Adenoviral βARKct Cardiac Gene Transfer Ameliorates Post-resuscitation Myocardial Injury in a Porcine Model of Cardiac Arrest

OBJECTIVE:To determine whether the inhibition of the G protein-coupled receptor kinase 2 by adenoviral βARKct cardiac gene transfer can ameliorate post-resuscitation myocardial injury in pigs with cardiac arrest (CA) and explore the mechanism of myocardial protection. METHODS: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. RESULTS: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, lactate after ROSC. Furthermore, in comparison with the control group, the adenoviral-βARKct treated animals showed increased levels of β1 adrenergic receptor, SERCA2a, RyR2 and decreased the level of GRK2. CONCLUSIONS:The inhibition of GRK2 by adenoviral βARKct cardiac gene transfer can ameliorate post-resuscitation myocardial injury through beneficial effects on restoring the sarcoplasmic reticulum Ca-handling proteins expression and upregulating the β1- adrenergic receptor level after cardiac arrest.