Personalizing Heart Failure Treatment with Genomics: A Clinical Trial to Understand the Mechanisms and Validate a Polygenic Risk Score for Beta-Blocker Response - PROJECT SUMMARY Beta-blockers (BB) are one of the few cornerstone therapies that provide significant benefit for patients with heart failure with reduced ejection fraction (HFrEF) on average, but the individual HFrEF patient responses to BB vary. Some HFrEF patients experience adverse effects from BB, and only a minority have a marked im- provement in their left ventricular ejection fraction (LVEF) with BB. Unfortunately, clinical characteristics do not predict how HFrEF patients will respond to BB, so research has recently focused on genetics. We developed a polygenic risk score (PRS) that predicts BB survival benefit in HFrEF patients, and it validated retrospectively in 4 independent datasets. Only ~22% of HFrEF patients with a low BB PRS had significant survival benefit from BB, whereas the ~78% with high BB PRS did not. However, 2 major knowledge gaps remain: the mech- anisms of the BB PRS are unknown, and it has not yet been prospectively validated in a clinical trial. Our pre- liminary data show the 44 genetic variants in the BB PRS regulate cardiovascular and BB metabolic path- ways, supporting both pharmacodynamic (PD) mechanisms (i.e., the cardiovascular effects of BB) and phar- macokinetic (PK) mechanisms (i.e., the metabolism of BB) of the BB PRS, respectively. Therefore, our central hypothesis is that BB have different PD and PK mechanisms in HFrEF patients with low vs. high BB PRS. Our overall approach is a mechanistic clinical trial comparing BB PD & PK in n = 50 HFrEF patients with low BB PRS vs. n = 50 with high BB PRS. HFrEF patients treated with no or low-dose BB will be enrolled, and then cardiovascular measurements, including cardiac MRI with contrast, cardiopulmonary exercise test, and EKG, will be performed at baseline and after 6 months of treatment with metoprolol succinate uptitrated to the guide- line-recommended target (200 mg daily) or maximally tolerated dose. Aim 1 is to determine differences in BB PD in HFrEF patients with low vs. high BB PRS. We hypothesize that HFrEF patients with high BB PRS will have less improvement in their LVEF with BB than patients with low BB PRS. Aim 2 is to determine differences in BB PK in HFrEF patients with low vs. high BB PRS. We hypothesize that HFrEF patients with high BB PRS will have lower plasma concentrations of metoprolol than patients with low BB PRS. Aim 3 is to determine dif- ferences in the BB PK/PD relationship in HFrEF patients with low vs. high BB PRS. We hypothesize that HFrEF patients with high BB PRS require higher BB plasma concentrations to achieve a similar reduction in exercise-induced heart rate than patients with low BB PRS. The expected outcomes are a mechanistic under- standing and prospective validation of the BB PRS in HFrEF patients. This mechanistic information is critically necessary to design a future clinical trial of genomic personalization of BB therapy for HFrEF patients: the PD mechanisms inform the additional and/or alternative drug therapies needed for HFrEF patients, whereas the PK mechanisms determine BB dose adjustments needed. This will have a major impact because it lays the foundation toward genomic personalization of BB therapy in HFrEF patients.
