Cardiac metabolism and arrhythmias

Abstract

Sudden cardiac death remains a leading cause of mortality in the Western world, accounting for up to 20% of all deaths in the U.S., The major causes of sudden cardiac death in adults age 35 and older are coronary artery disease (70–80%) and dilated cardiomyopathy (10–15%). At the molecular level, a wide variety of mechanisms contribute to arrhythmias that cause sudden cardiac death, ranging from genetic predisposition (rare mutations and common polymorphisms in ion channels and structural proteins) to acquired electrophysiological and structural remodeling in left ventricular hypertrophy and failure., A growing body of evidence suggests that altered ion channel function is closely linked to changes in metabolic activity in a wide variety of pathological conditions. In this review we focus on the mechanisms by which altered metabolic function impacts cardiac electrophysiology. We will review the specific molecular targets that allow cardiomyocytes to recognize alterations in their metabolic state and translate this information into changes in membrane excitability in various pathophysiological conditions including ischemia-reperfusion, heart failure (HF), left ventricular hypertrophy, diabetic cardiomyopathy and atrial fibrillation. A comprehensive understanding of the interrelated processes of metabolic and electrical remodeling promises to identify new molecular targets for the treatment of cardiac arrhythmias.

Figure 1. Pathophysiological processes associated with intracellular sodium overload during ischemia

Figure 2. Transcriptional co-regulatory patterns for SERCA2 (ATP2A2) and RYR2 in mouse myocardium

Genes that were co-regulated with SERCA2 and RYR2 were identified by StarNet and grouped into Gene Ontology categories. Mitochondrial transcripts showed the most significant co-expression pattern with SERCA2 and RYR2. (Bonferroni corrected p-values for the correlation coefficient across 239 mouse microarrays are indicated). OXPHOS = oxidative phosphorylation.

Figure 3. Pathophysiological processes associated with electrical instability in diabetic hearts