Growth hormone, angiotensin II and heart failure

There has been growing interest in the potential use of growth hormone and insulin-like growth factor 1 (IGF1) in the treatment of congestive heart failure. Several animal studies have shown the importance of growth hormone in normal cardiac development. The growth hormone receptor is expressed on the myocardium and in models of experimental cardiac failure growth hormone and/or IGF 1 have been shown to induce ventricular hypertrophy and improve myocardial function. Growth hormone is thought to act primarily by induction of IGF 1 expression. Acute administration of IGF 1 has been shown to improve cardiac function, potentially through an effect on cardiac contractility, as well as through a vasodilator effect. Recent studies in rats postmyocardial infarction show that growth hormone improves contractile reserve and intracellular calcium transients in myocytes. This effect may be due to increases in expression of the sarcoplasmic reticulum calcium/ATPase 2. To date eight studies of growth hormone treatment in chronic heart failure have been published. The number of patients treated, however, is small and the longest follow-up has been for three months. The clinical benefit of growth hormone administration in these trials has been very variable, although some effects to stimulate ventricular hypertrophy have been reported. There has been an increasing interest in the growth hormone IGF 1 axis as a result of recent data indicating that wasting and cardiac cachexia are independent risk factors for mortality in chronic heart failure. Predictors of weight loss in cachectic congestive heart failure patients include tumour necrosis factor (TNF) levels, testosterone levels and the ratio of IGF 1 to growth hormone levels. It is of note that hormone analysis in cachectic versus noncachectic heart failure patients indicates that the former have increased epinephrine, norepinephrine, plasma renin activity, and aldosterone levels. We have recently shown that infusion of angiotensin II in the rat causes weight loss through two distinct mechanisms, an anorexigenic effect and a non-anorexigenic effect related to skeletal muscle breakdown. Angiotensin II infusion causes a decrease in liver synthesis of IGF 1 with decreases in circulating IGF 1 levels. This effect is not pressor-related. Additionally angiotensin II decreases skeletal muscle IGF 1 expression. Contrary to its effects on circulating and skeletal IGF 1 angiotensin II causes increased cardiac expression of IGF 1 which likely serves to blunt the effect of angiotensin II on the circulating IGF 1 system. Preliminary studies suggest that angiotensin II enhances non-lysosomal calcium-independent protein degradation. The angiotensin II-induced increase in ubiquitin dependent protein degradation is accompanied by increases in ubiquitin expression in skeletal muscle. This increase in skeletal muscle ubiquitin expression is partially reversed by IGF 1 infusion, indicating that angiotensin II-induced increase in skeletal muscle protein degradation is partially related to a reduction in circulating IGF 1 levels. These data indicate a potentially important mechanism whereby activation of the renin-angiotensin system may stimulate skeletal muscle breakdown and promote cardiac cachexia. They have important implications for designing a future strategy to ameliorate the prognosis in patients with a chronic heart failure.