Physiology Commons^™

Editorial: Perturbations In Metabolic Cues: Implications For Adverse Cardiac Function Leading To Sudden Cardiac Death, Brian P. Delisle, Ademuyiwa S. Aromolaran

Physiology Faculty Publications

No abstract provided.

Editorial: Recent Advances In Cardiotoxicity Testing, Tamer M. A. Mohamed, Javid Moslehi, Jonathan Satin

Physiology Faculty Publications

No abstract provided.

Structural And Functional Properties Of Subsidiary Atrial Pacemakers In A Goat Model Of Sinus Node Disease, Luca Soattin, Zoltan Borbas, Jane Caldwell, Brian Prendergast, Akbar Vohra, Yawer Saeed, Andreas Hoschtitzky, Joseph Yanni, Andrew Atkinson, Sunil Jit Logantha

Section of Cardiology

Background: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases.
Methods: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through …

Dennd5b Regulates Intestinal Triglyceride Absorption And Body Mass, Scott M. Gordon, Edward B. Neufeld, Zhihong Yang, Milton Pryor, Lita A. Freeman, Xiao Fan, Iftikhar J. Kullo, Leslie G. Biesecker, Alan T. Remaley

Saha Cardiovascular Research Center Faculty Publications

Regulation of lipid absorption by enterocytes can influence metabolic status in humans and contribute to obesity and related complications. The intracellular steps of chylomicron biogenesis and transport from the Endoplasmic Reticulum (ER) to the Golgi complex have been described, but the mechanisms for post-Golgi transport and secretion of chylomicrons have not been identified. Using a newly generated Dennd5b^−/− mouse, we demonstrate an essential role for this gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. In mice, loss of Dennd5b results in resistance to western diet induced obesity, changes in plasma lipids, and reduced aortic atherosclerosis. In …

Antisense Oligonucleotides Targeting Angiotensinogen: Insights From Animal Studies, Chia-Hua Wu, Ya Wang, Murong Ma, Adam E. Mullick, Rosanne M. Crooke, Mark J. Graham, Alan Daugherty, Hong S. Lu

Saha Cardiovascular Research Center Faculty Publications

Angiotensinogen (AGT) is the unique substrate of all angiotensin peptides. We review the recent preclinical research of AGT antisense oligonucleotides (ASOs), a rapidly evolving therapeutic approach. The scope of the research findings not only opens doors for potentially new therapeutics of hypertension and many other diseases, but also provides insights into understanding critical physiological and pathophysiological roles mediated by AGT.

Macrophage-Derived Netrin-1 Promotes Abdominal Aortic Aneurysm Formation By Activating Mmp3 In Vascular Smooth Muscle Cells, Tarik Hadi, Ludovic Boytard, Michele Silvestro, Dornazsadat Alebrahim, Samson Jacob, Jordyn Feinstein, Krista Barone, Wes Spiro, Susan Hutchison, Russell Simon, Debra L. Rateri, Florence Pinet, David Fenyo, Mark Adelman, Kathryn J. Moore, Holger K. Eltzschig, Alan Daugherty, Bhama Ramkhelawon

Physiology Faculty Publications

Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) …

Rad Gtpase Deletion Atenuates Post-Ischemic Cardiac Dysfunction And Remodeling, Janet R. Manning, Lakshman Chelvarajan, Bryana R. Levitan, Catherine Nicole Kaminski Withers, Prabhakara R. Nagareddy, Christopher M. Haggerty, Brandon K. Fornwalt, Erhe Gao, Himi Tripathi, Ahmed Abdel-Latif, Douglas A. Andres, Jonathan Satin

Physiology Faculty Publications

The protein Rad interacts with the L-type calcium channel complex to modulate trigger Ca²⁺ and hence to govern contractility. Reducing Rad levels increases cardiac output. Ablation of Rad also attenuated the inflammatory response following acute myocardial infarction. Future studies to target deletion of Rad in the heart could be conducted to establish a novel treatment paradigm whereby pathologically stressed hearts would be given safe, stable positive inotropic support without arrhythmias and without pathological structural remodeling. Future investigations will also focus on establishing inhibitors of Rad and testing the efficacy of Rad deletion in cardioprotection relative to the time of …

Calpain Inhibition Attenuates Adipose Tissue Inflammation And Fibrosis In Diet-Induced Obese Mice, Latha Muniappan, Aida Javidan, Weihua Jiang, Shayan Mohammadmoradi, Jessica J. Moorleghen, Wendy S. Katz, Anju Balakrishnan, Deborah A. Howatt, Venkateswaran Subramanian

Saha Cardiovascular Research Center Faculty Publications

Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance. However, the mechanisms underlying these processes are not completely defined. Calpains are calcium-dependent neutral cysteine proteases that modulate cellular function and have been implicated in various inflammatory diseases. To define whether activated calpains influence diet-induced obesity and adipose tissue macrophage accumulation, mice that were either wild type (WT) or overexpressing calpastatin (CAST Tg), the endogenous inhibitor of calpains were fed with high (60% kcal) fat diet for 16 weeks. CAST overexpression did not influence high fat diet-induced body weight and fat mass gain throughout the study. …

Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Pharmacology and Nutritional Sciences Faculty Publications

Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr^−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated …

No Difference In Myosin Kinetics And Spatial Distribution Of The Lever Arm In The Left And Right Ventricles Of Human Hearts, Divya Duggal, S. Requena, Janhavi Nagwekar, Sangram Raut, Ryan Rich, Hriday Das, Vipul Patel, Ignacy Gryczynski, Rafal Fudala, Zygmunt Gryczynski, Cheavar Blair, Kenneth S. Campbell, Julian Borejdo

Physiology Faculty Publications

The systemic circulation offers larger resistance to the blood flow than the pulmonary system. Consequently, the left ventricle (LV) must pump blood with more force than the right ventricle (RV). The question arises whether the stronger pumping action of the LV is due to a more efficient action of left ventricular myosin, or whether it is due to the morphological differences between ventricles. Such a question cannot be answered by studying the entire ventricles or myocytes because any observed differences would be wiped out by averaging the information obtained from trillions of myosin molecules present in a ventricle or myocyte. …

Body Size Predicts Cardiac And Vascular Resistance Effects On Men's And Women's Blood Pressure, Joyce M. Evans, Siqi Wang, Christopher Greb, Vladimir Kostas, Charles F. Knapp, Qingguang Zhang, Eric S. Roemmele, Michael B. Stenger, David C. Randall

Biomedical Engineering Faculty Publications

Key Points Summary

• We report how blood pressure, cardiac output and vascular resistance are related to height, weight, body surface area (BSA), and body mass index (BMI) in healthy young adults at supine rest and standing.
• Much inter-subject variability in young adult's blood pressure, currently attributed to health status, may actually result from inter-individual body size differences.
• Each cardiovascular variable is linearly related to height, weight and/or BSA (more than to BMI).
• When supine, cardiac output is positively related, while vascular resistance is negatively related, to body size. Upon standing, the change in vascular resistance is positively related to size. …

Optimal Nutrition For Endurance Exercise: A Systematic Review, Sarah E. Andrus Ms, Bruce W. Andrus Md Ms

Dartmouth Scholarship

Introduction

As fatigue in endurance events correlates with depletion of muscle glycogen, the traditional approach to nutritional support has been carbohydrate loading. However, there has been recent interest in improving athletic endurance performance by novel diets in the days to weeks prior to endurance events, the pre-event meal, and during exercise.

Methods

We searched PubMed and SCOPUS for randomized trials published from 1992-2017 with a primary endpoint of endurance performance. We identified 407 citations which were examined against our inclusion criteria of randomization or crossover allocation to diet and for which a primary outcome was endurance performance.

Results

Twenty full …

Qt Prolongation Is Associated With Increased Mortality In End Stage Liver Disease, Sun Moon Kim, Bennet George, Diego Alcivar-Franco, Charles L. Campbell, Richard Charnigo, Brian P. Delisle, Jonathan Hundley, Yousef Darrat, Gustavo Morales, Samy-Claude Elayi, Alison L. Bailey

Internal Medicine Faculty Publications

AIM

To determine the prevalence of QT prolongation in a large series of end stage liver disease (ESLD) patients and its association to clinical variables and mortality.

METHODS

The QT interval was measured and corrected for heart rate for each patient, with a prolonged QT cutoff defined as QT > 450 ms for males and QT > 470 ms for females. Multiple clinical variables were evaluated including sex, age, serum sodium, international normalized ratio, creatinine, total bilirubin, beta-blocker use, Model for End-Stage Liver Disease (MELD), MELD-Na, and etiology of liver disease.

RESULTS

Among 406 ESLD patients analyzed, 207 (51.0%) had QT prolongation. …

Vestibular Activation Habituates The Vasovagal Response In The Rat, Bernard Cohen, Giorgio P. Martinelli, Yongqing Xiang, Theodore Raphan, Sergei B. Yakushin

Publications and Research

Vasovagal syncope is a significant medical problem without effective therapy, postulated to be related to a collapse of baroreflex function. While some studies have shown that repeated static tilts can block vasovagal syncope, this was not found in other studies. Using anesthetized, male Long–Evans rats that were highly susceptible to generation of vasovagal responses, we found that repeated activation of the vestibulosympathetic reflex (VSR) with ±2 and ±3 mA, 0.025 Hz sinusoidal galvanic vestibular stimulation (sGVS) caused incremental changes in blood pressure (BP) and heart rate (HR) that blocked further generation of vasovagal responses. Initially, BP and HR fell ≈20–50 …

Myocardial Relaxation Is Accelerated By Fast Stretch, Not Reduced Afterload, Charles S. Chung, Charles W. Hoopes, Kenneth S. Campbell

Physiology Faculty Publications

Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the …

Omecamtiv Mecarbil Enhances The Duty Ratio Of Human Β-Cardiac Myosin Resulting In Increased Calcium Sensitivity And Slowed Force Development In Cardiac Muscle, Anja M. Swenson, Wanjian Tang, Cheavar A. Blair, Christopher M. Fetrow, William C. Unrath, Michael J. Previs, Kenneth S. Campbell, Christopher M. Yengo

Physiology Faculty Publications

The small molecule drug omecamtiv mecarbil (OM) specifically targets cardiac muscle myosin and is known to enhance cardiac muscle performance, yet its impact on human cardiac myosin motor function is unclear. We expressed and purified human β-cardiac myosin subfragment 1 (M2β-S1) containing a C-terminal Avi tag. We demonstrate that the maximum actin-activated ATPase activity of M2β-S1 is slowed more than 4-fold in the presence of OM, whereas the actin concentration required for half-maximal ATPase was reduced dramatically (30-fold). We find OM does not change the overall actin affinity. Transient kinetic experiments suggest that there are …

Myofilament Calcium Sensitivity: Consequences Of The Effective Concentration Of Troponin I, Jalal K. Siddiqui, Svetlana B. Tikunova, Shane D. Walton, Bin Liu, Meredith Meyer, Pieter P. De Tombe, Nathan Neilson, Peter M. Kekenes-Huskey, Hussam E. Salhi, Paul M.L. Janssen, Brandon J. Biesiadecki, Jonathan P. Davis

Chemistry Faculty Publications

Control of calcium binding to and dissociation from cardiac troponin C (TnC) is essential to healthy cardiac muscle contraction/relaxation. There are numerous aberrant post-translational modifications and mutations within a plethora of contractile, and even non-contractile, proteins that appear to imbalance this delicate relationship. The direction and extent of the resulting change in calcium sensitivity is thought to drive the heart toward one type of disease or another. There are a number of molecular mechanisms that may be responsible for the altered calcium binding properties of TnC, potentially the most significant being the ability of the regulatory domain of TnC to …

Unusual Presentation Of A Young Man With Disseminated Tuberculosis And Right Ventricular Mass, Shahrukh Hashmani, Fateh Ali Tipoo Sultan, Muhammad Qamar Masood

Section of Cardiology

We report a 22-year-old man who presented to the emergency department with worsening shortness of breath and chronic fever for 2 months. Physical examination was unremarkable except for raised jugular venous pressure and palpable liver. Echocardiogram showed a large right ventricular mass causing obstruction at tricuspid valve. A subsequent chest CT scan confirmed the presence of a large mass in the right ventricle. There were multiple enlarged lymph nodes and consolidation in the right upper lobe. Diagnosis of disseminated tuberculosis(TB) was made and later confirmed by histopathology of lymph node biopsy along with positive sputum culture for acid-fast bacilli. Remarkable …

Cardiac Remodeling And Dysfunction In Childhood Obesity: A Cardiovascular Magnetic Resonance Study, Linyuan Jing, Cassi M. Binkley, Jonathan D. Suever, Nivedita Umasankar, Christopher M. Haggerty, Jennifer Rich, Christopher D. Nevius, Gregory J. Wehner, Sean M. Hamlet, David K. Powell, Aurelia Radulescu, H. Lester Kirchner, Frederick H. Epstein, Brandon K. Fornwalt

Pediatrics Faculty Publications

Background: Obesity affects nearly one in five children and is associated with increased risk of premature death. Obesity-related heart disease contributes to premature death. We aimed to use cardiovascular magnetic resonance (CMR) to comprehensively characterize the changes in cardiac geometry and function in obese children.

Methods and results: Forty-one obese/overweight (age 12 ± 3 years, 56 % female) and 29 healthy weight children (age 14 ± 3 years, 41 % female) underwent CMR, including both standard cine imaging and displacement encoded imaging, for a complete assessment of left ventricular (LV) structure and function. After adjusting for age, LV mass index …

Programming Heart Disease: Does Poor Maternal Nutrition Alter Expression Of Cardiac Markers Of Proliferation, Hypertrophy, And Fibrosis In Offspring?, Cathy Chun

Honors Scholar Theses

Maternal malnutrition can affect fetal organogenesis, metabolic processes, and factors involved in developmental regulation. Of the many physiological effects poor maternal nutrition can induce in offspring, one of the most important organs affected is the heart. Cardiovascular disease has been associated with poor maternal diet. It also been suggested that hypertension can originate during impaired intrauterine growth and development. Hypertension can trigger hypertensive heart disease and is associated with numerous heart complications. We hypothesized that poor maternal nutrition would alter critical growth factors associated with normal heart development, specifically, insulin-like growth factor (IGF)-1, IGF-2, transforming growth factor (TGF)β, and connective …

Single Nucleotide Polymorphisms Linked To Essential Hypertension In Kasigau, Kenya, Julia Carol Freeman

Masters Theses & Specialist Projects

Hypertension, or high blood pressure (BP), is an ever-growing epidemic in the developing world. Understanding the genetics behind essential hypertension (EH), or hypertension with no known cause, is especially important. In this study, three single nucleotide polymorphisms (SNPs) known to be linked to an increase in susceptibility to EH were quantified from a cohort of Kenyans living in the Kasigau region. The SNPs are located in three genes that are part of the renin angiotensin system, the primary regulatory pathway in humans controlling BP. They include: AGT (rs699), AGTR1 (rs5186), and HSD11β2 (rs5479). Overall, by using a fluorescent-based RT-PCR technique, …

Cardiovascular Fitness Associated With Cognitive Performance In Heart Failure Patients Enrolled In Cardiac Rehabilitation, Sarah Garcia, Michael L. Alosco, Mary Beth Spitznagel, Ronald Cohen, Naftali Raz, Lawrence Sweet, Richard Josephson, Joel Hughes, Jim Rosneck, Morgan L. Oberle, John Gunstad

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Reduced cognitive function is common in persons with heart failure (HF). Cardiovascular fitness is a known contributor to cognitive function in many patient populations, but has only been linked to cognition based on estimates of fitness in HF. The current study examined the relationship between fitness as measured by metabolic equivalents (METs) from a standardized stress test and cognition in persons with HF, as well as the validity of office-based predictors of fitness in this population.

Methods

Forty-one HF patients enrolled in cardiac rehabilitation completed a standardized exercise stress test protocol, a brief neuropsychological battery, the 2-minute step …

Characterization Of Secretory Sphingomyelinase Activity, Lipoprotein Sphingolipid Content And Ldl Aggregation In Ldlr-/- Mice Fed On A High-Fat Diet, Gergana M. Deevska, Manjula Sunkara, Andrew J. Morris, Mariana N. Nikolova‑Karakashian

Physiology Faculty Publications

The propensity of LDLs (low-density lipoproteins) for aggregation and/or oxidation has been linked to their sphingolipid content, specifically the levels of SM (sphingomyelin) and ceramide. To investigate this association in vivo, ldlr (LDL receptor)-null mice (ldlr-/-) were fed on a modified (atherogenic) diet containing saturated fats and cholesterol. The diet led to significantly elevated SM content in all serum lipoproteins. In contrast, ceramide increased only in the LDL particles. MS-based analyses of the lipid acyl chain composition revealed a marked elevation in C16:0 fatty acid in SM and ceramide, consistent with the prevalence of palmitic acid in the modified diet. …