P5999Heart failure rescue by high fat diet in a porcine model of hibernated myocardium
Authors: Martinez Milla J , Galan-Arriola C , Perez-Camargo D , Lobo M , Salinas B , Gonzalez D , Carnero M , Cobiella J , Mateo-Castro J , Vilchez J P , Cusso L , Lopez G J , Fuster V , Desco M , Ibanez B 
Published: October 2019

Abstract

Background
Extensive coronary artery disease without revascularization options results in ischemic hibernated myocardium and ultimately heart failure (HF). A metabolic reprogramming of the heart characterized by a shift from fatty acids (FFA) to glucose as the preferential metabolic substrate is frequent in HF and hibernated myocardium. Previous studies in mouse models of HF have shown that high fat diet (HFD) is able to reverse the metabolic reprogramming of the heart and improve cardiac function. Here we used a translational large animal model of ischemic HF evaluated by state-of-the-art imaging modalities

Methods
IHM was generated in Yucatan minipigs (N=50) by progressive stenosis of the proximal left anterior descending (LAD) after surgical insertion of a casein ameroid around the artery. Pigs underwent a serial multimodality imaging study including magnetic resonance imaging (MRI), multi-tracer PET/CT (18FDG & 14(R,S)-[18F]Fluoro-6-thia-heptadecanoic acid (18F-FTHA) 19F-palmitate in-house synthetized), and invasive coronary angiography (ICA). Once hibernated myocardium with metabolic switch was documented (complete occlusion of LAD, LVEF<50% on MRI, viable myocardium with dobutamine/MRI- evaluated contractile reserve, and metabolic substrate utilization shift towards glucose on PET/CT), animals were randomized to HFD or regular diet for 3 months

Results
The first part of the study was dedicated to establish the model in 42 pigs. Pigs were followed-up for 170±24 days with monthly ICA, MRI and PET/CT. Severe LAD stenosis was documented in all pigs 3–4 weeks after surgery. Mortality during follow-up was 57% (n=24) (15 peri-procedure, 2 between day 1 and 7, seven between day 7 and 45). Among those surviving beyond the sixth week, 90% (16/18) developed hibernated myocardium (mean LVEF 36±10%, absence of transmural delayed enhancement, contractile reserve and metabolic switch on PET/CT).
In the second part of the study, 5 long-term survivors were allocated to receive HFD (20% extra lard), while 3 pigs served as controls. Mean LVEF before HFD initiation was 35±8%, and 36±5% in controls. Three months HFD was associated with a LVEF improvement in all treated animals (mean LVEF at the end of follow-up was 45±9%). Control animals on regular diet did not show any change in LVEF (35±5% at the end of follow-up)

Conclusions
We present a large animal model of HF due hibernated myocardium by placing an ameroid around the LAD. Mortality of this model is high (approx. 55%) but long-term survivors resemble all features seen in patients: LAD progressive stenosis with final occlusion but viable myocardium, LVEF deterioration and metabolic switch
Feeding pigs with HFD to force cardiac reutilization of FFA, results in a consistent and large LVEF improvement in all animals
Cardiac metabolic switch might be implicated in the pathogenesis of systolic dysfunction in hibernated myocardium and is a potential target for nutritional approaches