A Proteomic Approach to Uncover Biomarkers of Risk and Novel Therapeutic Targets in Heart Failure

By Amil M. Shah, M.D., M.P.H.

Professor of Internal Medicine

Heart failure (HF) is a multisystem disorder that causes substantial morbidity and mortality. Despite the established role of neurohormonal activation, much remains unknown regarding HF pathophysiology, especially when in the setting of preserved left ventricular (LV) ejection fraction (HFpEF). Because proteins are the effectors of genes and their circulating levels are frequently influenced by genetic variation, studying the plasma proteome is a promising approach to discovery of novel mechanisms underlying HF. The major theme of my research group’s 10 scientific presentations at #AHA23 was leveraging large-scale plasma proteomics to identify proteins and protein networks underlying cardiac dysfunction and heart failure development.

We performed a series of studies based on measurement of ~5,000 plasma proteins in > 10,000 community-based individuals. We identified proteins associated with subclinical cardiac dysfunction, with risk of developing HFpEF and HF with reduced LVEF (HFrEF), and with distinct trajectories of cardiac function over 20 years from mid- to late-life. Using Mendelian randomization analyses for genetic causal inference, we identified a subset of proteins with evidence of a causal effect on HF and/or cardiac dysfunction. We further leveraged these approaches to identify potential protein mediators for the beneficial effects of exercise and for the adverse effects of socioeconomic deprivation on HF risk.

Ultimately, we believe that this proteomic approach will lead to the identification of novel biomarkers of risk as well as potential therapeutic targets for specific types of HF.