AJP-Heart and Circulatory Physiology Podcast

Estrogen and Human Arterioles

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

Cell Therapy and Endothelial Dysfunction in HFpEF

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

Guidelines for Cardiac Electrophysiology

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.00439.2022.

Global Allogeneic Cardiosphere-Derived Cells in Acute MI

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

Vascular Function During the Estrous Cycle

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

Sm22alpha in Keratinocytes

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

VO2 Kinetics and Chronotropic Responses After Severe COVID-19

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

Behind the Bench Episode 13

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

COVID-19 and Diabetes

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

Save Hearts, Improve Efficiency

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 & Co.) 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