Background-Cardiac hypertrophy is a major risk factor for arrhythmias and sudden cardiac death. However, the underlying signaling mechanisms involved in the induction of arrhythmia and electrophysiological remodeling in cardiac hypertrophy are unclear. Methods and Results-Using an inducible gene-switch approach, we achieved tissue-specific and temporally regulated induction of a well-established hypertrophic pathway, the Ras-Raf-mitogen-activated protein kinases pathway, in adult mouse heart. On Ras activation, the transgenic animal developed ventricular hypertrophy and arrhythmias. The development of ventricular arrhythmias was temporally correlated with electrophysiological remodeling in isolated ventricular myocytes, including action potential prolongation, increased sodium-calcium exchanger activity, reduced outward potassium currents, sarcoplasmic reticulum Ca 2ϩ defects, and loss of protein kinase A-dependent phospholamban phosphorylation. From genome-wide expression profiling, we discovered a selective induction of G␣ inhibiting subunit 1 (Gi␣1) expression in the Ras transgenic heart. Treatment of transgenic animals with the Gi/o inhibitor pertussis toxin normalized the phospholamban phosphorylation by protein kinase A, reversed the action potential prolongation, and significantly reduced the frequency of cardiac arrhythmias in Ras transgenic animals. Conclusions-These data suggest that selective induction of G␣ inhibiting subunit 1 expression and activity is a novel downstream event in hypertrophic signaling that may be a critical factor leading to cellular electrophysiological remodeling and cardiac arrhythmias in hypertrophic cardiomyopathy. Key Words: hypertrophy Ⅲ cardiomyopathy Ⅲ arrhythmia Ⅲ electrophysiology Ⅲ signal transduction H ypertrophic cardiomyopathy is the most common form of heart disease caused by genetic mutations of cardiac proteins, whereas left ventricular hypertrophy can be caused by mechanical overload associated with hypertension and valvular disease. Both may be characterized by myocyte hypertrophy, interstitial fibrosis, and induction of fetal gene expression. [1][2][3][4] Both the genetic and acquired forms of cardiac hypertrophy are risk factors for sudden cardiac death associated with electrophysiological remodeling and resultant cardiac arrhythmias. [5][6][7][8] Investigation of the underlying mechanisms of these manifestations has been the main focus of the field in recent years. Clinical Perspective p 605Ventricular arrhythmias are the most common cause of sudden cardiac death in hypertrophic cardiomyopathy and other cardiac diseases, including heart failure. 9 -11 Abnormal conduction and heterogeneous action potential propagation are the main causes of reentrant arrhythmias in ischemic hearts. In contrast, triggered arrhythmias caused by early or delayed afterdepolarizations are thought to be a major cause of ventricular arrhythmias in nonischemic cardiomyopathies. 12 Although prolonged action potential duration (APD), repressed outward K ϩ currents, and increased sodium...
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