Cardiac arrhythmias remain a leading cause of morbidity and mortality in the US. In multiple forms of cardiac disease, arrhythmias result from disturbances in intracellular calcium (Ca) cycling, the process that normally couples electrical excitation to mechanical function. Despite significant progress, the fundamental mechanisms underlying Ca-dependent arrhythmias remain elusive, owing mainly to the complex, nonlinear nature of cardiac Ca signaling, which hinders the development of effective antiarrhythmic therapies. Based on our work in the previous funding period, we have established that Ca signaling refractoriness provides a powerful concept for understanding cardiac intracellular Ca handling at multiple biological scales (from molecular and subcellular domains to myocardial tissue and intact heart) in normal and diseased hearts. Ca signaling refractoriness refers to a state of temporary deactivation of the sarcoplasmic reticulum (SR) Ca release channels (Ryanodine receptors, RyRs) in the wake of systolic release from the sarcoplasmic reticulum (SR). This Ca signaling refractoriness is critical in maintaining stable Ca-induced Ca release (CICR) by preventing aberrant diastolic Ca release (DCR) - a cause of arrhythmias. Using this new framework, our proposed research will establish the subcellular and molecular bases of aberrant Ca release synchronization, including the refractory properties of functionally distinct Ca release units and determine how these properties are influenced by genetic and acquired intrinsic RyR defects as well as by extrinsic local Na/Ca microdomain homeostasis and SR Ca load. Our quantitative studies of aberrant Ca-excitation coupling will provide a new understanding of characteristic differences in arrhythmogenic properties of ventricular and atrial tissue including ectopic firing propensity and self-sustaining Ca/Vm oscillations. Our multiscale studies of inhibition of arrhythmogenic propensity through the targeting of both intrinsic and extrinsic mechanisms using genetic mouse models of arrhythmia and pre- clinical models of cardiomyopathy as well as preparations from failing and rejected donor human hearts. Taken together these will provide a """"""""proof-of-principle"""""""" for new therapeutic strategies based on desynchronization of aberrant SR Ca release.
Cardiac arrhythmias (abnormal heart rhythms) remain a leading cause of death in the United States. While much has been learned about the causes of these arrhythmias in single cells from the heart, there remain questions about how events in individual cells cause the heart to malfunction. We seek to better understand arrhythmias with the long-term goal of improving arrhythmia prevention and treatment.
|Koleske, Megan; Bonilla, Ingrid; Thomas, Justin et al. (2018) Tetrodotoxin-sensitive Navs contribute to early and delayed afterdepolarizations in long QT arrhythmia models. J Gen Physiol 150:991-1002|
|Radwa?ski, Przemys?aw B; Johnson, Christopher N; Györke, Sándor et al. (2018) Cardiac Arrhythmias as Manifestations of Nanopathies: An Emerging View. Front Physiol 9:1228|
|Slabaugh, Jessica L; Brunello, Lucia; Elnakish, Mohammad T et al. (2018) Synchronization of Intracellular Ca2+ Release in Multicellular Cardiac Preparations. Front Physiol 9:968|
|Györke, Sándor; Belevych, Andriy E; Liu, Bin et al. (2017) The role of luminal Ca regulation in Ca signaling refractoriness and cardiac arrhythmogenesis. J Gen Physiol 149:877-888|
|Ho, Hsiang-Ting; Belevych, Andriy E; Liu, Bin et al. (2016) Muscarinic Stimulation Facilitates Sarcoplasmic Reticulum Ca Release by Modulating Ryanodine Receptor 2 Phosphorylation Through Protein Kinase G and Ca/Calmodulin-Dependent Protein Kinase II. Hypertension 68:1171-1178|
|Shettigar, Vikram; Zhang, Bo; Little, Sean C et al. (2016) Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease. Nat Commun 7:10794|
|Radwa?ski, Przemys?aw B; Ho, Hsiang-Ting; Veeraraghavan, Rengasayee et al. (2016) Neuronal Na+ Channels Are Integral Components of Pro-arrhythmic Na+/Ca2+ Signaling Nanodomain That Promotes Cardiac Arrhythmias During ?-adrenergic Stimulation. JACC Basic Transl Sci 1:251-266|
|Liu, Bin; Ho, Hsiang-Ting; Brunello, Lucia et al. (2015) Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT. Cardiovasc Res 108:299-311|
|Radwa?ski, Przemys?aw B; Brunello, Lucia; Veeraraghavan, Rengasayee et al. (2015) Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release. Cardiovasc Res 106:143-52|
|Glynn, Patric; Musa, Hassan; Wu, Xiangqiong et al. (2015) Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo. Circulation 132:567-77|
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