A Plant-based Diet in the Treatment of Coronary Microvascular Dysfunction (CMD)

About This Grant

PROJECT SUMMARY Ischemia with non-obstructive coronary artery disease (INOCA) afflicts mainly women and is responsible for an increased risk of heart failure, myocardial infarction, and cardiovascular deaths. One of the underlying pathological mechanisms that drive INOCA is coronary microvascular dysfunction (CMD), an impairment of cardiac microvessels due to vascular smooth muscle cell (VSMC) and endothelial cell (EC) dysfunction. Patients are typically prescribed a myriad of medications; however, hospitalizations tend to persist. Thus, new approaches, efficacious and free of side effects, are urgently needed. My preliminary clinical data indicates that an unrefined, polyphenol-rich plant-based diet (PBD) can treat vascular diseases, and that a dietary pattern comprising unrefined plant foods is associated with reduced angina frequency in those with CMD. My animal data indicates that a PBD can also reverse CMD. However, no clinical studies have specifically focused on CMD to test dietary interventions. Thus, the central goal of this proposal is to investigate my hypothesis that PBD consumption can treat human CMD. I propose the following specific aims. Aim 1) Specific Aim 1: Determine the adherence of a PBD intervention in adults with CMD and optimize interventional approaches (K99 phase), Aim 2) Determine the potential of an unrefined PBD to improve CMD and investigate the cellular and molecular parameters that mediate its impact (R00 phase), and Aim 3) Investigate whether dietary polyphenols from an unrefined PBD differentially impacts CMD based on sex with an established animal model (R00 phase). I will facilitate my career development with substantial training in clinical trials and expanded basic science techniques. In Aim 1, CMD patients will be counseled by a registered dietician, participate in an educational session, and provided prepared meals (3,000mg/1,000kcal polyphenols) to facilitate dietary adherence. Angina frequency and burden will be assessed, as will peripheral vascular function at baseline and following 8 weeks of the PBD. Feasibility of the intervention will be optimized for Aim 2, and cardiac magnetic resonance imaging with adenosine infusion will be obtained to directly assess CMD. ECs and VSMCs will be treated with serum from patients to assess reactive oxygen species production, nitric oxide signaling and cGMP- kinase function. Monocytes will be isolated from whole blood for redox assessments. Aminothiols via HPLC will be used to assess systemic oxidative stress, and serum polyphenols will be quantified. An animal model of CMD (Aim 3) using male and female spontaneously hypertensive rats (SHRs) will further elucidate mechanisms of polyphenols and potential sex differences, as these animals will consume a PBD for 3 months following 12 months of polyphenol deficiency. ECs and VSMCs will be isolated from hearts to assess similar measures as in Aim 2. Proteomic/phosphoproteomic changes of the myocardium will also be assessed. This project falls in line with NHLBI’s strategic goal of reducing human disease, as this proposed project investigates the efficacy of a PBD in the treatment of CMD, an understudied disease with clear sex differences.