Novel therapeutic targets for the treatment of heart failure

Key Points Heart failure is a heterogeneous, multifactorial and progressive syndrome that presents as a wide spectrum of phenotypes and is often accompanied by other comorbidities. It represents a major health problem owing to its high morbidity and mortality and substantial health-care costs. The goals of treatment are to reduce mortality and morbidity, prevent heart disease or its progression, and manage comorbidities that cause and/or contribute to the pathogenesis of heart failure. Despite considerable therapeutic advances, treatment of acute decompensated heart failure has not changed much over the past 25 years, as new drugs have failed to reduce morbidity and mortality rates compared to placebo. Furthermore, no treatment strategy has improved clinical outcomes in patients with heart failure with preserved left ventricular ejection fraction. There is an unmet need for the development of new drugs with a favourable safety profile that can improve cardiac performance and clinical outcomes in patients, and prevent the progression of heart failure. In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified and several promising new drugs are currently under investigation, both in experimental models and in clinical trials in patients with heart failure. However, the positive results that are obtained in preclinical and Phase II studies are not always confirmed in large Phase III trials. In this Review, we provide a detailed analysis of the possible explanations for this discrepancy. The development of new effective and safe drugs for the treatment of heart failure should be based on a better understanding of the pathophysiological mechanisms that are directly implicated in the onset and/or maintenance of heart failure, robust preclinical data and well-designed clinical trials. This Review highlights new therapeutic targets (for example, ventricular remodelling) and future perspectives of new drugs that are currently under development for the treatment of heart failure, and the possible explanations for the discrepancy between data from Phase II and Phase III trials. Despite considerable therapeutic advances, heart failure remains a medical and socioeconomic problem. Thus, there is a compelling need for new drugs that could improve clinical outcomes. In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified, and new drug