Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine (M.A.P., J.Y.C.L., J.J.M., J.J.R., M.J.H., S.N., O.J.R.), University of Oxford, United Kingdom.
Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences (W.T.C.), University of Oxford, United Kingdom.
Circulation. 2020 Jun 16;141(24):1971-1985. doi: 10.1161/CIRCULATIONAHA.119.043450. Epub 2020 May 22.
Why some but not all patients with severe aortic stenosis (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and flux is associated with this transition.
We recruited 102 participants to 5 groups: moderate aortic stenosis (ModAS) (n=13), SevAS, left ventricular (LV) ejection fraction ≥55% (SevAS-preserved ejection fraction, n=37), SevAS, LV ejection fraction <55% (SevAS-reduced ejection fraction, n=15), healthy volunteers with nonhypertrophied hearts with normal systolic function (normal healthy volunteer, n=30), and patients with nonhypertrophied, non-pressure-loaded hearts with normal systolic function undergoing cardiac surgery and donating LV biopsy (non-pressure-loaded heart biopsy, n=7). All underwent cardiac magnetic resonance imaging and P magnetic resonance spectroscopy for myocardial energetics. LV biopsies (AS and non-pressure-loaded heart biopsy) were analyzed for CK total activity, CK isoforms, citrate synthase activity, and total creatine. Mitochondria-sarcomere diffusion distances were calculated by using serial block-face scanning electron microscopy.
In the absence of failure, CK flux was lower in the presence of AS (by 32%, =0.04), driven primarily by reduction in phosphocreatine/ATP (by 17%, <0.001), with CK unchanged (=0.46). Although lowest in the SevAS-reduced ejection fraction group, CK flux was not different from the SevAS-preserved ejection fraction group (>0.99). Accompanying the fall in CK flux, total CK and citrate synthase activities and the absolute activities of mitochondrial-type CK and CK-MM isoforms were also lower (<0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity (=0.86, =0.003).
Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS and suggest that a fall in CK flux is not by itself a necessary cause of transition to systolic failure. However, because ATP demands increase with AS severity, this could increase susceptibility to systolic failure. As such, targeting CK capacity and flux may be a therapeutic strategy to prevent and treat systolic failure in AS.
为什么一些严重主动脉瓣狭窄（SevAS）患者会出现不明原因的收缩功能降低，但并非所有患者都会出现这种情况，其原因尚不清楚。我们提出了一个假设，即肌酸激酶（CK）的产生能力和通量降低与这种转变有关。
我们招募了 102 名参与者，分为 5 组：中度主动脉瓣狭窄（ModAS）（n=13）、SevAS、左心室射血分数≥55%（SevAS 保留射血分数，n=37）、SevAS、左心室射血分数<55%（SevAS 射血分数降低，n=15）、非肥厚、无压力负荷、收缩功能正常的健康志愿者（正常健康志愿者，n=30）和非肥厚、无压力负荷、收缩功能正常、接受心脏手术并捐献左心室活检的患者（无压力负荷心脏活检，n=7）。所有参与者均接受心脏磁共振成像和 P 磁共振波谱心肌能量代谢检查。对左心室活检（AS 和无压力负荷心脏活检）进行 CK 总活性、CK 同工酶、柠檬酸合酶活性和总肌酸的分析。通过连续块面扫描电子显微镜计算线粒体-肌节扩散距离。
在没有衰竭的情况下，AS 时 CK 通量降低（降低 32%，=0.04），主要是由于磷酸肌酸/ATP（降低 17%，<0.001）减少所致，而 CK 不变（=0.46）。尽管 SevAS 射血分数降低组的 CK 通量最低，但与 SevAS 保留射血分数组无差异（>0.99）。伴随着 CK 通量的下降，CK 总活性、柠檬酸合酶活性以及线粒体型 CK 和 CK-MM 同工酶的绝对活性也降低（<0.02，所有分析）。中位数线粒体-肌节扩散距离与 CK 总活性相关性良好（=0.86，=0.003）。
SevAS 患者的 CK 总活性降低，收缩功能衰竭患者的 CK 总活性最低，这与能量供应储备减少一致。尽管如此，在中度 AS 阶段，即 LV 功能仍保持正常时，静息 CK 通量的磁共振光谱测量提示 ATP 输送更早减少。这些发现表明，在中度 AS 中已经存在明显的能量损伤，并且表明 CK 通量的下降本身并不是向收缩功能衰竭转变的必要原因。然而，由于 AS 严重程度增加了 ATP 的需求，这可能会增加收缩功能衰竭的易感性。因此，靶向 CK 容量和通量可能是预防和治疗 AS 收缩功能衰竭的一种治疗策略。
