Modulation of in vivo cardiac hypertrophy with insulin-like growth factor-1 and angiotensin-converting enzyme inhibitor: relationship between change in myosin isoform and progression of left ventricular dysfunction.
OBJECTIVE
Supplemental myocardial hypertrophy induced by insulin-like growth factor (IGF)-1 may prevent transition from hypertrophy to heart failure under chronic mechanical overload.


BACKGROUND
Several studies have suggested that IGF-1 treatment may be beneficial in chronic heart failure. In addition, recent studies indicated that the amount of alpha-myosin heavy chain (MHC) plays a significant hemodynamic role in large animals including humans.


METHODS
We treated Dahl salt-sensitive hypertensive rats on a long-term basis with IGF-1. The effects were compared with those produced by treatment using a sub-antihypertensive dose of temocapril, an angiotensin-converting enzyme (ACE) inhibitor. At 11 weeks, when these rats displayed compensated left ventricular hypertrophy (LVH), they were randomized to three groups: 1) IGF group (3 mg/kg/day); 2) temocapril group (1 mg/kg/day); and 3) vehicle (control) group.


RESULTS
After 15 weeks, the control rats showed left ventricular (LV) enlargement and severe LV dysfunction and rapidly died of pulmonary congestion (mean survival time: 16.8+/-0.5 weeks). The survival time was significantly shortened (15.6+/-0.3 weeks) in the IGF-1 group but significantly prolonged (19.5+/-0.6 weeks) in the temocapril group. The rats in the IGF-1 group showed accelerated LV dilation and dysfunction. Of the several parameters investigated, it was found that the relative amounts of MHC isoforms differed among the three groups. The alpha-MHC mRNA level was decreased by 52% (p<0.01) in the IGF group, while it increased by 58% (p<0.01) in the temocapril group compared with the control group. These changes were related to the progression of LV dysfunction.


CONCLUSIONS
Supplemental myocardial hypertrophy with long-term IGF-1 treatment may not be beneficial if concentric LVH already exists. Our data suggest that IGF-1 may not protect myocardial performance when its hypertrophic effect aggravates the reduction of alpha-MHC. By contrast, the ACE inhibitor may improve myocardial function and prognosis by preventing the down-regulation of this isoform.
Iwanaga
Y
Y
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan.
Kihara
Y
Y
Yoneda
T
T
Aoyama
T
T
Sasayama
S
S
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control*; D005069:Evaluation Studies as Topic; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D008297:Male; D009206:Myocardium / Q000737:chemistry*; D018995:Myosin Heavy Chains / Q000032:analysis*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D013841:Thiazepines / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left
D000806:Angiotensin-Converting Enzyme Inhibitors; D013841:Thiazepines; D007334:Insulin-Like Growth Factor I; C055603:temocapril hydrochloride; D018995:Myosin Heavy Chains