**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** ISCHEMIA WITH NON-OBSTRUCTIVE CORONARY ARTERY DISEASE (INOCA) AFFLICTS MAINLY WOMEN AND IS RESPONSIBLE FOR AN INCREASED RISK OF CARDIOVASCULAR DEATHS, MYOCARDIAL INFARCTION, AND HEART FAILURE. THE UNDERLYING PATHOLOGICAL MECHANISM THAT DRIVES INOCA IS CORONARY MICROVASCULAR DYSFUNCTION (CMD), AN IMPAIRMENT OF THE CARDIAC MICROVESSELS OF THE EPICARDIUM. A MYRIAD OF UNTARGETED MEDICATIONS ARE USED TO TREAT THIS CONDITION; HOWEVER, NONE OF THESE DRUGS ARE FULLY EFFICACIOUS, AND NO TARGETED THERAPY CURRENTLY EXISTS IN TREATING INOCA. THUS, THE LONG-TERM GOAL OF THIS RESEARCH IS TO DEVELOP AN ALTERNATIVE SAFE, EFFICACIOUS, AND SIDE-EFFECT-FREE NUTRITIONAL STRATEGY TO BE USED IN THE CLINICAL SETTING TO IMPROVE INOCA AND ADVANCE OUR UNDERSTANDING OF THE INTERPLAY BETWEEN DIET, GUT MICROBIOTA, AND CARDIOVASCULAR DISEASE. PLANT-BASED DIETS HAVE BEEN ASSOCIATED WITH REDUCED CARDIOVASCULAR DISEASE INCIDENCE, AND PILOT CLINICAL STUDIES INDICATE THAT A POLYPHENOL-RICH PLANT-BASED DIET IS PROTECTIVE OF THE MACROVASCULATURE BOTH PERIPHERALLY AND IN THE HEART. ADDITIONALLY, THE GUT MICROBIOTA IS CRITICALLY INVOLVED IN THE METABOLISM OF POLYPHENOLS WHICH CAN ALSO RESULT IN A MICROBIAL POPULATION SHIFT. THUS, THE CENTRAL HYPOTHESIS OF THIS PROPOSED STUDY IS THAT THE CONSUMPTION OF A POLYPHENOL-RICH PLANT-BASED DIET CAN FAVORABLY ALTER GUT MICROBIAL POPULATIONS DUE TO THE POLYPHENOL CONTENT OF THE DIET AND THEREBY IMPROVE INOCA BY TARGETING CMD. THE FOLLOWING SPECIFIC AIMS HAVE BEEN PROPOSED: 1) INVESTIGATE WHETHER A PLANT-BASED DIET VIA THE MICROBIOME CAN PREVENT OR TREAT INOCA INDUCED BY HYPERTENSION IN FEMALE SPONTANEOUSLY HYPERTENSIVE RATS (SHRS), AND 2) INVESTIGATE WHETHER A PLANT-BASED DIET TARGETS CARDIAC MICROVASCULAR ENDOTHELIAL CELLS (ECS) AND VASCULAR SMOOTH MUSCLE CELLS (VSMCS) IN CMD VIA THE MICROBIOME. SHR'S WILL BE UTILIZED AS THEY DEVELOP CMD AND INOCA, AND FEMALE ANIMALS WILL BE UTILIZED SINCE INOCA AFFLICTS MOSTLY WOMAN. ANIMALS WILL BE FED A DIET SUPPLEMENTED WITH OR WITHOUT POLYPHENOL-RICH PLANT-FOODS IN ADDITION TO WITH OR WITHOUT ANTIBIOTICS TO ELUCIDATE THE ROLE OF THE GUT MICROBIOME IN MEDIATING THE EFFICACY OF THE INTERVENTION. ECHOCARDIOGRAPHY AND INNOVATIVE MAGNETIC RESONANCE IMAGING TECHNIQUES WILL BE UTILIZED TO ASSESS THE MICROVASCULAR FUNCTION OF THE HEART. POLYPHENOLS WILL BE QUANTIFIED IN BOTH SERUM AND WITHIN CARDIAC TISSUE VIA MASS SPECTROSCOPY. GUT MICROBIOTA POPULATION SHIFTS WILL BE ASSESSED WITH 16S RNA SEQUENCING IN FECES. ADDITIONALLY, ECS AND VSMCS WILL BE ISOLATED FROM THE HEART AND STIMULATED WITH THEIR SERUM CONTAINING MICROBIOTA-DERIVED POLYPHENOL METABOLITES. INTRACELLULAR OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIAL NITRIC OXIDE HANDLING , AND VSMC CALCIUM HOMEOSTASIS AND ELASTICITY WILL BE ASSESSED. THIS PROPOSED PROJECT INVESTIGATES THE EFFICACY OF A PLANT-BASED DIET IN THE TREATMENT OF INOCA, AN UNDERSTUDIED DISEASE THAT AFFLICTS MOSTLY FEMALES, A POPULATION FOR WHICH RESEARCH IS LACKING. THIS PROPOSED STUDY ALS,O WILL ADVANCE TRANSLATIONAL RESEARCH, AS SUBSTANTIAL PRELIMINARY DATA WILL BE GENERATED AND UTILIZED FOR CLINICAL TRIAL FUNDING IN FUTURE GRANT APPLICATIONS.