A5002625543- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Atrial Fibrillation Management and Outcomes
- Cardiomyopathy and Myosin Studies
- Cardiac Arrhythmias and Treatments
- Cardiovascular Function and Risk Factors
- Cardiovascular Effects of Exercise
- Histone Deacetylase Inhibitors Research
- Neuroscience and Neural Engineering
- Heart Failure Treatment and Management
- Connexins and lens biology
- Erythrocyte Function and Pathophysiology
- Cardiac Fibrosis and Remodeling
- Viral Infections and Immunology Research
- Diabetes and associated disorders
- Peptidase Inhibition and Analysis
- S100 Proteins and Annexins
- Muscle Physiology and Disorders
- Receptor Mechanisms and Signaling
- Fuel Cells and Related Materials
- Sports injuries and prevention
- Blood properties and coagulation
- Genetics and Physical Performance
- Nicotinic Acetylcholine Receptors Study
- Endoplasmic Reticulum Stress and Disease
Virginia Tech
2015-2022
Biomedical Research Institute
2022
The Ohio State University
2017-2021
The Ohio State University Wexner Medical Center
2017-2020
Lung Institute
2018
Virginia Commonwealth University
2017
Carilion Clinic
2016
University of Utah
2012
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with arrhythmias and an increased risk of sudden death. Currently, there are no approved treatments that address the underlying genetic cause this disease, representing significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding desmosomal protein, account for approximately 40% ARVC cases result reduced gene expression.
Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6's role HFpEF their shared mechanisms inflammation and metabolism. Here, show inhibiting HDAC6 TYA-018 effectively reverses established heart its associated symptoms male mouse models. Additionally, mice lacking...
Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with long-QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields depletion of local ion nanodomains. Models predict that significantly decreasing cleft widths slows conduction because reduced current driving force, termed "self-attenuation." We tested novel hypothesis self-attenuation...
Abstract Atrial fibrillation (AF) is the most common arrhythmia and associated with inflammation. AF patients have elevated levels of inflammatory cytokines known to promote vascular leak, such as endothelial growth factor A (VEGF). However, contribution leak consequent cardiac edema genesis atrial arrhythmias remains unknown. Previous work suggests that interstitial in heart can acutely ventricular by disrupting myocyte intercalated disk (ID) nanodomains rich sodium channels (Na V 1.5)...
Heart failure (HF) remains a major source of morbidity and mortality in the US. The multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) has emerged as critical regulator cardiac hypertrophy failure, although mechanisms remain unclear. Previous studies have established that cytoskeletal protein βIV-spectrin coordinates local CaMKII signaling. Here, we sought to determine role spectrin-CaMKII complex maladaptive remodeling HF. Chronic pressure overload (6 weeks transaortic...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with arrhythmias and an increased risk of sudden death. Mutations in the desmosome gene Plakophilin-2, PKP2, lead to reduction PKP2 protein collapse desmosomes that known compromise contractility electrical stability cardiomyocytes. Our previous studies demonstrated efficacy adeno-associated virus 9 (AAV9)-mediated restoration expression specific knock-out mouse model Pkp2 revealed profound...
Hypertrophic cardiomyopathy (HCM) affects approximately 600,000 people in the United States. Loss-of-function mutations Myosin Binding Protein C3, MYBPC3, are most common genetic cause of HCM, with majority resulting haploinsufficiency. To restore cardiac we use an adeno-associated virus (AAV9) vector and engineer optimized expression cassette a minimal promoter cis-regulatory elements (TN-201) to enhance packaging efficiency cardiomyocyte expression. Rather than simply preventing...
The mechanisms underlying Ca2+/calmodulin-dependent protein kinase II (CaMKII)-induced arrhythmias in ischemia-reperfusion (I/R) are not fully understood. We tested the hypothesis that CaMKII increases late Na+ current ( INa,L) via phosphorylation of Nav1.5 at Ser571 during I/R, thereby increasing arrhythmia susceptibility. To test our hypothesis, we studied isolated, Langendorff-perfused hearts from wild-type (WT) mice and expressing Nav channel variants Nav1.5-Ser571E (S571E)...
Increased fibrosis is a characteristic remodeling response to biomechanical and neurohumoral stress determinant of cardiac mechanical electrical dysfunction in disease. Stress-induced activation fibroblasts (CFs) critical step the fibrotic response, although precise sequence events underlying these cells vivo remain unclear. Here, we tested hypothesis that βIV-spectrin/STAT3 complex essential for maintenance quiescent phenotype (basal nonactivated state) CFs. We reported increased fibrosis,...
Abstract Background Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for development of AF. Although defective atrial myocyte excitability due to stress-induced remodeling ion channels commonly observed in setting AF, little known about mechanistic link between and Recent studies have identified increased cardiac late sodium current ( I Na,L ) downstream calmodulin-dependent kinase II (CaMKII) activation...
In the heart, pathways that transduce extracellular environmental cues (e.g. mechanical force, inflammatory stress) into electrical and/or chemical signals at cellular level are critical for organ-level response to chronic biomechanical/neurohumoral stress. Specifically, a diverse array of membrane-bound receptors and stretch-activated proteins converge on network intracellular signaling cascades control gene expression, protein translation, degradation regulation. These reprogramming events...
Many cardiac pathologies are associated with reduced gap junction (GJ) coupling, an important modulator of conduction velocity (CV). However, the relationship between phenotype and functional expression connexin GJ family proteins is controversial. For example, a 50% reduction coupling has been shown to have little impact on myocardial CV due concept known as reserve. This can be explained by ephaptic (EpC) theory whereby maintained combination low increased electrical fields generated in...
Rapid ventricular pacing rates induces two types of beats following cessation: recovery cycle length (RCL) prolongation (overdrive suppression) and RCL shortening excitation). The goals this study were to compare common experimental protocols for studying triggered activity in whole-heart preparations differentiate between using a new methodology. Post-pacing beat QRS normalized pre-paced R-R intervals analyzed K-means clustering algorithm. Control hearts only produced suppressed beats:...
Both β adrenergic and muscarinic receptor stimulation independently potentiate arrhythmogenesis. However, the effect of simultaneous on arrhythmogenesis is not well known. The purpose this study was to determine temporal response arrhythmia risk individual combined autonomic agonists. Guinea pig hearts were excised Langendorff-perfused. agonists isoproterenol (ISO, 0.6 μM) acetylcholine (ACh, 10 μM), respectively. All measurements with occurred over 21 min. ISO induced ectopic activity for...
Abstract Background Hypertrophic cardiomyopathy (HCM) affects an estimated 600,000 people in the U.S. and is leading cause of sudden cardiac arrest those under 18. Loss-of-function mutations Myosin Binding Protein C3 , MYBPC3 are most common genetic HCM. The majority causative for HCM result truncations. sarcomeric pathophysiology patients with appears to be due haploinsufficiency, as total amount protein incorporated into sarcomeres falls significantly below normal. Methods A clear path...
Abstract Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited associated with arrhythmias and increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause this disease, representing a significant unmet need. Purpose Mutations in desmosome gene Plakophilin-2 (PKP2) account for approximately 40% ARVC cases result reduced expression. Our goal to examine feasibility efficacy restoration PKP2...
slowed atrial conduction as assessed by optical voltage mapping (10 ± 0.4 vs. 21 1 cm/s at baseline, p < 0.05).Burst pacing induced AF in 4 hearts out of 5 tested following VEGF treatment but not before.In summary, indirect CLEM identifies ID nanodomain deadhesion and NaV1.5 translocation acute treatment.Importantly, these structural changes correlated with increased inducibility.These results suggest that vascular leak-induced remodeling may contribute to the development AF.
Background: Atrial fibrillation (AF), which is characterized by chaotic patterns of electrical activation the atria, affects over 4 million people in US alone. We previously identified nanoscale structural abnormalities hearts AF patients. Specifically, they displayed swelling gap junction (GJ) –adjacent perinexi, specialized nanodomains rich cardiac sodium channels (Na V 1.5) and located within intercalated disks (IDs; sites electromechanical contact between adjacent cells). However,...