Heart Failure as a Multiple Hormonal Deficiency Syndrome

Abstract

The classic neurohormonal model of heart failure (HF) is rooted in the overexpression of neurohormonal molecules. To complement this paradigm, increasing evidence indicates that a variety of hormones and metabolic signals may be downregulated in HF patients. The list of downregulated molecules includes growth hormone (GH), its tissue effector insulin-like growth factor-1 (IGF-1), thyroid hormone, and anabolic steroids.1–4 In addition, HF is complicated by insulin resistance (IR), which ultimately means downregulation of insulin signaling.5,6 This review examines the evidence in support of the concept that HF is a multiple hormonal and metabolic deficiency syndrome (MHD). Particular attention is focused on the relevance of MHD in terms of cardiac performance and physical capacity and its impact on HF progression. Translation of new concepts into potential therapeutic options is also discussed. ### IR and HF A bidirectional link exists between IR and HF. IR predicts HF independently of other risk factors.7 Conversely, patients with HF are predisposed to IR or type 2 diabetes.5,8 In the OPTIMIZE-HF study, 42% of patients hospitalized for HF also had diabetes.9 IR is present in about one third of nondiabetic. HF patients and associates with more severe HF symptoms, worse functional capacity, and poor survival.5,6 IR per se, independent of hyperglycemia and hyperinsulinemia, may exert deleterious cardiovascular effects.10 IR specifically involves the myocardial tissue. In a dog model of HF, myocardial glucose uptake was 32% lower ( P <0.01) than pre-HF values, and this decrease was associated with reduced translocation of GLUT4 and downregulation of phosphorylated Akt.11 A positron emission tomography study showed impaired myocardial uptake of glucose and increased uptake of free fatty acid (FFA) in HF patients.12 Several mechanisms may explain why HF is complicated by IR. A key factor is adrenergic overactivity. The insulin-antagonistic effect of catecholamines is well established. …