Sudden cardiac death is the single leading cause of heart failure mortality. The working hypothesis of our SCOR program is as follows: Delayed and dispersed repolarization in failing myocardium predisposes to fatal ventricular arrhythmias. Project 1 addresses this hypothesis by probing the biological basis of normal and abnormal repolarization. The overall goals are, first, ti dissect the relative roles of various genetically-defined potassium currents in the process of cardiac repolarization; second, to use that information to probe arrhythmic mechanisms at a cellular level; and a third, to lay the groundwork for gene therapy of complex excitability disorders. The project relies on transfer of ion channel genes and proteins into adult ventricular myocytes as central technologies for probing repolarization. While we rely predominantly on human or canine myocytes as central technologies for probing repolarization. While we rely predominantly on human or canine myocytes, from both normal and failing hearts, other mammalian species will be used as needed to probe specific aspects from both normal and failing hearts, other mammalian species will be used as needed to probe specific aspects of repolarization. A variety of wild-type and dominant-negative channel constructs will be introduced into myocytes by viral gene transfer or somatic cell fusion, and the functional consequences characterized. Selective enhancement or suppression of defined potassium current components will enable systematic assessment of the role of each component in the repolarization process. The findings will be interpreted in the context of biophysically- detailed models of the cardiac action potential. The information gained at a cellular level will guide gene transfer experiments designed to alter cardiac excitability in vivo, in a graded and reversible manner. Thus, Project 1 will not only increase our understanding of the molecular basis of cardiac repolarization; it will also take the first steps towards putting that information to practical therapeutic use.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
2P50HL052307-06
Application #
6302271
Study Section
Project Start
2000-04-15
Project End
2000-12-31
Budget Start
Budget End
Support Year
6
Fiscal Year
2000
Total Cost
$209,733
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhu, Guangshuo; Groneberg, Dieter; Sikka, Gautam et al. (2015) Soluble guanylate cyclase is required for systemic vasodilation but not positive inotropy induced by nitroxyl in the mouse. Hypertension 65:385-92
Ashikaga, Hiroshi; Leclercq, Christophe; Wang, Jiangxia et al. (2010) Hemodynamic improvement in cardiac resynchronization does not require improvement in left ventricular rotation mechanics: three-dimensional tagged MRI analysis. Circ Cardiovasc Imaging 3:456-63
Sachdev, Molly; Fetics, Barry J; Lai, Shenghan et al. (2010) Failure in short-term prediction of ventricular tachycardia and ventricular fibrillation from continuous electrocardiogram in intensive care unit patients. J Electrocardiol 43:400-7
Cheng, Alan; Dalal, Darshan; Fetics, Barry J et al. (2009) Ibutilide-induced changes in the temporal lability of ventricular repolarization in patients with and without structural heart disease. J Cardiovasc Electrophysiol 20:873-9
Deschenes, Isabelle; Armoundas, Antonis A; Jones, Steven P et al. (2008) Post-transcriptional gene silencing of KChIP2 and Navbeta1 in neonatal rat cardiac myocytes reveals a functional association between Na and Ito currents. J Mol Cell Cardiol 45:336-46
Armoundas, Antonis A; Rose, Jochen; Aggarwal, Rajesh et al. (2007) Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms. Am J Physiol Heart Circ Physiol 292:H1607-18
Tanskanen, Antti J; Alvarez, Luis H R (2007) Voltage noise influences action potential duration in cardiac myocytes. Math Biosci 208:125-46
Akar, Fadi G; Nass, Robert D; Hahn, Samuel et al. (2007) Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure. Am J Physiol Heart Circ Physiol 293:H1223-30
Tanskanen, Antti J; Greenstein, Joseph L; Chen, Alex et al. (2007) Protein geometry and placement in the cardiac dyad influence macroscopic properties of calcium-induced calcium release. Biophys J 92:3379-96
Takimoto, Eiki; Belardi, Diego; Tocchetti, Carlo G et al. (2007) Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation 115:2159-67

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