Abstract 562: Adeno-Associated Virus-Mediated Gene Transfer and Activation of Insulin-like Growth Factor-I Increases Cardiac Function in Chronic Severe Heart Failure
Background: Insulin-like growth factor-I (IGF-I) has pleiotropic effects, including positive inotropic, anti-apoptotic, angiogenic and pro-myogenic in the heart. We constructed a serotype 5 adeno-associated virus vector encoding IGF-I under tet-regulation (AAV5.IGFI-tet) to assess the effects of exogenous IGF-I expression on cardiac function in chronic severe heart failure induced by myocardial infarction (MI). We tested the hypothesis that increased cardiac expression of IGF-I would increase the function of the failing heart.
Methods and Results: Twenty-one 3-month old mice underwent indirect intracoronary delivery of AAV5.IGFI-tet (5x1011 vp), followed immediately by permanent left coronary artery occlusion. Five weeks later, the 10 mice that survived MI and met entry criteria (LVEF<40% and LV end-diastolic diameter>4.5 mm; echocardiography), randomly were assigned to receive doxycycline in their water supply, which activates cardiac IGF-I expression (IGF-On, n=5) or receive regular water (i.e., no treatment, IGF-Off, n=5). After 5 wk of treatment (10 wk from MI), echocardiography showed that IGF-On mice had increased LVEF while the IGF-Off mice showed continued decline (ΔLVEF, IGF-On: +2.3 ± 2.1%; IGF-Off: −5.6 ± 1.9%, n=5 for each group, p=0.03), and pressure-volume analyses showed increased cardiac output (IGF-On: 6.7 ± 1.1 ml/min; IGF-Off: 4.0 ± 0.3 ml/min, n=3 for each group, p=0.08) and stroke volume (IGF-On: 17 ± 3 μl; IGF-Off: 9 ± 1 μl, n=3 for each group, p=0.05). Rates of apoptosis, assessed by TUNEL staining, were reduced in viable LV (Border zone, IGF-On: 125 ± 5 /105 nuclei, n=3; IGF-Off: 416 ± 40 /105 nuclei, n=4, p<0.02; Remote zone, IGF-On: 85 ± 7 /105 nuclei, n=3; IGF-Off: 207 ± 28 /105 nuclei, n=4, p<0.01).
Conclusion: Increased cardiac expression of IGF-I improves LV function and reduces apoptosis in the failing heart. These data suggest a new potential treatment strategy for severe heart failure.