Response to Letter Regarding Article, “Anabolic Deficiency in Men With Chronic Heart Failure: Prevalence and Detrimental Impact on Survival”
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 (P<0.0001), lower left ventricular ejection fraction (P<0.0001), and higher plasma N-terminal-pro-brain natriuretic peptide levels (P<0.01). They also demonstrated reduced serum levels of total testosterone (P<0.01) and dehydroepiandrosterone sulfate (P<0.0001), and similar levels of insulin-like growth factor type 1 (P>0.2).
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 P<0.05) and, similarly, a number of anabolic deficiencies (P<0.001) 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.
Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006; 114: 1829–1837.
Allan CA, McLachlan RI. Androgen deficiency disorders. In: DeGroot LJ, Jameson JL, eds. Endocrinology. Philadelphia, Pa: Elsevier Saunders; 2006: 3176–3177.
Piepoli MF, Kaczmarek A, Francis DP, Davies LC, Rauchhaus M, Jankowska EA, Anker SD, Capucci A, Banasiak W, Ponikowski P. Reduced peripheral skeletal muscle mass and abnormal reflex physiology in chronic heart failure. Circulation. 2006; 114: 126–134.
Jankowska EA, Ponikowski P, Piepoli MF, Banasiak W, Anker SD, Poole-Wilson PA. Autonomic imbalance and immune activation in chronic heart failure—pathophysiological links. Cardiovasc Res. 2006; 70: 434–445.