A porcine model of heart failure with preserved ejection fraction: magnetic resonance imaging and metabolic energetics
A porcine model of heart failure with preserved ejection fraction: magnetic resonance imaging and metabolic energetics
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DOI：
10.1002/ehf2.12536
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发表时间：
2019-12-18
影响因子：
3.8
通讯作者：
Richards, A. Mark
中科院分区：
文献类型：
--
作者：
Charles, Christopher J.;Lee, Philip;Richards, A. Mark
目的：很大比例的心力衰竭（HF）患者具有HF保留射血分数（HFpEF）。HFpEF缺乏有效的治疗方法仍然是一个关键的未满足的需求。HFpEF治疗创新的一个关键障碍是缺乏临床前模型。尽管已经报道了几种大型动物模型，但很少有动物模型显示进展为失代偿性HF。我们建立了一个HFpEF模型，通过增强猪模型进行性左心室（LV）压力超负荷和特点HF在这个模型中，包括先进的心脏代谢成像，心脏磁共振成像和超极化碳-13磁共振波谱。方法和结果通过可充气主动脉袖带使猪经历渐进性LV压力超负荷。猪出现左心室肥大（与假手术对照组相比，壁厚增加50%，P < 0.001，质量增加2倍，P < 0.001），没有左心室扩张的证据，但左心房容积显著增加（P = 0.013）。心脏磁共振成像显示，与假手术猪相比，16/17个节段中的T1改良Look-Raw反转恢复值增加（P < 0.05-P < 0.001），表明整体心室纤维化。与假手术对照组相比，平均LV舒张末期（P = 0.047）和肺毛细血管楔压（P = 0.008）升高。三分之一的猪表现出明显的失代偿性HF临床体征，与假手术对照组相比，平均血浆BNP浓度升高（P = 0.008）。超极化碳-13磁共振波谱的心脏代谢成像与衰竭心脏中已知的代谢变化一致，即从脂肪酸向葡萄糖底物利用的转变。结论：生长猪进行性主动脉缩窄可诱导显著的左心室肥厚，伴有与左心房扩张相关的心脏纤维化，充盈压升高，以及转变为明显HF伴BNP升高而不降低LVEF的能力。该模型复制了以高血压为主要背景的临床HFpEF的许多方面，可用于促进对潜在病理学的理解，并用于新候选疗法的必要临床前测试。
Aims A significant proportion of heart failure (HF) patients have HF preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF remains a critical unmet need. A key obstacle to therapeutic innovation in HFpEF is the paucity of pre-clinical models. Although several large animal models have been reported, few demonstrate progression to decompensated HF. We have established a model of HFpEF by enhancing a porcine model of progressive left ventricular (LV) pressure overload and characterized HF in this model including advanced cardiometabolic imaging using cardiac magnetic resonance imaging and hyperpolarized carbon-13 magnetic resonance spectroscopy. Methods and results Pigs underwent progressive LV pressure overload by means of an inflatable aortic cuff. Pigs developed LV hypertrophy (50% increase in wall thickness, P < 0.001, and two-fold increase in mass compared to sham control, P < 0.001) with no evidence of LV dilatation but a significant increase in left atrial volume (P = 0.013). Cardiac magnetic resonance imaging demonstrated T1 modified Look-Locker inversion recovery values increased in 16/17 segments compared to sham pigs (P < 0.05-P < 0.001) indicating global ventricular fibrosis. Mean LV end-diastolic (P = 0.047) and pulmonary capillary wedge pressures (P = 0.008) were elevated compared with sham control. One-third of the pigs demonstrated clinical signs of frank decompensated HF, and mean plasma BNP concentrations were raised compared with sham control (P = 0.008). Cardiometabolic imaging with hyperpolarized carbon-13 magnetic resonance spectroscopy agreed with known metabolic changes in the failing heart with a switch from fatty acid towards glucose substrate utilization. Conclusions Progressive aortic constriction in growing pigs induces significant LV hypertrophy with cardiac fibrosis associated with left atrial dilation, raised filling pressures, and an ability to transition to overt HF with raised BNP without reduction in LVEF. This model replicates many aspects of clinical HFpEF with a predominant background of hypertension and can be used to advance understanding of underlying pathology and for necessary pre-clinical testing of novel candidate therapies.