2020 IARS Mentored Research Award
Kamrouz Ghadimi, MD
Duke University Medical Center
Associate Professor of Anesthesiology & Critical Care
Dr. Ghadimi’s Research
Right Ventricular Metabolic Dysregulation after Surgery for Heart Failure
Perioperative right heart failure (RHF) is the leading cause of death within thirty days of left ventricular assist device and heart transplant operations. To protect against early RHF development, cardiac anesthesiologists initiate inhaled pulmonary vasodilators (iPVD) to lower right ventricular (RV) afterload, which augments stroke volume by “coupling” RV contractility with pulmonary arterial (PA) vasodilation. Sadly, there is marked heterogeneity in the response to iPVD and nearly 50% of patients display persistently elevated RV afterload. Metabolically, elevated afterload can lead to dysregulated fatty acid oxidation in RV myocytes, normally reliant on mitochondrial transport of long-chain acylcarnitines for high-throughput ATP synthesis. This metabolic defect results in ceramide-induced lipotoxic apoptosis and acylcarnitine leakage into circulation. Leveraging the biorepository from a parent trial at our institution that is evaluating iPVD use to treat RV afterload following LVAD and heart transplant operations (NCT03081052), the overall objective in this application is to identify cardiometabolic pathways that underlie early RHF after these operations due to changes in RV afterload and heterogeneity in response to iPVD. Supported by preliminary metabolomic analyses, the central hypothesis posits that RV-PA coupling is optimized in the responder phenotype, which signals efficient fatty acid oxidation in RV myocardium. Aim 1 will quantify differences in key metabolites using targeted mass spectrometry in serial plasma and RV myocardial samples to determine cardiometabolic pathways, including dysregulated fatty acid oxidation, that underlie early RHF and heterogeneity in response to iPVD. Aim 2 will identify baseline biomarkers reflecting fatty acid oxidation defects that are associated with RV-PA coupling status, iPVD response phenotypes, and early RHF development to create an integrated clinical-molecular model for outcome prediction in critically-ill patients.
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