Towards precision medicine in heart failure

The number of therapies for heart failure (HF) with reduced ejection fraction has nearly doubled in the past decade. In addition, new therapies for HF caused by hypertrophic and infiltrative disease are emerging rapidly. Indeed, we are on the verge of a new era in HF in which insights into the biology of myocardial disease can be matched to an understanding of the genetic predisposition in an individual patient to inform precision approaches to therapy. In this Review, we summarize the biology of HF, emphasizing the causal relationships between genetic contributors and traditional structure-based remodelling outcomes, and highlight the mechanisms of action of traditional and novel therapeutics. We discuss the latest advances in our understanding of both the Mendelian genetics of cardiomyopathy and the complex genetics of the clinical syndrome presenting as HF. In the phenotypic domain, we discuss applications of machine learning for the subcategorization of HF in ways that might inform rational prescribing of medications. We aim to bridge the gap between the biology of the failing heart, its diverse clinical presentations and the range of medications that we can now use to treat it. We present a roadmap for the future of precision medicine in HF. In this Review, Weldy and Ashley summarize the biology of heart failure (HF), the mechanisms of action of HF drugs, and both the Mendelian genetics of cardiomyopathies and the complex genetics of HF. Finally, they present a roadmap for the future of precision medicine in HF. Key points The number of therapies for heart failure with reduced ejection fraction has nearly doubled in the past decade, with new therapies for hypertrophic and infiltrative disease emerging. We are on the verge of a new era in heart failure, in which basic biology can be matched to an understanding of genetic predisposition to inform precision therapy. The precision model of treatment for Mendelian disease is focused on treating the underlying mechanism, for which genetic therapy is increasingly in clinical development; genetic variants can also function as strong modifiers of complex disease, which might inform precision-based treatment of heart failure in the future. Important precision medicine approaches for the diagnosis and treatment of myocardial hypertrophy caused by hypertrophic cardiomyopathy, amyloidosis, Fabry disease or Noonan syndrome are available today but are underutilized. Machine learning tools to evaluate large clinical,