Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts.

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 afterdepolarization (EAD) or delayed afterdepolarizations in intact hearts isolated from adult and aged rats. Dual voltage and intracellular calcium ion (Ca(i)(2+)) 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 Ca(i)(2+) 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 (K(ATP)) channel blocker glibenclamide (1 μM) but not (0 out of 7) by mitochondrial K(ATP) block. The Ca-calmodulin-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 not occur. 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 K(ATP) channels CaMKII and NCX.

• Authors: Norishige Morita, Jong-Hwan Lee, Aneesh Bapat, Michael C Fishbein, William J Mandel, Peng-Sheng Chen, James N Weiss, Hrayr S Karagueuzian
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 301 Issue 1 Pg. H180-91 (Jul 2011) ISSN: 1522-1539 [Electronic] United States
• PMID: 21478408 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Connexin 43
• Fluorescent Dyes
• KATP Channels
• Sodium-Calcium Exchanger
• Adenosine Triphosphate
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium

Topics

• Action Potentials (physiology)
• Adenosine Triphosphate (metabolism)
• Aging (physiology)
• Animals
• Arrhythmia, Sinus (physiopathology)
• Calcium (metabolism, physiology)
• Calcium Signaling (physiology)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (drug effects, metabolism)
• Connexin 43 (metabolism)
• Electrophysiological Phenomena (physiology)
• Endocardium (physiology)
• Fibrosis (pathology)
• Fluorescent Dyes
• Glycolysis (drug effects)
• Heart (physiopathology)
• In Vitro Techniques
• KATP Channels (drug effects, metabolism)
• Male
• Microelectrodes
• Myocardium
• Oxidation-Reduction
• Rats
• Rats, Inbred F344
• Sodium-Calcium Exchanger (drug effects, metabolism)
• Tachycardia, Ventricular (physiopathology)
• Ventricular Fibrillation (chemically induced, physiopathology)