Regression of cardiac hypertrophy in health and disease: mechanisms and therapeutic potential

Left ventricular hypertrophy is a leading risk factor for cardiovascular morbidity and mortality. Although reverse ventricular remodelling was long thought to be irreversible, evidence from the past three decades indicates that this process is possible with many existing heart disease therapies. The regression of pathological hypertrophy is associated with improved cardiac function, quality of life and long-term health outcomes. However, less than 50% of patients respond favourably to most therapies, and the reversibility of remodelling is influenced by many factors, including age, sex, BMI and disease aetiology. Cardiac hypertrophy also occurs in physiological settings, including pregnancy and exercise, although in these cases, hypertrophy is associated with normal or improved ventricular function and is completely reversible postpartum or with cessation of training. Studies over the past decade have identified the molecular features of hypertrophy regression in health and disease settings, which include modulation of protein synthesis, microRNAs, metabolism and protein degradation pathways. In this Review, we summarize the evidence for hypertrophy regression in patients with current first-line pharmacological and surgical interventions. We further discuss the molecular features of reverse remodelling identified in cell and animal models, highlighting remaining knowledge gaps and the essential questions for future investigation towards the goal of designing specific therapies to promote regression of pathological hypertrophy.