, although both insulin-like growth factor-binding protein 4 and Dickkopf-related protein 1 are secreted beta-catenin pathway inhibitors, the former protected the ischemic heart by inhibiting beta-catenin, whereas the latter enhanced the injury response mainly through inducing lipoprotein-related protein 5 and 6 endocytosis and degradation. These findings really add to our understanding of the beta-catenin signaling pathway in ischemic injury and suggests that new therapeutic strategies in ischemic heart disease may involve fine-tuning these signaling pathways. The next paper from the International Consortium of Vascular Registries is the first study allowing an assessment of variations in repair of abdominal aortic aneurysms in 11 countries over 3 continents represented by the Society of Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from University of Alabama-Birmingham School of Medicine, and colleagues, looked at registry data for open and endovascular abdominal aortic aneurysm repair during 2010 to 2013, collected from 11 countries. These were Australia, Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland, Switzerland, Germany, and the United States. Among more than 51,000 patients, utilization of endovascular aortic repair for intact aneurysms varied from 28% in Hungary to 79% in the United States, and for ruptured aneurysms from 5% in Denmark to 52% in the United States. In addition to the between-country variations, significant variations were present between centers within each country in terms of endovascular aortic repair use and rate of small aneurysm repair. Countries that more frequently treated small aneurysms tended to use the endovascular approach more frequently. Octogenarians made up 23% of all patients, with a range of 12% in Hungary to 29% in Australia. In countries with a fee for service reimbursement systems, such as Australia, Germany, Switzerland, and the United States, the proportion of small aneurysms and octogenarians undergoing intact aneurysm repair was higher compared to countries with a population-based reimbursement model. In general, center-level variation within countries in the management of aneurysms was as important as variation between counties. Hence, this study shows that despite homogeneous guidelines from professional societies, there is significant variation in the management of abdominal aortic aneurysms, most notably for intact aneurysm diameter at repair, utilization of endovascular approaches, and the treatment of elderly patients. These findings suggest that there is an opportunity for further international harmonization of treatment algorithms for abdominal aortic aneurysms. This is discussed in an accompanying editorial entitled, Vascular Surgeons Leading the Way in Global Quality Improvement, by Dr. Fairman. The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and Harvard Medical School and colleagues, presents the results of the apoAI event reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter, randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of CSL112, which is an infusible, plasma-derived apoAI that has been studied in normal subjects and those with stable coronary artery disease, but now studied in the current study in patients with acute myocardial infarction. The trial showed that among patients with acute myocardial infarction, four weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was associated with a dose-dependent elevation of circulating apoAI and cholesterol efflux capacity without adverse hepatic or renal outcomes. The potential benefit of CSL112 to reduce major adverse cardiovascular events will need to be assessed in an adequately powered phase 3 trial. Now for our future discussion. Today I am delighted to have with us Dr. Kausik Ray from Imperial College London, who's the first and corresponding author of a new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start by congratulating you on this paper. I believe this is the first data that allows us to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE relationship extends below this level. Dr. Kausik Ray: Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at people down to an average LDL cholesterol of about 54, and with the new PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they give you the opportunity for a further 50 to 60% reduction. We actually get the chance to get people down to levels like 25 mg/dL, and the question is, does the benefit continue at that level? We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try and help predict what you might see in ODYSSEY outcomes, what you might see in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because there's probably been a lot of hype around the two New England Journal papers about 50, 60% reductions of all potential reductions based on small numbers of events. So the question is, if you reduce LDL by 39 mg/dL, how might that reduce your risk, and is the relationship continuous? So those were the aims. Dr. Carolyn Lam: That's great, and maybe could you give us an idea of the number of patients you are looking at and the number of events? Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had just about 6,700 person years' worth of followup. In total, we had 104 first MACE events. To put this into context, it's about one third of the number of events that the first [framing 00:12:53] of analysis had. It's an observation analysis rather than randomized trial data, so you got to bear that in mind with the usual caveats that go with observational data. But the same endpoints that were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization. This is the same endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard. Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line? What did you find? Dr. Kausik Ray: What we found was that there was a continuous relationship all the way down to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk went down by about 24%. If you looked at [apo-like 00:13:48] approaching be on non-HDL cholesterol, again, you found the same continuous relationship with a similar point estimate for a similar standardized difference in LDL cholesterol. We also looked at many of the guidelines, talk about percentage reduction. We actually looked at percentage reductions. If you start with a baseline LDL of X and you achieve a 50% further reduction in LDL, how much further benefit does that give you? A 50% further reduction gave you a 29% further lower risk of MACE. So we didn't find any threshold or limit all the way down to LDLs of about 25. Dr. Carolyn Lam: That's really a key, novel finding that you contributed, so congratulations once again. I suppose the question will always be, you're talking about relative risk reductions here. At such low levels, can you give us an idea of the absolute risk reductions? Dr. Kausik Ray: Yes. You've got to remember that the relative risk reductions are what you can apply to population differences. If you pick a high-risk patient population, you would expect to see a much bigger absolute risk reduction than maybe this study or another study. Similarly, if you pick a low-risk group, you are going to see a much smaller absolute benefit. I always try to advise a little bit of caution that if you basically look at the range ... If you start with let's say an LDL of 150 and you go down to let's say an LDL of 25, you are talking about a 1.25% absolute risk reduction. Remember, these patients are possibly going to be a slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes and into the [Fuliay 00:15:46] trial, for example. Dr. Carolyn Lam: I think you mentioned what I was going to just ask you about. This is observational. You had 104 events, and I suppose another limitation might be that your followup was two years at max, if I'm not wrong? What do you say about that, and are there plans for future analyses? Dr. Kausik Ray: Within the context of these studies, I think that the whole of this data will eventually become dwarfed by what we see with the big CDOTs, because you've got 18, 27,000 people, 3 years' worth of exposure and followups, so you are going to have many, many more events. That is a limitation, but I think what is interesting is that we know that the baseline LDL cholesterol level is around about 90 mg/dL. We don't actually know what the actual baseline ... because the baseline [characters 00:16:43] haven't been published for ODYSSEY Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark because that's what your baseline LDL is and that's what we'd predict in the regression lines that we observed here. I think that we're not going to get many more events in these studies because largely the randomized period of followup is now over. Many of these people are now into open labels, extensions for safety, so we won't get many more events from this. In terms of, I think, the way people should maybe look at this is possibly as a taster for what's to come in the next 18 months or so. I think for the time being it answers two questions. Is lower likely to be better? And it is. I think the other question it tells is how might you get people down to LDLs below 50? One of the important things was that if you were just on statins, in this population, if you were recruited on the basis of a high baseline LDL, you got no additional people down to LDLs below 50. You got under 10% with add-on [inaudible 00:18:05], but you got around about 50% when you used the PCSK9 inhibitor as an add-on to existing therapy. It tells you about how to get to such low levels as well. I think that's the other key thing that it actually gives you. We did an analysis of safety [inaudible 00:18:23], and I think that's really important. Once you see the efficacy, or if you see the MACE events continue to go down ... If you looked at treatment-emergent adverse events ... and I completely take the fact that it's every side effect reported altogether, which may or may not be linked to LDL levels specifically, but when we did that, the relationship actually was just a horizontal line, so there was no relationship with percentage reduction or on treatment LDL, so it gave us a nice idea of both safety and efficacy that we might experience in the big outcome studies. Dr. Carolyn Lam: All right. Obviously the big outcome studies are going to be game changers, and I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot of other things that need to be considered if this becomes the case, isn't it? Carol, I really appreciated that you invited an editorial, and the editorial is by Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents? Please tell us about the discussions about this paper that occurred. Dr. Carol Lam: I would again like to congratulate Dr. Ray on a fantastic paper, and I would like to reiterate exactly what he said. I think it really does give us some comfort about this class of medication and its relative safety. I think that's very important, because I can't tell you how many patients I get and how many referring physicians I get who worry when their patients come back with LDLs of 20 or below. I think that gave us some comfort, and I do also think it was very important to show that this would fall along the same regression line that statins perhaps would fall. As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this is a tasty little taster, and I appreciate and congratulate you for publishing this. The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it, Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there. Will the relative benefits that we can achieve with this class of medications make sense for the cost of these drugs? That's obviously a very separate issue from what was discussed in the manuscript, but it's something to think about. We understand that there are additional patients that will be helped if they can get their LDL down, and we hope that that will translate into the outcomes. Again, just as Dr. Ray mentioned, we will have to wait for the cardiovascular outcomes trials to be completed. When they are, if they do show the benefits that we hope, will their price point make them accessible to enough patients for this to be a widely applied, utilized therapy? Or will they not? That's part of what was discussed in Dr. Stone's editorial. Dr. Kausik Ray: When we were writing the manuscript and stuff like that, and we were doing this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need to balance all of these bits and reassure ... We've got an opportunity." So I suggested them giving those additional analyses, and you saw how big the online supplement was. There was a ton of work that we put into this, and to format it into a concise ... I really want to just thank the editorial board for giving us the chance and actually being able to help us and work with us on this, because it's really important. I hope people look at all of those things because it will help people also that question the LDL. They all talk about the hypothesis and the safety of really low LDLs, and people come off statins as a result. I think this will help. Dr. Carolyn Lam: You're listening to Circulation on the Run. Thank you so much for being with us, and don't forget to tune in next week.

Fat Basics Fats don't mix with water.  Some fats are liquid at room temperature (oils), some fats are solid at room temperature. Because so much of your body is made up of water, fats are very unhappy there.  So your body will take this "head" that likes water, and sticks it on the lipid "tails". *Correction: This combination is called a Phospholipid Then they will form a little ball where all the water-hating tails are inside, and all the water-liking heads are on the outside.  This is called a Lipoprotein. Cholesterol LDL = Low-density lipoprotein ("Bad") HDL = High-density lipoprotein ("Good") Density = the amount of stuff you can cram in a limited space - A lot of stuff in a small space = high density - A little bit of stuff in a big space = low density In the lipoproteins, extra proteins are added to help direct it where to go.  HDLs have more proteins to help them stay focused than LDLs, so LDLs are like distracted drivers... The Egg Controversy (while I avoid a lot of HuffPost articles, and I don't know much else about this author, I agree with 90% of what he says here - and that's more than I can say about other information I find out there) LDLs also have more triglycerides crammed into them.  Triglycerides have 3 water-hating tails instead of one. What's the magic number? You don't need your cholesterol number to be zero.  You need cholesterols to build cell membranes and hormones, you just don't want there to be too much of it. So the LDLs are less directed so they end up crashing into each other and sticking together.  Then if they crash into the artery wall, they may get stuck there and just becomes a place where more stuff can get stuck.  This is how atherosclerosis and blockages happens.  A bunch of cholesterol is stuck to the walls of the arteries. There is NO magic number! HDL: > 40 men, > 50 women LDL: < 100 Trigs: < 150 TC: < 200 The Bottom Line HDLs and LDLs are the types of packages your body uses to carry fatty acids around your body. The main hub of all this cholesterol packing and shipping and using is your liver.  Once the liver is done using all the fatty acids it needs, if there's a bunch extra, it starts packing them away into adipose (or fat) tissue and storing it wherever it can around your body.  And there is NO LIMIT to the size of the fat stores! The Statin Controversy (this is a great summary - the bottom line being that the people recommending "statins for everyone" stand to benefit greatly in their pocketbook if more people in the world actually started taking (aka buying) statins. Familial Hypercholesterolemia = genetically inherited high cholesterol Lifestyle changes (eating healthy foods and an appropriate amount of exercise) can never be bad for you! Risk Assessment If you take your coffee the "bulletproof" way, consult your doctor first. Connect with me Support us on Patreon *NEW* Join the Pharmacist Answers Podcast Community on Facebook Subscribe: iTunes, Stitcher, GooglePlay, TuneIn Radio Like the Facebook page Music Credits:  "Radio Martini" Kevin MacLeod (incompetech.com)  Licensed under Creative Commons: By Attribution 3.0  http://creativecommons.org/licenses/by/3.0/

Show Notes: Subscribe to the podcast on [iTunes](https://itunes.apple.com/us/podcast/ari-meisel-less-doing/id605938952?mt=2) Also Check out Ari's book "[Less Doing, More Living](http://www.amazon.com/Less-Doing-More-Living-Everything/dp/0399168524/ref=as_li_ss_til?tag=tlp03-20&linkCode=w01&creativeASIN=0399168524)" Get More Great Content at [LessDoing.com](http://www.lessdoing.com/) **Episode 101** **Summary:** In Episode #101 Ari interviews [Dr. Gil Blander](https://www.insidetracker.com/about/tracker.com%2Fabout%2F), initial founder and current president of InsideTracker, the maker of industry-leading health analytics tools for personal use. As they exchange thoughts on the importance of health, Ari and Gil cover DIY blood testing, Ari's Cholesterol and the true markers of optimal health. **Time Stamped Show Notes:** - 01:45 – Ari introduces Gil Blander (2nd time on podcast) of Inside Tracker - 01:55 – Full Disclosure: Ari is an advisor to Insider Tracker - 02:01 – Inside Tracker allows for self-blood testing in a way the doctor might not permit - 02:43 – Gil provides a full overview of Inside Tracker - 03:40 – General frequency recommendation for tracking blood markers - 04:02 – At the beginning, get three different blood tests - 04:40 – With the baseline tests as a launch pad, it becomes easier to establish blood-goals - 06:10 – Ari and Gil discuss Ari's latest results from Inside Tracker measurements - 10:09 – Ari's testosterone measurements are discussed - 11:20 – Fatigue and diet are directly correlated to testosterone production - 13:58 – CRP as a marker of inflammation - 15:55 – Inside Tracker is releasing a new product called PhysioAge - 16:38 – Ari and Gil touch on the vital importance of magnesium - 18:30 – People overlook the glucose marker - 18:50 – Glucose is the best indicator for longevity - 19:14 – It's important to keep glucose levels as low as possible - 20:30 – Gil's take-home message: _Keep glucose levels down_ - 20:45 – Cholesterol, HDLs and LDLs - 21:15 – Overall cholesterol number is not as important as it used to be - 21:38 – LDL and HDL numbers do not stand in a vacuum - 22:08 – If blood pressure is optimal and the person is not overweight, high LDL and HDL numbers aren't necessarily bad - 22:28 – Glucose levels are a far more important health marker than cholesterol levels - 23:17 – The information from the doctor isn't necessarily as complete as the information from a testing service - 23:39 – Seeing the “trend” of your blood work is vitally important - 24:09 – Start to maintain your health, wellness and longevity as effectively as you manage everything else ** ** **7 Key Points:** 1. Personal health management is vitally important 2. Home blood-testing allows for frequent blood marker tracking 3. Glucose level is the _best _marker for tracking longevity 4. Keep glucose levels as low as possible to encourage health 5. Cholesterol numbers are not as important as they used to be in measuring overall health 6. Being able to track blood trends is immensely important to health 7. Manage health and wellness as effectively as you manage everything else **Resources Mentioned:** - [InsideTracker](https://www.insidetracker.com/) – “A_ personalized health analytics company founded by leading scientists, physicians, nutritionists and exercise physiologists_” - [PhysioAge](https://www.insidetracker.com/blog/post/58241538667/insidetracker-scoop-interview-with-professor-leonard) – A new product designed to “_tell InsideTracker customers their age, which will be estimated by their body's health and probable life expectancy_” **Credits:** - Music and Audio Editing provided by [Felix Bird](http://2014.felixbird.com/) - Show Notes provided by [Mike Rossi](http://mikerossi.elance.com/) ------- [Get the FREE Optimize, Automate, Outsource Blueprint here.](https://go.lessdoing.com/blueprint?u --- Send in a voice message: https://anchor.fm/lessdoing/message

AIR DATE: March 1, 2012 at 7PM ETFEATURED EXPERT: FEATURED TOPIC: “What Questions Should I Ask My (Non-Low-Carb Friendly) Doc?” Famed low-carb clinician Dr. Mary Vernon, MD is the co-author of  with Jackie Eberstein, RN (who was our very first guest in ). She is a Past President of the American Society of Bariatric Physicians. Dr. Vernon is well-known amongst her medical professional peers as an expert on the therapeutic use of low-carb ketogenic diets on patients to treat a variety of health issues, including diabetes and metabolic syndrome. She is the CEO of  which seeks to educate her fellow physicians and medical professionals on how to use science-based modalities with patients. Dr. Vernon has a heart for arming doctors with practical ways to implement low-carb diets where they are necessary for improving key health markers. What better expert could we have to address what questions you should be asking your (non-low-carb friendly) doctor than her! Here are some of the questions we addressed in this podcast: KELLY ASKS:My frustration with doctors is they spout the conventional “wisdom” of the food pyramid or MyPlate or whatever it is now, but yet when it doesn’t work for me they say I’m just not trying hard enough – which is without a doubt not true. So I guess my question would be – If something isn’t working, wouldn’t it be smart to try something else? And really – where are the medical studies that back up that a low fat diet is better for my health? Where are the studies that correlate fat = heart disease? If I lose weight (even if it’s a small amount) and feel better and have lower blood sugar on a low-carb diet, then shouldn’t I stick to something that’s working? And is it so wrong that I want to be personally involved in my health enough that I HAVE done research and have looked up the studies and that I might actually have a working knowledge of what is best for my body? CONRAD ASKS:I am currently in the process of looking for a new Doctor (already checked http://lowcarbdoctors.blogspot.com/) What questions can I ask before visiting to find out if they might support a low carb lifestyle, other than the obvious “Do you support low-carb, high-fat diets?” I have read that I should make sure they perform and understand a VAP instead of standard cholesterol test. Are there any other tests or procedures I should be aware of and ask for? KATHY ASKS:I just got my lab work back from my doctor and my total cholesterol was 249 with LDL at 171 and my sugar at 103. That’s basically all he said and then of course, “I’d like to start you on a low dose statin, keep eating a low carb, low cholesterol diet”. The cholesterol is up a little and so is the LDL from 6 months ago. I am not a diabetic and have never had problem with that. I wanted him to run an NMR. My doctor called me and had absolutely no idea what the NMR Lipoprofile test was even after I gave him the CPT code. Then he went on to say “size doesn’t really matter and thats for HDL, not LDL. And if I went to any hospital they wouldn’t know what an NMR test was.” So, he is having me do a VAP profile test. He said, “elevated LDL is bad no matter what the size.” Mine isn’t horrible for a women without a risk factor, but it keeps going up. Any suggestions? MIKE ASKS:How do you have a conversation with your doctor about putting you on a statin drug with and HDL of 75 and triglycerides of 80 when your LDL is 225? I got these numbers in a blood test at my doctor’s office after consuming a low-carb diet. KATHY ASKS:How should patients deal with doctors who want to follow the guidelines put out by a group like the American Heart Association or American Diabetes Association if that association’s guidelines aren’t in keeping with our own opinions of current best evidence or even n=1 experiments we’ve done on ourselves? Sometimes doctors seem to think they have to follow those association-based guidelines to protect themselves against malpractice, do they have a point? How do we get around that if we believe those organizations aren’t up to date with their evidence or if we think the guidelines are politically motivated or otherwise flawed? JOHN ASKS:I’m a Type 1 diabetic and I believe I suffer from insulin resistance. I use 18.3 units for basal and my TDD on 10% carbs and 25% protein runs in the high 30’s. Whenever I fast, even for a single meal, I get a major liver dump at the next meal followed by some major cravings which seem to counter any benefits I might have seen from fasting. I’m stuck in my weight loss, and I think Metformin or a GLP-1 would help. Symlin is not an option where I live in Canada. My endocrinologist says my TDD insulin is already much lower than “normal” and refuses to consider giving me a prescription. He’s the local head of internal medicine and is known for not listening to colleagues. Any suggestions on how to proceed would be helpful. SPARKY ASKS:I would love to go to a doctor and find out what all my lipid numbers and thyroid numbers are. But I dread talking about my diet — I can’t defend it in terms of weight loss, because I weigh only about five pounds less than when I first started low-carbing 10 years ago. (Although a lot of women gain weight during their 40s, so maybe I’m better off than I think!) There are no low-carb friendly doctors where I am (at least none listed on Jimmy’s List of Low-Carb Doctors blog). I’m afraid of getting caught in the gears of the medical machinery. For example, what if my cholesterol is “high” and they want me to take statins? Can you just go to your family practice doctor and say, “I want these tests, please have them done for me”? What exact tests should I ask for? I don’t want just a couple of numbers that don’t REALLY tell anyone anything, which seems to be what most people wind up with. I suspect thyroid issues (20 extra pounds of fat won’t go away, cold hands and feet, dry skin). Also, one hand or the other occasionally gets a pins-and-needles feeling — I have no idea what that could mean. I just turned 50 and am in excellent health overall. I have regular periods, no change in that regard. I haven’t had a checkup for nearly 8 years, since my last postpartum checkup. I’ve never had cholesterol tested or a glucose tolerance test. Blood pressure has always been around 90/70. I’ve eaten mostly real, whole foods since I was a teenager (including 17 years of vegetarianism), and mostly low-carb/Paleo/Weston A. Price for the past several years. I keep the carbs to around 25-75g and rarely eat wheat or other grains. PENNY ASKS:While my mother’s doctor always congratulates her on her steady weight loss (and better blood sugar level control) he never fails to tell her that cutting back on her carbs is going to cause more problems in the long run. He points out that her cholesterol levels are elevated above normal, caused by eating too much saturated fat of course, and her refusing to take statins, which caused her muscle pain in the past, is leading her to a massive heart attack. She never knows how to respond to him so I thought perhaps giving him a book to read might be one solution. I was wondering if Dr. Vernon might suggest a book that she could give to her doctor that he might read? I know there are many books out there written for the average person who does not have a medical background. Is there a book that perhaps would carry more weight with an MD and not just be seen as a fad diet book? Because the doctor is probably not going to read that type of book. BRIAN ASKS:My low-carb doctor may lean even too far away from statins and other medications. When should I really think is the right time to take a pharmaceutical drug — in other words is there a risk of having too much of a low-carb friendly doc? JOCELYN ASKS:So, my friend went to see her doctor yesterday. Her HDL is 57, her LDL is 135. She got a heart scan a while back and got a value of 19. Her doctor prescribed a statin for her. My friend asked her Doctor to do a VAP test and the doctor said that she already knows that she is starting to have some heart disease starting, so she doesn’t need the VAP test. My friend has been starting to read Robb Wolf’s book and other Paleo people’s information, so, she’s getting wild ideas like saying no to statins. Her doctor is slightly insulted that my friend is ignoring her advice. “When you get heart disease will you go to your friends and the internet for help?” I told her to find another doctor, but she apparently wants to stay with this doctor. How would you approach this doctor? But, how would you educate a doctor who already seems to be on the defensive about learning new things about cholesterol and statins? ROCHELLE ASKS:I did attempt to speak with my doctor recently. I had recently gotten some blood work back and he said, for someone with such a high BMI (30) I didn’t deserve such good numbers. Total Cholesterol 222, HDL=90, LDL=118, non-HDL=132, Triglycerides=68, Glu=84, HbA1C=5.1 I told him that I had started eating Paleo. He did note that I still needed to lose some weight. I’ve lost about 30 lbs since starting Paleo. I asked him how he would suggest that I accomplish that. He said he recently decided that he needed to get his BMI down. He did what he tells his patients to do. He restricted his calories and exercised more. It’s painful, but it works. I asked him what he ate. He said a bagel in the morning. A yogurt for lunch and a regular dinner but no dessert. I asked him if he’d read “Good Calories, Bad Calories”. He said no, I don’t care about that. It doesn’t matter where the calories come from, you can eat 1200 calories of whale blubber and you’ll lose weight. I told him that I cut out the grains and sugar and it was *not* painful. He said, “Come back when you’re at your goal weight and we’ll redo all those numbers and we’ll talk.” He is about ready to retire. Should I even bother trying to talk to him about other ways of eating and getting healthy? Or should I find a new doctor? I looked on both the Paleo physicians network and the low-carb doc site and there are a couple of oriental medicine practitioners and a chiropractor. They don’t seem to be on my insurance plan. So…what’s a woman to do? DAN ASKS:I’m a type 2 diabetic who has been on low carb (Dr. Bernstein’s Plan) for about 6 years. Last year I found a low carb doc from Jimmy’s list. He favors South Beach phase 1. The only problem is that he believes in the lipid hypothesis. At my last visit, he told me that, as a diabetic, my LDL needs to be 70, even though my cholesterol would be “normal” for a non-diabetic. He said that controlling my blood sugar will not prolong my life. Only getting my LDL down to 70 will prolong my life. The strong implication is that I will die an early death unless I get my LDL down to 70. He is very pushy about statins, though I have resisted the pressure. I tried to tell him that the studies show no conclusive benefit to statins, but he won’t buy it. Do you have any suggestions on how to handle it in addition to being stubborn in refusing to take statins? HAROLD ASKS:I am a Type 2 diabetic. At the time of my diagnosis two years ago, my triglyceride/HDL ratio was 6 to 1. Now, after carefully watching my postprandial glucose levels (rarely, if ever over 110) my triglyceride/ HDL level is down to 1.6 to 1. My cardiologist couldn’t care less about my triglycerides and only focuses on my LDL (which were 120) and wants me on statins, I refuse them. Here’s my question, what can I use to convince her that controlling my diabetes and my trigs/HDL ratio are greater heart risk factors than LDLs. Filed Under: , 

Guest: Philip Barter, MD, PhD Host: Gary Kohn, MD Clinician and lipid researcher Dr. Philip Barter of the Heart Research Institute in Sydney, Australia, shares with us his research about the risk of low HDL, even in the face of very low LDL levels.

Thu, 15 Jan 2004 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/1728/ https://edoc.ub.uni-muenchen.de/1728/1/Jostarndt_Kristina.pdf Jostarndt, Kristina