Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF.
Ventricular fibrillation (VF) is an important cause of sudden cardiac arrest following myocardial infarction. Following resuscitation from VF, decreased cardiac contractile function is a common problem. During and following myocardial ischemia, decreased glucose oxidation, increased anaerobic glycolysis for cardiac energy production are harmful and energetically expensive. The objective of the present study is to determine the effects of dichloroacetate (DCA), a glucose oxidation stimulator, on cardiac contractile dysfunction following ischemia-induced VF. Male Sprague-Dawley rat hearts were Langendorff perfused in Tyrode's buffer. Once stabilized, hearts were subjected to 15 min of global ischemia and 5 min of aerobic reperfusion in the presence or absence of DCA. At the 6th min of reperfusion, VF was induced electrically, and terminated. Left ventricular (LV) pressure was measured using a balloon. Pretreatment with DCA significantly improved post-VF left ventricular developed pressure (LVDP) and dp/dtmax. In DCA-pretreated hearts, post-VF lactate production and pyruvate dehydrogenase (PDH) phosphorylation were significantly reduced, indicative of stimulated glucose oxidation, and inhibited anaerobic glycolysis by activation of PDH. Epicardial NADH fluorescence was increased during global ischemia above preischemic levels, but decreased below preischemia levels following VF, with no differences between nontreated controls and DCA-pretreated hearts, whereas DCA pretreatment increased NADH production in nonischemic hearts. With exogenous fatty acids (FA) added to the perfusion solution, DCA pretreatment also resulted in improvements in post-VF LVDP and dp/dtmax, indicating that the presence of exogenous FA did not affect the beneficial actions of DCA. In conclusion, enhancement of PDH activation by DCA mitigates cardiac contractile dysfunction following ischemia-induced VF.
The Hull Family Cardiac Fibrillation Management Laboratory, University Health Network, Toronto, Ontario, Canada;
Mohammed Ali
MA
Azam
The Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; and.
Cory S
CS
Wagg
The Hull Family Cardiac Fibrillation Management Laboratory, University Health Network, Toronto, Ontario, Canada;
Stéphane
S
Massé
The Hull Family Cardiac Fibrillation Management Laboratory, University Health Network, Toronto, Ontario, Canada;
Talha
T
Farid
The Hull Family Cardiac Fibrillation Management Laboratory, University Health Network, Toronto, Ontario, Canada;
Patrick F H
http://orcid.org/0000-0002-8355-7183
PF
Lai
The Hull Family Cardiac Fibrillation Management Laboratory, University Health Network, Toronto, Ontario, Canada;
Marjan
M
Kusha
The Hull Family Cardiac Fibrillation Management Laboratory, University Health Network, Toronto, Ontario, Canada;
John
J
Asta
The George Washington University, Washington, District of Columbia.
Rafael
R
Jaimes
The George Washington University, Washington, District of Columbia.
Sarah
S
Kuzmiak-Glancy
The George Washington University, Washington, District of Columbia.
Matthew W
MW
Kay
The Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; and.
Gary D
GD
Lopaschuk
The Hull Family Cardiac Fibrillation Management Laboratory, University Health Network, Toronto, Ontario, Canada; kumar.nanthakumar@uhn.ca.
Kumaraswamy
K
Nanthakumar
D000818:Animals; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011312:Pressure; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D014693:Ventricular Fibrillation / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D016277:Ventricular Function, Left / Q000187:drug effects*
D011768:Pyruvate Dehydrogenase Complex; D009243:NAD; D019344:Lactic Acid; D003999:Dichloroacetic Acid
cardiac metabolism; myocardial contractile dysfunction; myocardial infarction; ventricular fibrillation