Does postmenopausal estrogen therapy affect heart failure mortality?

The higher mortality from congestive heart failure in elderly women may be attributed to an age-related increase in the incidence of ischemic cardiomyopathy. Multiple observational studies have reported lower coronary event rates in postmenopausal estrogen users vs nonusers. These findings are supported by plausible biologic mechanisms including the benefits of estrogen in terms of low- and high-density lipoprotein cholesterol levels, improved endothelial function, and (in animals) delayed progression of atherosclerosis. However, these observational studies were confounded by prevention bias‚: specifically, women who took hormone replacement therapy were often younger and had lower cardiovascular risk profiles than those who did not. In one such observational study, a retrospective analysis of a large database of women with congestive heart failure, Reis et al showed that the lower mortality (due to sudden death, congestive heart failure, or myocardial infarction) of elderly estrogen users vs nonusers was independent of age or cardiomyopathy etiology.

The first randomized trial of hormone replacement therapy for secondary prevention of cardiovascular disease in postmenopausal women, the Heart and Estrogen/progestin Replacement Study (HERS), found no difference in cardiac events or mortality at 4 years, but did show an unexpected significant increase in myocardial infarction in the first treatment year. Because hormone therapy substantially increases the risk of venous thrombosis, many investigators have assumed that thrombosis is likely to be an early adverse effect of hormone replacement therapy.

The contrast between these two studies may be explained not only by randomization, but also by demographic differences. Few women in HERS (9.5%) had congestive heart failure before randomization, and only a small percentage (8.7%) were hospitalized for congestive heart failure during long-term follow-up. In the retrospective study by Reis et al, on the other hand, all subjects had significant symptomatic heart failure and less than half had coronary heart disease. Another difference is that HERS randomized women to combined estrogen/progestin therapy (progestin mitigates the cardioprotective effects of estrogen).

In light of the adverse effects of hormone replacement therapy (increased risk of venous thromboembolism and breast cancer after many years of treatment), and the data from HERS and other randomized studies regarding the increased risk of inducing or exacerbating coronary heart disease, it seems clear that postmenopausal hormone therapy should not be used to prevent coronary disease unless future data from well-designed randomized trials document its benefit.

Hrowth hormone plays a major role in maintaining cardiac integrity. Not only is cardiac function impaired by growth hormone deficiency, but growth hormone therapy restores wall thickness and normalizes cardiac performance. The experimental and clinical evidence suggests a role for adjuvant growth hormone in the therapy of congestive heart failure. In heart failure induced by myocardial infarction in rats, for instance, myocardial contractility responds to growth hormone, insulin-like growth factor-I (IGF-I), or a combination of both. The mechanism of action is unclear, but may involve increased myofilament responsiveness to an increased influx of Ca2+.

In 1996, in an uncontrolled study by Fazio et al in 7 patients with moderately severe heart failure due to idiopathic dilated cardiomyopathy, myocardial mass and exercise capacity improved after 3 months of growth hormone therapy. However, subsequent studies failed to confirm significant clinical benefit. Frustaci et al observed de novo arrhythmia and only mild improvement in left ventricular diameters and ejection fraction in 5 patients with severe heart failure. The difference in heart failure severity may account for the discrepancy. In 1997, Volterrani et al reported the acute effects of a 24-hour infusion of growth hormone 0.1 IU/kg in 12 patients with chronic heart failure. Mean concentrations of IGF-I, the main anabolic mediator of growth hormone, increased by about 50% vs baseline, the cardiac index improved by 57%, and mean pulmonary artery pressure decreased by 25%. The major problem with these initial studies was that they were open and uncontrolled.

Isgaard et al reported a double-blind, placebo-controlled study in 22 clinically stable patients with chronic heart failure (New York Heart Association [NYHA] functional class II-III) due to dilated cardiomyopathy. Eleven patients received recombinant human growth hormone 0.25 IU/kg weekly for 3 months. IGF-I levels increased significantly in the active treatment group, but there were no significant effects on ejection fraction, left ventricular mass, end-systolic and end-diastolic diameters, NYHA functional class, or exercise performance. Osterziel et al largely confirmed these findings in 50 chronic heart failure patients assigned to growth hormone


drug; growth hormone therapy; myocardial contractility; neurohumoral factor; therapeutic perspective

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