KCNJ2-Induced Arrhythmia Mechanisms in CPVT and Heart Failure.

KCNJ2 诱导 CPVT 和心力衰竭的心律失常机制。

• 批准号: 9975894
• 负责人: Lee Lochbaum Eckhardt
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975894
• 关键词: ANK2 gene; Address; Adrenergic Agents; Affinity; Ankyrins; Arrhythmia; Biophysical Process; Biophysics; CALM1 gene; Calcium; Calmodulin; Calsequestrin; Cardiac; Catecholaminergic Polymorphic Ventricular Tachycardia; Cause of Death; Cell model; Chronic; Clinical; Closure by clamp; Cyclic AMP-Dependent Protein Kinases; Electrophysiology (science); Evidence based treatment; Exhibits; Functional disorder; Generations; Genes; Genetic; Goals; Heart; Heart Diseases; Heart Ventricle; Heart failure; Homeostasis; Human; Image; Interruption; Ion Channel; Knock-in; Knock-in Mouse; Lead; Link; Mass Spectrum Analysis; Mediating; Membrane; Membrane Potentials; Methods; Modeling; Muscle Cells; Mutation; Optics; Organ; Outcomes Research; Patients; Pharmaceutical Preparations; Phase; Phenocopy; Phenotype; Phosphorylation; Phosphorylation Site; Pore Proteins; Predisposition; Prevention; Resolution; Rest; Ryanodine Receptor Calcium Release Channel; Short QT syndrome; Stress; Syndrome; Systolic heart failure; Techniques; Testing; Transgenic Mice; Triad Acrylic Resin; United States; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; adrenergic stress; biophysical properties; clinical phenotype; density; experimental group; genetic signature; improved; in vivo; innovation; inorganic phosphate; insight; loss of function; molecular dynamics; mouse model; mutant; optimal treatments; periodic paralysis; prevent; response; sudden cardiac death; triadin; voltage

Arrhythmic sudden cardiac death (SCD) is a leading cause of death in the United States and can be caused by ionic current abnormalities occurring in genetic arrhythmia syndromes or acquired heart disease such as heart failure. This project focuses on the impact of cardiac inward rectifier current (IK1) on -adrenergic-dependent genetic and acquired ventricular arrhythmias. IK1 maintains resting membrane potential, contributes to phase 3 repolarization, and is remodeled in heart failure. KCNJ2 encodes the ion channel Kir2.1 that forms the dominant protein pore subunit for IK1 in the human cardiac ventricle. Loss of function KCNJ2 mutations present with two clinical phenotypes, Adersen-Tawil Syndrome (ATS), composed of a triad of ventricular arrhythmias, dysmorphic features and periodic paralysis, or Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), which presents with adrenergic-dependent ventricular arrhythmias including polymorphic ventricular tachycardia (PMVT) and bidirectional VT (BiVT) with a lack non-cardiac ATS features. CPVT has been attributed to abnormal calcium (Ca2+) handling related to mutations in Ca2+ handling genes and the signature arrhythmia for CPVT, BiVT, is caused by Ca2+ overload. Unlike the other CPVT targets, Kir2.1 does not directly participate in Ca2+ homeostasis, yet Ca2+ modulates Kir2.1 by specifically blocking the outward Kir2.1 current. -adrenergic stimulation activates protein-kinase A (PKA), which phosphorylates Kir2.1 with subsequent increase in outward Kir2.1 current. How Kir2.1 with CPVT-causing mutations fail to respond to PKA is unknown, particularly since the known CPVT mutations are not phosphorylation sites. Our central hypothesis is that under -adrenergic stimulation, CPVT-causing Kir2.1 mutant channels have loss of outward current due to both lack of a PKA response and increased sensitivity to Ca2+ block, reducing outward current and thus repolarization drive causing membrane potential instability, favoring delayed after-depolarizations (DADs) triggered activity. Additionally, decreased IK1 in systolic heart failure is thought to be a key feature in ventricular arrhythmias and SCD. We hypothesize that IK1 is decreased predominately during -adrenergic stimulation due to elevated Ca2+ in a manner similar to CPVT-causing KCNJ2 mutations. In this study, we will address these questions using a variety of cellular models and transgenic mouse models to determine the biophysical properties, Ca2+ sensitivity, phosphorylation state and arrhythmia mechanism of KCNJ2 mutations associated with a CPVT or an ATS phenotype and compare that to a heart failure model. Our innovative methods will include high-definition mass spectrometry, optical mapping and calcium imaging. The outcomes of this research will allow us to elucidate the mechanism by which -adrenergic-dependent loss of IK1 can result in ventricular arrhythmia in CPVT and heart failure and compare that to an ATS arrhythmia mechanism. Elucidating the nuances of IK1 dysfunction and Ca2+ handling under -adrenergic stress will lead to more evidence-based treatment approaches and prevention of SCD.

心律失常性心源性猝死（SCD）是美国的主要死亡原因，可由以下因素引起