Growth hormone for the failing heart.

Idiopathic dilated cardiomyopathy is a common cause of heart failure. Despite advances in treatment, this disease has a mean survival time of 5 years (1). Currently, the only effective treatment for end-stage dilated cardiomyopathy is heart transplantation. However, additional, more conservative treatment options are being explored to prolong survival until an organ becomes available or even to obviate the necessity for transplantation. Left ventricular assist devices or partial left ventriculectomy, infusions of catecholamine analogs, and phosphodiesterase inhibitors are among some of the treatment options which are being experimentally evaluated (1 and references therein). In addition to these, growth hormone (GH) has emerged as a candidate for increasing cardiac performance, and thus possibly survival, in patients with failing hearts (2, 3). The rationale for exploring GH as a therapeutic option in idiopathic dilated cardiomyopathy builds on a large body of experimental data (2, 3). Evidence has accumulated that GH is a physiological regulator of myocardial growth and performance. In patients with congenital deficiency of GH, cardiac growth and function are impaired; GH administration in such patients increases wall thickness and normalizes cardiac performance which reverses after treatment is stopped (4–7). Furthermore, in a patient with GH deficiency and cardiomyopathy, GH treatment has been reported to increase myocardial contractility and cardiac performance (8). However, not all reports demonstrate a substantial effect of GH on cardiac function. A double-blind, placebo-controlled crossover study of 4 months of GH treatment in GH-deficient adults did not alter echocardiographic wall mass of the left ventricle, whilst resting and exercise-induced heart rate was increased during GH treatment as compared with placebo. The exercise-induced increment in maximum heart rate may be reflecting the anabolic effects of GH on skeletal muscle mass and its increased exercise performance, thus requiring increased cardiac performance (9, 10). In an additional study, which was also randomized and placebo-controlled, six months of GH treatment in GH-deficient adults revealed an increase in left ventricular myocardial mass (5%, which was comparable with increases in thigh muscle and lean body mass), increased left ventricular end-diastolic dimension and stroke volume (11). These changes were interpreted as being due to activation of the renin– aldosterone system and sodium retention during GH treatment, leading to small increases in left ventricular preload and myocardial hypertrophy without changes in mean arterial pressure reflecting anabolic actions of GH on the myocardium (11). An increase in cardiac stroke volume has previously been reported. In addition to increased preload, enhanced myocardial contractility may also underlie improved cardiac performance. Indeed, increases in myocardial shortening have been reported in some patients with acromegaly (12, 13), in normal subjects treated with human GH for 2 weeks (14) and in one patient with GH deficiency and cardiomyopathy (8). On the other hand, an excess of GH is accompanied by cardiac dysfunction. Most acromegalic patients present with cardiac hypertrophy, increased cardiac output, and decreased systemic vascular resistance, all of which are characteristic of a hyperkinetic heart syndrome (15–18). Some patients, however, develop congestive heart failure with dilated cardiomyopathy and/or ventricular dysrhythmias (16–19). Treatment of acromegaly can lead to an improvement of both the hyperkinetic and dilative forms of acromegalic cardiomyopathy (20–22). Cardiac hypertrophy has been observed in rats bearing GH-secreting transplantable tumors (23) or in rats repeatedly treated with GH injections (24). Reports on the hemodynamic effects of chronic GH excess in rats are conflicting in that a hyperkinetic heart syndrome (23) and depressed indices of cardiac pump function have both been observed (25). A third study found no change in the ratio of ventricular weight:body weight in rats bearing a GH secreting tumor for 18 weeks (26). However, the latter study reported a pattern of myocardial adaptation which allowed the muscle to improve its contractile performance and economy simultaneously, as assessed by myosin phenoconversion and increase in myosin ATPase enzymatic sites (26). The effects of GH appear, in part, to be mediated by insulin-like growth factor-I (IGF-I). There is experimental evidence that IGF-I enhances ventricular hypertrophy and function during the onset of experimental cardiac failure in mice with increased end-diastolic volume and stroke volume (27). IGF-I stimulates myofibril development and decreases smooth muscle a-actin of adult cardiomyocytes, suggesting that IGF-I may be involved in stress-induced changes of cardiomyocytes (28). IGF-I has been shown to stimulate cardiomyocyte contractility in vitro (29). In rats, administration of either GH or IGF-I alone, or both in combination (for 4 weeks) increased left ventricular muscle mass, increased cardiac index and reduced systemic vascular resistance. Each of the single treatments led to increased in vivo and in vitro cardiac function parameters, whereas the combination H IG H L IG H T European Journal of Endocrinology (1998) 139 476–478 ISSN 0804-4643