Fatty Acid Metabolic Drivers of Right Ventricular Dysfunction in Heart Failure Associated Pulmonary Hypertension

/ABSTRACT This K23 proposal aims to provide Dr. Jonah Garry with the skills and experience required to lead a patient oriented translational research program focused on pulmonary vascular disease and right ventricular (RV) function. Through mentored research and career development, he will gain skills in: 1) Advanced statistical methods for high-dimensional molecular data, 2) Human genomics, 3) Prospective cohort study design and execution, and 4) Scientific oral and written communication. This proposal is focused on right ventricular (RV) dysfunction in heart failure-associated pulmonary hypertension (HF-PH). RV dysfunction is a leading cause of morbidity and mortality in HF-PH, a condition that affects 2.4-5.6 million Americans. Despite its clinical significance, the molecular drivers of RV dysfunction in HF-PH remain unknown. The candidate’s preliminary data suggest that dysregulated fatty acid (FA) metabolism plays a key role, aligning with prior findings in pulmonary arterial hypertension. If confirmed, this would suggest shared molecular mechanisms of RV dysfunction across PH subtypes, potentially broadening the applicability of FA metabolism-directed treatments across PH etiologies. This animates the central hypothesis of this proposal that dysregulated FA metabolism drives RV dysfunction in HF-PH. Notably, Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i), which modulate FA metabolism, are already used in HF-PH and provide an ideal opportunity to study the effect of modulating FA metabolism on RV function. The research proposal includes three independent, integrated aims. In Aim 1 the candidate will assess whether FA metabolism-related proteins associate with RV dysfunction in HF-PH. Using a biorepository of plasma samples from HF-PH subjects with independent discovery and internal validation cohorts (both n=250 subjects), the candidate will determine whether a pre-specified set of 50 FA metabolism related proteins associate with RV dysfunction. In Aim 2 the candidate will assess whether the genetic determinants of FA metabolism are associated with RV dysfunction in HF-PH. He will use whole genome sequencing data from Vanderbilt’s de-identified biobank BioVU (n=6,368) and the Veterans Administration Million Veterans Project (n=~10,000) to determine whether validated genetic risk scores for FA metabolism protein expression associate with RV dysfunction. In Aim 3 the candidate will enroll a prospective observational cohort of HF-PH subjects (n = 40) who have recently been prescribed an SGLT2i. Participants will undergo clinical assessment, echocardiogram, cardiac magnetic resonance imaging and measurement of targeted metabolomics at the time of SGLT2i prescription and after 6 months. The candidate will determine whether SGLT2i therapy improves RV function and if changes in RV function correlate with improved FA oxidation and reduced myocardial lipid content. Completing these aims will provide fundamental in vivo, human subject insights into the mechanisms of RV dysfunction and may identify molecules of therapeutic interest. Project Number: 1K23HL183771-01 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Jonah Garry | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $190,188 | Activity Code: K23 | Study Section: Special Emphasis Panel[ZRG1 RCCS-U (94)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HL18377101