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American Heart Association

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Final ID: Mo102

Swine Model of Heart Failure with Preserved Ejection Fraction Driven by Lipoprotein Lipase Inhibition and Enhanced Cardiac Low-Density Lipoprotein Receptor Expression

Abstract Body: Background. Heart failure with preserved ejection fraction (HFpEF) poses an escalating public health threat, marked by growing incidence and high mortality. In the cardiometabolic phenogroup of HFpEF that includes diabetes and obesity, intramyocardial lipid content is a prognostic indicator of diastolic dysfunction and adverse outcome. Our group recently reported a mouse model of cardiometabolic HFpEF wherein myocardial lipotoxicity was induced by systemic inhibition of lipoprotein lipase (LPL) with Poloxamer 407 (P407) and cardiac overexpression of the LDL receptor (LDLR), conditions that have been documented in clinical HFpEF. The model demonstrates myocardial lipid accumulation, fibrosis, arrhythmia, and diastolic dysfunction. To reproduce this model in large animals we implemented the same protocol in pigs.
Methods. Female Yorkshire swine (~25 Kg) were subjected to one of two protocols including: 1) single intracoronary (i.c.) injection of 1013 AAV9-cTnT-LDLR particles and biweekly intraperitoneal (i.p.) P407 at 1g/Kg, (high dose, n=2), or 2) Double i.c. injections of 1013 AAV9-cTnT-LDLR particles and biweekly i.p. P407 at 0.25g/Kg) (low dose, n=2). Cardiac structure and function were evaluated by MRI, and hemodynamics measured by PV-Loop at baseline, 4, 8, and 12 weeks. Blood was collected biweekly for complete blood count (CBC), basic biochemistry, and liver and lipid panels. Tissues were collected for protein and histopathological analysis.
Results. In both strategies, the animals developed high LDL-cholesterol and cardiac hypertrophy with preserved EF. High dose P407 led to higher triglycerides, VLDL, HDL, liver injury (ALT > 200U/L), and steatosis at 4 weeks. One of the 2 pigs died at 3 weeks. Low dose P407 and high dose viral particles induced HFpEF at ~12 weeks with increased LV mass, relative wall thickness, end-diastolic pressure, and tau. Serum LDL-C accumulated from an initial value of 161 to 344.5mg/dL at 12 weeks. No significant liver injury was present until week 12 (ALT<88 U/L, AST<59 U/L). Both strategies did not exhibit abnormalities in CBC or other biochemical parameters.
Conclusions. Low dose inhibition of LPL combined with cardiac overexpression of LDLR confers HFpEF in swine.
  • Condor, Jose Manuel  ( University of Miami , Miami , Florida , United States )
  • Balkan, Wayne  ( University of Miami , Miami , Florida , United States )
  • Webster, Keith  ( Baylor college of medicine , Miami , Florida , United States )
  • Hare, Joshua  ( University of Miami , Miami , Florida , United States )
  • Shehadeh, Lina  ( UNIVERSITY OF MIAMI MILLER SCH MED , Miami , Florida , United States )
  • Robleto, Emely  ( University of Miami , Miami , Florida , United States )
  • Bagno, Luiza  ( University of Miami , Miami , Florida , United States )
  • Ionescu, Simona  ( University of Miami , Miami , Florida , United States )
  • Clavellina, Diana  ( University of Miami , Miami , Florida , United States )
  • Rosado, Marcos  ( University of Miami , Miami , Florida , United States )
  • Rodriguez, Jose  ( University of Miami , Miami , Florida , United States )
  • Saad, Ali  ( University of Miami , Miami , Florida , United States )
  • Takeuchi, Lauro  ( University of Miami , Miami , Florida , United States )
  • Author Disclosures:
    Jose Manuel Condor: DO NOT have relevant financial relationships | Wayne Balkan: No Answer | KEITH WEBSTER: No Answer | Joshua Hare: No Answer | Lina Shehadeh: DO NOT have relevant financial relationships | Emely Robleto: DO NOT have relevant financial relationships | Luiza Bagno: No Answer | Simona Ionescu: No Answer | Diana Clavellina: DO NOT have relevant financial relationships | Marcos Rosado: DO NOT have relevant financial relationships | Jose Rodriguez: No Answer | Ali Saad: No Answer | Lauro Takeuchi: DO NOT have relevant financial relationships
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception I

Monday, 07/22/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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