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

運動誘導(dǎo)的心臟T肌鈣蛋白升高：從基礎(chǔ)機制到臨床相關(guān)性

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

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

翻譯：苗 、丹妮，貓  排版：叮當(dāng)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：心臟肌鈣蛋白血清學(xué)評估（cTn）是臨床評價心肌損傷的金標(biāo)準(zhǔn)。在患者和一般人群中，較大程度的急性或慢性升高的cTn濃度與較低的無事件生存率相關(guān)。眾所周知，運動訓(xùn)練可改善心血管功能并延長壽命，但運動可導(dǎo)致cT n濃度急性升高，在相當(dāng)數(shù)量的個體中可能超過參考上限。運動誘導(dǎo)的cT升高是否可歸因于生理或病理反應(yīng)，以及它們是否與臨床相關(guān)，已經(jīng)爭論了幾十年。迄今為止，運動誘導(dǎo)的cT升高被認(rèn)為是唯一的良性cT升高形式。然而，最近的研究報告了有趣的發(fā)現(xiàn)，揭示了運動誘導(dǎo)cT升高的潛在機制和臨床相關(guān)性。我們將回顧cT n測定的生化特征，決定運動后cTn濃度大小的關(guān)鍵因素，釋放動力學(xué)，導(dǎo)致和促成運動誘導(dǎo)cTn釋放的潛在機制，以及運動誘導(dǎo)cTn升高的臨床相關(guān)性。我們還將解釋其與心功能的關(guān)系，與（亞臨床）心血管疾病的相關(guān)性，以及運動誘發(fā)的cTn升高對未來心血管事件的預(yù)測價值。最后，我們將提供解釋這些發(fā)現(xiàn)的建議，并為該領(lǐng)域的未來研究提供方向。

Key Words： apoptosis細(xì)胞凋亡 ? athletes運動員 ? cardiomegaly心臟肥大， exercise－induced 運動誘發(fā)? heart心臟 ? heart injuries心臟損傷 ? necrosis壞死

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

心肌肌鈣蛋白（Ctn）是鈣離子內(nèi)流后促進心肌細(xì)胞收縮的蛋白質(zhì)。由于其心臟特異性亞型，在臨床實踐中，對ctn的血清學(xué)評估是評估心肌損傷的金標(biāo)準(zhǔn)。1在患者2、3和普通人群中，慢性或急性升高的ctn濃度越大，無事件存活率越低。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．

運動訓(xùn)練改善心血管功能，降低心血管事件的風(fēng)險，并促進長壽。然而，一次運動可引起cT n濃度的急性升高，在大量個體中可能超過參考上限，符合心肌損傷的標(biāo)準(zhǔn)1在過去30年的多項研究中，不同類型、持續(xù)時間和強度的運動后，以及不同年齡、性別、健康狀況和訓(xùn)練狀態(tài)的受試者的cT n濃度均有所升高。5－7然而，由于研究的描述性、小樣本量和橫斷面設(shè)計，以及缺乏長期隨訪和機制研究，這些發(fā)現(xiàn)的臨床意義尚不明確。

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

最近的研究對運動誘發(fā)的潛在機制和臨床意義有了新的認(rèn)識cTn升高。例如，耐力運動可損害心肌細(xì)胞肌膜的完整性，8這可能導(dǎo)致cT n片段泄漏到循環(huán)中。9此外，運動引起的cT n濃度升高的幅度與隱匿性阻塞性冠狀動脈疾病10以及中年和老年個體死亡率和主要不良心血管事件風(fēng)險的增加有關(guān)。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．

這篇敘述性綜述將總結(jié)最近關(guān)于決定運動誘導(dǎo)cTn釋放強度的因素，導(dǎo)致這些升高的潛在機制，以及解釋運動誘導(dǎo)cTn濃度升高的臨床相關(guān)性和考慮因素。

ASSESSMENT OF CARDIAC TROPONINS Molecular Basis心臟肌鈣蛋白分子基礎(chǔ)評估

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

轉(zhuǎn)鐵蛋白（T－roponin，Tn）是一種細(xì)胞內(nèi)蛋白質(zhì)復(fù)合物，是心肌和骨骼肌收縮器的一部分。Tn由3個亞基（即I、T和C）組成，其中存在I和T的心臟和肌肉特異性異構(gòu)體。在心肌細(xì)胞內(nèi)，CTn蛋白復(fù)合體附著在原肌球蛋白上，原肌球蛋白是一種包裹在細(xì)絲上的結(jié)構(gòu)蛋白。隨著鈣離子的流入，鈣離子與T－NC亞基結(jié)合，導(dǎo)致CT－n復(fù)合物的構(gòu)象改變，使肌球蛋白頭部與肌動蛋白細(xì)絲結(jié)合，導(dǎo)致心肌細(xì)胞收縮（圖1）。除了與原肌球蛋白結(jié)合的CTn，CTn分子也存在于早期可釋放池中，這部分CTn可能比先前估計的要大得多（5％－10％）。12

Analytic Considerations分析考慮

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，第一批商業(yè)化的ct n檢測方法問世，但檢測技術(shù)的快速發(fā)展極大地提高了分析靈敏度。13高靈敏度ct n檢測的特點是，在表面健康的人身上建立的第99個百分位數(shù)或參考上限（URL）處的分析變異系數(shù)很低（變異系數(shù)＜10％），而且它們有能力量化那些＞50％的健康人的ct n水平。13男性通常有更高的靜息ct n水平，11，14強調(diào)了性別特異性的重要性。

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

市場上有20多種心肌肌鈣蛋白I（cT－nI）免疫分析方法可供選擇，從現(xiàn)代的高靈敏度檢測到定點檢測，每種方法都使用自己的針對cT－nI不同表位的單克隆抗體。盡管國際工作組做出了努力，cT nI測量的標(biāo)準(zhǔn)化仍然有限。15

Circulating cTn Forms 循環(huán)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．

在循環(huán)中發(fā)現(xiàn)了不同的Ctn形式和片段，可能是由細(xì)胞內(nèi)或細(xì)胞外過程引起的。16，17裂解過程尚不完全清楚，但可能依賴于降解、磷酸化、泛素化、復(fù)合物的形成以及與特定的抗Ct n免疫球蛋白的結(jié)合。對于心肌梗死患者，心肌肌鈣蛋白T（Ct NT）在出現(xiàn)后的第一個小時內(nèi)主要被發(fā)現(xiàn)完整（37 KDa），此后作為初級片段（29 KDa）和次級片段（15－20 kDa）。17初級片段在Ct NT的N端被切割，而次級片段在C端被進一步切割。18例終末期腎病患者僅有小的Ct nt片段，其分子量與心肌梗死的繼發(fā)性片段相當(dāng)。19這些繼發(fā)性Ct n形式在終末期腎病和心肌梗死患者中是否具有可比性，或者它們是否代表不同類型的疾病特異性片段仍有待確定。Ct n的形成（完整或碎片）如何從血液循環(huán)中清除也仍然是一個討論的話題，但人們認(rèn)為較小的蛋白通過腎小球膜進行清除。20然而，在急性心肌梗死后，腎外清除在大鼠的研究中占主導(dǎo)地位。21腎外清除可能與清道夫受體清除有關(guān)；然而，這一主題尚未完全闡明。

EXERCISE－INDUCED CARDIAC TROPONIN ELEVATIONS 運動性心肌肌鈣蛋白升高

Brief Historical Perspective短暫的歷史觀點

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．

大多數(shù)研究運動后心肌損傷可能性的研究都使用ctn作為選擇標(biāo)記物。然而，支持運動性心臟損傷概念的初步證據(jù)是基于測定血清肌酸激酶同工酶（CK－MB）的研究22雖然CK－MB被廣泛用于急性冠脈綜合征的臨床診斷和治療，但隨后發(fā)現(xiàn)它缺乏心臟組織特異性和敏感性，特別是在那些骨骼肌CK－MB濃度較高的運動員（馬拉松運動員腓腸肌CK－MB濃度較高（8．9±1．3％比3．3±0．7％，馬拉松運動員腓腸肌CK－MB濃度高于未經(jīng)訓(xùn)練的對照組的3．3±0．7％），并在運動性肌肉損傷后釋放CK－MB）。22因此，在重新定義心肌后，Ct－MB取代CK－MB成為心肌損傷的金標(biāo)準(zhǔn)標(biāo)志物。自第一代CT－n檢測方法問世以來，已發(fā)表了200多篇關(guān)于運動對CT－n釋放的影響的研究。

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簡單的運動前、運動后測量設(shè)計，再加上隨后的薈萃分析結(jié)果，6表明，在耐力運動后，＞50％的運動員循環(huán)中的ctni和ctnt濃度在URL以上。此外，有證據(jù)表明，跑步項目可能比自行車項目更有可能導(dǎo)致Ctn升高。6然而，沒有直接的比較。其機制也不清楚，但可能與跑步比騎自行車的強度更高有關(guān)。更多的研究和進一步的薈萃分析總體上重復(fù)了這些最初的發(fā)現(xiàn)，還記錄了各種人群運動后的ct n升高，包括兒童、青少年、絕經(jīng)后婦女和運動動物。5 ct n升高還與許多運動刺激有關(guān)，包括耐力跑、長征、籃球、高強度跑步機跑步、高強度騎自行車和臨床運動測試。23

Figure 1． cTn復(fù)合體在心肌細(xì)胞收縮中起著重要作用。

當(dāng)動作電位到達心肌細(xì)胞時，鈣離子進入細(xì)胞，導(dǎo)致鈣離子與T－NC亞基結(jié)合后的構(gòu)象變化。因此，肌球蛋白結(jié)合位點暴露，使肌球蛋白頭與肌動蛋白細(xì)絲結(jié)合，促進心肌細(xì)胞收縮。注意，大多數(shù)ct n復(fù)合體與肌動蛋白細(xì)絲結(jié)合，但也存在于早期可釋放池中。CT顯示心肌肌鈣蛋白。

Predictors： Exercise Duration and Intensity預(yù)測因素：運動持續(xù)時間和強度

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．

許多研究人員試圖研究哪些因素會導(dǎo)致心臟特異性生物標(biāo)志物的釋放。年齡、訓(xùn)練經(jīng)歷、血壓、環(huán)境因素、運動強度和運動持續(xù)時間是潛在地與運動后Ct n濃度的大小相關(guān)的預(yù)測因素。測試14、24－26（圖2）。然而，多變量預(yù)測模型解釋的方差很低（R2＜35％），而且似乎主要是由運動強度和持續(xù)時間驅(qū)動的。24然而，一項對2007年發(fā)表的26項研究的薈萃分析顯示，運動后的Ctn與運動持續(xù)時間呈負(fù)相關(guān)。6具體地說，更多的運動員在馬拉松賽跑后的Ctn濃度高于URL，而在超耐力項目后的Ctn濃度明顯高于URL。這些數(shù)據(jù)表明，運動強度，而不是持續(xù)時間，可能是更有效的刺激Ctn釋放的因素，27因為馬拉松比超耐力項目的強度更高。最近的一項研究記錄了運動心率（運動強度的替代指標(biāo)）和運動后ctn患病率之間的直接關(guān)系，7還提出了運動強度的重要性。

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．

為了直接檢驗運動持續(xù)時間和強度的影響，最近的一項研究比較了低強度（50％－60％乳酸閾值，60分鐘）、中等強度（60％－70％乳酸閾值，4小時）和高強度（80％－90％乳酸閾值，60分鐘）騎自行車后Ctni的釋放。28 CT nI在中強度和高強度運動后升高，但在低強度刺激后沒有升高。此外，短時間大強度運動后的Ctn濃度明顯高于長時間中強度運動后。28類似的研究比較了中等強度（60min，峰值心率的70％）和大強度（2組12×30s重復(fù)沖刺，峰值心率為90％）。29大強度運動后4h，CtNT顯著高于中強度運動。此外，對177名參加91公里山地自行車比賽的自行車手進行的實地研究表明，進行高強度運動（心率＞150 bpm）的時間是運動后Ctni和Ct nt濃度的獨立預(yù)測因子。30總體而言，這些數(shù)據(jù)表明運動后Ctn升高與總體心臟負(fù)荷有關(guān)，這是持續(xù)時間和強度的乘積。

Figure 2． 運動誘導(dǎo)肌鈣蛋白釋放大小的驅(qū)動因素。

各因素對運動后肌鈣蛋白濃度的影響在不同研究中差異很大，所有因素的預(yù)測價值都有限（r2＜35％）。運動強度和持續(xù)時間似乎對運動后濃度的影響最大，可能反映了整體心臟負(fù)荷。

Influence of Exercise Training 運動訓(xùn)練的影響

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

運動訓(xùn)練對心臟重塑的影響，促使多項研究探討運動訓(xùn)練狀態(tài)與運動后心臟重塑的關(guān)系，并以24、31次運動完成時間或運動年限作為運動訓(xùn)練的代理。在一些研究中，經(jīng)驗豐富的馬拉松運動員比經(jīng)驗不足的運動員在賽后不太可能有胸高，但是其他研究未能證實這種關(guān)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．

最近的兩項研究檢查了運動訓(xùn)練是否會改變運動后的CT n釋放。其中一人評估了干預(yù)和對照組在14周訓(xùn)練計劃之前和之后的靜息和60分鐘最大跑后的CT NT濃度。33在訓(xùn)練前，60分鐘最大跑在兩組中都產(chǎn)生了不同的CT NT反應(yīng)，71％的受試者超過了URL。33這可能是因為干預(yù)組在第二次最大跑時的負(fù)荷較大，表現(xiàn)為速度明顯較高（12．1±0．9比10．7±0．9 km／h，P＜0．05）。在訓(xùn)練后，干預(yù)組的基礎(chǔ)和運動后Ct NT均高于對照組。33這可能是因為干預(yù)組在第二次最大跑中的工作量較大，明顯高于對照組（12．1±0．9對10．7±0．9 km／h）。第二項研究隨機將48名久坐不動的年輕肥胖女性分為高強度間歇訓(xùn)練、中等強度持續(xù)訓(xùn)練和不訓(xùn)練3組，分別在相同的絕對和相對（60％最大攝氧量）運動刺激下測定CTNT水平。34T訓(xùn)練在60％最大攝氧量時顯著增加了工作量。運動前各組運動后CT－NT均升高，與運動前比較差異無顯著性（P＞0．05）。訓(xùn)練結(jié)束后，相同相對強度的靜息和運動后ct－NT濃度與訓(xùn)練前相近。但在相同絕對強度的運動后，CT NT并沒有升高。這些結(jié)果提示，在相同的絕對運動強度下，運動訓(xùn)練可以降低Ctn的升高，但不能降低相對運動強度下的Ctn升高。這些研究表明，運動后Ctn釋放的大小受到訓(xùn)練狀態(tài)和運動強度的共同影響，因為訓(xùn)練者需要更大的絕對運動刺激才能獲得相同的相對刺激。

Kinetics of cTn Concentrations CTn濃度的動力學(xué)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．

本文較好地描述了急性心肌梗死（AMI）35后CTn濃度的動態(tài)變化。CT ni和Ct NT峰值出現(xiàn)在ST段抬高后10～12小時，并持續(xù)升高4～10天，但由于心肌梗死的大小和再灌注對CT n消失速度的影響，不同患者的CT n升高模式和幅度差異很大。

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．

運動性CTn濃度的動態(tài)變化尚不清楚。Middleton等人36試圖描述馬拉松運動期間和之后的Ct n動力學(xué)，并報告了一種雙相釋放模式。隨后，其他幾項研究評估了運動后72小時內(nèi)CTn濃度隨時間的變化，其中的發(fā)現(xiàn)總結(jié)為TableS1（Ctnt）和TableS2（Ctni）。不同研究中運動持續(xù)時間、運動強度和運動方式的差異排除了進行結(jié)構(gòu)化薈萃分析的可能性。有限的數(shù)據(jù)可以支持或駁斥運動中雙相釋放的可能性，但仍然可以對運動后的濃度進行一些重要的觀察。首先，停止運動后，Ctn濃度似乎逐漸升高，峰值通常出現(xiàn)在運動后2至6小時（圖3A）。其次，CTn的增加幅度在不同的個體之間差異很大，37有些人的CTn濃度沒有變化或只有很小的變化，但另一些人報告的值超過了URL圖3B的幾倍。平均而言，運動后峰值Ctn濃度是≈的1到3倍。馬拉松跑步者從運動前到運動后濃度的中位數(shù)變化是10倍（四分位數(shù)范圍：5到19倍）。37第三，運動誘導(dǎo)的Ctn濃度升高是短暫的，運動后48到72小時后恢復(fù)到基線水平。運動后運動相關(guān)的Ctn升高較早且幅度較小，與AMI患者運動后Ctn升高幅度較大且峰值較晚形成鮮明對比。

UNDERL YING MECHANISMS 底層機制

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．

運動后Ctn升高的機制仍存在爭議。CTn升高最初被解釋為不可逆轉(zhuǎn)的損傷，因為心臟被認(rèn)為是有絲分裂后的器官，其心肌細(xì)胞不能修復(fù)或替換。因此，CT n的釋放被認(rèn)為是死亡的病原體。38，39然而，越來越多的證據(jù)表明，心臟有絲分裂確實發(fā)生在成年人中，每年有0．5％到1％的心肌細(xì)胞。40，41這種有絲分裂的比率可能會隨著運動訓(xùn)練而增加。42，43 T的短暫增加不僅發(fā)生在運動之后，也發(fā)生在心房起搏44和藥物應(yīng)激試驗之后，45甚至在健康的個體中，這突顯了并不是所有的CT釋放都可歸因于心肌細(xì)胞壞死。42，43的短暫增加不僅發(fā)生在運動后，而且發(fā)生在心房起搏44和藥物應(yīng)激試驗之后，45甚至在健康的人中也是如此，這突顯了并不是所有的Ct釋放都可歸因于心肌細(xì)胞壞死。歐洲心臟病學(xué)會的生物標(biāo)記物研究小組確定了導(dǎo)致Ct n濃度升高的3種可能原因46：（1）可歸因于細(xì)胞損傷、胞漿氣泡或細(xì)胞外小泡釋放的可逆性損傷；（2）可歸因于細(xì)胞凋亡的損傷；以及（3）可歸因于心肌壞死的不可逆損傷（圖4）。很少有直接數(shù)據(jù)支持或拒絕運動誘導(dǎo)的Ctn濃度升高的單一釋放機制，但現(xiàn)有證據(jù)如下所示。

圖3．運動誘導(dǎo)的cTn濃度升高的建議模式。

A1耐力運動后 ct n 濃度的動力學(xué)示意圖。運動過程中 ct n 濃度的變化尚不清楚（虛線） ，但累積數(shù)據(jù)顯示 ct n 濃度在運動停止后繼續(xù)上升，在運動后2ー6小時達到峰值。運動后24到72小時內(nèi)完全恢復(fù)正常。第99百分位數(shù)或正常參考上限以紅色顯示。B1，個人（n ＝ 151）在馬拉松后 ct ni 濃度的瀑布圖，突出了在進行類似耐力運動回合的運動員個人之間的巨大差異。數(shù)據(jù)來自波士頓37和恩德霍文26馬拉松比賽的參賽者。兩個曲線圖中的值都表示為CTn分析的URL的倍數(shù)。CT顯示心肌肌鈣蛋白。

Reversible Cardiac Injury可逆性心臟損傷

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細(xì)胞的質(zhì)膜上交換，這種釋放似乎是通過質(zhì)膜的短暫破壞發(fā)生的通過收縮、β－腎上腺素能刺激、4 7、4 8延伸、49、50或短暫缺血增加心肌細(xì)胞的大分子釋放率。組織學(xué)檢查未見心肌細(xì)胞死亡，但可能發(fā)生凋亡。相比之下，質(zhì)膜損傷不一定會導(dǎo)致心肌細(xì)胞死亡，因為（1）細(xì)胞質(zhì)是一種擴散受限的大分子凝膠，53（2）營養(yǎng)不良蛋白復(fù)合物通過在細(xì)胞外基質(zhì)和收縮的肌節(jié)之間形成連接來穩(wěn)定膜，54和（3）細(xì)胞創(chuàng)面修復(fù)可以恢復(fù)小膜復(fù)氧后的洞。48，54心肌細(xì)胞因此比以前認(rèn)為的更有彈性。

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．

心臟通過增加心率和每搏輸出量提供運動增加的大部分身體需氧量，進而增加心肌需氧量、冠脈血流量以及心臟前負(fù)荷和后負(fù)荷。這些反應(yīng)增加了心肌細(xì)胞的應(yīng)激反應(yīng)，并可能改變細(xì)胞膜的通透性，導(dǎo)致Ctn從細(xì)胞內(nèi)被動擴散到細(xì)胞外間隙。這一假說已經(jīng)在一項探索性的先導(dǎo)性研究中得到驗證（n＝11），使用心臟MRI的心肌組織水分?jǐn)U散率（MD）。8 MD是心肌細(xì)胞完整性的定量測量，MD的增加表明細(xì)胞膜通透性增加。馬拉松運動增加心肌CTni濃度和心肌MD，從而顯示細(xì)胞膜通透性增加。馬拉松后Ctni值與MD呈正相關(guān)（r＝0．66，P＝0．03），8提示運動后Ctni濃度升高，至少部分是由于心肌細(xì)胞膜通透性增加所致。Ctni和MD在馬拉松后2周內(nèi)均恢復(fù)到賽前水平，表明這些運動誘導(dǎo)的改變是短暫的。

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．

心肌細(xì)胞應(yīng)激后細(xì)胞膜通透性增加，提示CTn分子可從心肌細(xì)胞滲漏到循環(huán)中，這可能與CTn復(fù)合物的降解有關(guān)。已知缺血可使CTn復(fù)合體退化。例如，缺血減少了離體心臟的CT－Ni和CT－NT片段的大小。大鼠的心臟大小分別為24到15 kDa和35到25 kDa，55使它們更容易通過膜。在10名馬拉松運動員的賽后血清樣本中僅發(fā)現(xiàn)小的降解的CT NT片段（＜18 kDa）。9這些發(fā)現(xiàn)提示，在運動或缺血引起的心臟應(yīng)激時，較小的片段可能會泄漏到循環(huán)中，而較大的片段可能只有在心肌梗死后膜被破壞時才會逃逸。

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．

綜合考慮，運動誘導(dǎo)的Ctn升高可能至少部分歸因于存活心肌細(xì)胞的可逆性膜損傷（Table1）。目前尚不清楚這是導(dǎo)致運動性ctn升高的唯一機制，還是僅次于凋亡或壞死的機制。即使在相同的運動之后，個體間的CTn釋放的大小也是非常不同的。37可能有幾種機制導(dǎo)致了這種差異，運動后Ctn升高幅度低和高的個體之間的主導(dǎo)機制不同（圖3B）。此外，尚不清楚膜通透性的假定變化是完全生理性的，還是心臟易損性和隨后的心臟事件的早期標(biāo)志。

圖4．運動誘導(dǎo)cTn釋放的潛在潛在機制的示意圖概述。

可歸因于細(xì)胞損傷的心肌細(xì)胞膜通透性增加、細(xì)胞外小泡釋放和胞吐速率增加可被認(rèn)為是可逆性的心臟損傷，導(dǎo)致心肌肌鈣蛋白濃度的生理性升高。同樣，心肌細(xì)胞周轉(zhuǎn)率的增加可能會一過性地增加心肌肌鈣蛋白濃度。較高的凋亡率，尤其是壞死率，應(yīng)該歸類為心肌細(xì)胞的（微�。�損傷，這代表了對運動的一種病理反應(yīng)，這可能會對健康產(chǎn)生長期的影響。CT顯示心肌肌鈣蛋白。

Apoptosis 細(xì)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．

細(xì)胞凋亡或程序性細(xì)胞死亡是正常細(xì)胞周轉(zhuǎn)的一部分。凋亡過程可以通過氧化超負(fù)荷、缺血引起的應(yīng)激，以及細(xì)胞內(nèi)病原體檢測等其他細(xì)胞過程被激活。凋亡不應(yīng)產(chǎn)生cT n升高，因為當(dāng)?shù)蛲黾?xì)胞被其他細(xì)胞吞噬并破碎時，細(xì)胞內(nèi)的內(nèi)容不會釋放。

表1． 關(guān)于運動引起肌鈣蛋白濃度升高的基本機制的現(xiàn)有證據(jù)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可能在凋亡小體破壞或心肌細(xì)胞凋亡向繼發(fā)性死亡轉(zhuǎn)變過程中釋放。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．

很少有研究探討運動對細(xì)胞凋亡的影響。12周的運動訓(xùn)練減少了年齡誘導(dǎo)的大鼠左心室細(xì)胞凋亡，通過減少DNA片段化、末端脫氧核苷酸轉(zhuǎn)移酶dUTP缺口末端標(biāo)記陽性染色和caspase－3裂解來衡量。56隨后的研究表明，運動減少了與年齡相關(guān)的凋亡信號標(biāo)記物的增加。57一項大型研究（n＝64）58對年輕（6個月大）和中年（12個月大）的小鼠隨機分配到籠子里，放在籠子里或不放在籠子里。在年輕和中年跑步小鼠中，caspase非依賴、Fas依賴和線粒體依賴的凋亡通路均減少。58這些發(fā)現(xiàn)與人類的證據(jù)一致，即運動訓(xùn)練具有心臟保護作用，并有助于在衰老期間保護心臟功能。

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．

運動對細(xì)胞凋亡的急性影響還沒有得到很好的研究。一項針對小鼠（2個月大）的研究（n＝18）評估了在基線或跑步8、24、48和72小時后即刻的細(xì)胞凋亡，VO2峰值的60％到70％（n＝3只動物／時間點）。59運動導(dǎo)致運動后24小時心肌細(xì)胞凋亡率短暫增加150％，部分原因是兒茶酚胺能，而不是氧化應(yīng)激。這些發(fā)現(xiàn)表明，在動物中，運動顯著增加了細(xì)胞凋亡率，而長期運動訓(xùn)練則降低了細(xì)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．

運動中左心室前負(fù)荷的急劇增加可能導(dǎo)致細(xì)胞凋亡的增加。60只暴露于增加前負(fù)荷的離體大鼠心臟在沒有缺血的情況下表現(xiàn)出心肌內(nèi)的Ctni蛋白水解和Ctni釋放。61這種Ctni的降解被阻止內(nèi)源性Calain激活的抗體阻斷。鈣蛋白酶參與細(xì)胞信號和細(xì)胞周期進程。因此，Ctni的細(xì)胞鈣內(nèi)流和蛋白水解可能導(dǎo)致牽張誘導(dǎo)的心肌細(xì)胞凋亡。62這些發(fā)現(xiàn)已在活體豬模型中得到證實。注射苯腎上腺素產(chǎn)生的急性血流動力學(xué)超負(fù)荷引起一過性左心室（L V）功能障礙、牽張誘導(dǎo)的心肌細(xì)胞損傷、Ctni濃度升高和無缺血情況下的細(xì)胞凋亡。63另一項在豬身上的研究評估了左冠狀動脈前降支閉塞10分鐘后Ctni和細(xì)胞凋亡的變化。64短暫缺血導(dǎo)致Ctni釋放延遲，再灌注30分鐘后Ctni顯著升高。Ctni升高區(qū)持續(xù)了24小時。隨之而來的是細(xì)胞凋亡的短暫增加，在再灌注1小時后增加6倍，并在24小時恢復(fù)正常。64在人類，球囊閉塞冠狀動脈誘導(dǎo)缺血30、60和90秒后，無冠狀動脈疾�。–AD）患者的CT－n濃度升高，一直持續(xù)到取樣結(jié)束，在缺血4小時后。65在缺血90秒后，患者的CT－Ni和CT－NT在短暫缺血3小時后升高更大、更快，CT－Ni和CT－NT在短暫缺血后3小時均＞URL。65這些發(fā)現(xiàn)表明，在增加前負(fù)荷或短暫缺血后，可能會出現(xiàn)孤立的細(xì)胞凋亡，這些情況也可能發(fā)生在運動過程中。

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．

運動導(dǎo)致肌鈣蛋白水平升高的另一種解釋是，運動增加了心肌細(xì)胞的更新?lián)Q代。C／eBPβ是bHLH基因家族中的一員，可抑制心肌細(xì)胞的生長和增殖。42運動訓(xùn)練降低游泳訓(xùn)練小鼠心肌c／eBPβ的表達。此外，心臟C／EBPβ水平降低的小鼠對壓力超負(fù)荷引起的心力衰竭具有抵抗力。這些結(jié)果表明，運動訓(xùn)練降低了C／EBPβ，從而降低了其對心肌細(xì)胞周轉(zhuǎn)的抑制作用，提高了心臟對外界應(yīng)激的抵抗力。這一假設(shè)得到以下觀察的支持：8周的跑步使成年小鼠的新心肌細(xì)胞增加了4．6倍，沒有收縮功能障礙或細(xì)胞凋亡增加的證據(jù)。66兩項研究都表明，運動可以使新的心肌細(xì)胞數(shù)量增加4．6倍，而沒有收縮功能障礙或細(xì)胞凋亡增加的證據(jù)激活哺乳動物心臟的內(nèi)源性再生能力，這表明如果急性運動加速了這一過程，被替換的心肌細(xì)胞可能會將Ctn釋放到循環(huán)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．

運動和細(xì)胞凋亡之間的聯(lián)系似乎取決于時間框架。運動訓(xùn)練降低了凋亡率56－58，并增加了心肌細(xì)胞的生長和增殖。42，66相比之下，對未經(jīng)訓(xùn)練的動物的生理挑戰(zhàn)，如強迫跑步，59容量超負(fù)荷，61，63或缺血，64會增加細(xì)胞凋亡，并伴隨著Ctn濃度的增加（Table1）。目前還不清楚這些發(fā)現(xiàn)是否可以外推到人類身上。

Cardiomyocyte Necrosis心肌細(xì)胞壞死

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．

心肌壞死是CT升高最常見的原因，與運動無關(guān)。心肌缺血時，心肌細(xì)胞代謝從有氧途徑轉(zhuǎn)變?yōu)闊o氧途徑，從而產(chǎn)生A－TP。這種向無氧代謝的轉(zhuǎn)變最終會破壞肌膜。缺血＞15分鐘對心肌細(xì)胞造成不可逆轉(zhuǎn)的損害，1使細(xì)胞內(nèi)蛋白進入循環(huán)。有一種古老的假說67，即急性心肌梗死后，首先從早期的可釋放池中立即大量釋放Ctn，然后是由于較慢的肌原纖維降解過程引起的Ctn的較小峰值。1盡管這一假說一直存在爭議，12 Ctn釋放的確切機制仍有待解開。正如前面所討論的，運動后的Ctn釋放較小，似乎更早達到峰值，而且消退得比觀察到的急性心肌梗死更快。這些差異使得壞死不太可能導(dǎo)致運動誘導(dǎo)的CTn升高，但不排除輕微的壞死可能導(dǎo)致運動后脆弱個體的CTn濃度升高。

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）．

在活體內(nèi)不能確定急性心肌壞死。對馬尼托巴省68、倫敦69、底特律70馬拉松參賽者的心臟MRI研究發(fā)現(xiàn)，盡管運動后CTn濃度升高，但沒有心肌水腫或晚期釓增強。無心肌水腫或疤痕不利于心臟壞死，但心臟MR不夠敏感，不能發(fā)現(xiàn)少量的壞死。只有40 mg的大鼠心肌壞死使CtNT和CtNi＞URL，71但心臟MRI不能檢測到這一點�？梢酝茰y，長期的運動訓(xùn)練可能會因重復(fù)的單次運動而造成心肌損傷。這一假說得到以下觀察的支持，即終身耐力運動員比不運動的同齡人有更多的晚期釓增強（LGE），并且LGE的量隨著比賽完成次數(shù)和訓(xùn)練年限的增加而增加。72因此，盡管沒有直接證據(jù)表明運動后心肌壞死，但在某些情況下不能排除它是運動誘導(dǎo)的Ctn增加的原因（T Abable 1）。

Noncardiac Explanations 非心血管解釋

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．

已經(jīng)提出了幾種可供選擇的假說，以促進運動誘導(dǎo)的CTn濃度的升高（T表1）。首先，運動誘導(dǎo)的血液濃縮可能會影響運動后的Ctn濃度，但相對于Ctn濃度的升高，液體平衡標(biāo)記物的百分比變化（非常）很小。此外，任何血液濃度都有望在運動后補充水分后迅速恢復(fù)，這與運動后2至6小時內(nèi)CTn濃度的進行性升高相矛盾。證據(jù)還表明，血液稀釋可能發(fā)生在耐力運動后，73所以血液濃度在運動后升高的ctn濃度中的作用可能是有限的，如果不是可以忽略的話。

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，長時間的運動和脫水與腎功能受損有關(guān)，但運動引起的Ctn濃度的升高遠遠超過運動后立即觀察到的腎功能的輕微下降。74這種腎功能下降可能會降低腎臟的Ctn清除率，并導(dǎo)致Ctn濃度升高，但馬拉松后Ctn濃度升高的中位數(shù)為1000％，37而腎功能迅速恢復(fù)（＜24小時），74表明腎功能減弱對運動性Ctn升高幅度的貢獻是有限的，但Ctn濃度在馬拉松后升高的中位數(shù)為1000％，37而腎功能迅速恢復(fù)（＜24小時），74表明腎功能減弱對運動誘導(dǎo)的Ctn升高幅度的貢獻是有限的，但在馬拉松結(jié)束后，Ctn濃度升高的中位數(shù)為1000％，37而腎功能迅速恢復(fù)（＜24小時）。

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的升高被認(rèn)為是由于測定與骨骼Tn或骨骼肌損傷與Ctn釋放的交叉反應(yīng)所致。已經(jīng)報道了CT nT75的CT n測定與骨骼Tn的交叉反應(yīng)，以及CT nt的某些CT nI．76測定的交叉反應(yīng)，估計交叉反應(yīng)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，在橫紋肌溶解癥的臨床環(huán)境中，CK與CT nt或CT nt之間沒有關(guān)聯(lián)。78同樣，骨骼性肌病患者的血液CT NT濃度通常＞URL，而Ct ni很少升高。79因此，可以想見，骨骼肌損傷可能導(dǎo)致運動性CT NT升高，但很可能不會導(dǎo)致Ct ni升高。我們也不知道有數(shù)據(jù)顯示運動訓(xùn)練受試者的肌肉樣本中的Ctn增加，無論是T還是I。

CLINICAL RELEVANCE 臨床相關(guān)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．

傳統(tǒng)上，運動引起的Ctn升高被認(rèn)為是唯一良性的Ctn釋放形式，因為這些升高是溫和的，經(jīng)常發(fā)生在表面上健康的人身上，而且與心臟癥狀無關(guān)。然而，靜息狀態(tài)下的ctn濃度在大量人群和臨床研究中預(yù)測死亡率和心血管發(fā)病率，2，4甚至在正常范圍內(nèi)。3運動誘導(dǎo)的Ctn升高的預(yù)后價值很少被研究80，81，但可能在本文后面討論的一些人群中具有臨床相關(guān)性。

Postexercise cTn and Cardiac Function 運動后cTn與心功能

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

多項研究研究了運動后心功能下降與ct－n濃度之間的關(guān)系。7運動后心功能下降通常是輕微和短暫的，大多發(fā)生在馬拉松、鐵人三項和超長距離等長期耐力活動之后，7運動后的心功能下降通常是輕微的和短暫的，主要發(fā)生在馬拉松、鐵人三項和超長距離比賽之后。使用超聲心動圖的薈萃分析發(fā)現(xiàn)，運動后左心室射血分?jǐn)?shù)和舒張功能下降。7運動后ctn濃度與以E／A比值測量的舒張功能下降直接相關(guān)，但沒有發(fā)現(xiàn)ctn與左心室射血分?jǐn)?shù)的變化相關(guān)，因為只有幾項研究報道了顯著的相關(guān)性，而與標(biāo)準(zhǔn)的超聲心動圖參數(shù)無關(guān)。這可能是因為研究CTn和左心室射血分?jǐn)?shù)之間關(guān)系的研究數(shù)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）．

運動對右室功能的影響似乎大于對左心室功能的影響，可能是因為運動對右室壁應(yīng)力的相對增加大于左心室。82 項研究測量了右室功能和運動誘導(dǎo)的CTn濃度（TableS3）。8項研究中只有4項報告右室收縮功能顯著降低。在這4項研究中，只有2項研究報道了右室收縮功能與運動后Ctn濃度之間的關(guān)系，這兩項研究發(fā)現(xiàn)運動誘導(dǎo)的Ctn與RV射血分?jǐn)?shù)的降低（r＝0．49，P＝0．00283）、RV基礎(chǔ)應(yīng)變（r＝0．68）、MID（r＝0．7）和心尖應(yīng)變（r＝0．72）（均P＜0．001）有關(guān)。25僅有2項研究報告運動后RV功能的降低與運動后Ctn的關(guān)系，但這兩項研究的缺失與運動后的Ctn之間存在直接關(guān)聯(lián)，但這兩項研究均未發(fā)現(xiàn)運動誘導(dǎo)的Ctn與RV基礎(chǔ)應(yīng)變（r＝0．68）、MID應(yīng)變（r＝0．7）和心尖應(yīng)變（r＝0．72）之間的相關(guān)性。研究結(jié)果不一致的潛在解釋可能與耐力比賽的選擇、血液繪圖的時間以及包含不太敏感的收縮功能測量有關(guān)（應(yīng)變分析更有可能顯示心功能下降25，因為使用右心室應(yīng)變的兩項研究都發(fā)現(xiàn)右心室功能減退）。

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．

總而體來說，一些證據(jù)表明，運動后Ctn濃度與左心室舒張功能下降有關(guān)，并可能與左心室和右室收縮功能有關(guān)，但這只在少數(shù)研究中觀察到，而且這種聯(lián)系的強度是中等的�，F(xiàn)有證據(jù)的一個重要警告是，研究只使用單一的運動后評估來檢查CTn濃度和心功能之間的關(guān)系，通常是在運動停止后立即獲得的。由于運動后CTn動力學(xué)表現(xiàn)出一個延遲的峰值，單一的運動后Ctn可能掩蓋了Ctn與心功能之間的真實聯(lián)系。

Is Exercise－Induced cTn an Indicator of Subclinical Disease？運動性肌鈣蛋白是亞臨床疾病的指標(biāo)嗎？

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，運動誘導(dǎo)的Ctn升高是如何以及為什么發(fā)生的尚不清楚，但Ctn的升高可能反映了亞臨床心肌的脆弱性。流行病學(xué)和臨床研究表明，有心血管危險因素（CVRF）和疾�。–VD）的人的靜息Ctn濃度高于健康人11，84，84。以心力衰竭患者為例，在短強度自行車運動試驗后，心力衰竭患者的運動誘導(dǎo)CtnT濃度高于健康對照組。84在725名平均年齡為61歲的長距離步行者中，靜息Ctni濃度高于健康對照組（P＜0．001），但濃度＞URL的比例相似（P＝0．86．0 5），心力衰竭患者（n＝10 4，7例）中，靜息CtnI濃度較高（P＜0．05），但濃度＞URL的比例相似（P＝0．86），CVD患者的靜息CtnI濃度高于健康對照組（P＜0．05），但濃度＞URL的比例相似（P＝0．86）。3［0～9］ng／L，1．7％），健康對照組（n＝435，1［0～5］ng／L，1．2％）。步行30～55 km后，各組Ctni濃度均升高（P＜0．001），但Cvd組運動后Ctn濃度＞URL（16％）高于腦血管病組（10％）和對照組（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，因此幾項研究探索了運動引起的CT n升高幅度與顯著的CAD之間的關(guān)系，但結(jié)果并不一致。86－88幾項研究發(fā)現(xiàn)，在短時間（＜15分鐘）的臨床運動試驗后，冠心病患者的CTn沒有升高。89其他研究報告了在臨床運動或多巴酚丁胺負(fù)荷試驗后CT n顯著升高。最近的一項薈萃分析（包括2008年至2016年發(fā)表的研究）發(fā)現(xiàn)，在臨床運動負(fù)荷試驗后，Ctn濃度僅有輕微升高，在誘導(dǎo)性和非誘導(dǎo)性缺血患者之間運動誘導(dǎo)的Ctn濃度升高沒有差異（Ct NT：0．5［0－0．9］ng／L對1．1［0－2．2］ng／L，P＝0．29；CT－Ni：2．4［0．2－4．7］ng／L對1．8［0．6－3．0］ng／L，P＝0．61）。90藥理應(yīng)激試驗也有類似的發(fā)現(xiàn)。90總體來說，這些發(fā)現(xiàn)可能歸因于（1）運動強度或缺血閾值持續(xù)時間不足以產(chǎn)生足以區(qū)分有無嚴(yán)重冠心病或心肌缺血者的Ctn升高；（2）運動后測量Ctn濃度太早，錯過了Ctn峰值（圖3A）；（3）心肌缺血與運動性ctn升高之間缺乏相關(guān)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．

對長跑運動員和騎自行車的人的觀察在很大程度上證實了臨床研究的結(jié)果，大多數(shù)研究表明CTn濃度與CAD之間沒有關(guān)聯(lián)（表2）。例如，在27名參加帕沃－努爾米馬拉松比賽的運動員中，運動后CT＿（Nt）濃度與冠狀動脈鈣化積分之間沒有相關(guān)性（r＝－0．013，P＝0．95）。此外，冠脈鈣化積分大于或小于中位數(shù)的馬拉松運動員運動后CT＿（Nt）濃度也沒有差異（P＞0．99）。92北海耐力運動研究也發(fā)現(xiàn)91公里山地自行車比賽后3小時的CT＿n濃度之間也沒有關(guān)系。9例隱匿性梗阻性CAD患者運動后2 4h的CT ni和CT NT濃度明顯高于對照組。10梗阻性CAD患者的Ctn釋放延遲可能與梗阻性冠脈血流障礙有關(guān)，在AMI患者中也有同樣的表現(xiàn)。（2）隱性梗阻性CAD患者運動后24h的Ctn和Ctnt濃度明顯高于對照組（P＜0．01）。未來評估運動后Ctn是否是隱匿性CAD的標(biāo)記物的未來研究應(yīng)該包括多個時間點的評估。

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．

表面上健康的耐力運動員中也有心肌纖維化的報道。據(jù)我們所知，只有2項研究調(diào)查了運動后Ctn濃度與LGE存在之間的關(guān)系（表2）。有LGE的德國馬拉松運動員（n＝9）在馬拉松后即刻的Ctni濃度高于無LGE的運動員（n＝65）。92相反，有LGE的鐵人三項運動員（n＝10，49±8年）和無LGE的鐵人三項運動員（n＝20，42±10年）在運動后2．4±1．1小時的Ct－nt濃度沒有差異（40±26對65±103 ng／L）。93這兩項研究只包括19名有LGE的人，因此不可能確定。

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．

綜上所述，CVRF和CVD與較高的靜息和運動后Ctn濃度相關(guān)。大多數(shù)運動研究都沒有發(fā)現(xiàn)運動后Ctn升高與冠心病嚴(yán)重程度或心肌纖維化之間的關(guān)系，但很少有研究進行，他們使用了不同的運動強度、持續(xù)時間和采血方案。

Prognostic Value in Patients 患者的預(yù)后價值

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－h(huán)our 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．

我們知道只有2項運動負(fù)荷試驗研究評估了運動誘導(dǎo)的Ctn濃度80，81的預(yù)后價值（T表3）。兩人都沒有發(fā)現(xiàn)可預(yù)測的關(guān)系。在6個月的隨訪中，23名不穩(wěn)定型心絞痛患者和46名未復(fù)發(fā)心絞痛患者在運動后4小時的ct－nt濃度沒有差異。80另一項研究報道，在8－12和24小時ct－ni濃度大于或小于URL的冠心病患者中，復(fù)合終點（死亡、心肌梗死、急性血運重建、不穩(wěn)定心絞痛住院或心力衰竭）的發(fā)生率沒有差異（27％比17％，P＜0．05）。81缺乏運動Ctn與后續(xù)癥狀的關(guān)聯(lián)可能是由于運動持續(xù)時間短、樣本量小、采樣時間短、僅有少量臨床事件或缺乏臨床上重要的關(guān)系所致。（2）在36（15－49）個月的隨訪中，Ctn與隨后的癥狀之間沒有關(guān)聯(lián)，這可能是由于運動持續(xù)時間短、樣本量大、采樣時間短、臨床事件數(shù)量少，或者沒有臨床上重要的關(guān)系。

Prognostic Value in Exercising Individuals 運動個體的預(yù)后價值

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

與臨床上運動／CTn研究相對較少的是，有大量研究跟蹤耐力運動事件，但據(jù)我們所知，只有3個研究評估了這些CT nI升高的預(yù)后價值（TABL3）。74名男性馬拉松運動員（57±6歲）運動后CTni濃度從運動前到運動后逐漸升高，36．5％的跑步者運動后Ctni濃度＞URL。在6年的隨訪中，發(fā)生了6個CAD事件，平均分布在馬拉松后Ctni濃度大于或小于中位數(shù)的個體之間。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．

我們的小組之前跟蹤了725名長距離步行者（61．4［54．4－69．1］年），其中9％的人在步行30到55公里后10分鐘內(nèi)Ctni濃度＞URL。11在平均43（23－77）個月的隨訪中，62名參與者經(jīng)歷了復(fù)合終點死亡（n＝29，47％），心肌梗死（n＝6，10％），中風(fēng)（n＝17，27％），心力衰竭診斷（n＝4，6％），血管重建（n＝4，6％）。2％）。在運動后Ctni＞URL的個體中，27％的人經(jīng)歷了終點，而Ctni＜URL的個體中有7％的人經(jīng)歷了終點（粗風(fēng)險比5．21［95％CI，2．96－9．17］）。在調(diào)整了年齡、性別以及是否存在CVD和CVRF后，危險比為3．21（95％CI，1．79－5．77）。在調(diào)整基線CtnI后，這一數(shù)字進一步下降到2．48（95％CI，1．29－4．78）。當(dāng)將死亡率與其他終點分開時（圖5），死亡率與ctni的增加沒有顯著關(guān)聯(lián)（完全調(diào)整的風(fēng)險比，1．09［0．38－3．10］），而主要的心血管不良結(jié)局有很強的相關(guān)性（完全調(diào)整的風(fēng)險比，3．75［1．56－9．02］）。這可能是由于獨立結(jié)果的統(tǒng)計能力較低，或者是因為檢查了所有原因而不是心血管死亡率。研究隊列不是運動人群，而是來自普通人群的體力活動個體，包括患有腦血管病和腦血管病的老年人。因此，這些數(shù)據(jù)不適用于Ctn值＞URL的年輕運動員隊列，即使明顯升高。

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．

初步數(shù)據(jù)分析了參加北海91公里自行車賽的991名健康參與者（46［40－53］歲）的運動后Ctn濃度。94名參與者被跟蹤5年，其中12名（1．2％）在隨訪期間經(jīng)歷了心血管事件。Ctn＞URL在Ctni和Ct Nt中的患病率（3％）運動后24h分別為83％和92％，17％和27％。運動后3小時（對數(shù)秩檢驗，CT ni：P＝0．11，CT NT：P＝0．35）或24小時（CT ni：P＝0．45，CT NT：P＝0．06）的心血管事件與Ctn濃度＞URL無關(guān)。94低的事件發(fā)生率可能是導(dǎo)致兩者無相關(guān)性的原因之一，但值得注意的是24小時Ct NT的接近顯著的結(jié)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．

總之，這3項研究表明，運動后CTn的升高可能不是良性的，可能預(yù)示著老年人的心血管事件。目前還不清楚這些發(fā)現(xiàn)是否可以推斷到更年輕的受試者和進行劇烈運動的運動員。

表2．冠狀動脈粥樣硬化、心肌纖維化和運動誘導(dǎo)的cTn釋放之間的相關(guān)性

CAC indicates coronary artery calcification冠狀動脈鈣化； CAD， coronary artery disease冠心病； cTnI， cardiac troponin I心肌肌鈣蛋白I； CVD， cardiovascular disease心血管疾病

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

．Clinical Management and Considerations 臨床管理與思考

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

運動性CTn升高可能導(dǎo)致急診科的臨床混亂，當(dāng)個人在運動后出現(xiàn)CTn濃度升高時。

表3．評估運動性cTn釋放的預(yù)后價值的研究綜述

cTnI indicates cardiac troponin I心肌肌鈣蛋白I； CVD， cardiovascular disease心血管疾�。籋Radjusted， adjusted hazard ratio； HRmax估計的最大心率， estimated maximal heart rate； hs－cTnI， high sensitivity cardiac troponin I高敏心肌肌鈣蛋白I； hs－cTnT， high sensitivity cardiac troponin T高敏心肌肌鈣蛋白T； MACE， major adverse cardiovascular outcome主要不良心血管結(jié)果； and URL， upper reference limit參考上限

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．

已經(jīng)推薦了幾種臨床方法，并且仍然是合適的。臨床醫(yī)生應(yīng)該遵循通常的臨床規(guī)程，但要特別認(rèn)識到，運動可以使Ctn濃度遠遠高于URL，從而可以解釋運動后Ctn升高的原因。運動后出現(xiàn)任何臨床癥狀的急性冠脈綜合征患者（無論是否有Ctn升高）都應(yīng)該接受適當(dāng)?shù)脑u估，包括12導(dǎo)聯(lián)心電圖、系列Ctn測試，以及根據(jù)總體臨床情況進行某種形式的無創(chuàng)或有創(chuàng)風(fēng)險分層。然而，冠心病的評估（例如，冠狀動脈鈣化評分）并不僅僅基于運動后單獨的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．

監(jiān)督大眾體育賽事的臨床醫(yī)生不建議在明確的研究議程之外進行現(xiàn)場ct n測試，除非未來的研究支持其附加值。如果發(fā)現(xiàn)運動后Ctn升高，其臨床意義尚不清楚，盡管一些研究表明運動后Ctn升高可能預(yù)示著少數(shù)人未來的心臟事件。

圖5．基于Aengevaeren等人的數(shù)據(jù)，運動后肌鈣蛋白I的風(fēng)險比＞死亡率和MACE的正常參考上限，以及死亡率和MACE11

在43［23－77］個月的隨訪中，對725名年長的長距離步行者在步行30到55公里后10分鐘測量了t－roponin I，他們經(jīng)歷了62次事件、29次死亡和33次。MACE提示發(fā)生了嚴(yán)重的心血管不良事件。

FUTURE DIRECTIONS 未來方向

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．

許多研究都使用了運動后1個采血時間點，而這個時間點在不同的研究中往往不同，而只有少數(shù)研究研究了運動過程中CTn的釋放。未來的研究應(yīng)該對類似的結(jié)果測量使用類似的時間點。耐力運動后2～6小時可達峰值。需要更多的研究來確定特定的運動后時間點是否可以預(yù)測未來的死亡率和心血管結(jié)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．

有證據(jù)表明，生理性和可逆性以及病理性和不可逆性心肌損傷都可能參與運動性CTn反應(yīng)，這可能是由被研究人群介導(dǎo)的。機制也可能因人群不同而不同，因為運動誘導(dǎo)的ctn釋放可能更可能與健康個體的可逆性心肌損傷有關(guān)，而不可逆性心肌損傷可能更常見于潛在的CVD患者。需要細(xì)胞和動物模型、新的成像技術(shù)和新的生物標(biāo)記物分析來檢查這些可能性。例如，一項使用彌散加權(quán)MRI的研究可以評估患有CVRF的個體在運動誘導(dǎo)的Ctn濃度較大程度上的升高是否可歸因于心肌細(xì)胞完整性的較大下降。評估CTn片段的類型和大小以及凋亡生物標(biāo)志物的出現(xiàn)將有助于這一分析。未來研究健康受試者和有潛在心血管疾病的受試者的運動誘導(dǎo)的CTn釋放的工作應(yīng)檢查冠脈血流的影響，因為這些人群之間的不同反應(yīng)可能由冠狀動脈閉塞或血管反應(yīng)性的程度以及運動對Ctn的清除的必然影響來解釋。

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．

需要在臨床和休閑運動人群中進行大規(guī)模前瞻性研究，并進行長期隨訪，以確定運動誘發(fā)的CT是否可以預(yù)測未來的心血管事件。隨后的研究可以確定通過運動訓(xùn)練或藥物治療（例如：他汀類藥物或阿司匹林）改變CTn反應(yīng)是否能改變心血管結(jié)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．

不同類型、持續(xù)時間和強度的運動通常會增加Ctn，耐力運動后Ctn有一過性增加，峰值一般在運動后2～6h。其潛在的機制尚不清楚，但有證據(jù)支持這樣的假設(shè)，即可逆性心臟損傷引起的肌膜通透性允許早期可釋放池中的Ctn片段從心肌細(xì)胞中滲出。也有證據(jù)表明，心肌應(yīng)激或短暫缺血增加了心肌細(xì)胞凋亡或加速了心肌細(xì)胞的周轉(zhuǎn)。很少有研究調(diào)查運動誘導(dǎo)的Ctn對心血管事件的預(yù)測價值，但運動后Ctn濃度＞URL的老年長距離步行者發(fā)生更多的心血管事件。這些發(fā)現(xiàn)需要得到證實，CT＿n在年輕運動受試者中的預(yù)后意義需要確定。

       原文標(biāo)題 : 【文獻閱讀】運動誘導(dǎo)的心臟T肌鈣蛋白升高:從基礎(chǔ)機制到臨床相關(guān)性