Abstract
Aging increases the risk of cardiac pathologies including atrial fibrillation and can alter myocardial responsiveness to therapeutic agents. Here, seeking molecular correlates of myocardial aging processes, we performed global “whole transcript” analysis of 25,388 genes using 572,667 probes to compare the left atrial (LA) transcriptomes of young adult (9 months old) versus elderly (10 years old) female swine. NHE2 (>9-fold) and KChIP2 (3.8-fold) exhibited the highest aging-related expression increases. Real-time qPCR recapitulated these findings and indicated a 50% decrease in LA NHE1, a twofold increase in right atrial KChIP2, but no significant changes for these transcripts in either ventricle. Notably, even in young adult pigs, NHE2 transcript was detectable and enriched in the atria over the ventricles. NHE1, the recognized cardiac isoform of the sodium hydrogen exchanger, has proven a compelling but clinically disappointing therapeutic target with respect to reperfusion arrhythmias. Our data challenge the dogma that NHE1 is alone in the myocardium and suggest that NHE2 could negatively impact the pharmacological responsiveness of atrial tissue to NHE1-specific inhibitors. KChIP2 is a cytosolic β subunit essential for generation of I to. The increased KChIP2 expression we observed with aging substantially shortened in silico atrial myocyte action potential duration, a predisposing factor in atrial fibrillation. Consistent with this, 4/5 elderly swine sustained pacing-induced AF≥15 s after cessation of stimulation, compared to 0/3 young swine. Our findings uncover potential molecular bases for increased arrhythmogenicity and reduced pharmacologic efficacy in the aging atrium, in a large animal model of human cardiac physiology.
Highlights
Heart disease continues to be the leading global cause of mortality, accounting for one quarter of all deaths in the United States
Our results, obtained from an unbiased whole-transcript microarray analysis of the majority of known genes in the newly-sequenced porcine genome, uncover striking aging-related changes in various genes; here we focus on the two for which we found the highest left atrial transcript expression increase in aging – NHE2 and KChIP2
NHE inhibitors previously tested in clinical trials, namely cariporide, eniporide and zoniporide, are 30- to 200-fold less potent inhibitors of NHE2 than NHE1; the doses used in clinical trials would not be predicted to substantially inhibit NHE2
Summary
Heart disease continues to be the leading global cause of mortality, accounting for one quarter of all deaths in the United States. Coronary heart disease (CHD), the most common form of heart disease, killed more than 400,000 United States citizens in 2008, while as many as 1% of the US population may suffer from atrial fibrillation (AF). During and/or following ischemic episodes in the heart such as occur in CHD and heart failure, intracellular protons activate the cardiac myocyte sarcolemmal sodium hydrogen exchanger (NHE) to facilitate proton efflux and Na+ influx – causing, in turn, damaging cytosolic Ca2+ overload via the Na+/Ca2+ exchanger. Clinical trials of NHE1specific inhibitors (cariporide, eniporide and zoniporide) have been largely unsuccessful [5]. The subsequent EXPEDITION trial (2870 patients) showed that while cariporide reduced MI incidence, it significantly increased the rate of mortality associated with increased incidence of focal cerebrovascular events [10]
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