Abstract
Byline: Monique M Williams, Univ of Miami, Miller Sch, Miami, FL; Jose Manuel Condor Capcha, Miami, FL; Camila Iansen Irion, Univ of Miami, Miami, FL; Grace Seo, Univ of Miami Miller SOM, Miami, FL; Guerline Lambert, Univ of Miami, Miami, FL; Ali Kamiar, Miami, FL; Rosemeire M Kanashiro-Takeuchi, UNIVERSITY OF MIAMI, Miami, FL; Lauro Takeuchi, Univ of Miami, Miami, FL; Ali Saad, Univ of Miami, Miller Sch of Medicine, FL; Armando J Mendez, UNIVERSITY MIAMI, Miami, FL; Keith A Webster, UNIVERSITY MIAMI, Miami, FL; Jeffrey J Goldberger, Univ of Miami, Miami, FL; Joshua M Hare, UNIVERSITY OF MIAMI, Miami, FL; Lina A Shehadeh, UNIVERSITY OF MIAMI MILLER SCH MED, Miami, FL Background: HFpEF prevalence has surpassed that of HFrEF. Elevated accumulation of myocardial lipids is a prominent feature of HFpEF patients and the gene for lipoprotein lipase (LPL) in cardiac biopsies is decreased compared with HFrEF or healthy controls. Poloxamer-407 (p407) induces hyperlipidemia by blocking LPL and increasing plasma triglycerides (TG) and LDL cholesterol. We hypothesized that hyperlipidemia driven by p407 and overexpression (OE) of cardiac LDLR in mice mimics a subset of human HFpEF. Methods: WT-129 mice were subject to 4 wks of biweekly i.p. p407-injections with or without a single i.v. injection of AAV9-cTnT-LDLR (n=31); AAV9-cTnT-Luciferase control (n=11), or single i.v. injection with AAV9-cTnT-LDLR alone (n=10). Treatment groups were compared to an untreated group (n=26). Echo, blood pressure (BP), whole-body plethysmography (WBP), ECG telemetry, activity wheel monitoring (AWM), biochemical tests, and histological changes were assessed at 4-8 wks. Results: At 4 wks, p407 and LDLR OE led to diastolic dysfunction (DD) (prolonged IVRT, decreased E/A (p<0.05 and p<0.001 respectively)), preserved EF and increased LV wall thickness (LVID and LVAW, p<0.0001). BP and WBP were normal at 4 wks but respiration (breaths per minute) decreased at 8 wks (p<0.01). ECG and AWM respectively indicated heart block and decreased exercise activity (p<0.001). With the double treatment, total cholesterol increased in heart, skeletal muscle and liver (p<0.05), while TG was decreased only in hearts (p<0.001) and liver (p<0.05). Double treatment also promoted elevated myocardial lipids, fibrosis, increased Wet/Dry lung (p<0.001) and HW/BW (p<0.05). Xanthelasma, ascites, and cardiac ischemia were noted in the double and single, p407 + luciferase groups. Sudden death (SD) occurred between 6-12 wks in double and p407+Luciferase treatment groups. Conclusion: We present a unique model of early onset, rapidly evolving HFpEF where double treatment mice acquire DD, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved EF in the absence of obesity, HTN, CKD or DM. The model may represent a subset of HFpEF wherein hyperlipidemia drives a severe phenotype with SD as a prominent endpoint.