Cardiac arrhythmias are the leading cause of death among heart failure (HF) patients. A growing body of evidence indicates that dysregulation in intracellular Ca2+ is a critical factor in these arrhythmias. Importantly, alterations in myocyte Ca2+ release are also widely considered the central player in the pathophysiology of heart failure. Specifically, HF myocytes display reduced sarcoplasmic reticulum (SR) Ca2+ stores and a reduction in SR Ca2+ transients. However, Ca2+-dependent arrhythmias (e.g., delayed after-depolarizations, DADs) are normally induced by SR Ca2+ overload. A critical, but unresolved question about heart failure is: how can Ca2+-dependent arrhythmias occur during HF, in a setting of globally decreased SR Ca2+ content? This paradox is poorly understood. Our long-term objective is to gain a mechanistic understanding of the Ca2+-dependent arrhythmias in HF. We recently observed striking remodeling of the t-tubule (TT) system and orphaned ryanodine receptors (RyRs) in cardiomyocytes isolated from spontaneously hypertensive rats (SHR) with overt HF. Based on our published and preliminary results, we hypothesize that during HF, TT structural remodeling plays an important mechanistic role in unstable Ca2+ homeostasis and therefore Ca2+-depedent arrhythmogenesis. Moreover, we predict that signaling pathways (e.g., PKA hyperphosphorylation and CaMKII upregulation) utilized by myocytes to compensate in response to primary insults may modulate TT remodeling. To test these hypotheses, we will address three specific aims:
Aim 1 - Evaluate the relationship between alterations in TT system and dysfunctional EC coupling in failing cardiomyocytes;
Aim 2 - Determine the role of TT remodeling in Ca2+-dependent arrhythmogenesis in HF;
Aim 3 - Define the role of CaMKII and PKA signaling in TT ultrastructural remodeling, abnormal Ca2+ signaling, and Ca2+-dependent arrhythmogenesis in HF models. To achieve these aims, we will combine state-of-the-art techniques, including patch-clamp (whole-cell, loose-sealed patch clamp);high-resolution confocal imaging;immunofluorescence;and digital image processing. We will use these techniques to examine isolated myocytes and intact hearts from mouse experimental HF models, including control and genetic mice in which phosphorylation is `globally'inhibited (AC3-I) or where specific CaMKII and PKA phosphorylation sites are disabled (RyR- S2814A, RyR-S2808A). We anticipate that fulfilling the proposed project will improve our understanding of the mechanisms underlying Ca2+-dependent arrhythmias and sudden cardiac death in human cardiomyopathies, and provide important insights into the development of effective therapeutic strategies for preventing and treating human HF and fatal cardiac arrhythmias.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Krull, Holly
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
Zip Code
Huang, Chun-kai; Chen, Bi-yi; Guo, Ang et al. (2016) Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model. Acta Pharmacol Sin 37:473-82
Zhang, Wenjun; Qu, Xiuxia; Chen, Biyi et al. (2016) Critical Roles of STAT3 in β-Adrenergic Functions in the Heart. Circulation 133:48-61
Zhu, Yanqi; Zhang, Caimei; Chen, Biyi et al. (2016) Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes. J Mol Cell Cardiol 97:204-12
Hajj, Georges P; Chu, Yi; Lund, Donald D et al. (2015) Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice. Arterioscler Thromb Vasc Biol 35:1653-62
Wu, Yuejin; Rasmussen, Tyler P; Koval, Olha M et al. (2015) The mitochondrial uniporter controls fight or flight heart rate increases. Nat Commun 6:6081
Wei, Chaoliang; Qiu, Jinsong; Zhou, Yu et al. (2015) Repression of the Central Splicing Regulator RBFox2 Is Functionally Linked to Pressure Overload-Induced Heart Failure. Cell Rep :
Takeshima, Hiroshi; Hoshijima, Masahiko; Song, Long-Sheng (2015) Ca²⁺ microdomains organized by junctophilins. Cell Calcium 58:349-56
Zhang, Jingqun; Zhou, Qiang; Smith, Chris D et al. (2015) Non-β-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure. Biochem J 470:233-42
Chen, Biyi; Zhang, Caimei; Guo, Ang et al. (2015) In situ single photon confocal imaging of cardiomyocyte T-tubule system from Langendorff-perfused hearts. Front Physiol 6:134
Guo, Ang; Hall, Duane; Zhang, Caimei et al. (2015) Molecular Determinants of Calpain-dependent Cleavage of Junctophilin-2 Protein in Cardiomyocytes. J Biol Chem 290:17946-55

Showing the most recent 10 out of 44 publications