TY - JOUR
T1 - ATP—Sensitive Potassium Channel Opener Diazoxide Reduces Myocardial Stunning in a Porcine Regional With Subsequent Global Ischemia Model
AU - Velez, Ana K.
AU - Etchill, Eric
AU - Giuliano, Katherine
AU - Kearney, Sean
AU - Jones, Melissa
AU - Wang, Jie
AU - Cho, Brian
AU - Brady, Mary Beth
AU - Dodd-O, Jeffrey
AU - Meyer, Joseph M.
AU - Lawton, Jennifer S.
N1 - Funding Information:
This work was supported by the American Heart Association Grant-in-Aid 16GRNT31170 and philanthropic funding from the Magic That Matters Foundation (J.S.L), the Martin and Vera Kohn Research Fellowship in Cardiac Surgery (A.K.V.) and the Hugh R. Sharp Research Fellowship in Cardiac Surgery (A.K.V.).
Publisher Copyright:
© 2022, American Heart Association Inc. All rights reserved.
PY - 2022
Y1 - 2022
N2 - BACKGROUND: ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endog-enous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. METHODS AND RESULTS: Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; P=0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; P=0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; P<0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (P<0.01) and maximum change in ventricular pressure during isovolumetric contraction (P<0.01) in the diazoxide group at 30 minutes of reperfusion. CONCLUSIONS: Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting.
AB - BACKGROUND: ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endog-enous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. METHODS AND RESULTS: Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; P=0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; P=0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; P<0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (P<0.01) and maximum change in ventricular pressure during isovolumetric contraction (P<0.01) in the diazoxide group at 30 minutes of reperfusion. CONCLUSIONS: Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting.
KW - animals
KW - cardiopulmonary bypass
KW - diazoxide
KW - heart arrest, induced
KW - myocardial stunning
KW - swine
KW - ventricular function, left
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U2 - 10.1161/JAHA.122.026304
DO - 10.1161/JAHA.122.026304
M3 - Article
C2 - 36444837
AN - SCOPUS:85143608045
SN - 2047-9980
VL - 11
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 23
M1 - e7723
ER -