Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts

Norishige Morita, Jong Hwan Lee, Aneesh Bapat, Michael C. Fishbein, William J. Mandel, Peng Sheng Chen, James N. Weiss, Hrayr S. Karagueuzian

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Selective glycolytic inhibition(GI) promotes electromechanical alternans and triggered beats in isolated cardiac myocytes. We sought to determine whether GI promotes triggered activity by early after depolarization (EAD) or delayed after depolarizations in intact hearts isolated from adult and aged rats. Dual voltage and intracellular calcium ion (Cai2+) fluorescent optical maps and single cell glass microelectrode recordings were made from the left ventricular (LV) epicardium of isolated Langendorff-perfused adult (~4 mo) and aged (~24 mo) rat hearts. GI was induced by replacing glucose with 10 mM pyruvate in oxygenated Tyrode's. Within 20 min, GI slowed Cai2+ transient decline rate and shortened action potential duration in both groups. These changes were associated with ventricular fibrillation (VF) in the aged hearts(64 out of 66) but not in adult hearts (0 out of 18; P < 0.001). VF was preceded by a transient period of focal ventricular tachycardia caused by EAD-mediated triggered activity leading to VF within seconds. The VF was suppressed by the ATP-sensitive K (KATP) channel blocker gliben clamide (1 μM) but not (0 out of 7) by mitochondrial KATP block. The Ca-calmodul in-dependent protein kinase II (CaMKII) blocker KN-93 (1 μM) prevented GI-mediated VF (P < 0.05).Block of Na-Ca exchanger (NCX) by SEA0400 (2 μM) prevented GI-mediated VF (3 out of 6), provided significant bradycardia did notoccur. Aged hearts had significantly greater LV fibrosis and reduced connexin 43 than adult hearts (P < 0.05). We conclude that in aged fibrotic unlike in adult rat hearts, GI promotes EADs, triggered activity, and VF by activation of KATP channels CaMKII and NCX.

Original languageEnglish (US)
Pages (from-to)H180-H191
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume301
Issue number1
DOIs
StatePublished - Jul 1 2011

Keywords

  • Aging
  • Calcium cycling
  • Early after depolarizations
  • Fibrosis
  • Optical mapping
  • Triggered activity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Morita, N., Lee, J. H., Bapat, A., Fishbein, M. C., Mandel, W. J., Chen, P. S., Weiss, J. N., & Karagueuzian, H. S. (2011). Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts. American Journal of Physiology - Heart and Circulatory Physiology, 301(1), H180-H191. https://doi.org/10.1152/ajpheart.00128.2011