verbatim): Arrhythmias are a major health problem in cardiomyopathies of both ischemic and non-ischemic origin. As many as 50 percent of patients with congestive heart failure (CHF) die suddenly, accounting for more than 250,000 annual deaths. Pharmacological treatments of arrhythmias often fail, and internal defibrillators are expensive and limit quality of life. Inflammatory cytokines, including TNF-alpha, are increased in the serum and hearts of patients with CHF. TNF-alpha is also transiently increased following myocardial infarction, is elevated in inflammatory conditions such as sepsis, and increases with age and hypertrophy. All of these conditions are characterized by increased susceptibility to ventricular arrhythmias. The potential role of cytokines in the pathogenesis of arrhythmias has not been extensively studied. We have recently engineered mice that overexpress TNF-alpha in the heart and develop a cardiomyopathy characterized by atrial and ventricular dilatation, decreased ejection fraction, CHF, and decreased survival. Radio-telemetry monitoring of transgenic mice shows high-grade atrial and ventricular arrhythmias. Optical mapping studies of program-stimulated, Langendorff-perfused hearts using voltage- and Ca2+-sensitive dyes show inducible ventricular tachycardia (VT), slow conduction of premature beats, elevated diastolic and decreased peak systolic Ca2+, and prolongation of the Ca2+ transient. Mating of these mice to long QT transgenic mice yields offspring that die suddenly, without evidence of CHF. The goals of this project are to determine the mechanism(s) by which cytokines may promote arrhythmias and sudden death in acute and chronic cardiac conditions, and to test whether treatments for CHF reverse the effects. To this end, we will study ambulatory telemetry-monitored mice, isolated Langendorff-perfused hearts stained with voltage- and Ca2+-sensitive dyes, and isolated myocytes from control and transgenic mice. We will: 1) Test the hypothesis that acute exposure to TNF-alpha, IL-1 beta, and/or LPS predisposes to cardiac arrhythmias, and determine the mechanism(s) responsible; 2) Identify the mechanisms responsible for atrial and ventricular arrhythmias in the TNF-alpha mouse model of CHF. 3) Determine to what extent and by what mechanisms treatments of CHF with beta-blockers, ACE inhibitors, and soluble TNF receptors decrease arrhythmias; and 4) Examine to what extent and by what mechanisms repolarization abnormalities exacerbate arrhythmias and sudden death in this mouse model of CHF.
| Petkova-Kirova, Polina S; London, Barry; Salama, Guy et al. (2012) Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-?. Am J Physiol Heart Circ Physiol 302:H934-52 |
| Salama, Guy; Baker, Linda; Wolk, Robert et al. (2009) Arrhythmia phenotype in mouse models of human long QT. J Interv Card Electrophysiol 24:77-87 |
| Nilles, Kathy M; London, Barry (2007) Knockin animal models of inherited arrhythmogenic diseases: what have we learned from them? J Cardiovasc Electrophysiol 18:1117-25 |
| Salama, Guy; London, Barry (2007) Mouse models of long QT syndrome. J Physiol 578:43-53 |
| Petkova-Kirova, Polina S; Gursoy, Erdal; Mehdi, Haider et al. (2006) Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha. Am J Physiol Heart Circ Physiol 290:H2098-107 |
| Saba, Samir; Janczewski, Andrzej M; Baker, Linda C et al. (2005) Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}. Am J Physiol Heart Circ Physiol 289:H1456-67 |
| Chen, Hsiao-Huei; Baty, Catherine J; Maeda, Tomoji et al. (2004) Transcription enhancer factor-1-related factor-transgenic mice develop cardiac conduction defects associated with altered connexin phosphorylation. Circulation 110:2980-7 |
| Shusterman, Vladimir; Aysin, Benhur; Ermentrout, G Bard et al. (2003) Detecting instabilities of cardiac rhythm. J Electrocardiol 36 Suppl:219-26 |
| London, Barry; Baker, Linda C; Lee, Joon S et al. (2003) Calcium-dependent arrhythmias in transgenic mice with heart failure. Am J Physiol Heart Circ Physiol 284:H431-41 |
| Shusterman, Vladimir; Usiene, Irmute; Harrigal, Chivonne et al. (2002) Strain-specific patterns of autonomic nervous system activity and heart failure susceptibility in mice. Am J Physiol Heart Circ Physiol 282:H2076-83 |
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