Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal-dominant disease resulting from mutations in genes encoding sarcomeric proteins. Cardiac arrhythmias and sudden death are a major cause for the high mortality of patients with sarcomeric mutations. While there is a rough relationship between prognosis and the degree of cardiac hypertrophy and fibrosis, this genotype/phenotype correlation is weak. In particular, the mechanism(s) that cause ventricular arrhythmias in young patients with either limited or absent myocardial hypertrophy or fibrosis are poorly understood. In vitro studies have shown that most FHC-linked mutations in sarcomeric proteins (e.g., troponin T, troponin I, tropomyosin) increase myofilament Ca2+ sensitivity. Our work during the last funded period strongly suggests that increased Ca2+ sensitivity in and of itself may be pro-arrhythmic: Transgenic mice expressing Ca2+- sensitizing mutations of troponin T (TnT-I79N, TnT-F110I) have an increased incidence of ventricular arrhythmias that occur in the absence of myocardial hypertrophy or fibrosis. In contrast, transgenic mice expressing the relatively benign FHC-linked TnT-R278C mutation, which does NOT increase Ca2+ sensitivity, do NOT develop ventricular arrhythmias. Further supporting this hypothesis we showed that acutely increasing myofilament Ca2+ sensitivity with EMD57033 in wild-type animals also increased the risk for ventricular tachycardia (VT). Moreover, myofilament de-sensitization and contractile uncoupling prevented the pro- arrhythmic effects of the TnT-mutants and EMD. Based on these data we found that EMD exerted its effect by duplicating the altered myocyte Ca2+ handling, action potential remodeling, afterdepolarizations and ventricular arrhythmias seen in transgenic mouse hearts expressing Ca2+-sensitizing TnT mutants. Thus, we hypothesize that increased myofilament Ca2+ sensitivity contributes to the risk for ventricular arrhythmias.
Each AIM will examine specific mechanisms that could contribute to this chain of events. In addition to studying mice expressing FHC-linked mutations, we will also use Ca2+ sensitization by EMD to model effects of sarcomeric mutations in rabbits to test the hypothesis in a model with more human-like cardiac electrophysiology.
AIM 1 : To determine the effect of myofilament Ca2+ sensitization on cardiac Ca2+ handling AIM 2: To determine the effect of myofilament Ca2+ sensitization on the ventricular action potential and its heart rate dependence AIM 3: To determine the effect of myofilament Ca2+ sensitization on cell-cell coupling and on arrhythmia susceptibility in the intact heart The results of the proposed experiments will significantly advance our understanding of arrhythmia mechanisms responsible for the high rate of sudden cardiac death in sarcomeric cardiomyopathies.

Public Health Relevance

Research Lay Summary Familial hypertrophic cardiomyopathy is the most common inherited heart disease associated with heart enlargement and a high mortality rate from abnormal heart rhythms (=arrhythmias). The proposed research focuses on discovering the underlying mechanism(s) responsible for the arrhythmias. Result from our studies may provide new therapeutic strategies for this presently incurable disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071670-09
Application #
8242681
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2003-09-01
Project End
2013-12-11
Budget Start
2012-04-01
Budget End
2013-12-11
Support Year
9
Fiscal Year
2012
Total Cost
$378,180
Indirect Cost
$130,680
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Boczek, Nicole J; Gomez-Hurtado, Nieves; Ye, Dan et al. (2016) Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. Circ Cardiovasc Genet 9:136-46
Gomez-Hurtado, Nieves; Boczek, Nicole J; Kryshtal, Dmytro O et al. (2016) Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks. Circ Arrhythm Electrophysiol 9:
Hill, Adam P; Perry, Matthew D; Abi-Gerges, Najah et al. (2016) Computational cardiology and risk stratification for sudden cardiac death: one of the grand challenges for cardiology in the 21st century. J Physiol 594:6893-6908
Kryshtal, Dmytro O; Dawling, Sheila; Seger, Donna et al. (2016) In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning. J Med Toxicol 12:165-71
Boutaud, Olivier; Sosa, I Romina; Amin, Taneem et al. (2016) Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis. Cancer Prev Res (Phila) 9:855-865
Glukhov, Alexey V; Kalyanasundaram, Anuradha; Lou, Qing et al. (2015) Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1. Eur Heart J 36:686-97
Savio-Galimberti, Eleonora; Knollmann, Björn C (2015) Channel Activity of Cardiac Ryanodine Receptors (RyR2) Determines Potency and Efficacy of Flecainide and R-Propafenone against Arrhythmogenic Calcium Waves in Ventricular Cardiomyocytes. PLoS One 10:e0131179
Hwang, Hyun Seok; Kryshtal, Dmytro O; Feaster, T K et al. (2015) Comparable calcium handling of human iPSC-derived cardiomyocytes generated by multiple laboratories. J Mol Cell Cardiol 85:79-88
Liu, Bin; Ho, Hsiang-Ting; Brunello, Lucia et al. (2015) Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT. Cardiovasc Res 108:299-311
Feaster, Tromondae K; Cadar, Adrian G; Wang, Lili et al. (2015) Matrigel Mattress: A Method for the Generation of Single Contracting Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Circ Res 117:995-1000

Showing the most recent 10 out of 65 publications