| Autor: |
Kant R; Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, California, United States of America., Hu Z; Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, California, United States of America., Malhotra JK; Department of Anesthesiology, Weill Cornell Medical College, New York, New York, United States of America., Krogh-Madsen T; Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America., Christini DJ; Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America., Heerdt PM; Department of Anesthesiology, Weill Cornell Medical College, New York, New York, United States of America ; Department of Pharmacology, Weill Cornell Medical College, New York, New York, United States of America., Abbott GW; Bioelectricity Laboratory, Department of Pharmacology and Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, California, United States of America. |
| Abstrakt: |
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. |
