Targeted overexpression of growth hormone by adenoviral gene transfer preserves myocardial function and ventricular geometry in ischemic cardiomyopathy.
BACKGROUND
Post-infarction heart failure is characterized by progressive left ventricular dilatation and wall thinning, with both systolic and diastolic cardiac dysfunction. Human growth hormone (GH) stimulates cardiac hypertrophy when secreted in excess and directly enhances cardiomyocyte contractile function. We hypothesized that local myocardial overexpression of GH could prevent ventricular remodeling and heart failure following myocardial infarction (MI) in rats.


RESULTS
Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of adenovirus encoding human GH (n = 8) or null virus as control (n = 8). Six weeks following MI, Adeno-GH treated animals had significant preservation of both systolic and diastolic cardiac function compared to Null animals (maximum dP/dt GH 2927 +/- 83 vs Null 1622 +/- 159 mmHg/sec, p < 0.001; minimum dP/dt -2409 +/- 82 vs -1195 +/- 179 mmHg/sec, p < 0.01). GH animals had improved ventricular geometry with decreased chamber dilatation (13.2 +/- 0.13 vs 14.4+/-0.15 mm, p < 0.001) and increased wall thickness (2.02 +/- 0.10 vs 1.28 +/- 0.07 mm, p < 0.001), and this was associated with advantageous myocardial hypertrophy with increased cardiomyocyte fiber size. Local myocardial overexpression of GH protein was seen in Adeno-GH animals, while serum levels of human GH were undetectable after 6 weeks.


CONCLUSIONS
Treatment with Adeno-GH following MI resulted in reduced ventricular dilatation, increased local myocardial hypertrophy, and preservation of both systolic and diastolic cardiac function. No significant systemic exposure to growth hormone transgene was observed. The induction of regional hypertrophy is a novel approach to treating heart failure, and may be useful to treat or prevent post-infarction ischemic cardiomyopathy.
Jayasankar
Vasant
V
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Pirolli
Timothy J
TJ
Bish
Lawrence T
LT
Berry
Mark F
MF
Burdick
Jeffrey
J
Grand
Todd
T
Woo
Y Joseph
YJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D009202:Cardiomyopathies / Q000628:therapy*; D003971:Diastole; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D013006:Growth Hormone / Q000096:biosynthesis* / Q000235:genetics; D006321:Heart / Q000502:physiology; D006352:Heart Ventricles; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D009203:Myocardial Infarction; D017202:Myocardial Ischemia; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D013599:Systole; D013997:Time Factors; D019076:Transgenes; D020257:Ventricular Remodeling
D013006:Growth Hormone