A5064477997- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Cardiac Arrhythmias and Treatments
- Neuroscience and Neural Engineering
- Cardiac pacing and defibrillation studies
- Pluripotent Stem Cells Research
- Receptor Mechanisms and Signaling
- Mitochondrial Function and Pathology
- Viral Infections and Immunology Research
- Cardiovascular Function and Risk Factors
- Cardiac Ischemia and Reperfusion
- Congenital heart defects research
- Peptidase Inhibition and Analysis
- CRISPR and Genetic Engineering
- Inflammatory mediators and NSAID effects
- Atrial Fibrillation Management and Outcomes
- 3D Printing in Biomedical Research
- Genetic Neurodegenerative Diseases
- Nicotinic Acetylcholine Receptors Study
- Ion Channels and Receptors
- ECG Monitoring and Analysis
- Neuroscience and Neuropharmacology Research
- Cancer, Lipids, and Metabolism
Vanderbilt University Medical Center
2016-2025
Vanderbilt University
2016-2025
University of Minnesota
2014-2024
Lipscomb University
2023-2024
Hunter Medical Research Institute
2014-2024
Richard L. Roudebush VA Medical Center
2023
University of Cincinnati Medical Center
2023
Nebraska Medical Center
2023
University of Nebraska Medical Center
2023
San Diego Cardiac Center
2023
Cardiac calsequestrin (Casq2) is thought to be the key sarcoplasmic reticulum (SR) Ca2+ storage protein essential for SR release in mammalian heart. Human CASQ2 mutations are associated with catecholaminergic ventricular tachycardia. However, homozygous mutation carriers presumably lacking functional Casq2 display surprisingly normal cardiac contractility. Here we show that Casq2-null mice viable and contractile function under basal conditions. The exhibited striking increases volume near...
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are increasingly being used for modeling heart disease and under development regeneration of the injured heart. However, incomplete structural functional maturation hiPSC-CM, including lack T-tubules, immature excitation-contraction coupling, inefficient Ca-induced Ca release remain major limitations.Thyroid glucocorticoid hormones critical maturation. We hypothesized that their addition to standard protocols would promote...
Sodium accumulates in the interstitium and promotes inflammation through poorly defined mechanisms. We describe a pathway by which sodium enters dendritic cells (DCs) amiloride-sensitive channels including alpha gamma subunits of epithelial channel hydrogen exchanger 1. This leads to calcium influx via exchanger, activation protein kinase C (PKC), phosphorylation p47phox, association p47phox with gp91phox. The assembled NADPH oxidase produces superoxide subsequent formation immunogenic...
Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss Ctla4 the context complete genetic absence Pdcd1 leads to premature death approximately half mice. Premature results from myocardial infiltration by T cells and macrophages severe ECG abnormalities, closely...
KCNQ1 encodes KCNQ1, which belongs to a family of voltage-dependent K + ion channel proteins. associates with regulatory subunit, KCNE1, produce the cardiac repolarizing current, I Ks . Loss-of-function mutations in human gene have been linked Jervell and Lange–Nielsen Syndrome (JLNS), disorder characterized by profound bilateral deafness phenotype. To generate mouse model for JLNS, we created line transgenic mice that targeted disruption Kcnq1 gene. Behavioral analysis revealed −/− are deaf...
In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited acquired cardiomyopathies, created arrhythmia susceptibility mice, even absence abnormalities. mice expressing troponin T mutants cause hypertrophic cardiomyopathy humans, developing tachycardia was directly proportional degree sensitization...
Context.—Erythromycin is a widely used antibiotic that infrequently causes QT-prolongation and torsades de pointes cardiac arrhythmias. For antiarrhythmic drugs, women are at higher risk for these arrhythmias, but few other classes of drugs have been studied.Objectives.—To determine whether female sex factor arrhythmias associated with erythromycin, if this can be correlated in vitro measurements the QT-response to erythromycin male rabbit hearts.Design.—Food Drug Administration (FDA)...
Rationale: The lack of measurable single-cell contractility human-induced pluripotent stem cell–derived cardiac myocytes (hiPSC-CMs) currently limits the utility hiPSC-CMs for evaluating contractile performance both basic research and drug discovery. Objective: To develop a culture method that rapidly generates contracting single allows quantification cell shortening with standard equipment used studying adult CMs. Methods Results: Single were cultured 5 to 7 days on 0.4- 0.8-mm thick...
Heart muscle excitation-contraction (E-C) coupling is governed by Ca(2+) release units (CRUs) whereby influx via L-type channels (Cav1.2) triggers from juxtaposed (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution E-C remains unclear. Here, we identify role of using mice with ablation Trdn gene (Trdn(-/-)). The structure and composition CRU significantly altered...
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are being increasingly used to model heart diseases. hiPSC-CMs generated by earlier aggregation-based methods (i.e., embryoid body) often lack functional sarcoplasmic reticulum (SR) Ca stores characteristic of mature mammalian CMs. Newer monolayer-based cardiac differentiation Matrigel sandwich or small molecule-based differentiation) produce high purity and yield, but their handling has not been comprehensively...
Background— New drugs are routinely screened for I Kr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure phosphoinositide 3-kinase inhibitors used in cancer can prolong by inhibiting potassium currents increasing late sodium current ( Na-L ) cardiomyocytes. We tested the extent which blockers with known liability generate arrhythmias through this pathway. Methods Results— Acute dofetilide, an...
Background— Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels prevents CPVT mice humans. It not known whether other I drugs also block what extent channel inhibition contributes efficacy CPVT. Methods Results— We first measured effect of all marketed United States (quinidine, procainamide,...
<h3>Importance</h3> Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by with physical or emotional stress, for which current therapy β-blockers incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release—the cellular mechanism responsible triggering arrhythmias in CPVT—but has never been assessed prospectively. <h3>Objective</h3> To determine whether flecainide dosed to...
Calmodulin (CaM) mutations are associated with an autosomal dominant syndrome of ventricular arrhythmia and sudden death that can present divergent clinical features catecholaminergic polymorphic tachycardia (CPVT) or long QT (LQTS). CaM binds to inhibits ryanodine receptor (RyR2) Ca release channels in the heart, but whether arrhythmogenic mutants alter RyR2 function is not known.To gain mechanistic insight into how human affect channels.We studied recombinant CPVT (N54I N98S) LQTS (D96V,...
Ca binding to the troponin complex represents a major portion of cytosolic buffering. Troponin mutations that increase myofilament sensitivity are associated with familial hypertrophic cardiomyopathy and confer high risk for sudden death. In mice, sensitization causes ventricular arrhythmias, but underlying mechanisms remain unclear.To test hypothesis increases buffering determine resulting arrhythmogenic changes in homeostasis intact mouse heart.Using cardiomyocytes isolated from mice...
Background— The D1275N SCN5A mutation has been associated with a range of unusual phenotypes, including conduction disease and dilated cardiomyopathy, as well atrial ventricular tachyarrhythmias. However, when is studied in heterologous expression systems, most studies show near-normal sodium channel function. Thus, the relationship variant to clinical phenotypes remains uncertain. Methods Results— We identified patient flutter, standstill, disease, sinus node dysfunction. There was no major...
Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early severe expressivity. These LQTS-causative reduce CaM affinity Ca(2+) alter the properties cardiac L-type calcium channel (CaV1.2). also modulates NaV1.5 ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine spectrum prevalence cohort genetically elusive LQTS, functionally characterize novel...
Loss-of-function mutations in Calsequestrin 2 (CASQ2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT patients also exhibit bradycardia and atrial arrhythmias for which the underlying mechanism remains unknown. We aimed to study sinoatrial node (SAN) dysfunction due loss of CASQ2.In vivo electrocardiogram (ECG) monitoring, vitro high-resolution optical mapping, confocal imaging intracellular Ca(2+) cycling, 3D immunohistology were performed wild-type...
Background— The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including one we document here, demonstrate that can cause rapid, polymorphic ventricular tachycardia in absence QT prolongation, indicating a novel proarrhythmic syndrome. We investigated electrophysiological effects vivo vitro using mice, cardiomyocytes, human ion channels heterologously expressed embryonic...