Oxford Centre for Magnetic Resonance Research (W.D.W., P.G.G., A.J.M.L., P.A., L.V., S.N., O.J.R.), University of Oxford, UK.
Department of Cardiovascular Medicine (W.D.W.), University of Cambridge, UK.
Circulation. 2023 Jul 11;148(2):109-123. doi: 10.1161/CIRCULATIONAHA.122.062166. Epub 2023 May 18.
The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results.
To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo), invasive arteriovenous sampling and pressure-volume loops were performed (n=9).
At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; =0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; =0.009). Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; =0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; <0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism.
Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.
传统上认为衰竭的心脏代谢不灵活且缺氧，导致能量不足和收缩功能障碍。目前的代谢调节剂治疗旨在增加葡萄糖氧化以提高三磷酸腺苷生产的氧气效率，但结果喜忧参半。
为了研究衰竭心脏的代谢灵活性和氧输送，20 名非缺血性心力衰竭伴射血分数降低的患者（左心室射血分数 34.9±9.1）分别接受胰岛素+葡萄糖输注（I+G）或 Intralipid 输注。我们使用心血管磁共振评估心功能，并使用磷-31 磁共振光谱测量能量代谢。为了研究这些输注对心脏底物利用、功能和心肌耗氧量（MVo）的影响，进行了有创动静脉采样和压力-容积环（n=9）。
在休息时，我们发现心脏具有相当大的代谢灵活性。在 I+G 期间，心脏葡萄糖摄取和氧化占主导地位（用于三磷酸腺苷生产的总能量底物的 70±14%与 Intralipid 的 17±16%相比；=0.002）；然而，与基础条件相比，心功能没有变化。相比之下，在 Intralipid 输注期间，心脏长链脂肪酸（LCFA）的输送、摄取、LCFA 酰基辅酶 A 的产生和脂肪酸氧化均增加（LCFA 占总底物的 73±17%与 I+G 期间的 19±26%相比；=0.009）。与 I+G 相比，Intralipid 时心肌能量代谢更好（磷酸肌酸/三磷酸腺苷 1.86±0.25 与 2.01±0.33；=0.02），并且收缩和舒张功能得到改善（LVEF 34.9±9.1 基线、33.7±8.2 I+G、39.9±9.3 Intralipid；<0.001）。在增加心脏工作量期间，两种输注时 LCFA 摄取和氧化再次增加。在 65%最大心率时没有观察到收缩功能障碍或乳酸流出，这表明向脂肪的代谢转换不会引起有临床意义的缺血性代谢。
我们的发现表明，即使在射血分数降低的非缺血性心力衰竭伴严重收缩功能障碍的情况下，仍保留了显著的心脏代谢灵活性，包括改变底物利用以匹配动脉供应和工作负荷变化的能力。增加长链脂肪酸的摄取和氧化与改善心肌能量代谢和收缩力有关。这些发现共同挑战了现有心力衰竭代谢治疗基础理论的某些方面，并表明促进脂肪酸氧化的策略可能为未来的治疗奠定基础。
