Molecular Epidemiology of Heart Failure: Translational Challenges and Opportunities

Heart failure (HF) is the end-stage of all heart disease and arguably constitutes the greatest unmet therapeutic need in cardiovascular medicine today. Classic epidemiological studies have established clinical risk factors for HF, but the cause remains poorly understood in many cases. Biochemical analyses of small case-control series and animal models have described a plethora of molecular characteristics of HF, but a single unifying pathogenic theory is lacking. Heart failure appears to result not only from cardiac overload or injury but also from a complex interplay among genetic, neurohormonal, metabolic, inflammatory, and other biochemical factors acting on the heart. Recent development of robust, high-throughput tools in molecular biology provides opportunity for deep molecular characterization of population-representative cohorts and HF cases (molecular epidemiology), including genome sequencing, profiling of myocardial gene expression and chromatin modifications, plasma composition of proteins and metabolites, and microbiomes. The integration of such detailed information holds promise for improving understanding of HF pathophysiology in humans, identification of therapeutic targets, and definition of disease subgroups beyond the current classification based on ejection fraction which may benefit from improved individual tailoring of therapy. Challenges include: 1) the need for large cohorts with deep, uniform phenotyping; 2) access to the relevant tissues, ideally with repeated sampling to capture dynamic processes; and 3) analytical issues related to integration and analysis of complex datasets. International research consortia have formed to address these challenges and combine datasets, and cohorts with up to 1 million participants are being collected. This paper describes the molecular epidemiology of HF and provides an overview of methods and tissue types and examples of published and ongoing efforts to systematically evaluate molecular determinants of HF in human populations.