Submitted on July 11, 2006
Accepted on February 19, 2007
PRE-EMPTIVE HEME OXYGENASE-1 GENE DELIVERY REVEALS REDUCED MORTALITY AND PRESERVATION OF LEFT VENTRICULAR FUNCTION ONE YEAR AFTER ACUTE MYOCARDIAL INFARCTION
Xiaoli Liu1, Jeremy Andrew Simpson1, Keith Russel Brunt1, Christopher A. Ward1, Sean R. R. Hall1, Robert T Kinobe1, Valerie Barrette1, M. Yat Tse, Stephen C Pang2, Alok S Pachori3, Victor J Dzau4, Kofo Ogunyankin5, and Luis G Melo6*
1 Physiology, Queen's University, Kingston, Canada
2 Anatomy and Cell Biology, Queen's University, Kingston, Canada
3 Medicine, Duke University medical Center, Durham, North Carolina, United States
4 Chancellor's Office, Duke University, Durham, North Carolina, United States
5 Medicine, Queen's University, Kingston, Canada
6 Canada; Physiology, Queen's University, Kingston, Canada; Medicine, Queen's University, Kingston, Canada
* To whom correspondence should be addressed. E-mail: melol{at}post.queensu.ca.
We reported previously that pre-delivery of heme oxygenase-1 (HO-1) gene to the heart by adeno-associated virus-2 (AAV-2) markedly reduces ischemia and reperfusion (I/R) induced myocardial injury. However, the effect of pre-emptive HO-1 gene delivery on long-term survival and prevention of post-infarction heart failure has not been determined. We assessed the effect of HO-1 gene delivery on long term survival, myocardial function and LV remodeling one year after myocardial infarction (MI) using echocardiographic imaging, pressure-volume (PV) analysis and histomorphometric approaches. Two groups of Lewis rats were injected with 2 x 1011 particles of AAV-LacZ (control) or AAV-hHO-1 in the anterior-posterior apical region of the LV wall. Six weeks after gene transfer, animals were subjected to 30 min of ischemia by ligation of the left anterior descending (LAD) artery followed by reperfusion. Echocardiographic measurements and PV analysis of LV function were obtained at 2 weeks and 12 months after I/R. One year after acute MI, mortality was markedly reduced in the HO-1 treated animals compared to LacZ. PV analysis demonstrated significantly enhanced LV developed pressure, elevated maximal dP/dt and lower end diastolic volume in the HO-1 animals compared to the LacZ animals. Echocardiography showed a larger apical anterior-to-posterior wall ratio in HO-1 animals compared to the LacZ animals. Morphometric analysis revealed extensive myocardial scarring and fibrosis in the infarcted LV area of LacZ animals, which was reduced by 62% in HO-1 animals. These results suggest that pre-emptive HO-1 gene delivery may be useful as a therapeutic strategy to reduce post MI LV remodeling and heart failure.
