Ion channel dysfunction causes arrhythmic sudden death in both acquired and inherited arrhythmia syndromes. One such family of channels include potassium inward rectifier Kir2, Kir2.1, Kir2.2 and Kir2.3, and functionally make up IK1. KCNJ2 encodes the cardiac ion channel Kir2.1, the dominant component of IK1, and loss of function mutations in KNCJ2 causes LQT7 and adrenergic dependent loss of function causes CPVT3. IK1 is down-regulated in heart failure and has decreased beta-adrenergic sensitivity despite normal to increased protein and mRNA levels. The current gap in our knowledge is the detailed mechanisms causing loss of Kir2 function in both acquired and inherited arrhythmia syndromes. These mechanisms may depend on interactions with or regulation by other proteins as part of the Kir2.1 macromolecular complex, heretofore unknown. In cardiac myocytes, caveolae are characterized by the presence of Caveolin-3, encoded by CAV3, and form lipid microdomains for ion channels and receptor molecules. Mutations of CAV3 can cause ion channel dysfunction such as those associated with LQT9, leading to arrhythmia generation, and sudden cardiac death. Caveolin-3 (Cav3) is also down-regulated in heart failure as are caveolar domains. We have previously studied CAV3 LQT9 associated mutations and found that IK1 density is decreased due to decreased channel membrane expression. In this proposal we will determine the mechanism by which Cav3, either from mutations associated with LQT9 or by acquired remodeling in heart failure, causes dysregulation of IK1 and contributes to arrhythmogenesis in these conditions. We will utilize novel and innovative methods such as human induced pluripotent derived cardiac myocyte model and complementary heart failure models. The overall objective for this proposal is to identify the mechanism by which Cav3 can contribute or disrupt the macromolecular complex for Kir2.1 and the effects on IK1 function resulting in ventricular arrhythmias. Our long-term goal is to improve treatment options for individuals with inherited or acquired arrhythmias by characterizing and identifying the mechanisms involved in arrhythmogenesis related to abnormal IK1. With knowledge gained from this proposal, we will better understand the pathogenesis of arrhythmias caused by abnormal Cav3 with Kir2.1. The models developed in the proposal will also serve as a valuable test bed for therapeutics. Thus, the proposal will not only advance the field of arrhythmia research but also allow future development of treatment options and therapeutics for this and other arrhythmia syndromes.

Public Health Relevance

Every year sudden cardiac death occurs in individuals with structural heart disease such as heart failure and in otherwise healthy people that do not have structural heart disease due to inherited arrhythmia syndromes such as Long QT Syndrome (LQTS). In this proposal we test the hypothesis that some of these fatal heart rhythms can be caused by abnormalities in a cardiac protein, caveolin-3 (Cav3), and its interaction with a potassium inward rectifier protein. We will gain understanding of how these arrhythmias occur in LQTS and acquired arrhythmias, which will set the stage for the development of treatment options toward the prevention of sudden death.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Shi, Yang
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University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
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Vaidyanathan, Ravi; Van Ert, Hanora; Haq, Kazi T et al. (2018) Inward Rectifier Potassium Channels (Kir2.x) and Caveolin-3 Domain-Specific Interaction: Implications for Purkinje Cell-Dependent Ventricular Arrhythmias. Circ Arrhythm Electrophysiol 11:e005800
Vaidyanathan, Ravi; Reilly, Louise; Eckhardt, Lee L (2018) Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel. Front Physiol 9:1548
Van Ert, Hanora A; McCune, Elise C; Orland, Kate M et al. (2017) Flecainide treats a novel KCNJ2 mutation associated with Andersen-Tawil syndrome. HeartRhythm Case Rep 3:151-154
Eckhardt, Lee L; Makielski, Jonathan C (2017) Complexity of AF genetic susceptibility begets complexity of interpretation. Heart Rhythm 14:292-293
Vaidyanathan, Ravi; Markandeya, Yogananda S; Kamp, Timothy J et al. (2016) IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes. Am J Physiol Heart Circ Physiol 310:H1611-21
Eckhardt, Lee L (2016) Monomorphic ventricular tachycardia in Brugada syndrome: True-true but related? Heart Rhythm 13:683-5