Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine (J.J.R, M.A.P., W.D.W., S.N., O.J.R.), University of Oxford, John Radcliffe Hospital, United Kingdom.
Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional MRI of the Brain (W.T.C.), University of Oxford, John Radcliffe Hospital, United Kingdom.
Circulation. 2020 Apr 7;141(14):1152-1163. doi: 10.1161/CIRCULATIONAHA.119.042770. Epub 2020 Mar 6.
Obesity is strongly associated with exercise intolerance and the development of heart failure. Whereas myocardial energetics and diastolic function are impaired in obesity, systolic function is usually preserved. This suggests that the rate of ATP delivery is maintained, but this has never been explored in human obesity. We hypothesized that ATP transfer rate through creatine kinase (CK) () would be increased, compensating for depleted energy stores (phosphocreatine/ATP), but potentially limiting greater ATP delivery during increased workload. We hypothesized that these changes would normalize with weight loss.
We recruited 80 volunteers (35 controls [body mass index 24±3 kg/m], 45 obese [body mass index 35±5 kg/m]) without coexisting cardiovascular disease. Participants underwent body composition analysis, magnetic resonance imaging of abdominal, liver, and myocardial fat content, left ventricular function, and P magnetic resonance spectroscopy to assess phosphocreatine/ATP and CK kinetics, at rest and during dobutamine stress. Obese volunteers were assigned to a dietary weight loss intervention, before reexamination.
At rest, although myocardial phosphocreatine/ATP was 14% lower in obesity (1.9±0.3 versus 2.2±0.2, <0.001), was 33% higher (0.23±0.07 s versus 0.16±0.08 s, =0.002), yielding no difference in overall resting ATP delivery (obese 2.5±0.9 µmol·g·s versus control 2.2±1.1 µmol·g·s, =0.232). In controls, increasing cardiac workload led to an increase in both (+86%, <0.001) and ATP delivery (+80%, <0.001). However, in obesity, similar stress led to no significant increase in either (=0.117) or ATP delivery (=0.608). This was accompanied by reduced systolic augmentation (absolute increase in left ventricular ejection fraction, obese +16±7% versus control +21±4%, =0.031). Successful weight loss (-11±5% body weight) was associated with improvement of these energetic changes such that there was no significant difference in comparison with controls.
In the obese resting heart, the myocardial CK reaction rate is increased, maintaining ATP delivery despite reduced phosphocreatine/ATP. During increased workload, although the nonobese heart increases ATP delivery through CK, the obese heart does not; this is associated with reduced systolic augmentation and exercise tolerance. Weight loss reverses these energetic changes. This highlights myocardial energy delivery through CK as a potential therapeutic target to improve symptoms in obesity-related heart disease, and a fascinating modifiable pathway involved in the progression to heart failure, as well.
肥胖与运动不耐受和心力衰竭的发展密切相关。虽然肥胖会导致心肌能量代谢和舒张功能受损，但收缩功能通常保持正常。这表明 ATP 的输送速率得以维持，但在增加工作量时，这是否得到了探索尚不清楚。我们假设通过肌酸激酶 (CK) 的 ATP 转移率（）会增加，以弥补能量储备的消耗（磷酸肌酸/ATP），但可能会限制更大的 ATP 输送。我们假设这些变化会随着体重减轻而恢复正常。
我们招募了 80 名志愿者（35 名对照组[体重指数 24±3kg/m]，45 名肥胖组[体重指数 35±5kg/m]），无并存心血管疾病。参与者接受了身体成分分析、腹部、肝脏和心肌脂肪含量的磁共振成像、左心室功能以及 P 磁共振波谱检查，以评估磷酸肌酸/ATP 和 CK 动力学，在休息和多巴酚丁胺应激时。肥胖志愿者被分配到饮食减肥干预中，然后再进行检查。
在休息时，尽管肥胖症患者的心肌磷酸肌酸/ATP 降低了 14%（1.9±0.3 与 2.2±0.2，<0.001），但 升高了 33%（0.23±0.07 s 与 0.16±0.08 s，=0.002），导致整体静息 ATP 输送无差异（肥胖组 2.5±0.9 µmol·g·s 与对照组 2.2±1.1 µmol·g·s，=0.232）。在对照组中，增加心脏工作量会导致 和 ATP 输送都增加（增加 86%，<0.001）。然而，在肥胖症中，类似的压力并没有导致或 ATP 输送显著增加（=0.117）或（=0.608）。这伴随着收缩期增强的减少（左心室射血分数的绝对增加，肥胖组+16±7%与对照组+21±4%，=0.031）。成功减肥（体重减轻 11±5%）与这些能量变化的改善有关，与对照组相比无显著差异。
在肥胖静息状态下，心肌 CK 反应速率增加，尽管磷酸肌酸/ATP 减少，但仍能维持 ATP 输送。在增加工作量时，非肥胖心脏通过 CK 增加 ATP 输送，但肥胖心脏则不然；这与收缩期增强减少和运动耐量降低有关。减肥可以逆转这些能量变化。这凸显了通过 CK 进行心肌能量传递作为改善肥胖相关心脏病症状的潜在治疗靶点的重要性，同时也揭示了 CK 作为心力衰竭进展过程中的一个有趣的可改变途径。
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