ATP—Sensitive Potassium Channel Opener Diazoxide Reduces Myocardial Stunning in a Porcine Regional With Subsequent Global Ischemia Model

Abstract

Background ATP‐sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous 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.

Exploitation of KATP channels for cardiac surgery

“…function following a period of global ischemia [134] .Two subsequent studies were conducted in swine models. In the first, swine treated with hypothermic, hyperkalemic cardioplegia with diazoxide (single dose) prior to a 2-h global ischemic period were found to have improved systolic and diastolic ventricular function compared to cardioplegia alone [Figure 2] [135] . In the second, swine underwent 30 min of occlusion of the left anterior descending artery prior to 2 h of global ischemia protected with cardioplegia or cardioplegia with diazoxide (dosed every 20 min) [Figure 3] [136] .…”

“…This model simulates the clinical situation of a patient presenting to the operating room for a prolonged global ischemic period for cardiac surgery protected with one dose of cardioplegia [135] . This figure is used with permission from Elsevier (obtained September 4, 2023, license number 5621921258491) [135] . CPB: Cardiopulmonary bypass.…”

Diazoxide is a powerful cardioprotectant but is not feasible in a realistic infarct scenario

“…Pretreatment with diazoxide reduced infarct size in sexually immature Yorkshire pigs ( 27 ) and creatine kinase-MB release in female piglets ( 28 ). Also, the addition of diazoxide to a cardioplegic solution attenuated stunning in pig hearts following global I/R ( 29 , 30 ). However, in adult pigs when regional ischaemia was followed by cardioplegic arrest before reperfusion, diazoxide decreased infarct size in one study when added to cardioplegia ( 31 ) but not in another study with pretreatment of diazoxide before regional ischaemia ( 32 ); thus, the protection by diazoxide does not appear to be a robust finding.…”

Non-selective Del Nido and St Thomas cardioplegia in adults: analysis of early clinical experience using propensity matching

“…5,6 However, using conventional cardioplegia solutions results in cardiomyocyte depolarization because these solutions contain high potassium. 7 A spontaneous influx of sodium ions may occur as a result of progressive membrane depolarization, leading to an accumulation of intracellular calcium ions. 8,9 Further leakage of calcium ions from the sarcoplasmic reticulum occurs, 9 contributing to the ‘myocardial calcium overload’ that leads to the development of ischemic reperfusion injury.…”