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Am J Physiol Heart Circ Physiol 305: H1406, 2013; doi:10.1152/ajpheart.00659.2013. Letter to the Editor Reply to “Letter to the editor: ‘The role of short QT interval and elevated LV end-diastolic pressure in the genesis of ventricular tachycardia and fibrillation’” Matthew F. Pizzuto,2 Gen Suzuki,2,3 Michael D. Banas,2,3 Brendan Heavey,2 James A. Fallavollita,1,2,3 and John M. Canty, Jr.1,2,3,4,5 1 Veterans Affairs Western New York Health Care System, Buffalo, New York; 2Center for Research in Cardiovascular Medicine, University at Buffalo, Buffalo, New York; 3Department of Medicine, University at Buffalo, Buffalo, New York; 4 Department of Physiology and Biophysics, University at Buffalo, Buffalo, New York; and 5Department of Biomedical Engineering, University at Buffalo, Buffalo, New York We appreciate Dr. Karagueuzian’s (3) insight regarding the potential role of reduced cytosolic ATP (derived from glucose and glycogen) in explaining shortening of the QT interval (through activation of the ATP-sensitive K⫹ channel) as well as elevations in end-diastolic pressure (through reduced sarcoplasmic reticulum Ca2⫹ uptake and increased cytosolic Ca2⫹ during diastole) immediately before the development of ventricular tachycardia (VT)/ventricular fibrillation (VF) in swine with hibernating myocardium (5). This is an extremely interesting alternative interpretation of our results, but there are some observations that, at the same time, are somewhat difficult to completely reconcile with this hypothesis. These all center upon whether cytosolic ATP levels, which would initially be maintained by anaerobic glycolysis during ischemia, could fall to the levels promoting arrhythmogenesis within the time frame that spontaneous VT/VF developed. In swine with hibernating myocardium, ventricular fibrillation developed fairly quickly after the onset of sympathetic activation (median, 200 s; and mean, 422 s). In contrast, after a complete switch from glucose to pyruvate in the study of Morita et al. (4), myocardial glycogen content was sufficient to continue glycolysis (and presumably generate cytosolic ATP) with QT shortening and VF developing after a mean of 1,320 s. In addition, hibernating myocardium is actually protected from the development of metabolic evidence of ischemia during increases in demand (1) with slowed ATP depletion during simulated zero flow ischemia ex vivo (2). This may partially reflect an increase in myocyte glycogen content in hibernating myocardium (6). Despite these considerations, it is entirely possible that the intrinsic metabolic adaptations to ischemia, along with ischemia-induced remodeling of ion channels and contractile proteins, could vary temporally and lead to a transient situation where cytosolic ATP levels could fall more rapidly than one would predict from animals with hibernating J. M. Canty, Div. of Cardiovascular Medicine, Univ. at Buffalo Clinical and Translational Research Ctr., Ste. 7030, 875 Ellicott St., Buffalo, NY 142031034 (e-mail: [email protected]). H1406 myocardium that survive. Understanding whether the cellular and molecular substrate in myocardial tissue differs in animals developing VT/VF will require further study using high throughput discovery-based approaches such as proteomics to identify the targets. Regardless of whether reductions in glycolytically derived ATP arise through the development of subendocardial ischemia or transient alterations in myocyte protein expression, pharmacologically manipulating the ATPsensitive K⫹ channel to prevent QT shortening may prove to be an interesting intervention to prevent the clinical problem of sudden cardiac arrest from VT/VF in chronic ischemic heart disease. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s). AUTHOR CONTRIBUTIONS M.F.P., G.S., M.D.B., B.M.H., J.A.F., and J.M.C. approved final version of manuscript; J.M.C. drafted manuscript; J.M.C. edited and revised manuscript. REFERENCES 1. Fallavollita JA, Malm BJ, Canty JM Jr. Hibernating myocardium retains metabolic and contractile reserve despite regional reductions in flow, function, and oxygen consumption at rest. Circ Res 92: 48 –55, 2003. 2. Hu Q, Suzuki G, Young RF, Page BJ, Fallavollita JA, Canty JM Jr. Reductions in mitochondrial O2 consumption and preservation of highenergy phosphate levels after simulated ischemia in chronic hibernating myocardium. Am J Physiol Heart Circ Physiol 297: H223–H232, 2009. 3. Karagueuzian HS. Letter to the editor: “The role of short QT interval and elevated LV end-diastolic pressure in the genesis of ventricular tachycardia and fibrillation.” doi:10.1152/ajpheart.00581.2013. 4. Morita N, Lee JH, Bapat A, Fishbein MC, Mandel WJ, Chen PS, Weiss JN, Karagueuzian HS. Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts. Am J Physiol Heart Circ Physiol 301: H180 –H191, 2011. 5. Pizzuto MF, Suzuki G, Banas MD, Heavey B, Fallavollita JA, Canty JM Jr. Dissociation of hemodynamic and electrocardiographic indexes of myocardial ischemia in pigs with hibernating myocardium and sudden cardiac death. Am J Physiol Heart Circ Physiol 304: H1697–H1707, 2013. 6. Thomas SA, Fallavollita JA, Borgers M, Canty JM Jr. Dissociation of regional adaptations to ischemia and global myolysis in an accelerated swine model of chronic hibernating myocardium. Circ Res 91: 970 –977, 2002. http://www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.2 on May 8, 2017 REPLY: