Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension.
Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension.
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DOI：
10.1161/circulationaha.115.019351
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发表时间：
2016-05-17
期刊：
影响因子：
37.8
通讯作者：
Hemnes AR
中科院分区：
文献类型：
--
作者：
Brittain EL;Talati M;Fessel JP;Zhu H;Penner N;Calcutt MW;West JD;Funke M;Lewis GD;Gerszten RE;Hamid R;Pugh ME;Austin ED;Newman JH;Hemnes AR
肺动脉高压（PAH）右心室（RV）衰竭的机制知之甚少。在PAH的实验模型中已经描述了脂肪酸（FA）代谢的减少，但尚未在人类PAH中研究全身和心肌FA代谢。我们使用人体血液和RV组织以及非侵入性成像来表征PAH受试者和对照者FA代谢途径中的多个步骤。PAH患者与对照组相比，循环FFA和长链酰基肉毒碱升高。与对照组相比，PAH组人RV长链FA增加，长链酰基肉毒碱显著减少。使用质子磁共振波谱，与对照组相比，人PAH中的体内心肌甘油三酯含量升高（1.4 ± 1.3% TG vs. 0.22 ± 0.11% TG，p = 0.02）。与对照组相比，PAH RV中的神经酰胺（脂毒性介质）增加。使用遗传性PAH的动物模型，我们证明了通过棕榈酰肉毒碱刺激PAH RV中的耗氧量的失败来减少脂肪酸氧化。在人PAH的血液和心肌中可检测到脂肪酸代谢异常，并与体内心脏脂肪变性和脂毒性相关。小鼠数据表明，脂肪酸氧化减少可能导致脂毒性。
The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism have not been studied in human PAH. We used human blood and RV tissue and non-invasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating FFAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long chain FAs were increased and long chain acylcarnitines were markedly reduced in PAH versus controls. Using proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls (1.4 ± 1.3 %TG vs. 0.22 ± 0.11 %TG, p = 0.02). Ceramide, a mediator of lipotoxicity, was increased in PAH RVs versus controls. Using an animal model of heritable PAH we demonstrated reduced fatty acid oxidation via failure of palmitoylcarnitine to stimulate oxygen consumption in the PAH RV. Abnormalities in fatty acid metabolism can be detected in the blood and myocardium in human PAH and are associated with in vivo cardiac steatosis and lipotoxicity. Murine data suggests that lipotoxicity may arise from reduction in fatty acid oxidation.