The goal of these studies is to comprehensively characterize gender differences in Ca handling, ionic currents & beta-AR responsiveness that contribute to arrhythmogenesis, both in control and heart failure (HF), and how they are modulated by sex hormones. We have shown that VT in nonischemic HF arises primarily by nonreentrant mechanisms due to SR Ca overload activating a transient inward current (I/ti). Upregulated Na/Ca exchange (NCX) underlies greater I/ti, decreased inward rectifying K current (IK1) enhances the depolarization by I/ti and preserved beta-adrenergic receptor (beta-AR) responsiveness allows SR Ca overload. Gender differences in repolarization (prolonged QT interval & decreased K currents in females) are arrhythmogenic, but surprisingly females with HF have lower mortality and decreased arrhythmia inducibility. We hypothesize that there are gender-specific differences (due to sex hormones) in a) myocyte Ca handling, b) K currents, and c) beta-adrenergic responsiveness, and that these change differentially in HF, contributing to decreased arrhythmogenesis in HF females.
Specific Aims will focus on: 1. Sex differences in Ca handling, repolarization, and beta-AR response in Ctl & HF are due to sex hormones (focused in vivo & in vitro studies (repolarization, arrhythmogenesis, Ca handling) in gonadectomized rabbits, +/- estrogen or testosterone). 2. Gender differences in Ca handling +/- HF primarily involve SR Ca transport (delta(Ca)i, SERCA, phospholamban, NCX, Ica, EC coupling,beta -adrenergic receptor (beta-AR) pathway) 3. Electrophysiological gender differences +/- HF contribute to arrhythmias (APs, ion currents (e.g. IK, Ito, IK1), channel expression, AAP duration modulates SR Ca load, in vivo +/- beta-AR stimulation). Experimental approaches will include: assessment of repolarization & arrhythmogenesis in vivo, fluorescence measurement of (Ca)i, in vitro patch clamping (voltage, current, & AP clamp), measurement of mRNA & protein (of Ca transporters & ion channel protein), assays of Ca transport function. Detailed studies in a well-characterized arrhythmogenic rabbit model of nonischemic HF (+/- gonadectomy and hormone replacement) will be mechanistically assessed by focused studies in cells & tissue from nonfailing & HF human hearts. The results will provide the foundation for novel (and possibly gender-specific) therapeutic strategies to treat arrhythmias in HF based on cellular processes that are modulated by sex hormones.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL073966-01A1
Application #
6782762
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Przywara, Dennis
Project Start
2004-04-01
Project End
2008-03-30
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$421,908
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Han, Chengzong; Pogwizd, Steven M; Yu, Long et al. (2015) Imaging cardiac activation sequence during ventricular tachycardia in a canine model of nonischemic heart failure. Am J Physiol Heart Circ Physiol 308:H108-14
Han, Chengzong; Pogwizd, Steven M; Killingsworth, Cheryl R et al. (2013) Noninvasive cardiac activation imaging of ventricular arrhythmias during drug-induced QT prolongation in the rabbit heart. Heart Rhythm 10:1509-15
Zhu, Yujie; Ai, Xun; Oster, Robert A et al. (2013) Sex differences in repolarization and slow delayed rectifier potassium current and their regulation by sympathetic stimulation in rabbits. Pflugers Arch 465:805-18
Han, Chengzong; Pogwizd, Steven M; Killingsworth, Cheryl R et al. (2012) Noninvasive reconstruction of the three-dimensional ventricular activation sequence during pacing and ventricular tachycardia in the canine heart. Am J Physiol Heart Circ Physiol 302:H244-52
Gilbert, Stephen H; Benson, Alan P; Walton, Richard D et al. (2011) Slowed propagation across the compacta-trabeculata interface: a consequence of fiber and sheet anisotropy. Conf Proc IEEE Eng Med Biol Soc 2011:1688-92
Han, Chengzong; Pogwizd, Steven M; Killingsworth, Cheryl R et al. (2011) Noninvasive imaging of three-dimensional cardiac activation sequence during pacing and ventricular tachycardia. Heart Rhythm 8:1266-72
Ai, Xun; Jiang, Aiyang; Ke, Yunbo et al. (2011) Enhanced activation of p21-activated kinase 1 in heart failure contributes to dephosphorylation of connexin 43. Cardiovasc Res 92:106-14
Han, Chengzong; Pogwizd, Steven M; Killingsworth, Cheryl R et al. (2011) Noninvasive reconstruction of the three-dimensional ventricular activation sequence during pacing and ventricular tachycardia in the rabbit heart. Conf Proc IEEE Eng Med Biol Soc 2011:1684-7
Rinne, Andreas; Kapur, Nidhi; Molkentin, Jeffery D et al. (2010) Isoform- and tissue-specific regulation of the Ca(2+)-sensitive transcription factor NFAT in cardiac myocytes and heart failure. Am J Physiol Heart Circ Physiol 298:H2001-9
Attin, Mina; Ideker, Raymond E; Pogwizd, Steven M (2008) Mechanistic insights into ventricular arrhythmias from mapping studies in humans. Heart Rhythm 5:S53-8

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