A5035150743- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Neuroscience and Neural Engineering
- Receptor Mechanisms and Signaling
- Cardiomyopathy and Myosin Studies
- MicroRNA in disease regulation
- Cardiovascular Effects of Exercise
- Cardiac pacing and defibrillation studies
- CRISPR and Genetic Engineering
- Circular RNAs in diseases
- Pluripotent Stem Cells Research
- Cardiac Arrhythmias and Treatments
- RNA Interference and Gene Delivery
- 14-3-3 protein interactions
- Connexins and lens biology
- Neuroscience and Neuropharmacology Research
- Nicotinic Acetylcholine Receptors Study
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- ECG Monitoring and Analysis
- RNA regulation and disease
- Atrial Fibrillation Management and Outcomes
- Blood Coagulation and Thrombosis Mechanisms
- Cardiovascular Function and Risk Factors
- Ion Transport and Channel Regulation
The Ohio State University Wexner Medical Center
2023-2025
The Ohio State University
2020-2024
Cleveland State University
2023
Case Western Reserve University
2013-2022
MetroHealth Medical Center
2008-2021
Université de Sherbrooke
2020
MetroHealth
2007-2018
Western University of Health Sciences
2017
Chiang Mai University
2014
University Hospitals Cleveland Medical Center
2014
Brugada syndrome is associated with a high risk of sudden cardiac death and caused by mutations in the voltage-gated sodium channel gene. Previously, R282H-SCN5A mutation gene was identified patients syndrome. In family carrying mutation, an asymptomatic individual had common H558R-SCN5A polymorphism on separate chromosomes. Therefore, we hypothesized that could rescue mutation.In heterologous cells, expression alone did not produce current. However, coexpressing produced significantly...
Abstract Fast opening and closing of voltage-gated sodium channels are crucial for proper propagation the action potential through excitable tissues. Unlike potassium channels, channel α-subunits believed to form functional monomers. Yet, an increasing body literature shows inconsistency with traditional idea a single α-subunit functioning as monomer. Here we demonstrate that not only physically interact each other but they actually assemble, function gate dimer. We identify region involved...
Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized β1(SCN1B) -mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within (<30 nm) perinexal adjacent to gap junctions (GJs), facilitating coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with...
Familial long QT syndrome (LQTS) and Brugada are two distinct human hereditary cardiac diseases known to cause ventricular tachyarrhythmias (torsade de pointes) idiopathic fibrillation, respectively, which can both lead sudden death. Objective: In this study we have identified electrophysiologically characterized, in patients having either LQTS or syndrome, three mutations SCN5A (a sodium channel gene). Method: The mutant channels were expressed a mammalian expression system studied by means...
Kv4.3 encodes the pore‐forming subunit of cardiac transient outward potassium current ( I to ). hKv4.3‐encoded does not fully replicate , suggesting a functionally significant role for accessory subunits. KChIP2 associates with and modifies currents but native . We examined effect several ancillary subunits expressed in heart on currents. Remarkably, Kvβ 3 minK, MiRP‐1, Na channel β 1 increased density modified gating hKv4.3 current. promiscuously assembles vitro, modifying encoded currents;...
Calmodulin (CaM) is a calcium-sensing protein that binds to Na + channels, with unknown functional consequences. Wild-type CaM produced hyperpolarizing shift in the steady-state availability of expressed skeletal muscle (μ1) but not cardiac (hH1) channels. Mutant 1234 did alter voltage dependence or kinetics gating either μ1 hH1. Mutation highly conserved IQ motif carboxyl terminus both isoforms (IQ/AA) slowed current decay and abolished effect wild-type on μ1, hH1 currents. The IQ/AA...
Altered electrical activation of the heart by pacing or disease induces profound ventricular remodeling (VER), manifested electrocardiographically as T-wave memory and ultimately deleterious mechanical from heterogeneous strain. Although is associated with altered expression sarcolemmal ion channels, biophysical mechanisms responsible for triggering cardiac channels are unknown.To test hypothesis that mechanoelectrical feedback triggered regional strain a mechanism VER, dogs (n=6) underwent...
Recently, we reported that sarcoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in molecular mechanism cardiac alternans. Heart failure (HF) is associated with impaired myocardial handling, deficient SERCA2a, and increased susceptibility to Therefore, hypothesized restoring SERCA2a by gene transfer will significantly reduce arrhythmogenic alternans failing heart.Adult guinea pigs were divided into 3...
Brugada syndrome (BrS) is an autosomal-inherited cardiac arrhythmia characterized by ST-segment elevation in the right precordial leads of electrocardiogram and increased risk syncope sudden death. SCN5A, encoding sodium channel Nav1.5, main gene involved BrS. Despite fact that several mutations have been reported N-terminus functional role this region remains unknown. We aimed to characterize two BrS N-terminal mutations, R104W R121W, a construct where was deleted, ΔNter, only present,...
Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for variable phenotype severity observed some LQT2 families. Here, we identified contributors to expressivity family using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing a synergistic manner....
Abstract Objective To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. Methods Retrospective data from a cohort of 55 patients with myopathy, sequentially stratified by the presence proximal weakness, early remission, and corticosteroid IVIG use at treatment induction, were analyzed for optimal induction maintenance remission strategies. Results A total 14 achieved corticosteroid-free strategy (25%). In 41 treated corticosteroids, only 4 (10%) failed an...
Background: MicroRNAs (miRs) play critical roles in regulation of numerous biological events, including cardiac electrophysiology and arrhythmia, through a canonical RNA interference mechanism. It remains unknown whether endogenous miRs modulate physiologic homeostasis the heart noncanonical mechanisms. Methods: We focused on predominant miR (miR1) investigated miR1 could physically bind with ion channels cardiomyocytes by electrophoretic mobility shift assay, situ proximity ligation pull...
Background — The transient outward potassium current ( I to ) encoded by the Kv4 family of channels is important in repolarization cardiac myocytes. KChIPs are a recently identified group Ca 2+ -binding accessory subunits that modulate Kv4-encoded currents. KChIP2 only member expressed heart. Methods and Results We previously cloned 2 novel splice variants from human heart, named KChIP2S KChIP2T. transmural distribution mRNA protein canine left ventricle was examined using kinetic RT-PCR...
Chronic kidney disease progression can be predicted based on the degree of tubular atrophy, which is result proximal tubule apoptosis. The Na+/H+ exchanger NHE1 regulates cell survival through interaction with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], but pathophysiologic triggers for inactivation are unknown. Because glomerular injury permits luminal exposure and reabsorption fatty acid/albumin complexes, we hypothesized that accumulation amphipathic, long-chain acyl-CoA (LC-CoA)...
NOTCH1 pathogenic variants are implicated in multiple types of congenital heart defects including hypoplastic left syndrome, where the ventricle is underdeveloped. It unknown how regulates human cardiac cell lineage determination and cardiomyocyte proliferation. In addition, mechanisms by which lead to ventricular hypoplasia syndrome remain elusive.CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 genome editing was utilized delete induced pluripotent stem cells....
The Ca(2+)-independent transient outward K(+) current (I(to)) plays an important electrophysiological role in normal and diseased hearts. However, its contribution to ventricular repolarization remains controversial because of differences phenotypic expression function across species. dog, a frequently used model human cardiac disease, exhibits altered functional I(to). To better understand the relevance electrical remodeling dogs humans, we studied I(to) both species with...
Pentamidine is an antiprotozoal compound that clinically causes acquired long QT syndrome (acLQTS), which associated with prolonged intervals, tachycardias, and sudden cardiac arrest. delays terminal repolarization in human heart by acutely blocking inward rectifier currents. At the same time, pentamidine reduces surface expression of potassium channel I<sub>Kr</sub>/human ether à-go-go-related gene (hERG). This unusual acLQTS caused most often direct block current I<sub>Kr</sub>/hERG. The...
Nitric oxide (NO) derived from the activity of neuronal nitric synthase (NOS1) is involved in S-nitrosylation key sarcoplasmic reticulum (SR) Ca 2+ handling proteins. Deficient cardiac ryanodine receptor (RyR2) has a variable effect on SR leak/sparks isolated myocytes, likely dependent underlying physiological state. It remains unknown, however, whether such molecular aberrancies are causally related to arrhythmogenesis intact heart. Here we show heart, reduced NOS1 increased -mediated...