Abstract 3616: Endogenous Activation of Mitochondrial KATP Channels Protects Human Failing Myocardium From Hydroxyl Radical-induced Stunning
During myocardial ischemia/reperfusion (I/R), hydroxyl radicals (OH) induce contractile dysfunction (“stunning”), and the amount of OH in the plasma of patients after myocardial infarction predicts development of heart failure. While animal studies suggested that (quiescent) failing myocytes were more susceptible to OH-induced hypercontracture, the functional effects of OH in human failing myocardium have never been explored. Isolated, electrically stimulated (1 Hz) trabeculae of human left ventricular (LV) and right atrial (RA) myocardium from patients with terminal heart failure or nonfailing (NF) controls were exposed to Fe-NTA (0.1 mM) and H2O2 (1–3 mM) for 15 min, generating OH at a magnitude as observed in the coronary effluent of reperfused ischemic myocardium. In NF LV myocardium, OH decreased systolic force by ~50%, substantially increased diastolic tension and slowed relaxation. After removal of OH, systolic and diastolic dysfunction remained. Conversely, in failing LV myocardium, OH did not affect systolic force at all, and the increase in diastolic tension was 3-fold less pronounced than in NF myocardium (p<0.01 vs NF, respectively). Since mitochondrial (mitoKATP) and/or sarcolemmal KATP channels (sarcKATP) reduce infarct size in I/R, we tested whether their activation protects from OH-induced stunning. In RA trabeculae from NF hearts, activation of sarcKATP (with P-1075) or mitoKATP (with diazoxide) during OH improved force generation after removal of OH. These effects were blocked by the respective KATP-antagonists, HMR-1098 and 5-HD. Despite 2-fold upregulation of sarcKATP (Kir6.2/SUR2) protein expression in failing hearts, its inhibition (with HMR-1098) during OH did not impair contractile function in failing myocardium. In contrast, blocking mitoKATP (with 5-HD) during OH in failing myocardium reduced systolic force to levels comparable to OH-induced stunning in NF myocardium. We conclude that human failing myocardium is resistant to OH-induced stunning due to endogenous activation of mitoKATP, but not sarcKATP. These data could explain why in patients with diabetes and heart failure, the use of sulfonylurea drugs is associated with impaired ischemic tolerance and adverse outcome after myocardial infarction.