Abstract 335: Chronic Treatment with Sildenafil Three Days following Myocardial Infarction Improves Survival and Left Ventricular Function in Mice
Chronic treatment with phosphodiesterase-5 (PDE-5) inhibitor sildenafil starting at the onset of coronary artery occlusion attenuates ischemic cardiomyopathy, left ventricular (LV) dysfunction, cardiac hypertrophy, pulmonary edema and reduces necrosis and apoptosis in mice. To mimic more clinical scenarios, we hypothesized that chronic treatment with sildenafil beginning at 72 hr post infarction would also preserve LV function and improve survival. Adult male ICR mice underwent myocardial infarction (MI) by permanent ligation of the left anterior descending coronary artery (LAD) after baseline echocardiography was performed. Seventy two hours later, a repeat echocardiography was conducted and mice expressing LV fractional shortening (FS) less than 25% received sildenafil (0.71 mg/kg; ip; BID; Group I), or sildenafil (35 mg/kg; ip; BID; Group II), or volume-matched saline (Group III) for 4 days. At the completion of 7 days following MI, the mice underwent echocardiography prior to sacrifice. Group II expressed less LV dilatation than groups I and III, and groups I and II showed better contractility as compared with group III. LV end-diastolic diameter (LVEDD), increased from a baseline value of 3.4 ±0.1 mm to 4.3 ±0.2 at 72 hr post MI. At 7 days post MI, LVEDD was 5.0±0.2 mm for group I, 4.2±0.1 mm for group II (P=0.01 vs. I and III), and 4.9±0.1 mm for group III. Fractional shortening decreased from a baseline value of 47±1% to 19±1% at 72 hr following MI. At 7 days post MI, FS was 21±1% for group I, 21±1% for group II, and 15±1% for group III (P< 0.05 vs. I and II). Survival rate paralleled the decrease in LV dysfunction and was lower in groups I (90%) and II (86%) as compared to group III (57%) (P< 0.05). For the first time, these results show that chronic sildenafil treatment initiated at 72 hr post MI enhances survival and preserves FS. Higher dose of sildenafil also attenuated LV dilatation which was not observed with a lower dose. We propose that sildenafil, with careful dosing; can be a promising therapeutic tool for prevention of heart failure in patients with MI.