AJP-Heart and Circulatory Podcasts

The literature shows that the incidence of heart failure with preserved ejection fraction (HFpEF) increases significantly in postmenopausal women, but how can researchers study the underlying mechanisms? In our latest episode, Dr. Jonathan Kirk (Loyola University Chicago) interviews lead author Dr. Mei Methawasin (University of Missouri, Columbia) and expert Dr. Glen Pyle (University of Guelph) about the recent study by Methawasin and co-authors investigating sex differences, menopause and HFpEF. The authors created an animal model that resembles HFpEF in women undergoing natural menopause by using 4-vinylcyclohexene dioxide (VCD) to induce “ovary-intact” menopause, combined with the 2hit regimen (HFpEF inducing regimen) to model postmenopausal HFpEF. Combining echocardiography, pressure-volume and single-cell analyses, the authors found that VCD mice, compared to ovariectomized mice and premenopausal mice, have higher testosterone levels compared to other models. By developing this robust phenotype animal model, the authors open new avenues for investigating therapeutic targets in other hormones beyond estrogen alone. Ready to explore the estrobolome, the importance of animal models of human disease, and the complex family of hormones comprising estrogen? Listen now.   Mei Methawasin, Joshua Strom, Vito A. Marino, Jochen Gohlke, Julia Muldoon, Shelby R. Herrick, Robbert van der Piji, John P. Konhilas, Henk Granzier An ovary-intact postmenopausal HFpEF mouse model; menopause is more than just estrogen deficiency Am J Physiol Heart Circ Physiol, published March 10, 2025. DOI: 10.1152/ajpheart.00575.2024

What is the role of ferroptosis, programmed cell death characterized by intracellular iron accumulation and lipid peroxidation, in the context of ischemic injury related to heart transplantation? In this episode, Associate Editor Dr. Amanda LeBlanc (University of Louisville) interviews authors Dr. Kenneth Liao and Dr. Nandan Mondal (both at Baylor College of Medicine), along with expert Dr. Zachary Kiernan (Virginia Commonwealth University) about the latest study by Li et al. The authors found that prolonged cold storage increases the susceptibility of hearts donated after brain death (DBD) to ferroptotic cell death. In contrast, however, the authors found that warm ischemic injury increased the risk for ferroptotic cell death in hearts donated after circulatory death (DCD). Li et al. found that targeting ferroptosis could be beneficial for optimizing cold preservation for DBD hearts, while interventions for DCD hearts should focus on the early phase of warm ischemia. Heart transplantation is the gold standard therapy for patients with medically refractory advanced heart failure. However, demand greatly exceeds supply of donor hearts. Listen as we discuss the current state of the heart transplantation field and the many challenges it faces.   Shiyi Li, Katherine V. Nordick, Abdussalam E. Elsenousi, Rishav Bhattacharya, Randall P. Kirby, Adel M. Hassan, Camila Hochman-Mendez, Todd K. Rosengart, Kenneth K. Liao, and Nandan K. Mondal Warm-ischemia and Cold Storage Induced Modulation of Ferroptosis Observed in Human Hearts Donated After Circulatory Death and Brain Death Am J Physiol Heart Circ Physiol, published March 28, 2025. DOI: 10.1152/ajpheart.00806.2024

Can hormonal fluctuations across a single menstrual cycle alter arterial wave reflections and wasted pressure effort? In this episode, Associate Editor Dr. Jonathan Kirk (Loyola University Chicago) interviews author Dr. Ninette Shenouda (University of Delaware) and expert Dr. Sarah Baker (Mayo Clinic) about the latest study by Shenouda et al. investigating sex differences and ventricular arterial interactions. The authors wanted to understand how strategic phases of the menstrual cycle might affect the relationship between the left ventricle (LV) and the arterial system, as this relationship is crucial for maintaining adequate cardiac output and blood pressure. Given the established beneficial effects of estradiol on the vasculature, the authors hypothesized that their cohort of naturally menstruating premenopausal women would have favorable reductions in total peripheral resistance and favorable changes in the arterial wave reflection profile during the high hormone cycle phases, compared to age matched men. What were the unexpected findings? Listen now to find out.   Ninette Shenouda, Joseph M. Stock, Nicholas V. Chouramanis, Zoe R. Lincoln, Megan M. Wenner, Julio A. Chirinos, and David G. Edwards Favorable alterations in ventricular-arterial interactions across the menstrual cycle in healthy premenopausal women Am J Physiol Heart Circ Physiol, published February 28, 2025. DOI: 10.1152/ajpheart.00363.2024

In this episode, Deputy Editor Dr. Zamaneh Kassiri (University of Alberta) interviews authors Dr. Oliver H. Wearing (University of British Columbia), Dr. Naomi C. Chesler (University of California Irvine), Dr. Mitchel J. Colebank (University of South Carolina), Dr. Timothy A. Hacker (University of Wisconsin-Madison), Dr. John N. Lorenz (University of Cincinnati), and Dr. Christopher R. West (University of British Columbia) about their new Guidelines in Cardiovascular Research article. This must-read Guidelines article provides a thorough overview of ventricular pressure-volume (PV) measurements in the mouse heart. PV measurements are an invasive method for assessment of heart function, and if done correctly, can provide researchers with valuable information about heart hemodynamics and the relationship between changes in ventricular pressure and volume during a cardiac cycle. The authors discuss PV measurements as the gold standard for assessing cardiac in vivo function. How do PV measurements differ from, and provide a complement to, echocardiography measurements? Listen and find out more.   Oliver H. Wearing, Naomi C. Chesler, Mitchel J. Colebank, Timothy A. Hacker, John N. Lorenz, Jeremy A. Simpson, and Christopher R. West Guidelines for assessing ventricular pressure-volume relationships in rodents Am J Physiol Heart Circ Physiol, published January 2, 2025. DOI: 10.1152/ajpheart.00434.2024

In our latest episode, Dr. Jeff Saucerman (University of Virginia) interviews authors Dr. Naomi Chesler (University of California, Irvine) and Dr. Mitchel Colebank (University of South Carolina) about their new Guidelines in Cardiovascular Research article on incorporating mechanistic modeling into the analysis of experimental and clinical data to identify possible mechanisms of (ab)normal cardiovascular physiology. The authors' goal is to provide a consensus document that identifies best practices for in silico computational modeling in cardiovascular research. These guidelines provide the necessary methods for mechanistic model development, model analysis, and formal model calibration using fundamentals from statistics. Colebank et al. outline rigorous practices for computational, mechanistic modeling in cardiovascular research and discuss its synergistic value to experimental and clinical data. Would you like to understand how to apply a cone of uncertainty to your experimental data? Listen now to find out more.   Mitchel J. Colebank, Pim A. Oomen, Colleen M. Witzenburg, Anna Grosberg, Daniel A. Beard, Dirk Husmeier, Mette S. Olufsen, and Naomi C. Chesler Guidelines for mechanistic modeling and analysis in cardiovascular research Am J Physiol Heart Circ Physiol, published August 6, 2024. DOI: 10.1152/ajpheart.00253.2024

In this episode of Behind the Bench, we are talking with Hannah Cizauskas about her first, first-author article published in AJP-Heart and Circ. Born and raised in Detroit, Hannah moved to Chicago for what she thought would be just one rotation outside of the cancer genetics field. This led Hannah to work on a project related to atrial fibrillation and contractile dysfunction in Dave Barefield's lab at Loyola University Chicago's Cellular and Molecular Physiology Department. Now in the fourth year of her PhD, Hannah is a dog mom to Jake, she loves reading STEMinist novels, and she is researching sarcomere dysfunction in the context of AFib. Listen to this engaging interview with co-hosts Dr. Tommy Martin and Dr. Charlotte Usselman to find out more.   Hannah E. Cizauskas, Hope V. Burnham, Azaria Panni, Alexandra Peña, Alejandro Alvarez-Arce, M. Therese Davis, Kelly N. Araujo, Christine E. Delligatti, Eby Edassery, Jonathan A. Kirk, Rishi Arora, and David Y. Barefield Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation Am J Physiol Heart Circ Physiol, published August 5, 2024. DOI: 10.1152/ajpheart.00148.2024

In our latest episode, Executive Editor Kara Hansell Keehan interviews lead author Dr. Michaela Patterson and first author Kaelin Akins (both at the Medical College of Wisconsin) along with expert Dr. Ana Vujic (University of Cambridge) about the new study by Akins et al. Given that the heart has limited regenerative potential, repairing damage to cardiomyocytes after a heart attack is particularly challenging. Cardioregeneration researchers worldwide are searching for potential targets that can stimulate cardiomyocyte proliferation and cardiac regeneration. However, because cardiomyocytes can undergo incomplete cell division, multinucleation, and polyploidization, it is difficult to study true cardiomyocyte proliferation. Akins et al. examined the effect of Runx1 on cardiomyocyte cell cycle during postnatal development and cardiac regeneration using cardiomyocyte-specific gain- and loss-of-function mouse models. Listen now to learn more about how the authors determined that Runx1 is sufficient but not required for cardiomyocyte cell cycle activation.   Kaelin A. Akins, Michael A. Flinn, Samantha K. Swift, Smrithi V. Chanjeevaram, Alexandra L. Purdy, Tyler Buddell, Mary E. Kolell, Kaitlyn G. Andresen, Samantha Paddock, Sydney L. Buday, Matthew B. Veldman, Caitlin C. O'Meara, Michaela Patterson Runx1 is sufficient but not required for cardiomyocyte cell-cycle activation Am J Physiol Heart Circ Physiol, published July 21, 2024. DOI: 10.1152/ajpheart.00782.2023

What is the impact of central insulin on muscle sympathetic nerve activity (MSNA) and vascular conductance in the absence of peripheral insulin delivery? Listen as Associate Editor Dr. Jason Carter (Baylor University) interviews authors Neil McMillan and Dr. Jackie Limberg (both at University of Missouri), along with expert Dr. Manda Keller-Ross (University of Minnesota), about the new Short Report by McMillan et al. To gain a better understanding of the central sympathoexcitatory effects of insulin in humans, the authors recruited two groups of young, healthy individuals. One group served as a time control and the other group received intranasal insulin administration. McMillan et al. measured MSNA from the fibular nerve, combined with continuous monitoring of blood pressure and leg blood flow, before and after insulin administration. Limberg, McMillan and co-authors found that only the individuals who received insulin exhibited an increase in efferent sympathetic nervous system activity, which was coupled with peripheral vasoconstriction and increases in arterial blood pressure. How does this research influence our mechanistic understanding of the sympathetic and hemodynamic response to insulin? Listen now to find out.   Neil J. McMillan, Dain W. Jacob, Brian Shariffi, Jennifer L. Harper, Glen E. Foster, Camila Manrique-Acevedo, Jaume Padilla, and Jacqueline K. Limberg Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults Am J Physiol Heart Circ Physiol, published July 3, 2024. DOI: 10.1152/ajpheart.00253.2024

Sometimes experimental results are serendipitous. Listen as Associate Editor Dr. Crystal Ripplinger (University of California, Davis) talks with authors Dr. Nikki Posnack and Devon Guerrelli (both at Children's National Hospital and The George Washington University School of Engineering and Applied Science), along with expert Dr. Silvia Marchiano (University of Washington), about the new research by Guerrelli et al. published in our Call for Papers on Excitation-Contraction Coupling, Electrophysiology, and Arrhythmias. The Posnack Lab typically investigates environmental chemicals and their impact on cardiac function using microelectrode arrays to record electrical signals from human iPS cells. When performing cardiotoxicity experiments, the authors realized that their baseline measurements varied significantly between their different studies, making it difficult to combine datasets. In doing the legwork to identify potential sources of variability and improve their own internal lab protocols, the authors focused on the reproducibility of their experimental measurements using human iPSCs. Listen as we discuss important recommendations for investigators using these cells to improve their experimental reproducibility.   Devon Guerrelli, Jenna Pressman, Shatha Salameh, and Nikki Posnack hiPSC-CM Electrophysiology: Impact of Temporal Changes and Study Parameters on Experimental Reproducibility Am J Physiol Heart Circ Physiol, published June 9, 2024. DOI: 10.1152/ajpheart.00631.2023

Hormone modulation therapy is a growing area of research in cardiovascular science related to a number of factors, such as menopause and andropause, cancers in hormone-producing organs, as well as gender-affirming hormone therapy. So how do scientists and clinicians measure, monitor, and balance applications of hormone therapy? In our latest podcast, Associate Dr. Keith Brunt interviews authors Dr. Chantal Rytz (University of Calgary) and Dr. Sofia Ahmed (University of Alberta), along with expert Dr. Nina Stachenfeld (John B. Pierce Laboratory/Yale School of Medicine) about the recent article by Rytz et al. The authors review the use of estrogen in adult transgender, non-binary and gender diverse individuals who are medically managed with hormone modulation therapy for gender affirmation. Their findings indicate that the rate at which serum estrogen concentrations change may be important in order to optimize cardiovascular health and manage risk factors for obesity, hyperlipidemia, and elevated blood pressure. How should scientists account for and explore the hormone state of individuals within a cardiovascular context to improve the foundation of evidence for hormone modulation therapies for clinicians? Listen and learn more.   Chantal L. Rytz, Keila Turino Miranda, Paul E. Ronksley, Nathalie Saad, Satish R. Raj, Ranjani Somayaji, Sandra M. Dumanski, Heather Ganshorn, Dina N. Greene, David Collister, Amelia M. Newbert, Lindsay Peace, Sofia B. Ahmed Association between Serum Estradiol and Cardiovascular Health among Transgender Adults Using Gender-Affirming Estrogen Therapy Am J Physiol Heart Circ Physiol, published July 15, 2024. DOI: 10.1152/ajpheart.00151.2024

While decreased IL-33 signaling has been associated with preeclampsia, the mechanisms linking this signaling pathway to disease pathophysiology are not well understood. In this episode, Associate Editor Dr. Amanda LeBlanc (University of Louisville) interviews author Dr. Denise Cornelius (University of Mississippi Medical Center) and expert Dr. Stella Goulopoulou (Loma Linda University) about the new research study by Wang et al. Using the Reduced Uterine Perfusion Pressure (RUPP) rat model, the authors found evidence that mechanistically links reduced IL-33 with the inflammatory response and vascular dysfunction present in preeclampsia. Is the IL-33 signaling pathway a possible clinical therapeutic target for the treatment of preeclampsia? Listen now to learn more.   Xi Wang, Corbin Shields, Geilda Tardo, Greg Peacock, Emily Hester, Marissa Anderson, Jan M. Williams, Denise C. Cornelius IL-33 supplementation improves uterine artery resistance and maternal hypertension in response to placental ischemia Am J Physiol Heart Circ Physiol, published April 3, 2024. DOI: 10.1152/ajpheart.00045.2024

In this episode, Associate Editor Dr. Jonathan Kirk (Loyola University Chicago) interviews author Dr. Ed Lesnefsky (Richmond Department of Veterans Affairs Medical Center and Virginia Commonwealth University) and expert Dr. Chi Fung Lee (Oklahoma Medical Research Foundation) about the new Methods and Resources article by Chen et al. published in our Call for Papers on Impact of Aging on the Cardiovascular System. Lesnefsky and coauthors advanced a technique of isolating mitochondria with an emphasis on integrity of the mitochondrial organelles, their function, purity and characterization in order to develop benchmarks in the field for quality control to support collaboration across laboratories. In their research, the authors focus on mitochondrial-driven age-enhanced disease and on mitochondrial defects due to aging, which potentially increase the susceptibility of elderly patients' hearts to cardiovascular disease. Well-known techniques exist for isolating specific mitochondria populations in mouse hearts. However, Lesnefsky and collaborators found that this resulted in not enough sample to properly interrogate. Therefore Lesnefsky and coauthors investigated whether they could isolate one combined mixed population of mitochondria with a “wild type” physiological model of aging, and whether or not that would that reflect the phenotype. Listen as we discuss the importance of studying mitochondria in an aging model as well as the strategy Lesnefsky and colleagues used to develop their protocol for isolating a mixed mitochondria population. Don't miss the last few minutes of this conversation for pro tips about the value of networking and career-long mentors. Listen now.   Qun Chen, Jeremy Thompson, Ying Hu, and Edward J. Lesnefsky Aging-induced mitochondrial dysfunction: two distinct populations of mitochondria versus a combined population Am J Physiol Heart Circ Physiol, published January 12, 2024. DOI: 10.1152/ajpheart.00363.2023

In our latest episode, Consulting Editor Dr. Kristine DeLeon-Pennell (Medical University of South Carolina) interviews fellow co-authors Dr. Charlotte Usselman (McGill University), Dr. Judy Regensteiner (University of Colorado Anschutz Medical Campus), Dr. Kerrie Moreau (University of Colorado Anschutz Medical Campus), Dr. Austin Robinson (Indiana University Bloomington), Dr. Jesse Moreira-Bouchard (Boston University), and Dr. Quin Denfeld (Oregon Health and Science University) about their recently published guidelines on the use of sex and gender in cardiovascular research. Until recently, the effects of sex and gender in cardiovascular research have been largely ignored in research design and reporting. The result is that women and gender diverse individuals have been understudied in basic and clinical research, leading to a lack of understanding of sex and gender in cardiovascular health and disease. The goal of these guidelines is to provide researchers with practical and actionable advice on best practices to include sex and gender considerations in study design, data collection, analysis, and interpretation. As Dr. Judy Regensteiner points out, “We have to make it doable. We can't just say, ‘Go do this.' We have to show people how to do it.” Ready to get started? Listen now to learn more.   Charlotte W. Usselman, Merry L. Lindsey, Austin T. Robinson, Beth A. Habecker, Chloe E. Taylor, W. David Merryman, Derek Kimmerly, Jeffrey R. Bender, Judith G. Regensteiner, Kerrie L. Moreau, Louise Pilote, Megan M. Wenner, Myles O'Brien, Timur O. Yarovinsky, Nina S. Stachenfeld, Nisha Charkoudian, Quin E. Denfeld, Jesse D. Moreira-Bouchard, W. Glen Pyle, and Kristine Y. DeLeon-Pennell Guidelines on the use of sex and gender in cardiovascular research Am J Physiol Heart Circ Physiol, published December 21, 2023. DOI: 10.1152/ajpheart.00535.2023

After a yearlong hiatus, Behind the Bench is back, listeners! In this episode, we welcome back our B2B co-hosts Dr. Charlotte Usselman and Dr. Tommy Martin, who get the story behind the story from the one and only Dr. DeWayne Townsend, corresponding author of the recently published study by Stevens et al. Trust me, you are going to love listening to DeWayne talk about science! As DeWayne rightly points out, if we want to understand a disease before it's a disease, we have to model it in order to figure it out. From the “dastardly Krebs cycle” to grinding up hearts and shouting “fire in the hole!” before using the mouse heart pulverizer (it's a thing), Dewayne brings to this conversation his best science sound effects, wise insights, and a friendly PSA to contact your Congressional representatives and advocate for science funding. We discuss the resiliency of physiology and the redundancies in the heart that enable scientists to knockout things thought to be important, and as DeWayne points out, the body can still handle it. We cover DeWayne's interesting path from vet school to cardiovascular physiology, and his best advice to trainees. How do you deal with being wrong most of the time? According to DeWayne, when another beautiful hypothesis is slain by data, push on! It is a slog. Keep going and try to find a way to move the needle. While you're at it, DeWayne suggests that you learn how to fix your own equipment, try not to drink too much caffeine, and be inspired by other scientists, especially when that scientist is your Dad.   Jackie A. Stevens, Tyler C. Dobratz, Kaleb D. Fischer, Alexandria Palmer, Kira Bourdage, Anne J. Wong, Hector Chapoy-Villanueva, Daniel J. Garry, Julia C. Liu, Matthew W. Kay, Sarah Kuzmiak-Glancy, and DeWayne Townsend Mechanisms of reduced myocardial energetics of the dystrophic heart Am J Physiol Heart Circ Physiol, published January 22, 2024. DOI: 10.1152/ajpheart.00636.2023

In our latest episode, Associate Editor Dr. Amanda LeBlanc (University of Louisville) interviews author Prof. Pietro Modesti (University of Florence) and expert Dr. Alexandre da Silva (University of Mississippi Medical Center) about the new study by Pellegrino et al. that investigated the pattern of intraventricular hemodynamic forces associated with left ventricular function in women with uncomplicated twin pregnancy. The authors found that, in twin pregnancy, hemodynamic forces misalignment in the first trimester precedes a slight temporary decrease in left ventricular systolic function in the second trimester. In the third trimester, a rightward shift of the end diastolic pressure relationship (EDPR) was, in fact, associated with a realignment of hemodynamic forces and normalization of ventricular contractility indices. Why is twin pregnancy an ideal physiological condition to study increased ventricular workload over time? Listen to this insightful conversation and find out.   Alessio Pellegrino, Loira Toncelli, Lucia Pasquini, Giulia Masini, Federico Mecacci, Gianni Pedrizzetti, and Pietro Amedeo Modesti Left ventricular remodeling in twin pregnancy, noninvasively assessed using hemodynamic forces and pressure-volume relation analysis: prospective, cohort study Am J Physiol Heart Circ Physiol, published January 23, 2024. DOI: 10.1152/ajpheart.00699.2023

Ready Player One? In our latest episode, Dr. Keith Brunt (Dalhousie University) interviews lead author Dr. Joanne DiFrancisco-Donoghue (New York Institute of Technology) and expert Dr. Saurabh Thosar (Oregon Health and Science University Hospital) about a new article published in the AJP-Heart and Circ Call for Papers on Exercise, Physical Activity, and Cardiovascular Health. DiFrancisco-Donoghue et al. raise an important question about the risk for college level e-sport athletes, professionals, and recreational gamers to develop deep vein thromboses. Using Doppler ultrasound recordings of blood flow velocity and volume, the authors found a decrease in both measures when e-sport play was interrupted with a 6-minute walk. DiFrancisco-Donoghue and co-authors found a similar decrease when e-sport athletes wore compression sleeves during play. Could either a break in play for a brief walk or wearing compression stockings help e-sport athletes avoid the risk of deep vein thrombosis caused by prolonged sitting? What effects might this have on executive function, improvement in game play, and for that matter, sleep? If you are a recreational gamer or hoping to go professional, a casual e-sports spectator, or even an active member of the military sitting for prolonged periods of time, you don't want to miss this engaging and enlightening episode! Listen now.   Joanne DiFrancisco-Donoghue, Kelly Borges, Timothy Li, Olivia Ballone, Hallie Zwibel, and Peter C. Douris Reducing thrombotic risks in video gamers: investigating the benefits of walking and compression sleeves on blood hemodynamics Am J Physiol Heart Circ Physiol, published February 8, 2024. DOI: 10.1152/ajpheart.00669.2023     I Spy Physiology Blog by Erica Roth How Can Walking and Wearing Socks Help Video Gamers?

What is the relationship between cardiovascular developmental programming and the risk of stroke later in life? Listen as Guest Editor Dr. Helen E. Collins (University of Louisville) interviews author Dr. Nafisa Jadavji (Midwestern University) and expert Dr. Deanne Hryciw (Griffith University) about the latest research by Pull et al. looking at underlying mechanisms associated with a poor-quality diet during pregnancy. One-carbon metabolism is essential for biosynthesis of DNA and proteins, as well as methylation. Jadavji and co-authors demonstrated that maternal dietary deficiency in one-carbon (1C) metabolism, either in folic acid or choline, resulted in reduced cerebral blood flow in adult offspring after an ischemic stroke. Pull et al. focused their investigation on female offspring and identified this effect in 3-month-old offspring but not 11-month-old offspring. The results point to the key role that maternal diet has in early life programming, fetal development, and long-term cerebrovascular health. Are there many downstream pathways that are altered by one-carbon metabolism deficiencies? Is there a negative impact of folic acid over-supplementation? Listen now to find out.   Kasey Pull, Robert Folk, Jeemin Kang, Shaley Jackson, Brikena Gusek, Mitra Esfandiarei, and Nafisa M. Jadavji Impact of maternal dietary folic acid or choline dietary deficiencies on vascular function in young and middle-aged female mouse offspring after ischemic stroke   Am J Physiol Heart Circ Physiol, published October 30, 2023. DOI: 10.1152/ajpheart.00502.2023

Given that there appears to be variation in significant risk to the cardiovascular system following SARS-CoV2 infection with regard to age and sex, the latest study by Rouhana et al. provides a foundation for studying sex differences with a preclinical model of infection to the direct exposure to SARS-CoV-2 and the impact on the myocardium of ferrets. Listen as Associate Editor Dr. Keith Brunt (Dalhousie University) interviews authors Dr. Alyson Kelvin (University of Saskatchewan) and Dr. Glen Pyle (University of Guelph) along with expert Dr. Susan Cheng (Cedars-Sinai Smidt Heart Institute). The authors identified that phosphokinase expression, normally associated with cardiac stress remodeling, is distinct by time and sex effects. Additionally, the authors found that inflammatory patterns of macrophage markers showed inherent sex differences in immune responses at the level of the myocardium. Why are ferrets a such a useful preclinical model for understanding SARS-CoV2 infection? How do immune inflammatory responses differ by sex, timing, and age? As Dr. Brunt points out, “There is power in observation, collaboration, and when it comes to bugs and bodies…it's physiology.” Read the paper, listen to this podcast, and find out more.   Sarah Rouhana, Kathy Jacyniak, Magen E. Francis, Darryl Falzarano, Alyson A. Kelvin, W. Glen Pyle Sex differences in the cardiac stress response following SARS-CoV-2 infection of ferrets Am J Physiol Heart Circ Physiol, published October 18, 2023. DOI: 10.1152/ajpheart.00101.2023

What does a mouse heart have to do with an M&M candy (the regular kind, not the peanut variety)? In our latest episode, Associate Editor Dr. Crystal Ripplinger (University of California, Davis) interviews author Dr. Tim Domeier (University of Missouri) and expert Dr. DeWayne Townsend (University of Minnesota) about the recent study by Haffner et al et al. The authors examined cardiac calcium mishandling and damage in the setting of Duchenne muscular dystrophy (DMD). Using a genetic mouse model of DMD crossed with a mouse that expresses a genetically encoded calcium indicator, Domeier and colleagues investigated changes in intracellular calcium handling in response to increased preload. The unexpected finding was that after the acute preload challenge, many of the cells were missing-in-action. What was going on with these missing cells? Listen as we talk about how individual dystrophic cells blow up if stretched too far, and why pointing microscopes in different directions might be the next step to overcome optical imaging challenges. Don't miss this episode – the enthusiasm for science, tiny pumping mouse hearts, and squishy cells is contagious!   Vivian Haffner, Zahra Nourian, Erika M. Boerman, Michelle D. Lambert, Laurin M. Hanft, Maike Krenz, Christopher P. Baines, Dongsheng Duan, Kerry S. McDonald, Timothy L. Domeier Calcium handling dysfunction and cardiac damage following acute ventricular preload challenge in the dystrophin-deficient mouse heart Am J Physiol Heart Circ Physiol, published October 18, 2023. DOI: 10.1152/ajpheart.00265.2023

People living with HIV have an increased risk of developing cardiovascular disease, including coronary artery disease. Until now, it has been unclear why. In this episode, Guest Editor Dr. Ashley Walker (University of Oregon) interviews author Dr. Efthymios Ziogos (Johns Hopkins Medicine) and expert Dr. Jennifer Williams (McMaster University) about the recent study by Ziogos et al. published in the Call for Papers Impact of Aging on CV System. Ziogos and co-authors used advanced MRI to assess coronary endothelial function noninvasively and without contrast in order to compare endothelial-dependent vasoreactive responses in coronary arteries to isometric handgrip exercise, both in people living with HIV and HIV negative individuals. The authors found that coronary endothelial function was impaired in people living with HIV, compared to HIV negative individuals. While it is known that there is a negative correlation between age and coronary endothelial function in HIV negative individuals, the authors found no correlation between age and endothelial function in HIV positive individuals, suggesting early vascular aging in individuals with HIV. This study is truly an example of an important research question that went unaddressed until recently because of the need for the advanced measurement techniques used by Ziogos and collaborators. While there is still much to learn about HIV, this research offers new insights into the potential causes of increased coronary artery disease in people living with HIV, and provides new avenues for preventive cardiology research in this population. Listen now to find out more.   Efthymios Ziogos, Yaa A. Kwapong, Robert G. Weiss, Michael Schär, Todd T. Brown, Shashwatee Bagchi, Alborz Soleimanifard, Tarek Harb, Damani A. Piggott, Gary Gerstenblith, Thorsten M. Leucker, Allison G. Hays   Coronary Artery Endothelial Function and Aging in People with HIV and HIV-Negative Individuals   Am J Physiol Heart Circ Physiol, published October 9, 2023. DOI: 10.1152/ajpheart.00143.2023

What does it sound like when a young researcher meets one of his science heroes for the first time? Listen to this episode of The AJP-Heart and Circ Podcast to find out. Associate Editor Dr. Keith Brunt (Dalhousie University) interviews author Dr. Holger Burchert (University of Basel) and leading expert Dr. William Stringer (Lundquist Institute at Harbor-UCLA Medical Center) about a new Methods and Resources article published by Burchert and Klimpel as part of the recent Call for Papers on Exercise, Physical Activity, and Cardiovascular Health. The article by Burchert et al. is an important contribution of methodological advancement built upon a foundation of established literature, dating back to Fick's Principle, which first appeared as a two-paragraph conference abstract published in German in 1870 and later translated by The New England Journal of Medicine in 1948. Fick was the first to realize that cardiac output is equal to oxygen consumption divided by the arterial mixed venous oxygen content difference, allowing the first accurate determination of cardiac output. While non-invasive measurements of oxygen consumption and heart rate are now routine, sampling arterial and mixed venous blood is inherently challenging. This makes finding non-invasive techniques for these measurements incredibly important. Enter the OG of the linear method for determining the arterial mixed venous oxygen content difference, Dr. William Stringer. In his seminal 1997 article published in the Journal of Applied Physiology, “Cardiac output estimated noninvasively from oxygen uptake during exercise”, Dr. Stringer found that the arterial mixed venous oxygen content difference during incremental exercise can be estimated because it behaves in a predictable, linear fashion, thus avoiding the difficult blood sampling. Reading the article by Stringer et al., which was referenced in the CPET (cardiopulmonary exercise testing) machine manual Burchert used during his PhD work, sparked Burchert's interest to investigate the literature and ultimately build on Stringer's methodological approach by collaborating with this former school friend Dr. Fabian Klimpel. Burchert et al. found that a 3rd order polynomial S-curve described the arterial mixed venous oxygen content difference slightly better. More importantly, the authors also determined that the inflection point of this function could be related to the first ventilatory threshold and the inflection point of the oxygen dissociation curve. Why is this important? A deeper understanding of the mechanisms behind the s-shaped response has potential clinical translation, as the method could be further developed by tailoring it to individual patients. Listen as we discuss why it is important for early career researchers “to look back in order to look forward,” to use collaborators from other disciplines to support thinking creatively about cardiovascular physiology, and to align with mentors who facilitate young careers through constructive peer review and publication.   Holger Burchert and Fabian Klimpel Revisiting cardiac output estimated noninvasively from oxygen uptake during exercise: an exploratory hypothesis-generating replication study Am J Physiol Heart Circ Physiol, published August 25, 2023. DOI: 10.1152/ajpheart.00330.2023   William W. Stringer, James E. Hansen, and K. Wasserman Cardiac output estimated noninvasively from oxygen uptake during exercise J Appl Physiol, published March 1, 1997. DOI: 10.1152/jappl.1997.82.3.908   Fick, A On the Measurement of the Blood Quantum in the Ventricles of the Heart. Bauhaus-Universität Weimar, 1870, p. 16.

Come for the yoga metaphors, stay for the science. In this episode, Associate Editor Dr. Keith Brunt (Dalhousie University) interviews author Dr. Stacy Hunter (Texas State University) and expert Dr. Annet Kirabo (Vanderbilt University) about the new study by Hunter et al., which examined the impact of hot yoga on sodium-induced pressor responses and endothelial function of Black women. In a randomized control trial that combined the thermal stress of hot yoga and a salt challenge, the authors investigated human homeostatic regulation in terms of whole-body physiology, cardiorenal responses, physical activity, and the exercise environment. In their study, Hunter and collaborators controlled for sodium intake by separating participants into high and low sodium groups, with pre and post analyses of body mass, ambulatory blood pressure, urinalysis, and flow mediated dilation. The authors found that participants who actively engaged in hot yoga showed increased flow mediated dilation but not increased blood pressure. Why did the authors use a 3-day, not 5-day, hot yoga exercise protocol? What insights can be gained about salt-sensitivity in Black women from this study, which incorporated a form of exercise that activated both thermoregulation and the parasympathetic nervous system? Listen to find out. Stacy D. Hunter, Stavros A. Kavouras, and Mitra Rahimi Exploring heated exercise as a means of preventing the deleterious effects of high-sodium intake in Black women Am J Physiol Heart Circ Physiol, published May 4, 2023. DOI: 10.1152/ajpheart.00699.2022

What is the impact of female sex hormones on obesity, diabetes, and vascular dysfunction? In this episode, Deputy Editor Dr. Zam Kassiri (University of Alberta) interviews authors Dr. Bruna Visniauskas and Dr. Minolfa Prieto (both at Tulane University School of Medicine), along with expert Dr. Glen Pyle (IMPART Network at Dalhousie Medicine) about the new study by Visniauskas et al. Using a long-term high fat diet mouse model of type 2 diabetes, the authors found that male mice had higher increases in plasma levels of prorenin and renin soluble prorenin receptor and angiotensin 2, which was also associated with hypertension and carotid artery stiffness, compared to female mice. This led Visniauskas et al. to interrogate a potential causal role of soluble prorenin receptor in development of the diabetes phenotype in the mice fed the high fat diet. Since female mice were less prone to the diabetic phenotype than males, the authors ovariectomized female mice to interrogate the role of estrogen in the development of the diabetes phenotype. Prieto, Visniauskas, and co-authors observed the Type 2 diabetes phenotype in both males and ovariectomized females but not intact females. How does dipping vs. non-dipping hypertension factor in? Will the soluble prorenin receptor emerge as a more reliable biomarker for vascular pathologies related to diabetes? Listen and find out.   Bruna Visniauskas, Virginia Reverte, Caleb M. Abshire, Benard O. Ogola, Carla B. Rosales, Michelle Galeas-Pena, Venkata N. Sure, Siva S. V. P. Sakamuri, Nicholas R. Harris, Isabella Kilanowski-Doroh, Alexandra B. Mcnally, Alec C. Horton, Margaret Zimmerman, Prasad V. G. Katakam, Sarah H. Lindsey, and Minolfa C. Prieto High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet Am J Physiol Heart Circ Physiol, published April 25, 2023. DOI: 10.1152/ajpheart.00638.2022

When is it safe to have surgery after COVID? Listen as Associate Editor Dr. Jason Carter (Baylor University) interviews lead author Dr. Anai Kothari (Medical College of Wisconsin) and leading expert Dr. Michael Joyner (Mayo Clinic) about the groundbreaking new research study by SenthilKumar et al. that evaluated how pre-operative COVID infection might affect a patient's risk of post-operative major adverse cardiovascular and cerebrovascular events (MACE) by analyzing data from 457,804 patients within the National COVID Cohort Collaborative (N3C) Data Enclave. In fact, it was a surgical operation in October 2020 that inspired Dr. Kothari and collaborators to consider how the stress of surgery combined with the potential end-organ changes that happen with prior COVID infection would impact surgical outcomes. If patients had a prior history of COVID followed by a subsequent non-emergency surgery, the authors found a 12% increase in overall risk of having a major adverse cardiovascular or cerebrovascular event after surgery. The authors found that most patients had surgery more than 8 weeks after COVID infection. However, if patients had surgery in the first 4 weeks after COVID infection, there was a slight increase in the number of post-surgical MACE. Disease severity had a major impact on post-surgical incidence of MACE. In contrast, vaccination against COVID decreased the risk of MACE without increasing the risk of any post-operative negative outcomes that the group assessed. Listen as these experts discuss surgical timing and the role of COVID vaccines to not only reduce risk of post-surgical MACE for patients but also to protect immunocompromised individuals in the greater population.   Gopika SenthilKumar, Nathaniel B. Verhagen, Salma A. Sheriff, Xin Yang, Carlos E. Figueroa Castro, Aniko Szabo, Brad W. Taylor, Njeri Wainaina, Kathryn Lauer, Jon C. Gould, and Anai N. Kothari on behalf of the N3C Consortium Preoperative SARS-CoV-2 infection increases risk of early postoperative cardiovascular complications following noncardiac surgery Am J Physiol Heart Circ Physiol, published April 25, 2023. DOI: 10.1152/ajpheart.00097.2023

What does being a good ally look like? In a new Perspective, authors Dr. Karla Haack (Merck), Dr. Austin Robinson (Auburn University), Dr. Dexter Lee (Howard University College of Medicine), Dr. Keisa Mathis (University of North Texas Health Science Center), and Dr. Junie Paula Warrington (University of Mississippi Medical Center) discuss how the American Physiological Society (APS) can promote Black physiologists and support them in the challenges they face. The authors sat down with The AJP-Heart and Circ Podcast for a wide-ranging interview at the cross-section of social justice and science. The authors feel that APS has a unique opportunity as an international organization to be at the forefront of supporting Black physiologists and boosting the success of underrepresented minority APS members. As the authors note, Black students are often first-generation college students, and therefore mentoring and K-12 physiology outreach are critically important. Robinson et al. discuss issues around the underrepresentation of Black physiologists at the faculty level, as well as challenges with access to pilot funding to support Black early career researchers. The authors discuss many actionable steps, such as inviting Black physiologists to be scientific co-investigators and co-authors on studies, as well as partnering with Historically Black Colleges and Universities to help build a pipeline of future Black physiologists. The authors take-home message? Don't underestimate the power of being an ally and using your voice to amplify the voices of Black physiologists. As Dr. Junie Paula Warrington stated, “One person at a time, we can make a huge impact.”   Austin T. Robinson, Nathaniel D. M. Jenkins, Sofia O. Sanchez, Karla K. V. Haack, Dexter L. Lee, Keisa W. Mathis, and Junie P. Warrington Supporting and promoting Black physiologists: how can the APS help? Am J Physiol Heart Circ Physiol, published May 4, 2023. DOI: 10.1152/ajpheart.00082.2023

How can researchers capture the most accurate demographic data possible on intake surveys for human participant studies? Listen as author and moderator Dr. Karla Haack (Merck) interviews co-authors Dr. Jesse Moreira (Boston University) and Dr. Troy Roepke (Rutgers, The State University of New Jersey) about their recent Perspective regarding how researchers can do inclusive and precise research with an open mindset in order to avoid excluding groups of people when developing survey demographic questions for human participant research studies. In their article, Moreira et al. offer actionable steps to develop inclusive survey language for the LGBTQIA2S+ community with precise science at the forefront. The goal is to increase participation among LGBTQIA2S+ people and collect demographic data in a manner that does not alienate or marginalize anyone who may already be experiencing marginalization. The authors make the case that researchers should not be afraid to be precise, and careful attention to language does not involve extra effort on the part of researchers. For example, researchers can include a semi-exhaustive list of gender along with a fill-in “I self-describe as" field. If researchers introduce themselves using their own preferred pronouns, the authors explained, and then ask what pronouns study participants prefer to use, it can make an enormous difference to the sense of belonging for potential study participants. Words help science to be more exact. Simply stated, words matter. Listen to learn more.   Jesse D. Moreira, Karla Haack, Vee White, Melissa L. Bates, Deepa M. Gopal, and Troy A. Roepke Importance of survey demographic questions to foster inclusion in medicine and research and reduce health inequities for LGBTQIA2S+ individuals Am J Physiol Heart Circ Physiol, published May 12, 2023. DOI: 10.1152/ajpheart.00152.2023

Heart failure with preserved ejection fraction (HFpEF) is, in many ways, a fascinating tale of modern cardiovascular medicine that, according to lead author Dr. Joshua Hare (University of Miami Miller School of Medicine), has taught cardiovascular researchers and clinicians a lot of humility. Understanding HFpEF in a variety of animal models has led to a paradigm shift away from heart failure linked to low ejection fraction. In this episode Associate Editor Dr. Jonathan Kirk (Loyola University Chicago Stritch School of Medicine) interviews Dr. Hare along with expert Dr. Julie McMullen (Baker Heart and Diabetes Institute, Melbourne, Australia) about the latest study by Kanashiro-Takeuchi et al. The Hare Lab was originally attracted to a cardiometabolic model of HFpEF pioneered by Dr. Joseph Hill, because in a large proportion of human patients, HFpEF is due to metabolic syndrome, which is a combination of obesity, diabetes, and hypertension. Armed with the ability to create this cardiometabolic HFpEF model, Hare and co-authors decided to test growth hormone-releasing hormone-agonist using a powerhouse of methods to determine if exercise intolerance could be improved. Kanashiro-Takeuchi et al. found that diastolic function and exercise performance improved, and myocyte hypertrophy and fibrosis were restored. Essentially all of the features of cardiometabolic HFpEF responded to treatment with GHRH-agonist. The authors did not see a reduction in blood pressure or weight, indicating a direct myocardial effect. In a wide-ranging discussion that touches on skeletal muscle, aging, sarcomeric proteins, and the technical complexities of running titin gels and PV loops, our experts explain why HFpEF is such a challenging syndrome to treat and why this translational research is so important. Listen now.   Rosemeire M. Kanashiro-Takeuchi, Lauro M. Takeuchi, Raul A. Dulce, Katarzyna Kazmierczak, Wayne Balkan, Renzhi Cai, Wei Sha, Andrew V. Schally, Joshua M. Hare Efficacy of a Growth Hormone-Releasing Hormone Agonist in a Murine Model of Cardiometabolic Heart Failure with Preserved Ejection Fraction Am J Physiol Heart Circ Physiol, published April 25, 2023. DOI: 10.1152/ajpheart.00601.2022.

“You cannot make good predictions for patients until you understand the physiology,” stated Dr. Kristian Becker (Icahn School of Medicine at Mount Sinai). Becker and co-authors demonstrated for the first time echocardiographic evidence of a transition in the left ventricular vortex patterns of the heart from the newborn period to the adult period. Listen as Associate Editor Dr. Amanda LeBlanc (University of Louisville) interviews Dr. Becker and expert Dr. Ann Chiao (Oklahoma Medical Research Foundation) about how the authors used vector flow mapping to identify changes in cardiovascular efficiency, which were marked by increased energy loss during infancy. In this Rapid Report, which was published in the Call for Papers on the Impact of Aging in the Cardiovascular System, Becker and co-authors found that one early diastolic vortex in newborns transitions to two early diastolic vortices by 2 years of age. Vector flow mapping is an echocardiographic technique that combines doppler ultrasound and blood speckle tracking to follow the direction and velocity of blood in the heart. As a bridge between cardiac MRI and traditional ultrasound, vector flow mapping gives researchers and pediatric cardiologists an understanding of how blood is flowing in the heart and whether heart defects or cardiomyopathies affect blood flow. Given that the heart is a master adapter—it grows from about the size of a walnut at birth to the size of a peach in adulthood—mapping energy loss when the heart is transitioning in size and shape with age is critically important to clinicians. The authors want to take their research from bench to bedside, and back to the bench, for a complete understanding of the heart. Listen now to find out more.   Kristian C. Becker, Jennifer Cohen, Jon D. Nyce, Jen Lie Yau, Santosh C. Uppu, Partho P Sangupta, and Shubhika Srivastava Age Related Changes in Left Ventricular Vortex and Energy Loss Patterns: From Newborns to Adults Am J Physiol Heart Circ Physiol, published March 10, 2023. DOI: 10.1152/ajpheart.00002.2023

While anxiety disorders are the most common mental health issue in the United States and are known to increase the risk of hypertension and cardiovascular disease, the links between anxiety, muscle sympathetic nerve activity and blood pressure have not been interrogated to date. Listen as host Dr. Megan Wenner (University of Delaware) interviews author Dr. Jeremy Bigalke (Montana State University) and expert Dr. Jody Greaney (The University of Texas at Arlington) about the latest research by Bigalke et al. Leveraging a large dataset of 88 young adults, the authors examined the relationship between anxiety, blood pressure and resting muscle sympathetic nerve activity using seated blood pressure measurements and the Spielberger State/Trait Anxiety Inventory, which denotes an individual's propensity for anxiousness along a spectrum. After controlling for several key characteristics including age and sex, Bigalke and collaborators determined that there was a modest relationship between anxiety symptom severity and resting sympathetic outflow in young otherwise healthy adults. Do these changes in sympathetic regulation of blood pressure indicate a significantly increased long-term risk for cardiovascular comorbidities later in life? Our experts discuss this work in the context of the dramatic increase in patients diagnosed with anxiety and associated mental health disorders during the COVID pandemic, and delve into the consideration of sex as a biological variable in the prevalence of anxiety diagnoses among women compared with men. Why are multi-center collaborations critical to the future of research linking subjective psychological characteristics to physiological outcomes? Listen and find out.   Jeremy A. Bigalke, John J. Durocher, Ian M. Greenlund, Manda Keller-Ross, and Jason R. Carter Blood pressure and muscle sympathetic nerve activity are associated with trait anxiety in humans Am J Physiol Heart Circ Physiol, published February 17, 2023. DOI: 10.1152/ajpheart.00026.2023

What effects do COVID symptomology and time since diagnosis have on cardiac autonomic function? Listen as Guest Editor Dr. Tiago Peçanha (Manchester Metropolitan University) interviews first author Dr. Rachel Skow (The University of Texas at Arlington) and expert Dr. Chris Minson (University of Oregon) about the research by Skow et al, aimed at better understanding the mechanisms underlying increased cardiovascular risk associated with COVID infection. Skow and co-authors set out to study the cardiovascular health of young adults diagnosed during the early variants of COVID-19 compared to those who had never had COVID. The authors measured resting cardiac baroreflex sensitivity and heart rate variability in order to determine whether having COVID impacted these measures of cardiac autonomic function. Their results were very encouraging: Skow et al. did not show an impact of COVID-19 on cardiac baroreflex sensitivity nor heart rate variability. The authors also studied the impact of symptomology by stratifying their study participants with COVID into different groups – comparing those with persistent symptoms at the time of their assessment to those who did not have persistent symptoms. The authors found no difference between these groups on markers of cardiac autonomic function. However, when Skow and co-authors analyzed their COVID participant group according to date of diagnosis, the authors found better cardiac autonomic function in participants who were studied after a longer time since diagnosis had elapsed, indicating a potential transient effect on cardiac autonomic function in these otherwise healthy young adults. Listen as we discuss the need to study more subjects overall, particularly more diverse patient populations especially in terms of age and co-morbidities, in order to better understand the time course of cardiovascular and autonomic dysregulation during and after COVID.   Rachel J. Skow, Nicole A. Garza, Damsara Nandadeva, Brandi Y. Stephens, Alexis N. Wright, Ann-Katrin Grotle, Benjamin E. Young and Paul J. Fadel Impact of COVID-19 on cardiac autonomic function in healthy young adults: potential role of symptomatology and time since diagnosis Am J Physiol Heart Circ Physiol, published November 21, 2022. DOI: 10.1152/ajpheart.00520.2022

What happens when your hypothesis is…wrong? Listen as host Dr. Dan Tyrrell (University of Michigan Medical School) interviews lead author Dr. Julie Freed (Medical College of Wisconsin) and content expert Dr. Chi Fung Lee (Oklahoma Medical Research Foundation) about the new Rapid Report by SenthilKumar et al., which investigated the function of estradiol on human microvessels. In contrast to their hypothesis, Freed and co-authors found that exogenous estradiol treatment of arterioles isolated from both young and older women promoted endothelial dysfunction. In addition, the authors found that estradiol treatment of microvessels isolated from men led to endothelial and smooth muscle dysfunction. The timing of this article is key, given the new AJP-Heart and Circ requirements launched in January 2023 for considering sex as a biological variable. Freed and collaborators originally hypothesized that estrogen may activate the enzyme sphingosine kinase, and therefore mediate cardioprotective effects in the vasculature. However, that was not the case. Freed summed up their surprising results: “There is something going on here. Do we have all the answers yet? No. But we're going to figure this out.” Listen as we discuss the complexities of human tissue banking, and the grit and flexibility necessary for all researchers to follow the science where it leads.   Gopika SenthilKumar, Boran Katunaric, Henry Bordas-Murphy, Micaela Young, Erin L. Doren, Mary E. Schulz, Michael E. Widlansky, and Julie K. Freed 17β-Estradiol Promotes Sex-Specific Dysfunction in Isolated Human Arterioles Am J Physiol Heart Circ Physiol, published January 6, 2023. DOI: 10.1152/ajpheart.00708.2022

Is inflammation the driving force for diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF)? In this episode, Deputy Editor Dr. Zamaneh Kassiri (University of Alberta) interviews author Dr. Thassio Mesquita (Cedars-Sinai Medical Center) and expert Dr. Darryl Davis (University of Ottawa Heart Institute) about the research by de Couto et al. Using a Dahl salt-sensitive rat model of HFpEF, the authors delivered cardiosphere-derived cells (CDCs) via intracoronary injection into the microcirculation. After 2 weeks of treatment with CDCs, the hypertensive rats showed improved endothelial-dependent vasodilation, reduced oxidative stress, restored expression of endothelial nitric oxide synthase, and reduced inflammation. Overall, the authors found that CDCs made significant improvements in the cardiovascular health of hypertensive rats with HFpEF. What is the therapeutic potential of cardiosphere-derived cells for treating heart failure with preserved ejection fraction (HFpEF)? Listen and learn more.   Geoffrey de Couto, Thassio Mesquita, Xiaokang Wu, Alex Rajewski, Feng Huang, Akbarshakh Akhmerov, Na Na, Di Wu, Yizhou Wang, Liang Li, My Tran, Peter Kilfoil, Eugenio Cingolani, and Eduardo Marbán Cell therapy attenuates endothelial dysfunction in hypertensive rats with heart failure and preserved ejection fraction Am J Physiol Heart Circ Physiol, published October 17, 2022. DOI: 10.1152/ajpheart.00287.2022

The world of cardiac electrophysiology can be daunting, so we suggest that you listen to this insightful conversation with the experts. Deputy Editor Dr. Zamaneh Kassiri (University of Alberta) interviews authors Dr. Crystal Ripplinger (University of California Davis), Dr. Nikki Posnack (The George Washington University and Children's National Hospital), Dr. Alexey Glukhov (University of Wisconsin-Madison), Dr. Matthew Kay (The George Washington University), Dr. Carol Ann Remme (Amsterdam University Medical Centers), and Dr. Alex Quinn (Dalhousie University) about their comprehensive new guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals. This thorough guidelines article by Ripplinger et al. covers many common electrophysiology approaches used in the field at the tissue level, whole heart level, and in vivo measurements. In addition, the authors dive into what parameters investigators may want to measure, providing helpful and clear guidance on how to calculate such parameters and what those parameters might mean in terms of electrophysiology remodeling and arrhythmia propensity. Both senior investigators and trainees will find these guidelines approachable and useful. Listen and learn from the experts.   Crystal M. Ripplinger, Alexey V. Glukhov, Matthew W. Kay, Bastiaan J. Boukens, Nipavan Chiamvimonvat, Brian P. Delisle, Larissa Fabritz, Thomas J. Hund, Bjorn C. Knollmann, Na Li, Katherine T. Murray, Steven Poelzing, T. Alexander Quinn, Carol Ann Remme, Stacey L. Rentschler, Robert A. Rose, and Nikki G. Posnack Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals Am J Physiol Heart Circ Physiol, published November 21, 2022. DOI: 10.1152/ajpheart.00369.2022.

Is a pre-treatment with low dose cyclosporine immunosuppression necessary to limit allogeneic cardiosphere-derived cell therapy rejection? Listen as Associate Editor Dr. Amanda LeBlanc (University of Louisville) interviews senior author Dr. John Canty (University of Buffalo) and expert Dr. Fabio Recchia (Scuola Superiore Sant'Anna; Temple University) about the latest study by Techiryan et al. In this blinded randomized controlled trial using swine, the authors tested whether low dose cyclosporine could be initiated at the time of reperfusion. In contrast to previous studies, the authors were not able to reproduce the cardioprotective effects demonstrated by allogeneic CDCs without cyclosporine. Conducting large animal studies is like conducting an orchestra, with many members of the lab playing specific roles. What is it like to take a pig with a balloon occluder in their anterior descending artery 100 yards down the hall to the imaging center for a CT scan while the animal is having an acute infarction? Listen as we discuss the challenges of blinded preclinical studies and how large animal studies can offer unique preclinical insights that may translate more effectively to clinical treatment of cardiovascular disease.   George Techiryan, Brian R. Weil, Rebeccah F. Young, and John M. Canty Jr. Widespread intracoronary allogeneic cardiosphere-derived cell therapy with and without cyclosporine in reperfused myocardial infarction Am J Physiol Heart Circ Physiol, published October 17, 2022. DOI: 10.1152/ajpheart.00373.2022

When Dr. Ashley Walker (University of Oregon) began to study sex differences with vascular aging and cognitive decline, she and her team went to the literature for guidance on research study design to account for the confounding variable of estrous cycle in young female mice. Problem: There were no recommendations in the literature. Solution: The Walker Lab got to work. In our latest episode, Dr. Amanda LeBlanc (University of Louisville) interviews lead author Dr. Ashley Walker and first author Ms. Mackenzie Kehmeier (University of Oregon), along with expert Dr. Sarah Lindsey (Tulane University) about the novel study by Kehmeier et al. – the first of its kind – to show that the impact of estrogen on vascular stiffness changes with each day of the female mouse estrous cycle. The authors found that estrous phase was associated with lower in vivo large artery stiffness in mice, but ex vivo resistance artery endothelial function was not different between estrous cycle phases. Kehmeier et al. determined that estrogen receptor expression is modulated by the estrous cycle in an artery dependent manner, which means that estrous cycle phase in young female mice should be considered when measuring in vivo arterial stiffness. What techniques do the authors recommend for other investigators to best determine accurate staging of the estrous cycle? Listen to find out.   Mackenzie N. Kehmeier, Bradley R. Bedell, Abigail E. Cullen, Aleena Khurana, Holly J. D'Amico, Grant D. Henson, Ashley E. Walker In vivo arterial stiffness, but not isolated artery endothelial function, varies with the mouse estrous cycle Am J Physiol Heart Circ Physiol, published October 14, 2022. DOI: 10.1152/ajpheart.00369.2022

Have you ever had an experimental design deviate from expectations? Well, this episode is for you. Associate Editor Dr. Keith Brunt (Dalhousie University) interviews Deputy Editor Dr. Zamaneh Kassiri (University of Alberta) about her recently published article by Hu et al., along with content expert Dr. Joshua Man ( Tufts Medical Center), to discuss how unexpected results and negative findings can, in and of themselves, lead to new discoveries. Kassiri and co-authors used a Cre/lox system to study the role of disintegrin and metalloproteinase-17 (Adam17) in smooth muscle cells (SMC) in a mouse model of atherosclerosis. LDL-deficient mice that consumed a high fat diet had normal skin. However, mice with floxed alleles of Adam17 driven by Sm22alpha developed severe skin lesions. The loss of gene function and Sm22alpha expression was apparent in keratinocytes. Adam17 deletion by a different SMC driver, Myh11-Cre, did not result in skin lesions in the same atherosclerosis model. Staying true to the expression that experience is what you get when you don't get what you want, Hu et al. published their results in the hopes of helping other labs and animal care & use committees avoid similar pitfalls. What are the potential ramifications for cardiovascular researchers, keratinocyte biologists, and dermatologists? Listen and find out.   Mei Hu, Sho Hiroyasu, David J. Granville, Zamaneh Kassiri Implications of Sm22alpha-Cre expression in keratinocytes and unanticipated inflammatory skin lesion in a model of atherosclerosis  Am J Physiol Heart Circ Physiol, published August 31, 2022. DOI: 10.1152/ajpheart.00325.2022

Why do many severe COVID-19 survivors experience exercise intolerance as a lingering consequence of their viral infection? In this episode, Guest Editor Dr. Tiago Peçanha (Manchester Metropolitan University) interviewed lead author Dr. Hamilton Roschel (University of Sao Paulo) and expert Dr. John Durocher (Purdue University Northwest) about the latest study by Longobardi et al., which investigated the impact of previous severe COVID-19 infection on cardiorespiratory responses to a maximal exercise test. The authors enrolled survivors of severe COVID-19 who had previously been admitted to an intensive care unit during the acute phase of their illness in this cross-sectional study within a randomized controlled trial. The authors found that VO2 kinetics were significantly impaired at the onset and recovery phases of the exercise protocol in the COVID survivors. What do these experts think about the central and peripheral factors underlying the exertional intolerance and chronotropic incompetence in COVID survivors? Listen now.   Igor Longobardi, Danilo Marcelo Leite do Prado, Karla Fabiana Goessler, Matheus Molina Meletti, Gersiel Nascimento de Oliveira Júnior, Danieli Castro Oliveira de Andrade, Bruno Gualano, Hamilton Roschel Oxygen uptake kinetics and chronotropic responses to exercise are impaired in survivors of severe COVID-19 Am J Physiol Heart Circ Physiol, published September 2, 2022. DOI: 10.1152/ajpheart.00291.2022

In our latest episode of Behind the Bench from AJP-Heart and Circ, co-hosts Dr. Tommy Martin and Dr. Charlotte Usselman interview bioengineer and first author Dr. Amy Garrett. Dr. Garrett joined the Auckland Bioengineering Institute in 2016, where she completed a Masters in Engineering followed by a PhD. After joining the cardiac energetics group for her post-doc, Dr. Garrett embarked on a research journey tackling the development of the Windkessel loading system for work-loop contractions. What's that, you're wondering? The work-loop calorimeter is an experimental device fine-tuned by the Auckland Bioengineering Institute over the past 20 years. The device performs stress-length work-loops on cardiac trabeculae. It is both fascinating and complicated. Good news: Dr. Garrett explains everything! Find out more about her scientific journey, and why Windkessel loaded loops are important. Listen now. Amy S. Garrett, Denis S. Loiselle, Andrew J. Taberner, June-Chiew Han Slower shortening kinetics of cardiac muscle performing Windkessel work-loops increase mechanical efficiency Am J Physiol Heart Circ Physiol, published August 31, 2022. DOI: 10.1152/ajpheart.00074.2022

What is a cytokine storm in COVID-19 patients and how does it adversely affect organ systems in diabetes patients? In our latest episode, Associate Editor Dr. Keith Brunt (Dalhousie University) interviews lead author Dr. Dinender Singla (University of Central Florida) and expert Dr. Mark Chappell (Wake Forest University) about the new Review by Narasimhulu and Singla on the pathophysiology of the SARS-CoV2 virus as it relates to diabetes. As we now know, the virus enters cells through the angiotensin converting enzyme 2 receptors, which is especially concerning for patients with pre-existing cardiovascular complications and co-morbidities such as diabetes, given that renin-angiotensin system is a driving force of cardiovascular disease. In this insightful and wide-ranging interview, our experts discuss viral variance, sex differences, the need for more sophisticated pre-clinical models, long COVID, and implications for co-morbidity management. Where does the field go from here? Read, listen, learn.   Chandrakala Aluganti Narasimhulu and Dinender K. Singla Mechanisms of COVID-19 pathogenesis in diabetes  Am J Physiol Heart Circ Physiol, published August 4, 2022. DOI: 10.1152/ajpheart.00204.2022

How do the 3 Rs of Research – Refinement, Reduction, Replacement – factor into a methodological paper regarding a novel quantitative method for using an electrocardiogram to determine which animals have infarcts that reflect successful coronary ligation? Listen as Consulting Editor Dr. Ganesh Halade (University of South Florida) interviews lead author and Consulting Editor Dr. Kristine DeLeon-Pennell (Medical University of South Carolina) and content expert Dr. Corey Reynolds (Merck) about the recent work by Broughton et al. What started as an internal project to improve The DeLeon-Pennell Lab's surgical success grew into a research article published as part of a Call for Papers on Innovation in Improving Rigor and Reproducibility in Cardiovascular Research. The DeLeon-Pennell Lab was interested in streamlining infarct size between lab members, students, and technicians during the surgical procedures used for their mouse studies. Aiming for a threshold of 35% infarct size, the DeLeon-Pennell Lab wanted to move beyond looking only at the elevation of the T wave to confirm infarct size. To do so, Broughton et al. designed a new ECG method that provides real-time feedback during the procedure. Broughton et al. found that area under the QRS curve is stronger for predicting successful MI surgeries with an infarct size greater than 35%. This new method will ultimately allow researchers to reduce the time spent performing surgical experiments and the overall number of animals used. Listen now to find out more.   Philip Broughton, Miguel Troncoso, Alexa Corker, Alexus Williams, Dawson Bolus, Gualberto Munoz, Caroline McWhorter, Hallie Roerden, Penny Huebsch, and Kristine Y. DeLeon-Pennell Riding the wave: a quantitative report of electrocardiogram utilization for myocardial infarction confirmation Am J Physiol Heart Circ Physiol, published August 3, 2022. DOI: doi.org/10.1152/ajpheart.00201.2022

Is it bad for our cardiovascular health to “spring forward” into Daylight Saving Time? On March 15, 2022, the U.S. Senate passed the Sunshine Protection Act, which aims to make Daylight Saving Time permanent and eliminate bi-annual seasonal clock changes in the spring and fall. In this episode, Consulting Editor Dr. Austin Robinson (Auburn University) interviews lead author and Associate Editor Dr. Jason Carter (Montana State University) and expert Dr. Josiane Broussard (Colorado State University) about a Perspective by Carter et al. which unpacks the negative impacts on overall cardiovascular health, as well as the increased risks of adverse cardiovascular events associated with changing our clocks between Standard Time and Daylight Saving Time. While the proposed Sunshine Protection Act legislation appears to offer a solution—instituting Daylight Saving Time as the permanent time – both the American Academy of Sleep Medicine and the Society for Research on Biological Rhythms argue that the healthier choice is Standard Time. Studies have shown that the shift to Daylight Saving Time results in increased incidence of myocardial infarction, stroke, and hospital admissions attributed to atrial fibrillation. In addition, the decrease in morning light with Daylight Saving Time has potential adverse effects on mental health, because morning sunshine plays a critical role in synchronizing our internal clocks to avoid circadian misalignment. Could shifting 30 minutes rather than 60 minutes be a reasonable compromise? Listen now to find out.   Jason R. Carter, Kristen L. Knutson, Babak Mokhlesi Taking to “heart” the proposed legislation for permanent daylight saving time Am J Physiol Heart Circ Physiol, published June 13, 2022. DOI: doi.org/10.1152/ajpheart.00218.2022

The eyes are the window to the soul, as the old saying goes, but are the eyes also the window to cardiovascular disease? Diabetic retinopathy is a common diabetic microvascular disease and a leading cause of blindness in diabetes patients worldwide. Defects in the blood-retinal barrier caused by increased production of vascular endothelial growth factor-A isoforms promote angiogenesis and permeability. Listen as Consulting Editor Dr. Shawn Bender (University of Missouri, Columbia) interviews first author Dr. Naseeb Malhi (City of Hope National Medical Center), senior author Dr. David Bates (University of Nottingham), and expert Dr. Jerome Breslin (University of South Florida) about the new study by Malhi et al, which investigated whether serine-arginine-rich protein kinase-1 (SRPK1) inhibition can attenuate the pathophysiology of diabetic retinopathy. The authors conducted a combination of mechanistic in vitro studies using human retinal pigment epithelial cells and studies in type 1 diabetic rats to investigate whether SRPK1 is activated in diabetes, and whether an SRPK1 inhibitor (SPHINX31) switches VEGF splicing in diabetic retinopathy to prevent increased vascular permeability into the retina. The novel intervention design of delivering the SRPK1 inhibitor via eyedrop in the authors' diabetic rat model was used preventatively at the outset of the diabetes phenotype. Does this unique treatment modality offer promise for treating established diabetic retinopathy? Listen and learn.   Naseeb K. Malhi, Claire L. Allen, Elizabeth Stewart, Katherine L. Horton, Federica Riu, Jennifer Batson, Winfried Amoaku, Jonathan C. Morris, Kenton P. Arkill, David O. Bates Serine-arginine-rich protein kinase-1 inhibition for the treatment of diabetic retinopathy Am J Physiol Heart Circ Physiol, published May 10, 2022. DOI: 10.1152/ajpheart.00001.2022

This episode of Behind the Bench with AJP-Heart and Circ is full of connections. Returning co-host Dr. Charlotte Usselman is joined by her new co-host Dr. Tommy Martin. We first met Tommy when we interviewed him last year for Behind the Bench episode 10 as a trainee in the lab of AJP-Heart and Circ Associate Editor Dr. Jonathan Kirk. Jonathan was the original co-host of Behind the Bench along with Dr. Lisandra de Castro Brás. Speaking of Jonathan and Lis… big shout out to the original Behind the Bench co-hosts for their stellar insights and witty humor! Fast forward to the proverbial passing of the Behind the Bench microphone to Charlotte and Tommy and their wide-ranging interview with Dr. Jody Greaney, lead author of a new study interrogating vascular dysfunction as one mechanism, of the many potential mechanisms, linking major depressive disorder to CV disease risk. Greaney and co-authors investigated upstream mechanisms of vascular dysfunction and increased vascular superoxide by targeting inflammation with short-term salicylate treatment in a young adult population with major depressive disorder and found that this treatment did improve microvascular endothelium-dependent dilation. Listen as Jody discusses how she persevered with her small proof-of-concept study through finishing her post-doc, obtaining a faculty position, navigating the start-up her own lab, pandemic related interruptions to basic research, and peer reviewer comments that seemed daunting to overcome. Could depression, at its core, be characterized as an inflammatory disease? Are you at a critical career fork in the road and need some insight? Listen now.   Jody L. Greaney, Erika F. H. Saunders, Lacy M. Alexander Short-term salicylate treatment improves microvascular endothelium-dependent dilation in young adults with major depressive disorder Am J Physiol Heart Circ Physiol, published April 14, 2022. DOI: 10.1152/ajpheart.00643.2021

First, a thank you to frontline healthcare workers, clinical researchers, and one determined master's student Michelle Cristina-Oliveira of the Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo for their bravery and dedication to science and medicine! In this episode we bring you a conversation between Associate Editor Dr. Jason Carter (Montana State University), lead author Dr. Tiago Pecanha (Universidade de São Paulo, and Manchester Metropolitan University), and expert Dr. Paul Fadel (The University of Texas at Arlington). From June 2020 to May 2021 first author Michelle Cristina-Oliveira screened over 600 patients at the height of the COVID-19 pandemic in São Paulo, Brazil in order to enroll 211 COVID-19 patients within 72 hours of hospital admission. The authors sought to determine whether brachial artery flow-mediated dilation and carotid intima-media thickness measured upon hospital admission were associated with acute outcomes in hospitalized COVID-19 patients. Based on initial case reports, Cristina-Oliveira et al. felt that the endothelium could be an important target for SARS-CoV2. The authors hypothesized that measuring markers of endothelial function and atherosclerosis upon hospital admission could provide critically important information about potential risks of mortality, admission to ICU, and requirement for mechanical ventilation. Did the authors find that endothelial function and atherosclerosis were useful in predicting major clinical outcomes of COVID-19 patients? This study lends further insight into understanding the role of reduced flow mediated dilation in mediating the negative effects of COVID on cardiovascular health. Listen to find out why.   Michelle Cristina-Oliveira, Kamila Meireles, Saulo Gil, Fábio Cavalcante Assis, João Carlos Geber-Júnior, Samuel Katsuyuki Shinjo, Heraldo Possolo de Souza, Alfredo Nicodemos Cruz Santana, Paul A. Swinton, Luciano F. Drager, Bruno Gualano, Hamilton Roschel, and Tiago Peçanha Carotid intima-media thickness and flow-mediated dilation do not predict acute in-hospital outcomes in patients hospitalized with COVID-19 Am J Physiol Heart Circ Physiol, published April 22, 2022. DOI: 10.1152/ajpheart.00026.2022

How does in utero glucocorticoid administration impact autonomic control of the heart in adult offspring in a sex-dependent manner? In this episode, Associate Editor Dr. Crystal Ripplinger (University of California – Davis) interviews authors Dr. Taben Hale and Lakshmi Madhavpeddi (University of Arizona) along with expert Dr. Glen Pyle (University of Guelph) about the new work by Madhavpeddi et al. The authors administered dexamethasone to pregnant rats using a dose and timing that closely mimicked clinical application of dexamethasone administration to pregnant women at risk for preterm delivery to prevent respiratory distress in newborns. At baseline, the authors did not observe any differences between the prenatally-exposed offspring and controls. In response to an experimental stressor, however, the authors found that prenatal exposure to dexamethasone resulted in exaggerated blood pressure and heart rate only in adult female rats. Prenatally-exposed adult male rats did not exhibit any stress response changes in cardiovascular function. In addition, only the dexamethasone-exposed adult female offspring showed a reduction in the high frequency component of heart rate variability, indicating withdrawal of parasympathetic activity. What role does angiotensin II play in the altered autonomic response induced by prenatal dexamethasone exposure? Can we derive important potential clinical applications of this work related to the long-term impact on offspring from treatments administered during their mothers' pregnancies? Listen now to find out.   L. Madhavpeddi, B. Hammond, D. L. Carbone, P. Kang, R. J Handa, T. M. Hale Impact of angiotensin II receptor antagonism on the sex-selective dysregulation of cardiovascular function induced by in utero dexamethasone exposure Am J Physiol Heart Circ Physiol, published March 17, 2022. DOI: 10.1152/ajpheart.00587.2021

Who knew that back in 2010, when previous Editor-in-Chief Dr. Bill Stanley said, “Podcasts! I don't know anything about them, but I think we should do them!,” that we would still be producing The AJP-Heart and Circ Podcast 12 years and 299 episodes later?!  Since then we have talked with hundreds of authors, experts and editors around the world about the innovative and impactful research published in AJP-Heart and Circulatory Physiology. In this special anniversary episode #300, we turn the tables on our usual format. Executive Editor and podcast producer Kara Hansell Keehan interviews Editor-in-Chief Dr. Merry Lindsey (University of Nebraska Medical Center), Deputy Editor Dr. Zamaneh Kassiri (University of Alberta), and Associate Editors Dr. Keith Brunt (Dalhousie University), Dr. Jason Carter (Montana State University), Dr. Jonathan Kirk (Loyola University Chicago), Dr. Petra Kleinbongard (University of Duisburg-Essen Medical School), Dr. Amanda Jo LeBlanc (University of Louisville), and Dr. Crystal Ripplinger (University of California-Davis). Why should authors submit to AJP-Heart and Circ? What advice do the AJP-Heart and Circ editors have for early career researchers? And finally, what do the editors have to say about the value of The AJP-Heart and Circ Podcast for our listeners?  There is only one way to find out. Listen now.

Are failing hearts addicted to glutamine? In this special episode of The AJP-Heart and Circ Podcast, we bring you a conversation in both Japanese and English with Editorial Board member Dr. Junichi Sadoshima (Rutgers University-New Jersey Medical School), Consulting Editor Dr. Jun Yoshioka (City University of New York School of Medicine), and corresponding author Dr. Manabu Nagao (Kobe University Graduate School of Medicine) about the new study by Yoshikawa et al. that explores the interaction between metabolism and pathophysiological cardiac hypertrophy. It is well known that the heart uses various substrates to produce ATP during cardiac hypertrophy. Earlier observations about how cancer cells rapidly consume glutamine during the tumor growth phase led the authors to interrogate the role of glutamine metabolism in cardiac hypertrophy. Nagao and co-authors show that glutaminase is upregulated during cardiac hypertrophy, and that suppression of glutaminase 1 (GLS1) attenuates cardiac hypertrophy. GLS1-mediated glutaminolysis contributes to maladaptive cardiac remodeling by increasing anabolic reactions for hypertrophy and proliferation. Glutamine metabolism is essential for cardiomyocytes. Interestingly, glutaminolysis is activated much faster than glucolysis in response to acute stress. Yoshikawa et al. show that a counter-clockwise shift of the tricarboxylic acid cycle contributes to cardiac remodeling. This study is a game-changer. Listen to learn why.   Sachiko Yoshikawa, Manabu Nagao, Ryuji Toh, Masakazu Shinohara, Takuya Iino, Yasuhiro Irino, Makoto Nishimori, Hidekazu Tanaka, Seimi Satomi-Kobayashi, Tatsuro Ishida, and Ken-Ichi Hirata Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling Am J Physiol Heart Circ Physiol, published March 30, 2022. DOI: 10.1152/ajpheart.00692.2021

Are failing hearts addicted to glutamine? In this special episode of The AJP-Heart and Circ Podcast, we bring you a conversation in both Japanese and English with Editorial Board member Dr. Junichi Sadoshima (Rutgers University-New Jersey Medical School), Consulting Editor Dr. Jun Yoshioka (City University of New York School of Medicine), and corresponding author Dr. Manabu Nagao (Kobe University Graduate School of Medicine) about the new study by Yoshikawa et al. that explores the interaction between metabolism and pathophysiological cardiac hypertrophy. It is well known that the heart uses various substrates to produce ATP during cardiac hypertrophy. Earlier observations about how cancer cells rapidly consume glutamine during the tumor growth phase led the authors to interrogate the role of glutamine metabolism in cardiac hypertrophy. Nagao and co-authors show that glutaminase is upregulated during cardiac hypertrophy, and that suppression of glutaminase 1 (GLS1) attenuates cardiac hypertrophy. GLS1-mediated glutaminolysis contributes to maladaptive cardiac remodeling by increasing anabolic reactions for hypertrophy and proliferation. Glutamine metabolism is essential for cardiomyocytes. Interestingly, glutaminolysis is activated much faster than glucolysis in response to acute stress. Yoshikawa et al. show that a counter-clockwise shift of the tricarboxylic acid cycle contributes to cardiac remodeling. This study is a game-changer. Listen to learn why.   Sachiko Yoshikawa, Manabu Nagao, Ryuji Toh, Masakazu Shinohara, Takuya Iino, Yasuhiro Irino, Makoto Nishimori, Hidekazu Tanaka, Seimi Satomi-Kobayashi, Tatsuro Ishida, and Ken-Ichi Hirata Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling Am J Physiol Heart Circ Physiol, published March 30, 2022. DOI: 10.1152/ajpheart.00692.2021

Impactful findings with reverberating consequences – this is what AJP-Heart and Circ Rapid Reports are here for. Listen as Associate Editor Dr. Jonathan Kirk (Loyola University Chicago Stritch School of Medicine) interviews lead author Dr. Susan Steinberg (Columbia University) and expert Dr. Michael Kapiloff (Stanford University) about this novel work by Zhu and Steinberg. More than 20 years ago, Steinberg and collaborators used immunoblot analysis to implicate compartmentalization as a mechanism that imparts beta-adrenergic receptor subtype signaling specificity. Of note, these studies also provided the unexpected observation that the beta1-adrenergic receptor subtype accumulates as both full-length and N-terminally truncated species; in contrast, beta2-adrenergic receptors are expressed exclusively as a single full-length species. The Steinberg laboratory went on to identify the molecular mechanisms that control the maturational processing of the full-length receptor to an N-terminally truncated form (including the role of a member of the matrix metalloproteinase family of enzymes) and the functional importance of this finding. They showed that full-length and N-terminally truncated beta1-adenergic receptors differ in their signaling phenotype; the N-terminally truncated beta1-adenergic receptor plays a unique role to constitutively activate an AKT signaling pathway that is cardioprotective.   This Rapid Report expands upon the previous studies by showing that the beta1-adrenergic receptor is also cleaved by trypsin, an enzyme used in protocols to isolate cardiomyocytes from ventricular tissue. This finding suggests that studies on cardiomyocytes isolated in this manner should be interpreted with caution. In the broader context, the cleavage mechanism that regulates beta1-adrenergic receptor signaling uncovered by Zhu and Steinberg has important clinical implications given the fact that beta-adrenergic receptors are first-line targets for heart failure (with beta blockers one of the most prescribed medications). The podcast discusses several questions. Are beta1-adrenergic receptors also cleaved (and hence catecholamine responsiveness also altered) by functionally relevant inflammatory proteases in the setting of cardiac injury or myocarditis? Do the full-length and truncated forms of the beta1-adrenergic receptor play distinct roles in the evolution of heart failure? This research clearly is a springboard for future studies. Listen and find out why.   Jing Zhu and Susan F. Steinberg Trypsin cleavage of the beta1-adrenergic receptor Am J Physiol Heart Circ Physiol, published March 1, 2022. DOI: 10.1152/ajpheart.00005.2022

While echocardiography is commonly used to assess cardiac structure and function in mouse models of heart disease, can this non-invasive technique also be used to accurately measure infarct size? Listen as Deputy Editor Dr. Zamaneh Kassiri (University of Alberta) interviews co-authors Dr. Erin Mulvihill (University of Ottawa) and Dr. Craig Goergen (Purdue University), along with content expert Dr. Daniele Panetta (Institute of Clinical Physiology CNR - Pisa). Dann et al. measured and monitored infarct size by comparing and contrasting 2-D echo imaging results with 4-D echo imaging results in a myocardial infarction mouse model. 4-D ultrasound imaging allowed the authors to measure the entire volume of the left ventricle throughout the cardiac cycle, as well as analyze the progression of asymmetric ventricular remodeling. In addition, this work illustrates how authors from two different academic institutions found a novel way to collaborate during the COVID-19 pandemic and ensuing international travel restrictions. The study by Dann et al. provides a unique visualization of the infarct in 3-D, which then allowed for volumetric analysis to use contouring of the heart to produce dynamic strain maps. Listen as we discuss how the innovative imaging modalities utilized by Dann et al. allow researchers to focus on animal specific differences as well as the inclusion of both female and male animals for robust rigor and reproducibility.   Melissa M. Dann, Sydney Q. Clark, Natasha A. Trzaskalski, Conner C. Earl, Luke E. Schepers, Serena M. Pulente, Ebonee N. Lennord, Karthik Annamalai, Joseph M. Gruber, Abigail D. Cox, Ilka Lorenzen-Schmidt, Richard Seymour, Kyoung-Han Kim, Craig J. Goergen, and Erin E. Mulvihill Quantification of murine myocardial infarct size using 2-D and 4-D high-frequency ultrasound   Am J Physiol Heart Circ Physiol, published February 8, 2022. DOI: doi.org/10.1152/ajpheart.00476.2021

Despite the establishment of NIH guidelines for inclusion of women in clinical studies, as well as clear expectations for rigor and reproducibility in reporting sex as a biological variable in NIH grant submissions, women and females are still understudied populations in human and animal research. Enter this important primer on incorporating sex as a biological variable into basic and clinical research. Listen as Consulting Editor Austin Robinson, PhD (Assistant Professor, Neurovascular Physiology Laboratory, Auburn University) interviews lead author Quin Denfeld, PhD, RN (Assistant Professor, School of Nursing and Division of Cardiovascular Medicine, School of Medicine, Oregon Health & Science University) and women's health expert Judith Regensteiner, PhD (Director of the Ludeman Family Center for Women's Health Research and Professor of Medicine, Divisions of Internal Medicine and Cardiology, University of Colorado Anschutz Medical Campus).  Denfeld and co-authors heeded the call to action outlined in the recent editorial by the AJP-Heart and Circ Editors on “Reinforcing rigor and reproducibility expectations for use of sex and gender in cardiovascular research”, along with its accompanying podcast episode and Call for Papers on Considering Sex as a Biological Variable in Cardiovascular Research.    In their Perspective article, Denfeld et al. offered practical and actionable ideas for how to include women and females in research studies, demystifying the process for fellow researchers by addressing common concerns such as sample size, cost, statistical analysis, and study participant recruitment challenges. In this episode, our experts tackled these subjects head on, championing the value of looking at data, even pilot data, through the lens of sex differences.   Don't miss hearing about career development opportunities available to researchers from the NIH Office of Research on Women's Health and Building Interdisciplinary Research Careers in Women's Health (BIRCWH) Program.  Including both sexes and genders in research studies is not difficult to accomplish with foresight, planning, and perhaps a little creative thinking. This insightful conversation is invaluable to all researchers. Listen now.   Recommended Reading in AJP-Heart and Circ: Quin E. Denfeld, Christopher S. Lee, and Beth A. Habecker  A primer on incorporating sex as a biological variable into the conduct and reporting of basic and clinical research studies Am J Physiol Heart Circ Physiol, published February 8, 2022. DOI: 10.1152/ajpheart.00605.2021   Austin T. Robinson, Megan M. Wenner, Kanokwan Bunsawat, Joseph C. Watso, Gabrielle E. W. Giersch, and Nisha Charkoudian When it's time for the sex talk, words matter  Am J Physiol Heart Circ Physiol, published December 13, 2021. DOI: 10.1152/ajpheart.00556.2021   Special Article Collection on Considering Sex as a Biological Variable