Abstract 16331: Myeloperoxidase Promotes Ventricular Tachycardia Upon Myocardial Ischemia and Reperfusion
Background: Myeloperoxidase (MPO), a heme enzyme abundantly expressed and released by polymorphonuclear neutrophils (PMN), has emerged as an important mediator in cardiovascular inflammatory diseases. Being identified recently as a critical mediator of atrial remodelling and arrhythmias, we investigated whether MPO might also influence structural and electrical remodelling in ventricular myocardium.
Methods and Results: Wild-type C57bl/6J (WT) and MPO-deficient (Mpo-/-) mice underwent either sham surgery or 30 minutes of myocardial ischemia induced by ligation of the left descending coronary artery followed by 7 days of reperfusion (I/R). Echocardiography revealed an impaired left ventricular function upon I/R without differences between both genotypes. However, right ventricular electrophysiological investigations disclosed profoundly increased vulnerability for ventricular tachycardia (VT) in I/R treated WT as compared to Mpo-/- mice (number of VT episodes I/R: 9.5 ± 1.35 vs. 2.78 ± 0.81, p<0.001, sham: 1.0 ± 0.4 vs. 0.75 ± 0.5, p = 0.7; total time of VT episodes I/R: 4476.25 ± 1127.3 vs. 1718.59 ± 916.19 msec, p<0.05, sham: 301.25 ± 108.27 vs. 252.87 ± 146.02 msec, p = 0.32). Moreover, I/R treated WT mice displayed an increased infiltration of PMN in the peri-infarction area proved by immunohistochemical analysis as compared to Mpo-/- mice. Importantly, immunohistochemical and immunoblot analysis disclosed decreased protein amount and diminished phosphorylation of connexin43 in the peri-infarction area of WT mice as compared to Mpo-/- mice. In addition, MPO incubation of isolated WT cardiomyocytes induced a decrease in connexin43 protein amount. This degradation and dephosphorylation of myocardial connexin43 is known to serve as a critical prerequisite for electrical instability in ventricular myocardium subjected to I/R.
Conclusions: The current data reveal that MPO increases the vulnerability for ventricular arrhythmias upon myocardial ischemia and reperfusion in part by an impairment of connexin43 integrity, not only indicating that leukocyte activation might critically contribute to malignant arrhythmias following myocardial infarction but also pointing towards MPO as a potential pharmacological target.
- © 2012 by American Heart Association, Inc.