Cerebroarterial Dysfunction in Swedish-Arctic AD Mice

In a true chicken-and-egg question, can researchers accurately pinpoint if cerebrovascular pathology or Alzheimer's disease (AD) present sequentially or simultaneously? Listen as Guest Editor Vincenzo Lionetti (Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy) interviews lead author Mario Merlini (University of Zurich, Switzerland, and Gladstone Institute of Neurological Disease, UCSF) and content expert Roy Weller (University of Southampton School of Medicine) about the novel work by Merlini et al that seeks to untangle the complicated web of cerebrovascular pathology, AD pathology, and vascular dementia, as well as neuronal and endothelial tau pathology. In this extended podcast, we speculate on the role that endothelial tau may play in disrupting nitric oxide synthase in the nucleus. Our experts consider whether endothelial dysfunction at the onset of AD is a gene or age-dependent phenomenon. Why did Merlini and co-authors use histology to investigate the loss of cyclic-GMP in the absence of amyloid deposits in the basilar artery? Does the Swedish-Arctic mouse model accurately reflect the AD clinical condition? Listen to this intriguing conversation and find out.


Mario Merlini, Yi Shi, Stephan Keller, Gianluigi Savarese, Alexander Akhmedov, Rebecca Derungs, Remo D. Spescha, Luka Kulic, Roger M. Nitsch, Thomas F. Lüscher, Giovanni G. Camici Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer’s disease Am J Physiol Heart Circ Physiol, published February 1, 2017. DOI: 10.1152/ajpheart.00607.2016


Renin-Angiotensin System Signaling in Aged and Age-Exercised Rats

Does aging influence myocardial angiotensin II levels in the heart? Listen as Editor in Chief Irving H. Zucker (University of Nebraska Medical Center) interviews lead author Dong Sun (New York Medical College) and content expert Zsolt Bagi (Augusta University) about the recent study by Froogh et al, which compared three experimental groups (young sedentary, aged sedentary, and aged exercising rats) to determine why there is a mismatch between angiotensin II and angiotensin 1 – 7 in the aged heart. Does perivascular chymase and angiotensin production specifically target blood vessels? What do the authors speculate is the mechanisms by which exercise can alter ACE and ACE 2, including chymase? Find out this and more. Listen now.


Ghezal Froogh, John T Pinto, Yicong Le, Sharath Kandhi, Yeabsra Aleligne, An Huang, Dong Sun Chymase-dependent production of angiotensin II: an old enzyme in old hearts Am J Physiol Heart Circ Physiol, published online November 4, 2016. DOI: 10.1152/ajpheart.00534.2016


Parental Vitamin D Deficiency Increases BP in Offspring

Do we really know the potential effects of maternal, and paternal, diets on offspring genotype and phenotype? In this podcast, Associate Editor Nancy Kanagy (University of New Mexico School of Medicine) interviews lead author Rudolf de Boer (University Medical Center Groningen) and content expert Mingyu Liang (Medical College of Wisconsin) about the exciting new work by Meems et al which investigated the cardiovascular effects on offspring born to vitamin D deficient parents. While the initial idea for this work by de Boer and colleagues sprang from the well-documented clinical observation that Dutch people born to parents who survived the post- World War II famine have excess cardiovascular risk, the study opens the door to discuss vitamin D and other dietary deficiency multi-generational effects on offspring. Is there a consensus among researchers on how to analyze epigenetic methylation data? Listen and find out.


Laura M. G. Meems, Hasan Mahmud, Hendrik Buikema, Jörg Tost, Sven Michel, Janny Takens, Rikst N. Verkaik-Schakel, Inge Vreeswijk-Baudoin, Irene V. Mateo-Leach, Pim van der Harst, Torsten Plösch, Rudolf A. de Boer Parental vitamin D deficiency during pregnancy is associated with increased blood pressure in offspring via Panx1 hypermethylation Am J Physiol Heart Circ Physiol, published online December 1, 2016. DOI: 10.1152/ajpheart.00141.2016


Mitochondrial Dynamics Impact Endothelial Function

What role does mitochondrial fragmentation play in endothelial dysfunction under conditions of low glucose? Listen as Consulting Editor Michael Wolin (New York Medical College) interviews lead author Michael Widlansky (Medical College of Wisconsin) and content expert Prasad Katakam (Tulane University School of Medicine) about the new work by Tanner et al which investigated the often-overlooked condition of low glucose in humans. Does the mitochondrial fission protein dynamin-related protein 1 (DRP1) regulate vascular endothelial function through ROS production? Our experts explore the work by Widlansky and colleagues that leads to new and engaging open questions. How is DRP1 activated and what docking proteins may be involved? Listen and find out.


Michael John Tanner, Jingli Wang, Rong Ying, Tisha B Suboc, Mobin Malik, Allison Couillard, Amberly Branum, Venkata Puppala, Michael Eric Widlansky Dynamin-Related Protein 1 Mediates Low Glucose-Induced Endothelial Dysfunction in Human Arterioles Am J Physiol Heart Circ Physiol, published online December 6, 2016. DOI: 10.1152/ajpheart.00499.2016


TLR9 in Post-Infarct Cardiac Rupture

Is myocardial rupture in acute myocardial infarction preventable? Perhaps, according to new research by Omiya et al into the mechanisms underlying myocardial rupture in a toll-like receptor 9 knockout mouse model compared to a permanent coronary ligation model. In this podcast, Associate Editor Junichi Sadoshima (Rutgers New Jersey Medical School) interviews lead author Kinya Otsu (King's College London British Heart Foundation Centre of Excellence) and content expert Richard Kitsis (Albert Einstein College of Medicine) about the work by Otsu and colleagues exploring why toll-like receptor 9 shows cardioprotective effects on myocardial rupture but does not play a role in inflammation. Why are myocardial fibroblasts affected but inflammatory cells are not affected by TLR-9 knockout, and what exactly is the role of myofibroblasts in preventing cardiac rupture? What are the clinical implications for acute MI patients going forward? Listen and find out.


Shigemiki Omiya, Yosuke Omori, Manabu Taneike, Andrea Protti, Osamu Yamaguchi, Shizuo Akira, Ajay M. Shah, Kazuhiko Nishida, Kinya Otsu Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation Am J Physiol Heart Circ Physiol, published online December 1, 2016. DOI: 10.1152/ajpheart.00481.2016


Metaboreflex-induced Functional Coronary Vasoconstriction

How does the muscle metaboreflex work to regulate coronary blood flow during exercise, particularly in the cardiovascular disease state of hypertension? Listen as Editor in Chief Irving H. Zucker (University of Nebraska Medical Center) interviews lead author Donal O’Leary (Wayne State University School of Medicine) and content expert David Stepp (Augusta University) about the large animal study conducted by O’Leary and colleagues, a technical tour de force which explored whether blocking an increase in vasoconstriction due to increased sympathetic activity in the heart would actually increase coronary blood flow and increase ventricular function. Does this elegant study make the case for focusing on coronary blood flow, rather than blood pressure, as a potential therapeutic target for the treatment of hypertension? Listen to find out.


Marty D. Spranger, Jasdeep Kaur, Javier A. Sala-Mercado, Abhinav C. Krishnan, Rania Abu-Hamdah, Alberto Alvarez, Tiago M. Machado, Robert A. Augustyniak, Donal S. O'Leary Exaggerated coronary vasoconstriction limits muscle metaboreflex-induced increases in ventricular performance in hypertension Am J Physiol Heart Circ Physiol, published online October 21, 2016. DOI: 10.1152/ajpheart.00417.2016


Acute Progesterone Modifies Cardiac Contraction

If cardiovascular scientists use only male animals in animal model studies, will important observations be missed? Yes, according to a new study by Feridooni et al. In this podcast, Editor in Chief Irving H. Zucker interviews lead author Susan Howlett (Dalhousie University, Canada) and content expert Lea Delbridge (University of Melbourne, Australia) about the work by Howlett and colleagues which explored the acute effects of progesterone on the heart. The key finding is that in female mouse hearts—but not in male mouse hearts—progesterone markedly slowed and attenuated contractions in multicellular ventricular muscle, but had no effect on the underlying calcium transients. This surprising data might never have been discovered if Howlett and colleagues had conducted their experiments only on male mice. Does the estrous cycle in female rodents create physiological heterogeneity that is too confounding to experimentally overcome? Does the negative inotropic impact of progesterone shown in vitro translate to the in vivo setting? Listen and learn more.


Hirad A Feridooni, Jennifer K MacDonald, Anjali Ghimire, W. Glen Pyle, Susan E. Howlett Acute exposure to progesterone attenuates cardiac contraction by modifying myofilament calcium sensitivity in the female mouse heart Am J Physiol Heart Circ Physiol, published online October 28, 2016. DOI: 10.1152/ajpheart.00073.2016


Role of FOXO3a in Heart Failure

Does the transcription factor FOXO3a regulate BNIP3 gene expression in the heart? In this podcast, Associate Editor Ajay Shah (King’s College London) interviews lead author Antoine Chaanine (Mayo Clinic) and content expert Christoph Maack (Universitatsklinikum des Saarlandes) about the new work by Chaanine and co-authors exploring whether FOXO3a plays a role in mitochondrial dysfunction and myocardial remodeling via BNIP3. Looking at both myocytes and in vivo responses, the authors focus on the microdomain between the sarcoplasmic reticulum and the mitochondria, as well as the intricate balance of SR calcium release and mitochondrial calcium uptake. Is the FOXO3a-BNIP3 pathway involved in diastolic dysfunction in heart failure, or is the primary effect on adverse myocardial remodeling which in turn affects end-diastolic function? Listen to find out.


Antoine Heni Chaanine, Erik Kohlbrenner, Scott I. Gamb, Adam J. Guenzel, Katherine A. Klaus, Ahmed U. Fayyaz, K Sreekumaran Nair, Roger J. Hajjar, Margaret M. Redfield FOXO3a Regulates BNIP3 and Modulates Mitochondrial Calcium, Dynamics and Function in Cardiac Stress Am J Physiol Heart Circ Physiol, published September 30, 2016. DOI: 10.1152/ajpheart.00549.2016


Heart Rate Modeling

Can increasing heart rate in patients with heart failure with preserved ejection fraction (HFpEF) improve outcomes? Yes, according to the new study by Klein et al. In this podcast Associate Editor Fabio Recchia (Temple University Lewis Katz School of Medicine, and Scuola Superiore Sant'Anna, Pisa, Italy) interviews lead author Markus Meyer (University of Vermont College of Medicine) and content expert Jonathan Kirk (Loyola University Chicago) about the work by Meyer and co-authors, which challenges the “canonical thought” of heart pacing in HFpEF patients. Using a large animal model of HFpEF, and taking key inspiration from a unique bedside-to-bench experience, Meyer and colleagues found that two weeks of cardiac pacing at a fixed rate 30 beats per minute above spontaneous heart rate in pigs resulted in slightly increased heart chamber volumes, but reduced left ventricular wall thickness, decreased myocardial fibrosis, and improved diastolic compliance. Does this approach improve left ventricular response to stress? Listen and learn.


Franziska J. Klein, Stephen Bell, K. Elisabeth Runte, Robert Lobel, Takamuru Ashikaga, Lilach O. Lerman, Martin M. LeWinter, Markus Meyer Heart rate-induced modifications of concentric left ventricular hypertrophy: exploration of a novel therapeutic concept Am J Physiol Heart Circ Physiol, published October 1, 2016. DOI: 10.1152/ajpheart.00301.2016


TNF and Cardiac Stem Cell Differentiation

Why is the post- myocardial infarction micro environment of the heart so hostile for cardiac stem cells? In this podcast, Deputy Editor Merry Lindsey (University of Mississippi Medical Center) interviews lead author Sumanth Prabhu (University of Alabama at Birmingham) and content expert Richard Gumina (Vanderbilt University) about the work by Hamid et al, which determined that tumor necrosis factor (TNF) signaling inhibits endogenous cardiac stem cell repair and blunts stem cell treatment efficacy in human heart failure. What relationship did Prabhu and co-authors uncover between TNF-alpha and adrenergic activation? How did the authors manage the biological variability of primary stem cell isolates in their technically nuanced study? Finally, if “timing is everything” holds true, does this study provide a clinical translation roadmap for timing TNF receptor blockade post-MI? Listen to learn more.

Tariq Hamid, Yuanyuan Xu, Mohamed Ameen Ismahil, Qianhong Li, Steven P. Jones, Aruni Bhatnagar, Roberto Bolli, Sumanth D. Prabhu TNF receptor signaling inhibits cardiomyogenic differentiation of cardiac stem cells and promotes a neuroadrenergic-like fate Am J Physiol Heart Circ Physiol, published November 1, 2016. DOI: 10.1152/ajpheart.00904.2015