Adenoviral βARKct Cardiac Gene Transfer Ameliorates Postresuscitation Myocardial Injury in a Porcine Model of Cardiac Arrest.

Abstract

The aim of the study was to determine whether the inhibition of the G-protein-coupled receptor kinase 2 by adenoviral βARKct cardiac gene transfer can ameliorate postresuscitation myocardial injury in pigs with cardiac arrest (CA) and explore the mechanism of myocardial protection. Male landrace domestic pigs were randomized into the sham group (anesthetized and instrumented, but ventricular fibrillation was not induced) (n = 4), control group (ventricular fibrillation 8 min, n = 8), and βARKct group (ventricular fibrillation 8 min, n = 8). Hemodynamic parameters were monitored continuously. Blood samples were collected at baseline, 30 min, 2 h, 4 h, and 6 h after the return of spontaneous circulation (ROSC). Left ventricular ejection fraction was assessed by echocardiography at baseline and 6 h after ROSC. These animals were euthanized, and the cardiac tissue was removed for analysis at 6 h after ROSC. Compared with those in the sham group, left ventricular +dp/dtmax, -dp/dtmax, cardiac output (CO), and ejection fraction (EF) in the control group and the βARKct group were significantly decreased at 6 h after the restoration of spontaneous circulation. However, the βARKct treatment produced better left ventricular +dp/dtmax, -dp/dtmax, CO, and EF after ROSC. The βARKct treatment also produced lower serum cardiac troponin I, CK-MB, and lactate after ROSC. Furthermore, the adenoviral βARKct gene transfer significantly increased β1 adrenergic receptors, SERCA2a, RyR2 levels, and decreased GRK2 levels compared to control. The inhibition of GRK2 by adenoviral βARKct cardiac gene transfer can ameliorate postresuscitation myocardial injury through beneficial effects on restoring the sarcoplasmic reticulum Ca-handling proteins expression and upregulating the β1-adrenergic receptor level after cardiac arrest.