运动诱导的心脏T肌钙蛋白升高：从基础机制到临床相关性

Exercise－Induced Cardiac T roponin Elevations： From Underlying Mechanisms to Clinical Relevance

运动诱导的心脏T肌钙蛋白升高：从基础机制到临床相关性

Circulation． 2021 Dec 14；144（24）：1955－1972．

doi： 10．1161／CIRCULATIONAHA．121．056208． Epub 2021 Dec 13．

翻译：苗 、丹妮，猫 排版：叮当丸子麻

ABSTRACT： Serological assessment of cardiac troponins （cT n） is the gold standard to assess myocardial injury in clinical practice． A greater magnitude of acutely or chronically elevated cT n concentrations is associated with lower event－free survival in patients and the general population． Exercise training is known to improve cardiovascular function and promote longevity， but exercise can produce an acute rise in cT n concentrations， which may exceed the upper reference limit in a substantial number of individuals． Whether exercise－induced cT n elevations are attributable to a physiological or pathological response and if they are clinically relevant has been debated for decades． Thus far， exercise－induced cT n elevations have been viewed as the only benign form of cT n elevations． However， recent studies report intriguing findings that shed new light on the underlying mechanisms and clinical relevance of exercise－induced cT n elevations． We will review the biochemical characteristics of cT n assays， key factors determining the magnitude of postexercise cT n concentrations， the release kinetics， underlying mechanisms causing and contributing to exercise－induced cT n release， and the clinical relevance of exercise－induced cT n elevations． We will also explain the association with cardiac function， correlates with （subclinical） cardiovascular diseases and exercise－induced cT n elevations predictive value for future cardiovascular events． Last， we will provide recommendations for interpretation of these findings and provide direction for future research in this field．

摘要：心脏肌钙蛋白血清学评估（cTn）是临床评价心肌损伤的金标准。在患者和一般人群中，较大程度的急性或慢性升高的cTn浓度与较低的无事件生存率相关。众所周知，运动训练可改善心血管功能并延长寿命，但运动可导致cT n浓度急性升高，在相当数量的个体中可能超过参考上限。运动诱导的cT升高是否可归因于生理或病理反应，以及它们是否与临床相关，已经争论了几十年。迄今为止，运动诱导的cT升高被认为是唯一的良性cT升高形式。然而，最近的研究报告了有趣的发现，揭示了运动诱导cT升高的潜在机制和临床相关性。我们将回顾cT n测定的生化特征，决定运动后cTn浓度大小的关键因素，释放动力学，导致和促成运动诱导cTn释放的潜在机制，以及运动诱导cTn升高的临床相关性。我们还将解释其与心功能的关系，与（亚临床）心血管疾病的相关性，以及运动诱发的cTn升高对未来心血管事件的预测价值。最后，我们将提供解释这些发现的建议，并为该领域的未来研究提供方向。

Key Words： apoptosis细胞凋亡 ? athletes运动员 ? cardiomegaly心脏肥大， exercise－induced 运动诱发? heart心脏 ? heart injuries心脏损伤 ? necrosis坏死

Cardiac troponins （cTn） are proteins that facilitate the contraction of cardiomyocytes after the influx of calcium into the cell． Because of their cardiac－specific isoforms， serological assessment of cT n is the gold standard to assess myocardial injury in clinical practice．1 A greater magnitude of chronically or acutely elevated cT n concentration is associated with lower event－free survival in patients2，3 and the general population．4

心肌肌钙蛋白（Ctn）是钙离子内流后促进心肌细胞收缩的蛋白质。由于其心脏特异性亚型，在临床实践中，对ctn的血清学评估是评估心肌损伤的金标准。1在患者2、3和普通人群中，慢性或急性升高的ctn浓度越大，无事件存活率越低。4

Exercise training improves cardiovascular function， lowers the risk for cardiovascular events， and promotes longevity． However， a bout of exercise can produce an acute rise in cTn concentrations，5 which may exceed the upper reference limit in a substantial number of individuals and meet the criteria for myocardial injury．1 Multiple studies over the past 3 decades have reported elevated cTn concentrations after exercise of different types， durations， and intensities and among subjects of different ages， sex， and health and training status．5–7 However， the clinical significance of such findings was not clear because of the descriptive nature， small sample size， and cross－sectional design of the studies， as well as a lack of long－term follow－up and mechanistic studies．

运动训练改善心血管功能，降低心血管事件的风险，并促进长寿。然而，一次运动可引起cT n浓度的急性升高，在大量个体中可能超过参考上限，符合心肌损伤的标准1在过去30年的多项研究中，不同类型、持续时间和强度的运动后，以及不同年龄、性别、健康状况和训练状态的受试者的cT n浓度均有所升高。5－7然而，由于研究的描述性、小样本量和横断面设计，以及缺乏长期随访和机制研究，这些发现的临床意义尚不明确。

Recent studies shed new light on the underlying mechanisms and clinical relevance of exercise－induced

最近的研究对运动诱发的潜在机制和临床意义有了新的认识cTn升高。例如，耐力运动可损害心肌细胞肌膜的完整性，8这可能导致cT n片段泄漏到循环中。9此外，运动引起的cT n浓度升高的幅度与隐匿性阻塞性冠状动脉疾病10以及中年和老年个体死亡率和主要不良心血管事件风险的增加有关。11

This narrative review will summarize recent insights into factors determining the magnitude of exerciseinduced cT n release， the underlying mechanisms responsible for these elevations， and the clinical relevance and considerations for the interpretation of exercise－induced elevations in cT n concentrations．

这篇叙述性综述将总结最近关于决定运动诱导cTn释放强度的因素，导致这些升高的潜在机制，以及解释运动诱导cTn浓度升高的临床相关性和考虑因素。

ASSESSMENT OF CARDIAC TROPONINS Molecular Basis心脏肌钙蛋白分子基础评估

T roponin （Tn） is an intracellular protein complex that is part of the contractile apparatus of cardiac and skeletal muscle． T n consists of 3 subunits （ie， I， T， and C） of which cardiac－ and muscle－specific isoforms for I and T exist． Within cardiomyocytes， the cTn protein complex is attached to tropomyosin， a structural protein that is wrapped around the thin filament． With the influx of calcium， calcium ions bind to the T nC subunit， leading to a conformational change of the cT n complex， allowing the myosin head to bind to the actin filament， and leading to cardiomyocyte contraction （Figure 1）． In addition to tropomyosin－bound cT n， cT n molecules are also present in an early releasable pool， and this fraction of cT n may be significantly larger than previously estimated （5％–10％）．12

转铁蛋白（T－roponin，Tn）是一种细胞内蛋白质复合物，是心肌和骨骼肌收缩器的一部分。Tn由3个亚基（即I、T和C）组成，其中存在I和T的心脏和肌肉特异性异构体。在心肌细胞内，CTn蛋白复合体附着在原肌球蛋白上，原肌球蛋白是一种包裹在细丝上的结构蛋白。随着钙离子的流入，钙离子与T－NC亚基结合，导致CT－n复合物的构象改变，使肌球蛋白头部与肌动蛋白细丝结合，导致心肌细胞收缩（图1）。除了与原肌球蛋白结合的CTn，CTn分子也存在于早期可释放池中，这部分CTn可能比先前估计的要大得多（5％－10％）。12

Analytic Considerations分析考虑

The first commercial cT n assays became available in 1996， but the rapid evolution of assay technology has tremendously improved the analytic sensitivity．13 High sensitivity cT n assays are characterized by a low analytic coefficient of variation （coefficient of variation ＜10％） at the 99th percentile or upper reference limit （URL） established in apparently healthy individuals， and they have the ability to quantify cT n levels in ＞50％ of those healthy individuals．13 Men typically have higher resting cT n levels，11，14 underlining the importance of sex－specific URLs．

1996年，第一批商业化的ct n检测方法问世，但检测技术的快速发展极大地提高了分析灵敏度。13高灵敏度ct n检测的特点是，在表面健康的人身上建立的第99个百分位数或参考上限（URL）处的分析变异系数很低（变异系数＜10％），而且它们有能力量化那些＞50％的健康人的ct n水平。13男性通常有更高的静息ct n水平，11，14强调了性别特异性的重要性。

More than 20 immunoassays are commercially available for cardiac troponin I （cT nI）， ranging from contemporary， high－sensitivity to point－of－care assays， each using their own monoclonal antibodies specific to different epitopes of cT nI． Despite efforts by international workgroups， the standardization of cT nI measurements remains limited．15

市场上有20多种心肌肌钙蛋白I（cT－nI）免疫分析方法可供选择，从现代的高灵敏度检测到定点检测，每种方法都使用自己的针对cT－nI不同表位的单克隆抗体。尽管国际工作组做出了努力，cT nI测量的标准化仍然有限。15

Circulating cTn Forms 循环cTn形式

Different cT n forms and fragments have been identified in the circulation， caused either by intracellular or extracellular processes．16，17 The fragmentation process is not completely understood but may depend on degradation， phosphorylation， ubiquitination， complex formation， and binding to specific anti－cT n immunoglobulins． For patients with myocardial infarction， cardiac troponin T （cT nT） has predominantly been found intact （37 kDa） in the first hours after presentation， and as primary （29 kDa） and secondary fragments （15–20 kDa） thereafter．17 The primary fragment is cleaved at the N－terminal end of cT nT， whereas the secondary fragments are further cleaved at the C－terminal end．17 ，18 Patients with endstage renal disease had only small cT nT fragments with molecular weights comparable to the secondary fragments as seen with myocardial infarction．19 It remains to be determined whether these secondary cT n forms are comparable between patients with end－stage renal disease and myocardial infarction or whether they represent different types of disease－specific fragments． It also remains a topic of discussion how cT n forms （either intact or fragments） are cleared from the blood circulation， but it is thought that smaller proteins pass through the glomerular membrane for clearance．20 After an acute myocardial infarction， however， extrarenal clearance turned out to dominate in studies on rats．21 Extrarenal clearance might be associated with scavenger receptor clearance； however， this topic has not been fully elucidated．

在循环中发现了不同的Ctn形式和片段，可能是由细胞内或细胞外过程引起的。16，17裂解过程尚不完全清楚，但可能依赖于降解、磷酸化、泛素化、复合物的形成以及与特定的抗Ct n免疫球蛋白的结合。对于心肌梗死患者，心肌肌钙蛋白T（Ct NT）在出现后的第一个小时内主要被发现完整（37 KDa），此后作为初级片段（29 KDa）和次级片段（15－20 kDa）。17初级片段在Ct NT的N端被切割，而次级片段在C端被进一步切割。18例终末期肾病患者仅有小的Ct nt片段，其分子量与心肌梗死的继发性片段相当。19这些继发性Ct n形式在终末期肾病和心肌梗死患者中是否具有可比性，或者它们是否代表不同类型的疾病特异性片段仍有待确定。Ct n的形成（完整或碎片）如何从血液循环中清除也仍然是一个讨论的话题，但人们认为较小的蛋白通过肾小球膜进行清除。20然而，在急性心肌梗死后，肾外清除在大鼠的研究中占主导地位。21肾外清除可能与清道夫受体清除有关；然而，这一主题尚未完全阐明。

EXERCISE－INDUCED CARDIAC TROPONIN ELEVATIONS 运动性心肌肌钙蛋白升高

Brief Historical Perspective短暂的历史观点

The majority of studies examining the possibility of myocardial injury after exercise have used cT n as the marker of choice． However， initial evidence supporting the concept of exercise－induced cardiac injury was based on studies measuring serum CK－MB （creatine kinase myocardial band）．22 Although CK－MB was widely adopted for the clinical diagnosis and management of acute coronary syndromes， it was subsequently shown to lack cardiac tissue specificity and sensitivity， especially among athletes in whom skeletal muscle CK－MB concentrations were higher （8．9±1．3％ versus 3．3±0．7％ in the gastrocnemius muscle of marathoners compared with untrained controls）， and released in response to exercise－induced muscle injury．22 Accordingly， cT n replaced CK－MB as the gold－standard marker for myocardial injury following the Redefinition of Myocardial Infarction in 2000． Since the development of the first－generation cT n assays， ＞200 studies examining the effect of exercise on cT n release have been published．

大多数研究运动后心肌损伤可能性的研究都使用ctn作为选择标记物。然而，支持运动性心脏损伤概念的初步证据是基于测定血清肌酸激酶同工酶（CK－MB）的研究22虽然CK－MB被广泛用于急性冠脉综合征的临床诊断和治疗，但随后发现它缺乏心脏组织特异性和敏感性，特别是在那些骨骼肌CK－MB浓度较高的运动员（马拉松运动员腓肠肌CK－MB浓度较高（8．9±1．3％比3．3±0．7％，马拉松运动员腓肠肌CK－MB浓度高于未经训练的对照组的3．3±0．7％），并在运动性肌肉损伤后释放CK－MB）。22因此，在重新定义心肌后，Ct－MB取代CK－MB成为心肌损伤的金标准标志物。自第一代CT－n检测方法问世以来，已发表了200多篇关于运动对CT－n释放的影响的研究。

Findings from the initial descriptive studies using a simple preexercise， postexercise measurement design， coupled with the results of subsequent meta－analyses，6 suggest that circulating cT nI and cT nT concentrations are above the URL in ＞50％ of athletes after endurance activities． In addition， evidence suggests that running events may be more likely to cause cT n elevation than cycling events．6 However， direct comparisons are not available． The mechanism is also unclear but may relate to the higher intensity of running versus cycling． Additional studies and further meta－analyses have replicated these initial findings， in general， and have also documented postexercise cT n elevations in a variety of populations including children， adolescents， postmenopausal women， and athletic animals．5 cT n elevation has also been associated with numerous exercise stimuli including endurance running， prolonged marching， basketball， high－intensity treadmill running， high－intensity cycling， and clinical exercise tests．23

最初的描述性研究采用简单的运动前、运动后测量设计，再加上随后的荟萃分析结果，6表明，在耐力运动后，＞50％的运动员循环中的ctni和ctnt浓度在URL以上。此外，有证据表明，跑步项目可能比自行车项目更有可能导致Ctn升高。6然而，没有直接的比较。其机制也不清楚，但可能与跑步比骑自行车的强度更高有关。更多的研究和进一步的荟萃分析总体上重复了这些最初的发现，还记录了各种人群运动后的ct n升高，包括儿童、青少年、绝经后妇女和运动动物。5 ct n升高还与许多运动刺激有关，包括耐力跑、长征、篮球、高强度跑步机跑步、高强度骑自行车和临床运动测试。23

Figure 1． cTn复合体在心肌细胞收缩中起着重要作用。

当动作电位到达心肌细胞时，钙离子进入细胞，导致钙离子与T－NC亚基结合后的构象变化。因此，肌球蛋白结合位点暴露，使肌球蛋白头与肌动蛋白细丝结合，促进心肌细胞收缩。注意，大多数ct n复合体与肌动蛋白细丝结合，但也存在于早期可释放池中。CT显示心肌肌钙蛋白。

Predictors： Exercise Duration and Intensity预测因素：运动持续时间和强度

Numerous investigators have tried to examine which factors contribute to the release of cardiac－specific biomarkers． Age， training experience， blood pressure， environmental factors， exercise intensity， and exercise duration are among the predictors potentially associated with the magnitude of postexercise cT n concen－trations14，24–26 （Figure 2）． The variance explained by multivariate prediction models is low （r2＜35％）， however， and appears to be driven primarily by the intensity and duration of exercise． Early studies suggested that the magnitude of cT n release was positively related to the duration of exercise．24 However， a meta－analysis of 26 studies published in 2007 with exercise durations from 0．5 to 22 hours showed that postexercise cT n was inversely associated with exercise duration．6 Specifically， more athletes had a cT n concentration greater than the URL after marathon running than after substantially longer ultraendurance events． These data suggest that exercise intensity， rather than duration， may be the more potent stimulus for cT n release，27 because marathons are run at a higher intensity than ultraendurance events． In a recent study that documented a direct relationship among exercise heart rate， a surrogate for exercise intensity， and the prevalence of cT n after exercise，7 the importance of exercise intensity was also suggested．

许多研究人员试图研究哪些因素会导致心脏特异性生物标志物的释放。年龄、训练经历、血压、环境因素、运动强度和运动持续时间是潜在地与运动后Ct n浓度的大小相关的预测因素。测试14、24－26（图2）。然而，多变量预测模型解释的方差很低（R2＜35％），而且似乎主要是由运动强度和持续时间驱动的。24然而，一项对2007年发表的26项研究的荟萃分析显示，运动后的Ctn与运动持续时间呈负相关。6具体地说，更多的运动员在马拉松赛跑后的Ctn浓度高于URL，而在超耐力项目后的Ctn浓度明显高于URL。这些数据表明，运动强度，而不是持续时间，可能是更有效的刺激Ctn释放的因素，27因为马拉松比超耐力项目的强度更高。最近的一项研究记录了运动心率（运动强度的替代指标）和运动后ctn患病率之间的直接关系，7还提出了运动强度的重要性。

To directly examine the effect of exercise duration and intensity， a recent study compared cT nI release following cycling at low （50％–60％ lactate threshold for 60 minutes）， moderate （60％–70％ lactate threshold for 4 hours）， and high intensities （80％–90％ lactate threshold for 60 minutes）．28 cT nI was elevated after both moderate－ and high－intensity exercise but not after the low－intensity stimulus． Furthermore， cT n concentrations were significantly higher after the short－duration， high－intensity exercise than after the long－duration， moderate－intensity exercise．28 A similar study compared running at a moderate （60 minutes at 70％ of peak heart rate） or high intensity （2 series of 12×30－second repeated sprints at 90％ peak heart rate）．29 cT nT was statistically higher 4 hours after the high－intensity than the moderate－intensity exercise． Also， a field study among 177 cyclists participating in a 91－km mountain bike race showed that the time spent performing high－intensity exercise （heart rate ＞150 bpm） was an independent predictor of postexercise cT nI and cT nT concentrations．30 In aggregate， these data suggest that postexercise cT n elevations are related to overall cardiac workload， the product of both duration and intensity．

为了直接检验运动持续时间和强度的影响，最近的一项研究比较了低强度（50％－60％乳酸阈值，60分钟）、中等强度（60％－70％乳酸阈值，4小时）和高强度（80％－90％乳酸阈值，60分钟）骑自行车后Ctni的释放。28 CT nI在中强度和高强度运动后升高，但在低强度刺激后没有升高。此外，短时间大强度运动后的Ctn浓度明显高于长时间中强度运动后。28类似的研究比较了中等强度（60min，峰值心率的70％）和大强度（2组12×30s重复冲刺，峰值心率为90％）。29大强度运动后4h，CtNT显著高于中强度运动。此外，对177名参加91公里山地自行车比赛的自行车手进行的实地研究表明，进行高强度运动（心率＞150 bpm）的时间是运动后Ctni和Ct nt浓度的独立预测因子。30总体而言，这些数据表明运动后Ctn升高与总体心脏负荷有关，这是持续时间和强度的乘积。

Figure 2． 运动诱导肌钙蛋白释放大小的驱动因素。

各因素对运动后肌钙蛋白浓度的影响在不同研究中差异很大，所有因素的预测价值都有限（r2＜35％）。运动强度和持续时间似乎对运动后浓度的影响最大，可能反映了整体心脏负荷。

Influence of Exercise Training 运动训练的影响

The heart remodels in response to exercise training， prompting several studies to examine the relationship of fitness or training status to postexercise cT n release．24，31 Event completion times or years of training were used as surrogates of fitness． More experienced marathon runners were less likely to have cT n elevations after the events than less experienced runners in several studies， but other studies have failed to confirm this relationship．26，32

运动训练对心脏重塑的影响，促使多项研究探讨运动训练状态与运动后心脏重塑的关系，并以24、31次运动完成时间或运动年限作为运动训练的代理。在一些研究中，经验丰富的马拉松运动员比经验不足的运动员在赛后不太可能有胸高，但是其他研究未能证实这种关系

Two recent studies have examined whether exercise training alters postexercise cT n release． One assessed cT nT concentrations at rest and after a 60－minute maximal run， before and after a 14－week training program in the intervention and control group．33 Before training， the 60－minute maximal run produced a heterogeneous cT nT response in both groups with 71％ of subjects exceeding the URL． Baseline and postexercise cT nT were higher after training in the intervention group than in the control group．33 This may be because of a higher workload in the intervention group during the second maximal run as evidenced by a substantially higher speed （12．1±0．9 versus 10．7±0．9 km／h， P＜0．05）． The second study randomly assigned 48 young sedentary obese women to 12 weeks of high－intensity interval training， moderateintensity continuous training， or no training and measured cT nT levels after the same absolute and relative （60％ of Vo2max） exercise stimulus．34 T raining significantly increased workload at 60％ Vo2max． Before training， cT nT increased in all groups after exercise． After training， resting and postexercise cT nT concentrations at the same relative intensity were similar to pretraining values． However， cT nT did not increase after exercise at the same absolute intensity． These results suggest that exercise training reduces cT n increase after the same absolute， but not relative， intensity exercise． These studies collectively suggest that the magnitude of postexercise cT n release is affected by a combination of both training status and exercise intensity， because trained individuals require a greater absolute exercise stimulus to achieve the same relative stimulus．

最近的两项研究检查了运动训练是否会改变运动后的CT n释放。其中一人评估了干预和对照组在14周训练计划之前和之后的静息和60分钟最大跑后的CT NT浓度。33在训练前，60分钟最大跑在两组中都产生了不同的CT NT反应，71％的受试者超过了URL。33这可能是因为干预组在第二次最大跑时的负荷较大，表现为速度明显较高（12．1±0．9比10．7±0．9 km／h，P＜0．05）。在训练后，干预组的基础和运动后Ct NT均高于对照组。33这可能是因为干预组在第二次最大跑中的工作量较大，明显高于对照组（12．1±0．9对10．7±0．9 km／h）。第二项研究随机将48名久坐不动的年轻肥胖女性分为高强度间歇训练、中等强度持续训练和不训练3组，分别在相同的绝对和相对（60％最大摄氧量）运动刺激下测定CTNT水平。34T训练在60％最大摄氧量时显著增加了工作量。运动前各组运动后CT－NT均升高，与运动前比较差异无显著性（P＞0．05）。训练结束后，相同相对强度的静息和运动后ct－NT浓度与训练前相近。但在相同绝对强度的运动后，CT NT并没有升高。这些结果提示，在相同的绝对运动强度下，运动训练可以降低Ctn的升高，但不能降低相对运动强度下的Ctn升高。这些研究表明，运动后Ctn释放的大小受到训练状态和运动强度的共同影响，因为训练者需要更大的绝对运动刺激才能获得相同的相对刺激。

Kinetics of cTn Concentrations CTn浓度的动力学研究

The kinetics of cT n concentrations after an acute myocardial infarction （AMI） are well described． Peak values of cT nI and cT nT occur ≈10 to 12 hours after an STsegment–elevation AMI35 and remain elevated for 4 to 10 days， although the pattern and magnitude of cT n elevations is highly variable among patients because of both the size of the AMI and the rapidity of cT n washout influenced by reperfusion．

本文较好地描述了急性心肌梗死（AMI）35后CTn浓度的动态变化。CT ni和Ct NT峰值出现在ST段抬高后10～12小时，并持续升高4～10天，但由于心肌梗死的大小和再灌注对CT n消失速度的影响，不同患者的CT n升高模式和幅度差异很大。

The kinetics of exercise－induced cT n concentrations are less clear． Middleton et al36 attempted to describe cT n kinetics during and after marathon exercise and reported a biphasic release pattern． Subsequently， several other studies assessed time－dependent changes in cT n concentrations up to 72 hours after exercise， of which the findings are summarized in T able S1 （cT nT） and T able S2 （cT nI）． Differences in exercise duration， exercise intensity， and mode of exercise across studies exclude the possibility to perform a structured metaanalysis． Limited data are available to support or refute the potential of a biphasic release during exercise， but some important observations can nonetheless be made regarding postexercise concentrations． First， concentrations of cT n appear to progressively increase after exercise cessation with peak values typically occurring between 2 and 6 hours after exercise （Figure 3A）． Second， the magnitude of cT n increase varies greatly among individuals，37 with some individuals demonstrating no or only very small changes in cT n concentrations， but others reporting values exceeding several times the URL Figure 3B． On average， peak postexercise cT n concentrations are ≈1 to 3 times the URL． The median change from baseline to postexercise concentrations was 10－fold （interquartile range： 5－ to 19－fold） in marathon runners．37 Third， exercise－induced elevations in cT n concentrations are transient， with values returning to baseline after 48 to 72 hours postexercise． The early peak and smaller magnitude of exercise－related cT n elevations postexercise contrast with the greater magnitude and later peaking of cT n in AMI．

运动性CTn浓度的动态变化尚不清楚。Middleton等人36试图描述马拉松运动期间和之后的Ct n动力学，并报告了一种双相释放模式。随后，其他几项研究评估了运动后72小时内CTn浓度随时间的变化，其中的发现总结为TableS1（Ctnt）和TableS2（Ctni）。不同研究中运动持续时间、运动强度和运动方式的差异排除了进行结构化荟萃分析的可能性。有限的数据可以支持或驳斥运动中双相释放的可能性，但仍然可以对运动后的浓度进行一些重要的观察。首先，停止运动后，Ctn浓度似乎逐渐升高，峰值通常出现在运动后2至6小时（图3A）。其次，CTn的增加幅度在不同的个体之间差异很大，37有些人的CTn浓度没有变化或只有很小的变化，但另一些人报告的值超过了URL图3B的几倍。平均而言，运动后峰值Ctn浓度是≈的1到3倍。马拉松跑步者从运动前到运动后浓度的中位数变化是10倍（四分位数范围：5到19倍）。37第三，运动诱导的Ctn浓度升高是短暂的，运动后48到72小时后恢复到基线水平。运动后运动相关的Ctn升高较早且幅度较小，与AMI患者运动后Ctn升高幅度较大且峰值较晚形成鲜明对比。

UNDERL YING MECHANISMS 底层机制

The mechanisms responsible for postexercise cT n increases remain controversial． cT n elevations were initially interpreted as irreversible damage， because the heart was considered a postmitotic organ whose cardiomyocytes could not be repaired or replaced． Hence， cT n release was considered pathognomonic of necrosis．38，39 There is increasing evidence， however， that cardiac mitosis does occur in adults at a rate of 0．5％ to 1％ of cardiomyocytes per year．40，41 This rate of mitosis may increase with exercise training．42，43 T ransient increases in cT n occur not only after exercise， but also after atrial pacing44 and pharmacological stress testing，45 even in healthy individuals， highlighting the probability that not all cT n release is attributable to cardiomyocyte necrosis． The European Society of Cardiology’s Study Group on Biomarkers identified 3 possible causes for elevated cT n concentrations46： （1） reversible injury attributable to cell wounds， cytoplasmatic blebbing， or extracellular vesicle release； （2） injury attributable to apoptosis； and （3） irreversible injury attributable to myocardial necrosis （Figure 4）． There are few direct data to support or reject a single release mechanism for exercise－induced elevations of cT n concentrations， but available evidence is presented in the following．

运动后Ctn升高的机制仍存在争议。CTn升高最初被解释为不可逆转的损伤，因为心脏被认为是有丝分裂后的器官，其心肌细胞不能修复或替换。因此，CT n的释放被认为是死亡的病原体。38，39然而，越来越多的证据表明，心脏有丝分裂确实发生在成年人中，每年有0．5％到1％的心肌细胞。40，41这种有丝分裂的比率可能会随着运动训练而增加。42，43 T的短暂增加不仅发生在运动之后，也发生在心房起搏44和药物应激试验之后，45甚至在健康的个体中，这突显了并不是所有的CT释放都可归因于心肌细胞坏死。42，43的短暂增加不仅发生在运动后，而且发生在心房起搏44和药物应激试验之后，45甚至在健康的人中也是如此，这突显了并不是所有的Ct释放都可归因于心肌细胞坏死。欧洲心脏病学会的生物标记物研究小组确定了导致Ct n浓度升高的3种可能原因46：（1）可归因于细胞损伤、胞浆气泡或细胞外小泡释放的可逆性损伤；（2）可归因于细胞凋亡的损伤；以及（3）可归因于心肌坏死的不可逆损伤（图4）。很少有直接数据支持或拒绝运动诱导的Ctn浓度升高的单一释放机制，但现有证据如下所示。

图3．运动诱导的cTn浓度升高的建议模式。

A1耐力运动后 ct n 浓度的动力学示意图。运动过程中 ct n 浓度的变化尚不清楚（虚线） ，但累积数据显示 ct n 浓度在运动停止后继续上升，在运动后2ー6小时达到峰值。运动后24到72小时内完全恢复正常。第99百分位数或正常参考上限以红色显示。B1，个人（n ＝ 151）在马拉松后 ct ni 浓度的瀑布图，突出了在进行类似耐力运动回合的运动员个人之间的巨大差异。数据来自波士顿37和恩德霍文26马拉松比赛的参赛者。两个曲线图中的值都表示为CTn分析的URL的倍数。CT显示心肌肌钙蛋白。

Reversible Cardiac Injury可逆性心脏损伤

Macromolecules can exchange over the plasma membranes of viable cardiomyocytes and such release seems to occur through transient disruptions in the plasma membrane．47 Stressing the cardiomyocytes by contraction， β－adrenergic stimulation，4 7，4 8 stretching，49，50 or brief ischemia51，52 increases the rate of macromolecule release． These studies did not observe cardiomyocyte death on histological examination， but apoptosis could have occurred． In contrast， plasma membrane injury does not necessarily lead to cardiomyocyte death because （1） the cytoplasm is a macromolecular gel with restricted diffusion，53 （2） dystrophin complexes stabilize the membrane by forming links between the extracellular matrix and the contracting sarcomere，54 and （3） cell wound repair can restore small membrane holes after reoxygenation．48，54 Cardiomyocytes are therefore more resilient than previously thought．

大分子可以在活心肌细胞的质膜上交换，这种释放似乎是通过质膜的短暂破坏发生的通过收缩、β－肾上腺素能刺激、4 7、4 8延伸、49、50或短暂缺血增加心肌细胞的大分子释放率。组织学检查未见心肌细胞死亡，但可能发生凋亡。相比之下，质膜损伤不一定会导致心肌细胞死亡，因为（1）细胞质是一种扩散受限的大分子凝胶，53（2）营养不良蛋白复合物通过在细胞外基质和收缩的肌节之间形成连接来稳定膜，54和（3）细胞创面修复可以恢复小膜复氧后的洞。48，54心肌细胞因此比以前认为的更有弹性。

The heart supplies most of the increased total body oxygen demand of exercise by increasing heart rate and stroke volume， which， in turn， increases myocardial oxygen demand， coronary blood flow， and cardiac preload and afterload． These responses increase cardiomyocyte stress and may alter membrane permeability， leading to passive diffusion of cT n from the cell to the extracellular space． This hypothesis has been examined in an explorative pilot study （n＝11） using cardiac MRI of myocardial tissue water diffusivity （MD）．8 MD is a quantitative measure of cardiomyocyte integrity and an increase in MD is indicative of increased cell membrane permeability． Marathon running increased cT nI concentrations and myocardial MD， thus demonstrating increased cell membrane permeability． Postmarathon cT nI values correlated directly with MD （r＝0．66， P＝0．03），8 suggesting that higher postexercise cT nI concentrations result， at least， in part， from greater cardiomyocyte membrane permeability． Both cT nI and MD returned to prerace values within 2 weeks after the marathon， indicating that these exerciseinduced changes were transient．

心脏通过增加心率和每搏输出量提供运动增加的大部分身体需氧量，进而增加心肌需氧量、冠脉血流量以及心脏前负荷和后负荷。这些反应增加了心肌细胞的应激反应，并可能改变细胞膜的通透性，导致Ctn从细胞内被动扩散到细胞外间隙。这一假说已经在一项探索性的先导性研究中得到验证（n＝11），使用心脏MRI的心肌组织水分扩散率（MD）。8 MD是心肌细胞完整性的定量测量，MD的增加表明细胞膜通透性增加。马拉松运动增加心肌CTni浓度和心肌MD，从而显示细胞膜通透性增加。马拉松后Ctni值与MD呈正相关（r＝0．66，P＝0．03），8提示运动后Ctni浓度升高，至少部分是由于心肌细胞膜通透性增加所致。Ctni和MD在马拉松后2周内均恢复到赛前水平，表明这些运动诱导的改变是短暂的。

The increase in membrane permeability after cardiomyocyte stress suggests that cT n molecules can leak from cardiomyocytes into the circulation， and this may be aided by degradation of cT n complexes． Ischemia is known to degrade cT n complexes． For example， ischemia reduces the size of cT nI and cT nT fragments in isolated rat hearts from 24 to 15 kDa and from 35 to 25 kDa， respectively，55 making them more readily able to pass through the membrane． Only small， degraded， cT nT fragments （＜18 kDa） were found in postrace serum samples obtained from 10 marathon runners．9 These findings suggest that smaller fragments may leak into the circulation with the cardiac stress associated with exercise or ischemia， whereas larger fragments might only escape with destruction of the membrane after myocardial infarction．

心肌细胞应激后细胞膜通透性增加，提示CTn分子可从心肌细胞渗漏到循环中，这可能与CTn复合物的降解有关。已知缺血可使CTn复合体退化。例如，缺血减少了离体心脏的CT－Ni和CT－NT片段的大小。大鼠的心脏大小分别为24到15 kDa和35到25 kDa，55使它们更容易通过膜。在10名马拉松运动员的赛后血清样本中仅发现小的降解的CT NT片段（＜18 kDa）。9这些发现提示，在运动或缺血引起的心脏应激时，较小的片段可能会泄漏到循环中，而较大的片段可能只有在心肌梗死后膜被破坏时才会逃逸。

Taken together， it is possible that exercise－induced cT n elevations are attributable， at least， in part， to reversible membrane damage of viable cardiomyocytes （T able 1）． Whether this is the only mechanism responsible for exercise－induced cT n elevations， or occurs next to apoptosis or necrosis， is unknown． The magnitude of cT n release across individuals is extremely variable， even after the same exercise．37 It is possible that several mechanisms contribute to this variability and that the dominant mechanism differs between individuals with low and high magnitudes of postexercise cT n elevations （Figure 3B）． Furthermore， it is unknown whether the putative changes in membrane permeability are entirely physiological or are an early marker of cardiac vulnerability and subsequent cardiac events．

综合考虑，运动诱导的Ctn升高可能至少部分归因于存活心肌细胞的可逆性膜损伤（Table1）。目前尚不清楚这是导致运动性ctn升高的唯一机制，还是仅次于凋亡或坏死的机制。即使在相同的运动之后，个体间的CTn释放的大小也是非常不同的。37可能有几种机制导致了这种差异，运动后Ctn升高幅度低和高的个体之间的主导机制不同（图3B）。此外，尚不清楚膜通透性的假定变化是完全生理性的，还是心脏易损性和随后的心脏事件的早期标志。

图4．运动诱导cTn释放的潜在潜在机制的示意图概述。

可归因于细胞损伤的心肌细胞膜通透性增加、细胞外小泡释放和胞吐速率增加可被认为是可逆性的心脏损伤，导致心肌肌钙蛋白浓度的生理性升高。同样，心肌细胞周转率的增加可能会一过性地增加心肌肌钙蛋白浓度。较高的凋亡率，尤其是坏死率，应该归类为心肌细胞的（微小）损伤，这代表了对运动的一种病理反应，这可能会对健康产生长期的影响。CT显示心肌肌钙蛋白。

Apoptosis 细胞凋亡

Apoptosis or programmed cell death is part of normal cell turnover． Apoptotic processes can be activated through stress caused by oxidative overload， ischemia， and processes in other cells such as the detection of intracellular pathogens． Apoptosis should not produce cT n elevations， because intracellular content is not released when the apoptotic cell is fragmented and engulfed by other cells．

细胞凋亡或程序性细胞死亡是正常细胞周转的一部分。凋亡过程可以通过氧化超负荷、缺血引起的应激，以及细胞内病原体检测等其他细胞过程被激活。凋亡不应产生cT n升高，因为当凋亡细胞被其他细胞吞噬并破碎时，细胞内的内容不会释放。

表1． 关于运动引起肌钙蛋白浓度升高的基本机制的现有证据摘要

However， cTn could be released during the destruction of apoptotic bodies or as cardiomyocyte apoptosis transitions to secondary necrosis．20

然而，CTn可能在凋亡小体破坏或心肌细胞凋亡向继发性死亡转变过程中释放。20

Few studies have explored the effects of exercise on apoptosis． T welve weeks of exercise training reduced age－induced apoptosis in the left ventricle of rats， measured by less DNA fragmentation， terminal deoxynucleotidyl transferase dUTP nick end labeling–positive staining， and caspase－3 cleavage．56 A subsequent study demonstrated that exercise reduces the age－related increase in apoptotic signaling markers．57 A large study （n＝64）58 of young （6－month－old） and middle－aged （12－monthold） mice randomly assigned the animals to cages with or without a functioning running wheel． Caspase－independent， Fas－dependent， and mitochondrial－dependent apoptotic pathways were reduced in both the young and middle－aged running mice．58 These findings agree with evidence in humans that exercise training is cardioprotective and helps preserve cardiac function during aging．

很少有研究探讨运动对细胞凋亡的影响。12周的运动训练减少了年龄诱导的大鼠左心室细胞凋亡，通过减少DNA片段化、末端脱氧核苷酸转移酶dUTP缺口末端标记阳性染色和caspase－3裂解来衡量。56随后的研究表明，运动减少了与年龄相关的凋亡信号标记物的增加。57一项大型研究（n＝64）58对年轻（6个月大）和中年（12个月大）的小鼠随机分配到笼子里，放在笼子里或不放在笼子里。在年轻和中年跑步小鼠中，caspase非依赖、Fas依赖和线粒体依赖的凋亡通路均减少。58这些发现与人类的证据一致，即运动训练具有心脏保护作用，并有助于在衰老期间保护心脏功能。

The acute effects of exercise on apoptosis are not well studied． A study （n＝18） of young mice （2－monthold） assessed apoptosis at baseline or immediately after 8， 24， 48， and 72 hours of running at 60％ to 70％ of Vo2peak （n＝3 animals per time point）．59 Exercise pro duced a transient 150％ increase in the rate of myocardial apoptosis at 24 hours after exercise， in part， because of catecholaminergic， but not oxidative， stress． These findings suggest that， in animals， exercise acutely increases the rate of apoptosis， whereas apoptotic rates are reduced with chronic exercise training．

运动对细胞凋亡的急性影响还没有得到很好的研究。一项针对小鼠（2个月大）的研究（n＝18）评估了在基线或跑步8、24、48和72小时后即刻的细胞凋亡，VO2峰值的60％到70％（n＝3只动物／时间点）。59运动导致运动后24小时心肌细胞凋亡率短暂增加150％，部分原因是儿茶酚胺能，而不是氧化应激。这些发现表明，在动物中，运动显著增加了细胞凋亡率，而长期运动训练则降低了细胞凋亡率。

The acute increase in left ventricular preload during exercise could contribute to increased apoptosis．60 Isolated rat hearts exposed to increased preload demonstrate intramyocardial cT nI proteolysis and cT nI release in the absence of ischemia．61 This cT nI degradation was blocked by antibodies that prevent the activation of endogenous calpains． Calpains are involved in cell signaling and cell cycle progression． Therefore， cellular calcium entry and proteolysis of cT nI may produce stretch－induced cardiomyocyte apoptosis．62 These findings have been confirmed in an in vivo swine model． Acute hemodynamic overload produced by phenylephrine infusion provoked transient left ventricular （L V） dysfunction， stretch－induced cardiomyocyte injury， elevated cT nI concentrations， and apoptosis in the absence of ischemia．63 Another study in swine evaluated changes in cT nI and apoptosis after 10 minutes of left anterior descending coronary artery occlusion with subsequent reperfusion for 24 hours．64 Brief ischemia produced a delayed cT nI release， with significant cT nI elevations starting 30 minutes after reperfusion． The cT nI elevations persisted for 24 hours． There was a concomitant， transient increase in apoptosis， with a 6－fold increase 1 hour after reperfusion， which normalized at 24 hours．64 In humans， 30， 60， and 90 seconds of balloon－induced coronary artery occlusion to induce ischemia increased cT n concentrations in patients without coronary artery disease （CAD）， which continued to increase up to the end of sampling， 4 hours after ischemia．65 After 90 seconds of ischemia， patients had larger and quicker increases in cT n． cT nI and cT nT were ＞URL 3 hours after brief ischemia in 11％ to 25％ and 75％ of patients， respectively．65 These findings indicate that isolated apoptosis can occur after increased preload or brief ischemia， conditions that may also occur during exercise．

运动中左心室前负荷的急剧增加可能导致细胞凋亡的增加。60只暴露于增加前负荷的离体大鼠心脏在没有缺血的情况下表现出心肌内的Ctni蛋白水解和Ctni释放。61这种Ctni的降解被阻止内源性Calain激活的抗体阻断。钙蛋白酶参与细胞信号和细胞周期进程。因此，Ctni的细胞钙内流和蛋白水解可能导致牵张诱导的心肌细胞凋亡。62这些发现已在活体猪模型中得到证实。注射苯肾上腺素产生的急性血流动力学超负荷引起一过性左心室（L V）功能障碍、牵张诱导的心肌细胞损伤、Ctni浓度升高和无缺血情况下的细胞凋亡。63另一项在猪身上的研究评估了左冠状动脉前降支闭塞10分钟后Ctni和细胞凋亡的变化。64短暂缺血导致Ctni释放延迟，再灌注30分钟后Ctni显著升高。Ctni升高区持续了24小时。随之而来的是细胞凋亡的短暂增加，在再灌注1小时后增加6倍，并在24小时恢复正常。64在人类，球囊闭塞冠状动脉诱导缺血30、60和90秒后，无冠状动脉疾病（CAD）患者的CT－n浓度升高，一直持续到取样结束，在缺血4小时后。65在缺血90秒后，患者的CT－Ni和CT－NT在短暂缺血3小时后升高更大、更快，CT－Ni和CT－NT在短暂缺血后3小时均＞URL。65这些发现表明，在增加前负荷或短暂缺血后，可能会出现孤立的细胞凋亡，这些情况也可能发生在运动过程中。

An alternative explanation to increased cT n levels with exercise is that exercise increases cardiomyocyte turnover． C／EBPβ is a member of the bHLH gene family of DNA－binding transcription factors and decreases cardiomyocyte growth and proliferation．42 Exercise training decreased the expression of C／EBPβ in mice with swim training． Furthermore， the mice with reduced cardiac C／ EBPβ levels were resistant to cardiac failure produced by pressure overload． These results indicate that exercise training decreases C／EBPβ， thereby decreasing its inhibition of cardiomyocyte turnover and increasing cardiac resilience to external stress． This hypothesis is supported by the observation that 8 weeks of running increased new cardiomyocytes 4．6－fold in adult mice， without evidence of systolic dysfunction or increased apoptosis．66 Both studies demonstrate that exercise activates the endogenous regenerative capacity of the mammalian heart， suggesting that replaced cardiomyocytes could release cT n into the circulation if this process is accelerated by an acute bout of exercise．

运动导致肌钙蛋白水平升高的另一种解释是，运动增加了心肌细胞的更新换代。C／eBPβ是bHLH基因家族中的一员，可抑制心肌细胞的生长和增殖。42运动训练降低游泳训练小鼠心肌c／eBPβ的表达。此外，心脏C／EBPβ水平降低的小鼠对压力超负荷引起的心力衰竭具有抵抗力。这些结果表明，运动训练降低了C／EBPβ，从而降低了其对心肌细胞周转的抑制作用，提高了心脏对外界应激的抵抗力。这一假设得到以下观察的支持：8周的跑步使成年小鼠的新心肌细胞增加了4．6倍，没有收缩功能障碍或细胞凋亡增加的证据。66两项研究都表明，运动可以使新的心肌细胞数量增加4．6倍，而没有收缩功能障碍或细胞凋亡增加的证据激活哺乳动物心脏的内源性再生能力，这表明如果急性运动加速了这一过程，被替换的心肌细胞可能会将Ctn释放到循环中。

The association between exercise and apoptosis appears dependent on the time frame． Exercise training reduces apoptotic rates56–58 and increases cardiomyocyte growth and proliferation．42，66 In contrast， （supra） physiological challenges to untrained animals， such as forced running，59 volume overload，61，63 or ischemia，64 increase apoptosis with associated increases in cT n concentrations （T able 1）． Whether these findings can be extrapolated to humans is not presently clear．

运动和细胞凋亡之间的联系似乎取决于时间框架。运动训练降低了凋亡率56－58，并增加了心肌细胞的生长和增殖。42，66相比之下，对未经训练的动物的生理挑战，如强迫跑步，59容量超负荷，61，63或缺血，64会增加细胞凋亡，并伴随着Ctn浓度的增加（Table1）。目前还不清楚这些发现是否可以外推到人类身上。

Cardiomyocyte Necrosis心肌细胞坏死

Myocardial necrosis is the most frequent cause of cT n elevations unrelated to exercise． Cardiomyocyte metabolism shifts from aerobic to anaerobic pathways to produce A TP during myocardial ischemia． This shift to anaerobic metabolism eventually disrupts the sarcolemma． Ischemia ＞15 minutes irreversibly damages the cardiomyocyte，1 allowing intracellular proteins to enter the circulation． There is an old hypothesis67 that， after AMI， there is first an immediate and substantial release of cT n from an early releasable pool， followed by a smaller peak of cT n caused by the slower process of degrading myofibrils．1 Although this hypothesis has been disputed，12 the exact mechanism of cT n release remains to be unraveled． As discussed earlier， the cT n release after exercise is smaller， appears to peak sooner， and resolves faster than that observed with AMI． These differences make it unlikely that necrosis causes exercise－induced cT n elevations but does not exclude the possibility that a small degree of necrosis could produce elevated cT n concentrations in vulnerable individuals after exercise．

心肌坏死是CT升高最常见的原因，与运动无关。心肌缺血时，心肌细胞代谢从有氧途径转变为无氧途径，从而产生A－TP。这种向无氧代谢的转变最终会破坏肌膜。缺血＞15分钟对心肌细胞造成不可逆转的损害，1使细胞内蛋白进入循环。有一种古老的假说67，即急性心肌梗死后，首先从早期的可释放池中立即大量释放Ctn，然后是由于较慢的肌原纤维降解过程引起的Ctn的较小峰值。1尽管这一假说一直存在争议，12 Ctn释放的确切机制仍有待解开。正如前面所讨论的，运动后的Ctn释放较小，似乎更早达到峰值，而且消退得比观察到的急性心肌梗死更快。这些差异使得坏死不太可能导致运动诱导的CTn升高，但不排除轻微的坏死可能导致运动后脆弱个体的CTn浓度升高。

Acute cardiac necrosis cannot be definitely determined in vivo． Cardiac MRI studies of participants in the Manitoba，68 London，69 and Detroit70 marathons found no myocardial edema or late gadolinium enhancement despite increased cT n concentrations after exercise． The absence of myocardial edema or scar argue against cardiac necrosis， but cardiac MR is not sensitive enough to detect a small degree of necrosis． Only 40 mg of rat myocardial necrosis increases cT nT and cT nI ＞URL，71 but this would not be detected by cardiac MRI． It could be speculated that long－term exercise training could produce myocardial damage from repetitive single exercise sessions． This hypothesis is supported by the observation that lifelong endurance athletes have more late gadolinium enhancement （LGE） than their physically inactive peers and that the amount of LGE increases with the number of race completions and years of training．72 Thus， although no direct evidence exists of myocardial necrosis after exercise， it cannot be excluded as contributing to exercise－induced cT n increases in some cases （T able 1）．

在活体内不能确定急性心肌坏死。对马尼托巴省68、伦敦69、底特律70马拉松参赛者的心脏MRI研究发现，尽管运动后CTn浓度升高，但没有心肌水肿或晚期钆增强。无心肌水肿或疤痕不利于心脏坏死，但心脏MR不够敏感，不能发现少量的坏死。只有40 mg的大鼠心肌坏死使CtNT和CtNi＞URL，71但心脏MRI不能检测到这一点。可以推测，长期的运动训练可能会因重复的单次运动而造成心肌损伤。这一假说得到以下观察的支持，即终身耐力运动员比不运动的同龄人有更多的晚期钆增强（LGE），并且LGE的量随着比赛完成次数和训练年限的增加而增加。72因此，尽管没有直接证据表明运动后心肌坏死，但在某些情况下不能排除它是运动诱导的Ctn增加的原因（T Abable 1）。

Noncardiac Explanations 非心血管解释

Several alternative hypotheses have been suggested to contribute to exercise－induced elevations of cT n concentrations （T able 1）． First， exercise－induced hemoconcentration may impact postexercise cT n concentrations， but the percentage change of fluid balance markers is （very） small relative to the increases in cT n concentrations． Also， any hemoconcentration is expected to be quickly restored with postexercise rehydration， which is contradictory to the progressive increase in cT n concentrations up to 2 to 6 hours after exercise． Evidence also suggests that hemodilution may occur after endurance exercise，73 so the role of hemoconcentration in elevated cT n concentrations after exercise is likely limited if not negligible．

已经提出了几种可供选择的假说，以促进运动诱导的CTn浓度的升高（T表1）。首先，运动诱导的血液浓缩可能会影响运动后的Ctn浓度，但相对于Ctn浓度的升高，液体平衡标记物的百分比变化（非常）很小。此外，任何血液浓度都有望在运动后补充水分后迅速恢复，这与运动后2至6小时内CTn浓度的进行性升高相矛盾。证据还表明，血液稀释可能发生在耐力运动后，73所以血液浓度在运动后升高的ctn浓度中的作用可能是有限的，如果不是可以忽略的话。

Second， prolonged exercise and dehydration are associated with a compromised kidney function， but exerciseinduced increases in cT n concentrations far exceed the modest reduction in renal function observed immediately after exertion． Cystatin C increased 21％ to 25％ immediately after a marathon run， indicating a similar relative decrease in renal function．74 This reduction in renal function may reduce renal cT n clearance and contribute to increased cT n concentrations， but cT n concentrations increase a median 1000％ postmarathon，37 whereas renal function quickly recovers （＜24 hours），74 demonstrating that the contribution of attenuated renal function to the magnitude of exercise－induced cT n elevations is limited．

第二，长时间的运动和脱水与肾功能受损有关，但运动引起的Ctn浓度的升高远远超过运动后立即观察到的肾功能的轻微下降。74这种肾功能下降可能会降低肾脏的Ctn清除率，并导致Ctn浓度升高，但马拉松后Ctn浓度升高的中位数为1000％，37而肾功能迅速恢复（＜24小时），74表明肾功能减弱对运动性Ctn升高幅度的贡献是有限的，但Ctn浓度在马拉松后升高的中位数为1000％，37而肾功能迅速恢复（＜24小时），74表明肾功能减弱对运动诱导的Ctn升高幅度的贡献是有限的，但在马拉松结束后，Ctn浓度升高的中位数为1000％，37而肾功能迅速恢复（＜24小时）。

Third， increases in cT n were hypothesized to be attributable to the cross－reactivity of the assay with skeletal T n or skeletal muscle damage with cT n release． Cross－reactivity of cT n assays with skeletal T n has been reported for cT nT75 and for certain assays of cT nI．76 For cT nT， it was estimated that cross－reactivity is limited to 0．003％ （package insert Roche Diagnostics ［201703， V9．0 English］） to 0．02％75 and for cT nI， 0．04％ to 0．44％．76 Nevertheless， in a clinical setting of rhabdomyolysis， no association between CK and cT nT or cT nT was reported．77 In patients with neuromuscular diseases， endstage renal disease， and even in healthy human skeletal muscle samples， cT nT but not cT nI was detected．78 Similarly， blood cT nT concentrations were often ＞URL in patients with skeletal myopathies， whereas cT nI was rarely elevated．79 Thus， skeletal muscle injury could conceivably contribute to exercise－induced cT nT increases but likely could not contribute to cT nI increases． We are also unaware of data showing increases in cT n， either T or I in muscle samples from exercise－trained subjects．

第三，Ctn的升高被认为是由于测定与骨骼Tn或骨骼肌损伤与Ctn释放的交叉反应所致。已经报道了CT nT75的CT n测定与骨骼Tn的交叉反应，以及CT nt的某些CT nI．76测定的交叉反应，估计交叉反应限制在0．003％（Package Insert Roche Diagnostics［201703，V9．0 English］）至0．02％75和Ctni的0．04％至0．44％．76。然而，在横纹肌溶解症的临床环境中，CK与CT nt或CT nt之间没有关联。78同样，骨骼性肌病患者的血液CT NT浓度通常＞URL，而Ct ni很少升高。79因此，可以想见，骨骼肌损伤可能导致运动性CT NT升高，但很可能不会导致Ct ni升高。我们也不知道有数据显示运动训练受试者的肌肉样本中的Ctn增加，无论是T还是I。

CLINICAL RELEVANCE 临床相关性

Exercise－induced increases in cT n have traditionally been interpreted as the only benign form of cT n release， because these elevations are mild， occur often， in apparently healthy individuals， and are not related to cardiac symptoms． However， cT n concentrations taken at rest in large populations and clinical studies predict mortality and cardiovascular morbidity，2，4 even within the normal range．3 The prognostic value of exercise－induced increases in cT n has rarely been studied80，81 but may have clinical relevance in some populations as discussed later on in this article．

传统上，运动引起的Ctn升高被认为是唯一良性的Ctn释放形式，因为这些升高是温和的，经常发生在表面上健康的人身上，而且与心脏症状无关。然而，静息状态下的ctn浓度在大量人群和临床研究中预测死亡率和心血管发病率，2，4甚至在正常范围内。3运动诱导的Ctn升高的预后价值很少被研究80，81，但可能在本文后面讨论的一些人群中具有临床相关性。

Postexercise cTn and Cardiac Function 运动后cTn与心功能

A number of studies have examined the association between postexercise reductions in cardiac function and cT n concentrations．7 Reductions in cardiac function after exercise are typically mild and transient and occur mostly after prolonged endurance events such as marathons， triathlons， and ultraraces． A meta－analysis using echocardiography found reductions in LV ejection fraction and diastolic function after such races．7 Postexercise cT n concentrations correlated directly with reductions in diastolic function measured as E／A ratio， but no association between cT n and change in LV ejection fraction was found， because only a few studies reported a significant association and not with the standard echocardiographic parameters． This is probably because of the limited number of studies （4／22） investigating the association between cT n and LV ejection fraction．7

多项研究研究了运动后心功能下降与ct－n浓度之间的关系。7运动后心功能下降通常是轻微和短暂的，大多发生在马拉松、铁人三项和超长距离等长期耐力活动之后，7运动后的心功能下降通常是轻微的和短暂的，主要发生在马拉松、铁人三项和超长距离比赛之后。使用超声心动图的荟萃分析发现，运动后左心室射血分数和舒张功能下降。7运动后ctn浓度与以E／A比值测量的舒张功能下降直接相关，但没有发现ctn与左心室射血分数的变化相关，因为只有几项研究报道了显著的相关性，而与标准的超声心动图参数无关。这可能是因为研究CTn和左心室射血分数之间关系的研究数量有限（4／22）。7

Exercise appears to affect right ventricular （RV） more than L V function， possibly because the relative increase in RV wall stress with exercise is greater than in the L V．82 Eight studies measured RV function and exercise－induced cT n concentrations （T able S3）． Only 4 of 8 studies reported a significant reduction in RV systolic function． Of those 4 studies， only 2 reported associations between RV systolic function and postexercise cT n concentrations， which found an association between exercise－induced cT n and the reduction in RV ejection fraction （r＝0．49， P＝0．00283）， and RV basal （r＝0．68）， mid （r＝0．70）， and apical （r＝0．72） strain （P＜0．001 for all）．25 The only 2 studies reporting postexercise reductions in RV function and associations with postexercise cT n found a direct correlation， but the absence of an association in the other studies may not have been reported． Potential explanations for discrepant outcomes between studies likely relate to the selection of endurance races， the timing of blood drawings， and the inclusion of less sensitive measures of systolic function （strain analyses were more likely to reveal reductions in cardiac function25 because both studies that used RV strain found reductions in RV function）．

运动对右室功能的影响似乎大于对左心室功能的影响，可能是因为运动对右室壁应力的相对增加大于左心室。82 项研究测量了右室功能和运动诱导的CTn浓度（TableS3）。8项研究中只有4项报告右室收缩功能显著降低。在这4项研究中，只有2项研究报道了右室收缩功能与运动后Ctn浓度之间的关系，这两项研究发现运动诱导的Ctn与RV射血分数的降低（r＝0．49，P＝0．00283）、RV基础应变（r＝0．68）、MID（r＝0．7）和心尖应变（r＝0．72）（均P＜0．001）有关。25仅有2项研究报告运动后RV功能的降低与运动后Ctn的关系，但这两项研究的缺失与运动后的Ctn之间存在直接关联，但这两项研究均未发现运动诱导的Ctn与RV基础应变（r＝0．68）、MID应变（r＝0．7）和心尖应变（r＝0．72）之间的相关性。研究结果不一致的潜在解释可能与耐力比赛的选择、血液绘图的时间以及包含不太敏感的收缩功能测量有关（应变分析更有可能显示心功能下降25，因为使用右心室应变的两项研究都发现右心室功能减退）。

Overall， some evidence suggests that postexercise cT n concentrations are associated with decreased LV diastolic function and possibly with LV and RV systolic function， but this was observed in only a few studies， and the strength of the association was moderate． An important caveat of available evidence is that studies have only examined associations between cT n concentrations and cardiac function using a single postexercise assessment， most often acquired immediately after exercise cessation． Because cT n kinetics appear to show a delayed peak after exercise， a single postexercise cT n may obscure the true association between cT n and cardiac function．

总而体来说，一些证据表明，运动后Ctn浓度与左心室舒张功能下降有关，并可能与左心室和右室收缩功能有关，但这只在少数研究中观察到，而且这种联系的强度是中等的。现有证据的一个重要警告是，研究只使用单一的运动后评估来检查CTn浓度和心功能之间的关系，通常是在运动停止后立即获得的。由于运动后CTn动力学表现出一个延迟的峰值，单一的运动后Ctn可能掩盖了Ctn与心功能之间的真实联系。

Is Exercise－Induced cTn an Indicator of Subclinical Disease？运动性肌钙蛋白是亚临床疾病的指标吗？

How and why exercise－induced cT n increases occur in ostensibly healthy people is unclear， but increases in cT n may reflect subclinical myocardial vulnerability． Epidemiological and clinical studies demonstrate that individuals with cardiovascular risk factors （CVRFs） and diseases （CVDs） have higher resting cT n concentrations11，84，85 than their healthy counterparts． Similarly， after short and prolonged exercise， individuals with CVD and CVRF showed larger cT n increases than their healthy peers．11，84 For example， patients with heart failure have higher baseline， exercise－induced cT nT concentrations than healthy controls after a short－graded bicycle exercise test．84 Among 725 long－distance walkers with an average age of 61 years， resting cT nI concentrations were higher （P＜0．001）， but the proportion of concentrations ＞URL was similar （P＝0．86）， in individuals with CVD （n＝104， 7 ［2–15］ ng／L， 1．0％ ＞URL）， CVRF （n＝186， 3 ［0–9］ ng／L， 1．7％）， and healthy controls （n＝435， 1 ［0–5］ ng／L， 1．2％）． After 30 to 55 km of walking， cT nI concentrations increased in all groups （P＜0．001）， but patients with CVD more often had a postexercise cT n concentration ＞URL （16％） compared with individuals with CVRF （10％） and controls （6％； P＝0．003）．11

在表面上健康的人中，运动诱导的Ctn升高是如何以及为什么发生的尚不清楚，但Ctn的升高可能反映了亚临床心肌的脆弱性。流行病学和临床研究表明，有心血管危险因素（CVRF）和疾病（CVD）的人的静息Ctn浓度高于健康人11，84，84。以心力衰竭患者为例，在短强度自行车运动试验后，心力衰竭患者的运动诱导CtnT浓度高于健康对照组。84在725名平均年龄为61岁的长距离步行者中，静息Ctni浓度高于健康对照组（P＜0．001），但浓度＞URL的比例相似（P＝0．86．0 5），心力衰竭患者（n＝10 4，7例）中，静息CtnI浓度较高（P＜0．05），但浓度＞URL的比例相似（P＝0．86），CVD患者的静息CtnI浓度高于健康对照组（P＜0．05），但浓度＞URL的比例相似（P＝0．86）。3［0～9］ng／L，1．7％），健康对照组（n＝435，1［0～5］ng／L，1．2％）。步行30～55 km后，各组Ctni浓度均升高（P＜0．001），但Cvd组运动后Ctn浓度＞URL（16％）高于脑血管病组（10％）和对照组（6％；P＝0．003）。11

cT n elevations may indicate demand ischemia， so several studies have explored the association between the magnitude of exercise－induced cT n increases and significant CAD， but the results are inconsistent．86–88 Several studies have found no increase in cT n after a shortduration （＜15 minutes） clinical exercise test in individuals with CAD．89 Other studies have reported significant cT n increases after clinical exercise or dobutamine stress tests． A recent meta－analysis including studies published between 2008 and 2016 found only minor increases in cT n concentrations after clinical exercise stress tests， with no difference in exercise－induced elevations of cT n concentrations between patients with inducible and noninducible ischemia （cT nT： 0．5 ［0–0．9］ ng／L versus 1．1 ［0–2．2］ ng／L， P＝0．29； cT nI： 2．4 ［0．2–4．7］ ng／L versus 1．8 ［0．6–3．0］ ng／L， P＝0．61）．90 Similar findings were reported for pharmacological stress testing．90 Overall， these findings may be attributable to （1） exercise intensity or duration at the ischemia threshold being insufficient to produce cT n elevations sufficient to discriminate between those with and without severe CAD or myocardial ischemia； （2） cT n concentrations being measured too early after exercise and missing the cT n peak （Figure 3A）； or （3） the lack of an association between myocardial ischemia and exercise－induced cT n elevations．

CTn升高可能表明需求缺血，因此几项研究探索了运动引起的CT n升高幅度与显著的CAD之间的关系，但结果并不一致。86－88几项研究发现，在短时间（＜15分钟）的临床运动试验后，冠心病患者的CTn没有升高。89其他研究报告了在临床运动或多巴酚丁胺负荷试验后CT n显著升高。最近的一项荟萃分析（包括2008年至2016年发表的研究）发现，在临床运动负荷试验后，Ctn浓度仅有轻微升高，在诱导性和非诱导性缺血患者之间运动诱导的Ctn浓度升高没有差异（Ct NT：0．5［0－0．9］ng／L对1．1［0－2．2］ng／L，P＝0．29；CT－Ni：2．4［0．2－4．7］ng／L对1．8［0．6－3．0］ng／L，P＝0．61）。90药理应激试验也有类似的发现。90总体来说，这些发现可能归因于（1）运动强度或缺血阈值持续时间不足以产生足以区分有无严重冠心病或心肌缺血者的Ctn升高；（2）运动后测量Ctn浓度太早，错过了Ctn峰值（图3A）；（3）心肌缺血与运动性ctn升高之间缺乏相关性。

Observations among long－distance runners and cyclists largely confirm the findings from clinical studies with the majority of studies showing no association between cT n concentrations and CAD （T able 2）． For example， no relation was found between postexercise cT nT concentrations and coronary artery calcification scores （r＝–0．013， P＝0．95） in 27 participants of the Paavo Nurmi marathon．91 Also， postexercise cT nI concentrations were not different between marathon runners with coronary artery calcification scores greater than or less than the median score （P＞0．99）．92 The North Sea Race Endurance Exercise Study （n＝120） also found no relation between cT n concentrations 3 hours after a 91－km mountain bicycle race， although cyclists with occult obstructive CAD （n＝9） had significantly higher cT nI and cT nT concentrations 24 hours after exercise than controls．10 The delayed cT n release in individuals with obstructive CAD may relate to impaired blood flow through the obstructed coronary arteries as is also seen with AMI． Future studies that evaluate whether postexercise cT n is a marker for occult CAD should include multiple time points of assessment．

对长跑运动员和骑自行车的人的观察在很大程度上证实了临床研究的结果，大多数研究表明CTn浓度与CAD之间没有关联（表2）。例如，在27名参加帕沃－努尔米马拉松比赛的运动员中，运动后CT＿（Nt）浓度与冠状动脉钙化积分之间没有相关性（r＝－0．013，P＝0．95）。此外，冠脉钙化积分大于或小于中位数的马拉松运动员运动后CT＿（Nt）浓度也没有差异（P＞0．99）。92北海耐力运动研究也发现91公里山地自行车比赛后3小时的CT＿n浓度之间也没有关系。9例隐匿性梗阻性CAD患者运动后2 4h的CT ni和CT NT浓度明显高于对照组。10梗阻性CAD患者的Ctn释放延迟可能与梗阻性冠脉血流障碍有关，在AMI患者中也有同样的表现。（2）隐性梗阻性CAD患者运动后24h的Ctn和Ctnt浓度明显高于对照组（P＜0．01）。未来评估运动后Ctn是否是隐匿性CAD的标记物的未来研究应该包括多个时间点的评估。

Myocardial fibrosis has also been reported in ostensibly healthy endurance athletes． Only 2 studies to our knowledge have investigated the association between postexercise cT n concentrations and the presence of LGE （T able 2）． German marathon runners with LGE （n＝9） had higher cT nI concentrations immediately postmarathon than those without LGE （n＝65）．92 In contrast， triathletes with （n＝10， 49±8 years） and without LGE （n＝20， 42±10 years）， showed no difference in postexercise cT nT concentrations collected at 2．4±1．1 hours posttriathlon （40±26 versus 65±103 ng／L）．93 These 2 studies included only 19 individuals with LGE， so it is impossible to determine whether a relation exists．

表面上健康的耐力运动员中也有心肌纤维化的报道。据我们所知，只有2项研究调查了运动后Ctn浓度与LGE存在之间的关系（表2）。有LGE的德国马拉松运动员（n＝9）在马拉松后即刻的Ctni浓度高于无LGE的运动员（n＝65）。92相反，有LGE的铁人三项运动员（n＝10，49±8年）和无LGE的铁人三项运动员（n＝20，42±10年）在运动后2．4±1．1小时的Ct－nt浓度没有差异（40±26对65±103 ng／L）。93这两项研究只包括19名有LGE的人，因此不可能确定。

In summary， CVRF and CVD are associated with higher resting and postexercise cT n concentrations． Most exercise studies have found no association between postexercise cT n elevations and CAD severity or myocardial fibrosis， but few studies have been performed and they used different exercise intensities， durations， and blood sampling protocols．

综上所述，CVRF和CVD与较高的静息和运动后Ctn浓度相关。大多数运动研究都没有发现运动后Ctn升高与冠心病严重程度或心肌纤维化之间的关系，但很少有研究进行，他们使用了不同的运动强度、持续时间和采血方案。

Prognostic Value in Patients 患者的预后价值

We are aware of only 2 exercise stress test studies evaluating the prognostic value of exercise－induced cT n concentrations80，81 （T able 3）． Neither found a predictive relationship． There was no difference in 4 hours postexercise cT nT concentrations between patients with unstable angina who did （n＝23） or did not （n＝46） develop recurrent angina at 6－month follow－up．80 Another study reported no difference in the incidence of a composite end point （death， myocardial infarction， acute revascularization， hospitalization for unstable angina， or heart failure） in patients with CAD with 8 to 12 and 24－hour postex ercise cT nI concentrations greater than versus less than the URL （27％ versus 17％， P＞0．05） during 36 （15–49） months of follow up．81 The absence of an association of exercise cT n with subsequent symptoms may be attributable to the short duration of exercise， sample size， sampling times， only a small number of clinical events， or the absence of a clinically important relationship．

我们知道只有2项运动负荷试验研究评估了运动诱导的Ctn浓度80，81的预后价值（T表3）。两人都没有发现可预测的关系。在6个月的随访中，23名不稳定型心绞痛患者和46名未复发心绞痛患者在运动后4小时的ct－nt浓度没有差异。80另一项研究报道，在8－12和24小时ct－ni浓度大于或小于URL的冠心病患者中，复合终点（死亡、心肌梗死、急性血运重建、不稳定心绞痛住院或心力衰竭）的发生率没有差异（27％比17％，P＜0．05）。81缺乏运动Ctn与后续症状的关联可能是由于运动持续时间短、样本量小、采样时间短、仅有少量临床事件或缺乏临床上重要的关系所致。（2）在36（15－49）个月的随访中，Ctn与随后的症状之间没有关联，这可能是由于运动持续时间短、样本量大、采样时间短、临床事件数量少，或者没有临床上重要的关系。

Prognostic Value in Exercising Individuals 运动个体的预后价值

In contrast with a paucity of exercise／cT n studies in the clinical setting， a plethora of studies exist that follow endurance exercise events， but to our knowledge only 3 studies have assessed the prognostic value of these cT n elevations （T able 3）． cT nI concentrations increased from baseline to postexercise in 7 4 male marathon runners （57±6 years）， with 36．5％ of the runners demonstrating postexercise cT nI concentrations ＞URL． During 6 years of follow－up， 6 CAD events occurred， evenly split between individuals with postmarathon cT nI concentrations greater than and less than the median value．92

与临床上运动／CTn研究相对较少的是，有大量研究跟踪耐力运动事件，但据我们所知，只有3个研究评估了这些CT nI升高的预后价值（TABL3）。74名男性马拉松运动员（57±6岁）运动后CTni浓度从运动前到运动后逐渐升高，36．5％的跑步者运动后Ctni浓度＞URL。在6年的随访中，发生了6个CAD事件，平均分布在马拉松后Ctni浓度大于或小于中位数的个体之间。92

Our group previously followed 725 long－distance walkers （61．4 ［54．4–69．1］ years）， 9％ of whom had a cT nI concentration ＞URL ±10 minutes after walking 30 to 55 km．11 During a median follow－up of 43 （23– 77） months， 62 participants experienced a composite end point of death （n＝29， 47％）， myocardial infarction （n＝6， 10％）， stroke （n＝17 ， 27％）， heart failure diagnosis （n＝4， 6％）， revascularization （n＝5， 8％）， or resuscitated sudden cardiac arrest （n＝1， 2％）． Of individuals with postexercise cT nI ＞URL， 27％ experienced an end point compared with 7％ of those with cT nI URL， even when markedly elevated．

我们的小组之前跟踪了725名长距离步行者（61．4［54．4－69．1］年），其中9％的人在步行30到55公里后10分钟内Ctni浓度＞URL。11在平均43（23－77）个月的随访中，62名参与者经历了复合终点死亡（n＝29，47％），心肌梗死（n＝6，10％），中风（n＝17，27％），心力衰竭诊断（n＝4，6％），血管重建（n＝4，6％）。2％）。在运动后Ctni＞URL的个体中，27％的人经历了终点，而Ctni＜URL的个体中有7％的人经历了终点（粗风险比5．21［95％CI，2．96－9．17］）。在调整了年龄、性别以及是否存在CVD和CVRF后，危险比为3．21（95％CI，1．79－5．77）。在调整基线CtnI后，这一数字进一步下降到2．48（95％CI，1．29－4．78）。当将死亡率与其他终点分开时（图5），死亡率与ctni的增加没有显著关联（完全调整的风险比，1．09［0．38－3．10］），而主要的心血管不良结局有很强的相关性（完全调整的风险比，3．75［1．56－9．02］）。这可能是由于独立结果的统计能力较低，或者是因为检查了所有原因而不是心血管死亡率。研究队列不是运动人群，而是来自普通人群的体力活动个体，包括患有脑血管病和脑血管病的老年人。因此，这些数据不适用于Ctn值＞URL的年轻运动员队列，即使明显升高。

Preliminary data examined postexercise cT n concentrations in 991 healthy participants （46 ［40–53］ years） in the North Sea Race 91－km bike race．94 Participants were followed for 5 years， and 12 （1．2％） experienced a cardiovascular event during follow－up． The prevalence of cT n ＞URL for cT nI and cT nT at 3 and 24 hours after exercise were 83％ and 92％， and 17％ and 27％， respectively． Postexercise cT n concentrations ＞URL were not associated with cardiovascular events at 3 （log－rank test， cT nI： P＝0．11， cT nT： P＝0．35） or 24 hours （cT nI： P＝0．45， cT nT： P＝0．06）．94 The low event rate may have contributed to the absence of an association， but the near－significant result for cT nT at 24 hours is noteworthy．

初步数据分析了参加北海91公里自行车赛的991名健康参与者（46［40－53］岁）的运动后Ctn浓度。94名参与者被跟踪5年，其中12名（1．2％）在随访期间经历了心血管事件。Ctn＞URL在Ctni和Ct Nt中的患病率（3％）运动后24h分别为83％和92％，17％和27％。运动后3小时（对数秩检验，CT ni：P＝0．11，CT NT：P＝0．35）或24小时（CT ni：P＝0．45，CT NT：P＝0．06）的心血管事件与Ctn浓度＞URL无关。94低的事件发生率可能是导致两者无相关性的原因之一，但值得注意的是24小时Ct NT的接近显著的结果。

Together， these 3 studies suggest that exaggerated postexercise cTn elevations may not be benign and may portend cardiovascular events in older individuals． It is unknown whether these findings can be extrapolated to younger subjects and to athletes performing vigorous activities．

总之，这3项研究表明，运动后CTn的升高可能不是良性的，可能预示着老年人的心血管事件。目前还不清楚这些发现是否可以推断到更年轻的受试者和进行剧烈运动的运动员。

表2．冠状动脉粥样硬化、心肌纤维化和运动诱导的cTn释放之间的相关性

CAC indicates coronary artery calcification冠状动脉钙化； CAD， coronary artery disease冠心病； cTnI， cardiac troponin I心肌肌钙蛋白I； CVD， cardiovascular disease心血管疾病

； hs－cTnT， high sensitivity cardiac troponin T高敏心肌肌钙蛋白T； hs－cTnI， high sensitivity cardiac troponin I高敏心肌肌钙蛋白I； and URL， upper reference limit参考上限

．Clinical Management and Considerations 临床管理与思考

Exercise－induced cTn elevations can lead to clinical confusion in the emergency department when individuals present postexercise with elevated cT n concentrations．

运动性CTn升高可能导致急诊科的临床混乱，当个人在运动后出现CTn浓度升高时。

表3．评估运动性cTn释放的预后价值的研究综述

cTnI indicates cardiac troponin I心肌肌钙蛋白I； CVD， cardiovascular disease心血管疾病；HRadjusted， adjusted hazard ratio； HRmax估计的最大心率， estimated maximal heart rate； hs－cTnI， high sensitivity cardiac troponin I高敏心肌肌钙蛋白I； hs－cTnT， high sensitivity cardiac troponin T高敏心肌肌钙蛋白T； MACE， major adverse cardiovascular outcome主要不良心血管结果； and URL， upper reference limit参考上限

Several clinical approaches have been suggested5 and remain appropriate． Clinicians should follow usual clinical protocols but be especially cognizant that exercise can increase cT n concentrations far above the URL and thus can explain cT n elevations after exercise． Patients presenting postexercise with any clinical concern for an acute coronary syndrome （with elevated cT n or not） should undergo the appropriate evaluation including 12－lead ECG， serial cT n testing， and some form of either noninvasive or invasive risk stratification as dictated by the overall clinical picture． However， assessment of CAD （eg， with coronary artery calcification scoring） is not indicated solely on the basis of lone postexercise cT n elevations．

已经推荐了几种临床方法，并且仍然是合适的。临床医生应该遵循通常的临床规程，但要特别认识到，运动可以使Ctn浓度远远高于URL，从而可以解释运动后Ctn升高的原因。运动后出现任何临床症状的急性冠脉综合征患者（无论是否有Ctn升高）都应该接受适当的评估，包括12导联心电图、系列Ctn测试，以及根据总体临床情况进行某种形式的无创或有创风险分层。然而，冠心病的评估（例如，冠状动脉钙化评分）并不仅仅基于运动后单独的ctn升高。

Clinicians who oversee mass sporting events are not recommended to do on－site cT n testing outside of a clear research agenda unless future research supports its added value． If postexercise cT n elevations are found， the clinical significance is unclear， although some studies suggest that postexercise cT n elevations may portend future cardiac events in a small number of individuals．

监督大众体育赛事的临床医生不建议在明确的研究议程之外进行现场ct n测试，除非未来的研究支持其附加值。如果发现运动后Ctn升高，其临床意义尚不清楚，尽管一些研究表明运动后Ctn升高可能预示着少数人未来的心脏事件。

图5．基于Aengevaeren等人的数据，运动后肌钙蛋白I的风险比＞死亡率和MACE的正常参考上限，以及死亡率和MACE11

在43［23－77］个月的随访中，对725名年长的长距离步行者在步行30到55公里后10分钟测量了t－roponin I，他们经历了62次事件、29次死亡和33次。MACE提示发生了严重的心血管不良事件。

FUTURE DIRECTIONS 未来方向

Many studies have used 1 phlebotomy time point after exercise， and this time point often varies among studies， whereas only a few studies have investigated cT n release during exercise． Future studies should use similar time points for similar outcome measures． It appears that peak cTn values are achieved at 2 to 6 hours after a bout of endurance exercise． More research is needed to determine whether a specific postexercise time point may be predictive of future mortality and cardiovascular outcome．

许多研究都使用了运动后1个采血时间点，而这个时间点在不同的研究中往往不同，而只有少数研究研究了运动过程中CTn的释放。未来的研究应该对类似的结果测量使用类似的时间点。耐力运动后2～6小时可达峰值。需要更多的研究来确定特定的运动后时间点是否可以预测未来的死亡率和心血管结果。

There is evidence that both physiological and reversible， and pathological and irreversible myocardial injury， as well， might contribute to the exercise－induced cT n response， and this may be mediated by the population being studied． Mechanisms may also differ between populations because exercise－induced cT n release may be more likely related to reversible myocardial injury in healthy individuals， whereas irreversible myocardial injury might be more common in individuals with underlying CVD． Cellular and animal models， novel imaging techniques， and novel biomarker assays are needed to examine these possibilities． For example， a study using diffusion－weighted MRI could assess whether the larger exercise－induced elevations in cT n concentrations in individuals with CVRF are attributable to larger decreases in cardiomyocyte integrity． Assessing the types and sizes of cT n fragments and the appearance of apoptotic biomarkers would contribute to this analysis． Future work examin ing exercise－induced cT n release in healthy participants， and those with underlying cardiovascular disease， should examine the influence of coronary blood flow， because the differential response between these populations may be explained by the degree of coronary occlusion or vessel reactivity and the corollary impact on the washout of cT n stimulated by exercise．

有证据表明，生理性和可逆性以及病理性和不可逆性心肌损伤都可能参与运动性CTn反应，这可能是由被研究人群介导的。机制也可能因人群不同而不同，因为运动诱导的ctn释放可能更可能与健康个体的可逆性心肌损伤有关，而不可逆性心肌损伤可能更常见于潜在的CVD患者。需要细胞和动物模型、新的成像技术和新的生物标记物分析来检查这些可能性。例如，一项使用弥散加权MRI的研究可以评估患有CVRF的个体在运动诱导的Ctn浓度较大程度上的升高是否可归因于心肌细胞完整性的较大下降。评估CTn片段的类型和大小以及凋亡生物标志物的出现将有助于这一分析。未来研究健康受试者和有潜在心血管疾病的受试者的运动诱导的CTn释放的工作应检查冠脉血流的影响，因为这些人群之间的不同反应可能由冠状动脉闭塞或血管反应性的程度以及运动对Ctn的清除的必然影响来解释。

Large prospective studies in clinical and recreational athletic populations with prolonged follow－up are needed to determine whether exercise－induced cT n predicts future cardiovascular events． Subsequent studies can then determine if altering the cT n response by exercise training or pharmacological treatment （eg， statins or aspirin） can alter cardiovascular outcomes．

需要在临床和休闲运动人群中进行大规模前瞻性研究，并进行长期随访，以确定运动诱发的CT是否可以预测未来的心血管事件。随后的研究可以确定通过运动训练或药物治疗（例如：他汀类药物或阿司匹林）改变CTn反应是否能改变心血管结果。

CONCLUSIONS

Exercise of different types， durations， and intensities commonly increases cT n． cT n transiently increases after the performance of endurance exercise with peak values typically 2 to 6 hours after exercise． The underlying mechanisms are not clearly defined， but evidence supports the hypothesis that sarcolemmal permeability from reversible cardiac injury permits cT n fragments from an early releasable pool to leak from the cardiomyocyte． Evidence also suggests increased apoptosis or accelerated cardiomyocyte turnover attributable to myocardial stress or brief ischemia． Few studies have investigated the predictive value of exercise－induced cT n for cardiovascular events， but older long－distance walkers with a postexercise cT n concentration ＞URL experienced increased cardiovascular events． These findings need to be confirmed and the prognostic significance of cT n in younger athletic subjects needs to be determined．

不同类型、持续时间和强度的运动通常会增加Ctn，耐力运动后Ctn有一过性增加，峰值一般在运动后2～6h。其潜在的机制尚不清楚，但有证据支持这样的假设，即可逆性心脏损伤引起的肌膜通透性允许早期可释放池中的Ctn片段从心肌细胞中渗出。也有证据表明，心肌应激或短暂缺血增加了心肌细胞凋亡或加速了心肌细胞的周转。很少有研究调查运动诱导的Ctn对心血管事件的预测价值，但运动后Ctn浓度＞URL的老年长距离步行者发生更多的心血管事件。这些发现需要得到证实，CT＿n在年轻运动受试者中的预后意义需要确定。

原文标题:【文献阅读】运动诱导的心脏T肌钙蛋白升高:从基础机制到临床相关性