Blocking the development of postischemic cardiomyopathy with viral gene transfer of the apoptosis repressor with caspase recruitment domain.
OBJECTIVE
Apoptosis caused by acute ischemia and subsequent ventricular remodeling is implicated as a mediator of heart failure. This study was designed to assess the efficacy of in vivo viral gene transfer of the antiapoptotic factor apoptosis repressor with caspase recruitment domain to block apoptosis and preserve ventricular geometry and function.


METHODS
In a rabbit model of regional ischemia followed by reperfusion, an experimental group treated with adenovirus-apoptosis repressor with caspase recruitment domain was compared with empty vector adenovirus-null controls. Cardiac function was assessed by echocardiography and sonomicrometry of the border zone compared with the normal left ventricle. Animals were killed at 6 weeks with measurements of ventricular geometry and apoptosis.


RESULTS
Animals with the apoptosis repressor with caspase recruitment domain (ARC group) maintained higher ejection fractions at 4 and 6 weeks, and sonomicrometry demonstrated greater protection of border zone fractional shortening at 6 weeks compared with the control group. The ARC group maintained superior preservation of left ventricular geometry with less ventricular dilation and wall thinning. Finally, there was reduced apoptosis in the rabbits treated with apoptosis repressor with caspase recruitment domain compared with the controls.


CONCLUSIONS
Gene transfer of apoptosis repressor with caspase recruitment domain preserves left ventricular function after ischemia. The benefit at 6 weeks is postulated to result from an apoptosis repressor with caspase recruitment domain-mediated reduction in apoptosis and ventricular remodeling. Adenovirus-apoptosis repressor with caspase recruitment domain administration offers a potential strategy after myocardial ischemia to protect the heart from late postischemic cardiomyopathy.
Chatterjee
Subhasis
S
Division of Cardiothoracic Surgery and Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Bish
Lawrence T
LT
Jayasankar
Vasant
V
Stewart
Allan S
AS
Woo
Y Joseph
YJ
Crow
Michael T
MT
Gardner
Timothy J
TJ
Sweeney
H Lee
HL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D009202:Cardiomyopathies / Q000209:etiology / Q000517:prevention & control*; D018014:Gene Transfer Techniques; D009124:Muscle Proteins / Q000235:genetics*; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury; D011817:Rabbits; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling
D009124:Muscle Proteins