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

OBJECTIVES Supplemental myocardial hypertrophy induced by insulin-like grow th 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 benef icial in chronic heart failure. In addition, recent studies indicated that the amount of cu-myosin heavy chain (MHC) plays a significant hemodynamic r ole in large animals including humans. METHODS We treated Dahl salt-sensitive hypertensive rats on a long-term bas is with IGF-1. The effects were compared with those produced by treatment u sing a sub-antihypertensive dose of temocapril, an angiotensin-converting e nzyme (ACE) inhibitor. At 11 weeks, when these rats displayed compensated l eft ventricular hypertrophy (LVH), they were randomized to three groups: 1) TGF 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) enlar gement and severe LV dysfunction and rapidly died of pulmonary congestion ( mean survival time: 16.8 +/- 0.5 weeks). The survival time was significantl y shortened (15.6 +/- 0.3 weeks) in the IGF-1 group but significantly prolo nged (19.5 +/- 0.6 weeks) in the temocapril group. The rats in the IGF-1 gr oup showed accelerated LV dilation and dysfunction. Of the several paramete rs investigated, it was found that the relative amounts of MHC isoforms dif fered 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 t emocapril 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 treatm ent may not be beneficial if concentric LVH already exists. Our data sugges t that IGF-1 may not protect myocardial performance when its hypertrophic e ffect aggravates the reduction of alpha-MHC. By contrast, the ACE inhibitor may improve myocardial function and prognosis by preventing the down-regul ation of this isoform. (C) 2000 by the American College of Cardiology.