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Lapses in self-care are commonly cited as a major cause of poor outcomes in persons with heart failure (HF). Not surprisingly, self-care is assumed to be central to improving health outcomes in this patient population. Empirically, however, this assumption is not well supported, and mechanistically, relationships between self-care and outcomes in HF have not yet been described. In this review, it is proposed that effective self-care maintenance (adherence) and self-care management (symptom evaluation and management) practices are complementary to optimal medical management in delaying HF progression and improving health outcomes in this population. Potential mechanisms through which effective HF self-care practices are complementary to pharmacological therapy in improving outcomes include (a) facilitating partial blockade and partial deactivation of deleterious neurohormones, (b) limiting inflammatory processes, (c) decreasing the need for administration of detrimental pharmacological agents, and (d) minimizing myocardial hibernation. Because these mechanisms are hypothetical, research findings are required to establish their validity. Several strategic research questions are proposed.