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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.
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