Response to Letter Regarding Article, “Anabolic Deficiency in Men With Chronic Heart Failure: Prevalence and Detrimental Impact on Survival”

Abstract

We thank Pascual-Figal et al for their insightful comments on our article, 1 in which we have demonstrated that multiple anabolic deficiency is common in men with stable systolic chronic heart failure (CHF) and adversely relates to long-term survival.Spironolactone interacts with androgen steroid synthesis and metabolism; it is not clear whether a reduction in serum levels of sex steroids in men is a consequence of spironolactone therapy. 2 Of 208 CHF men in our study, 53 (25.5%) were treated with spironolactone at baseline (25 mg per 24 h). According to European Society of Cardiology guidelines, low-dose spironolactone therapy should be restricted to patients with severe CHF. The men treated with spironolactone had more advanced CHF, as evidenced by higher New York Heart Association class (PϽ0.0001), lower left ventricular ejection fraction (PϽ0.0001), and higher plasma N-terminal-pro-brain natriuretic peptide levels (PϽ0.01). They also demonstrated reduced serum levels of total testosterone (PϽ0.01) and dehydroepiandrosterone sulfate (PϽ0.0001), and similar levels of insulin-like growth factor type 1 (PϾ0.2).To assess the impact of spironolactone therapy on relationships between anabolic deficiency and survival, we undertook multivariate analyses (see Table 4 of our original article), 1 further adjusting for spironolactone therapy at the beginning of follow-up. Serum levels of all anabolic hormones (all PϽ0.05) and, similarly, a number of anabolic deficiencies (PϽ0.001) were independently related to prognosis in men with CHF, irrespective of spironolactone treatment.In our study, the use of spironolactone was associated with worse symptoms and cardiac function, both important prognosticators; it also was associated with lower serum total testosterone and dehydroepiandrosterone sulfate. In clinical trials, spironolactone improves survival in patients with advanced heart failure; this is the opposite of what would be expected if one considered only the results of association studies. We cannot know from our study whether there is a cause-and-effect relationship between spironolactone treatment and anabolic deficiency. Prospective studies comparing effects of spironolactone or eplerenone versus placebo are needed to establish these relationships. But, we can conclude that spironolactone does not impact the strong relationship between multiple anabolic deficiency and survival in men with CHF.Patients with CHF often suffer from muscle wasting and cachexia. 3 Improving anabolic status in these patients may translate into improvements of exercise capacity, quality of life, and, possibly, survival. This approach may need to be accompanied by nutritional and/or antiinflammatory interventions. 4 We need to start prospective intervention trials, and the best option would be to focus on patients with anabolic deficiency. DisclosuresNone. Ewa

The Effects of Androgen Deprivation Therapy on Cardiac Function and Heart Failure: Implications for Management of Prostate Cancer

“…...Impaired anabolic metabolism may be a generalized phenomenon seen in the course of CHF that begins at an early stage of disease and accelerates the endocrine changes that normally occur in the course of male aging." 49 In contrast, in another study, low testosterone correlated with worse prognosis, but on multivariate analysis of confounders, the association vanished. The authors concluded that low testosterone might be a result of heart failure, and questioned testosterone deficiency as a causative agent of heart failure.…”

“…Low testosterone has been associated with heart failure, but impaired androgen metabolism has not been proven to be a cause of heart failure. 48,49 In contrast, consistent evidence from a number of small randomized studies have shown that testosterone therapy for heart failure in men improves exercise tolerance, cardiorespiratory function, and functional status, but does not appear to directly improve left ventricular function. [50][51][52][53] Selected effects of androgens on cardiac function are represented in Figure 1.…”

Androgen Deficiency in Heart Failure

“…Of note, this prevalence is in the same order of magnitude as described for patients with heart failure (ie, 20%-30%) [10,11]. In addition, the increase in SHBG levels and the tendency toward lower levels of albumin in patients with heart failure may result in relatively lower levels of bioavailable or free testosterone compared to healthy patients of similar age [12,13].…”

“…In a prospective cohort study of 206 middle-aged men with chronic systolic heart failure, 36% died during a median follow-up of 3.1 years. Higher total and free testosterone levels independently predicted better survival after adjustment in multivariable analysis [12]. In a similar cohort of 193 middle-aged men with chronic heart failure followed for 2.3 years (28% mortality), lower levels of free, but not total testosterone were associated with higher mortality risk in analyses adjusting for age and New York Heart Association (NYHA) class.…”

Association of IGF-I and IGFBP-3 with health care costs and hospitalization: Results from a prospective observational study

“…Thus important aspects of illness, such as pain and suffering [39] as well as social isolation [40] may contribute to the excess cost. Multisystem disorders that are widely prevalent in aging, such as the metabolic syndrome, frailty syndrome, and chronic heart failure are more significantly associated with endocrine disruptors of the GH/IGF-I axis [41].…”