Cardiovascular disease is a major health problem in the western world and in the United States alone accounts for an estimated 500,000 deaths each year. The underlying mechanisms behind sudden cardiac death remain poorly understood. Many types of cardiovascular disorders including ischemic heart disease and heart failure are associated with extensive fibrosis. A critical event in the development of cardiac fibrosis is the transformation of fibroblasts into an active phenotype or myofibroblast. The question of whether fibroblast activation results in a different electrical phenotype that makes the heart susceptible to arrhythmic events remains to be explored. In this proposal, we will investigate the electrical phenotype of fibroblasts isolated from infarcted tissue. We will also work toward identifying new therapeutic approaches designed to alter the electrical phenotype of these cells. The overall aims of the grant are directed at determining whether preventing, delaying or limiting the activation of cardiac fibroblasts has potential beneficial antiarrhythmic effects. We have proposed three specific aims:
Specific Aim 1 is to determine the potential of fibroblasts isolated from infarcted hearts to influence impulse propagation and arrhythmogenesis in heterocellular cultures of myocytes and adult fibroblasts. We hypothesize that cardiac injury alters the electrical phenotype of fibroblasts as assessed by high resolution optical mapping of heterocellular cultures.
Specific Aim 2 is to determine the electrophysiological mechanisms of fibroblast activation. Here we hypothesize that the electrophysiological phenotype of fibroblasts isolated from infarcted tissue results from the combined effect of an increase in the level of intercellular coupling and a change in the resting membrane potential.
Specific Aim 3 is to determine whether one of the pleiotropic effects of the HMG-CoA reductase inhibitors includes improving the conduction properties of infarcted tissue and rescuing the electrical phenotype of fibroblasts isolated from infarcted hearts. In this aim, we hypothesize that the anti-fibrotic properties of statins will attenuate the electrophysiological effects of fibroblast activation as assessed in isolated infarcted hearts and heterocellular cultures of myocytes and fibroblasts. To achieve these aims, we will utilize a combination of molecular biological and cellular electrophysiological techniques, as well as high resolution optical mapping technology at the organ and cellular levels.

Public Health Relevance

Cardiovascular disease is a major health problem accounting for an estimated 500,000 deaths each year in the United States. Fibrosis is associated with many forms of cardiovascular disease and may contribute to the development of lethal arrhythmias. The question of whether fibroblast activation alters the electrophysiological substrate remains to be explored. In this proposal, we will investigate fibroblast activation and identify new therapeutic approaches designed to alter their electrical phenotype.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076751-08
Application #
8257559
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2004-04-01
Project End
2013-07-31
Budget Start
2012-05-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$436,166
Indirect Cost
$178,841
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Lader, Joshua M; Vasquez, Carolina; Bao, Li et al. (2011) Remodeling of atrial ATP-sensitive Kýýý channels in a model of salt-induced elevated blood pressure. Am J Physiol Heart Circ Physiol 301:H964-74
Remo, Benjamin F; Qu, Jiaxiang; Volpicelli, Frank M et al. (2011) Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias. Circ Res 108:1459-66
Bao, Li; Kefaloyianni, Eirini; Lader, Joshua et al. (2011) Unique properties of the ATP-sensitive K? channel in the mouse ventricular cardiac conduction system. Circ Arrhythm Electrophysiol 4:926-35
Vasquez, Carolina; Benamer, Najate; Morley, Gregory E (2011) The cardiac fibroblast: functional and electrophysiological considerations in healthy and diseased hearts. J Cardiovasc Pharmacol 57:380-8
Morrow, John P; Katchman, Alexander; Son, Ni-Huiping et al. (2011) Mice with cardiac overexpression of peroxisome proliferator-activated receptor ? have impaired repolarization and spontaneous fatal ventricular arrhythmias. Circulation 124:2812-21
Bernstein, Scott A; Duggirala, Srikant; Floberg, Michael et al. (2011) Spatiotemporal electrophysiological changes in a murine ablation model. Europace 13:1494-500
Rentschler, Stacey; Harris, Brett S; Kuznekoff, Laura et al. (2011) Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways. J Clin Invest 121:525-33
Vasquez, Carolina; Mohandas, Poornima; Louie, Karen L et al. (2010) Enhanced fibroblast-myocyte interactions in response to cardiac injury. Circ Res 107:1011-20
Danik, Stephan B; Rosner, Gregg; Lader, Joshua et al. (2008) Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts. FASEB J 22:1204-12
Lehnart, Stephan E; Mongillo, Marco; Bellinger, Andrew et al. (2008) Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J Clin Invest 118:2230-45

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