脂肪酸结合蛋白在急性心肌梗死诊断中的应用

急性心肌梗死诊断的生物化学指标中现阶段主要采用肌钙蛋白检测,心肌中存在肌钙蛋白T(Tn T)和肌钙蛋白I(Tn I),当AMI心肌出现损伤后血清中肌钙蛋白的水平开始逐渐升高,肌钙蛋白在血液中能够检测出一般在心肌损伤后的3~6h后,肌钙蛋白诊断窗口为3h-14d,如何能更早的预测AMI的发生,缩短治疗时间。根据临床观察及统计分析结果显示H-FABP检测在胸痛后3h内对心肌梗死诊断的敏感性、特异性均高于c Tn T。因此同肌钙蛋白相比,心型脂肪酸结合蛋白对于急性心肌梗死患者的早期诊断特别是胸痛时间在3h内较肌钙蛋白具有更高的特异性和敏感性,同时各项对于H-FABP的研究也提示其有较好的敏感性、特异性。     

肌钙蛋白升高对非急性冠脉综合征的诊断价值

急性冠脉综合征(ACS)包括从不稳定型心绞痛到急性心肌梗死的一系列临床状态。心肌酶标志物，尤其肌钙蛋白是其诊断、评估风险及预后、指导抗栓、制定再血管化策略的重要指标。肌钙蛋白作为心肌兴奋收缩偶联中起重要作用的调节蛋白，其存在于血清中提示心肌损害或心肌细胞膜完整性被破坏。因而肌钙蛋白的升高仅仅提示心肌损伤的存在，并不能说明心肌损伤的机制。除心肌梗死外，有一系列临床情况可以导致肌钙蛋白的升高。因此，清楚地认识一系列导致肌钙蛋白升高的病理情况对于胸痛的鉴别诊断具有重要意义。本文将对于ACS以外的导致肌钙蛋白升高的疾患加以综述。     

心肌肌钙蛋白Ⅰ与临床

心肌肌钙蛋白Ⅰ(cTnI)为心肌肌钙蛋白的三个亚单位之一,仅存在于心肌收缩蛋白的细肌丝上。近年研究结果表明:cTnI是心脏特异性抗原,其释放入血液循环是心肌细胞损伤的高敏感、高特异性指标,对心肌损伤性疾病的临床诊断及病情、疗效、预后判断等具有十分重要意义。现就cTnI综述如下。     

心型脂肪酸结合蛋白在老年急性重度一氧化碳中毒心肌损伤患者诊断中的应用效果

目的通过观察比较老年急性一氧化碳中毒(AOCP)心肌损伤患者血清中心型脂肪酸结合蛋白(H-FABP)与传统的心肌受损标志物肌红蛋白(Myo)、心肌肌钙蛋白(c Tn I)及肌酸激酶同工酶(CK-MB)的含量变化及敏感性和特异性高低,探讨H-FABP在老年AOCP心肌损伤患者诊断中的应用效果。方法 86例老年AOCP患者为观察组,另选80名健康体检人员作为对照组,采集每位患者的静脉血,取血清进行H-FABP、Myo、CK-MB及c Tn I的检测,随后对两组H-FABP、Myo、CK-MB及c Tn I四项指标情况、敏感性和特异性进行比较分析。结果老年AOCP患者血清中HFABP、Myo、CK-MB以及c Tn I四项指标的水平在不同时间段(3 h,3~8 h,8且≤12 h及12 h以上)均明显高于对照组(P0.01)。另外,老年AOCP患者在中毒后的早期(3 h和3~8 h),H-FABP和Myo对AOCP患者心肌损伤的敏感度均高于CK-MB和c Tn I(P0.05),H-FABP对老年AOCP患者心肌损伤的敏感度略高于Myo(P0.05)。H-FABP和c Tn I对AOCP患者心肌损伤的特异性均高于CK-MB和Myo(P0.05)。结论 HFABP作为一种新型心肌损伤生化指标,在心肌损伤的早期诊断中具有重要价值,有利于指导临床治疗。     

心肌肌钙蛋白Ⅰ与心脏疾病

心肌肌钙蛋白Ⅰ是心肌特有的一种收缩调节蛋白。当缺血性心脏病发病时，血浆肌钙蛋白Ⅰ的水平明显升高，因其具有高度的心肌特异性，因此，它可作为心肌损伤的一种特异性指标，对心脏病的诊断、治疗和预后有十分重要的意义。     

心肌损伤标志物与心力衰竭

心力衰竭时心肌受损,患者血清中的一些非酶类标志物如肌钙蛋白I、肌钙蛋白T、心肌肌凝蛋白轻链1、心肌型脂肪酸结合蛋白含量在没有心肌缺血的情况下会升高,有利于估测心衰患者病情,指导治疗,判断预后。     

心肌肌钙蛋白的临床应用

肌钙蛋白（Troponin，Tn）是横纹肌收缩的重要调节蛋白，由三个亚基组成：肌钙蛋白C（TnC），肌钙蛋白T（TnT）和肌钙蛋白I（TnT）。对心肌损伤的诊断，在诸多诊断急性心肌梗塞（AMI）的临床生化指标中，CK—MB曾一度被认为是诊断AMI的“金标准”，已广泛应用多年。随着心肌肌钙蛋白（cTn）深入研究，无论是对心肌的特异性还是诊断敏感性，CK—MB的地位都受到了严重挑战。患有各种冠状动脉疾患的病人必然会发生心肌细胞损伤，有些病人的临床表现可能不完全符合WHO关于AMI诊断标准（不稳定心绞痛就是其中之一），但却伴有某些心…     

心肌肌钙蛋白T与心血管病

肌钙蛋白Ｔ是肌钙蛋白调节复合物的原肌凝蛋白－结合蛋白，位于收缩单位的细肌丝上，在肌肉收缩和舒张过程中起着重要作用。心肌肌钙蛋白Ｔ是心脏特异性抗原，其释放入血循环是心肌细胞损伤的敏感和高度特异的标志，对某些心血管病的诊断、预后及疗效判断等具有重要意义。     

心肌肌钙蛋白Ⅰ与心脏疾病

心肌肌蛋白Ｉ是心肌特有的一定收缩调节蛋白。当缺血性心脏病发病时，血浆肌钙蛋白Ｉ的水平明显升高，因其具有高度的心肌特异性，因此，它可作为心肌损伤的一种特异性指标，对心脏病的诊断，治疗和预后有十分重要的意义。     

心肌肌钙蛋白T对慢性充血性心力衰竭心肌损伤的诊断价值

目的　探讨心肌肌钙蛋白 T( cardiac Troponin T,c Tn T)对慢性充血性心力衰竭心肌损伤的诊断价值。方法　应用 ELISA方法对 42例心力衰竭患者 c Tn T进行测定。结果　心力衰竭组血 c Tn T测定值和异常检出率均明显高于对照组 ( P<0 .0 1) ;心功能 级组 c Tn T测定值及异常检出率显著高于心功能 级组 ( P<0 .0 5 ) ;冠心病组心力衰竭患者 c Tn T测定值与非冠心病患者无显著性差异 ( P>0 .0 5 )。结论　血清 c Tn T是判断心力衰竭患者心肌损伤的一个高度敏感和特异指标     

Single amino acid substitutions define isoform-specific effects of troponin I on myofilament Ca2+ and pH sensitivity

Troponin I isoforms play a key role in determining myofilament Ca2+ sensitivity in cardiac muscle. The goal here was to identify domain clusters and residues that confer troponin I isoform-specific myofilament Ca2+ and pH sensitivities of contraction. Key domains/residues that contribute to troponin I isoform-specific Ca2+ and pH sensitivity were studied using gene transfer of a slow skeletal troponin I (ssTnI) template, with targeted cardiac troponin I (cTnI) residue substitutions. Substitutions in ssTnI with cognate cTnI residues R125Q, H132A, and V134E, studied both independently and together (ssTnIQAE), resulted in efficient stoichiometric replacement of endogenous myofilament cTnI in adult cardiac myocytes. In permeabilized myocytes, the pCa50 of tension ([Ca2+] required for half maximal force), and the acidosis-induced rightward shift of pCa50 were converted to the cTnI phenotype in myocytes expressing ssTnIQAE or ssTnIH132A, and there was no functionally additive effect of ssTnIQAE versus ssTnIH132A. Interestingly, only the acidosis-induced shift in Ca2+ sensitivity was comparable to cTnI in myocytes expressing ssTnIV134E, while ssTnIR125Q fully retained the ssTnI phenotype. An additional ssTnIN141H substitution, which lies within the same structural region of TnI as V134, produced a shift in myofilament Ca2+ sensitivity comparable to cTnI at physiological pH, while the acidic pH response was similar to the effect of wild-type ssTnI. Analysis of sarcomere shortening in intact adult cardiac myocytes was consistent with the force measurements. Targeted substitutions in the carboxyl portion of TnI produced residue-specific influences on myofilament Ca2+ and pH sensitivity of force and give new molecular insights into the TnI isoform dependence of myofilament function.     

Cardiac troponin I as prognostic marker in heart failure patients discharged from emergency department

Despite evidence that cardiac troponin I (cTnI) identifies patients with advanced heart failure (HF) at risk of death, data on heterogeneous HF populations are scarce. Our purpose was to verify and analyze the prognostic role of cTnI in acute HF patients admitted to the emergency department. This was an observational longitudinal prospective study carried out in an urban hospital. We studied 99 patients discharged from the department between March and December 2002 with a HF diagnosis and samples of cTnI. Patients with acute coronary syndromes, myocarditis or renal failure were excluded. The main outcome was death from any cause. The detection level of the cTnI assay was 0.05 ng/ml. cTnI was detected in 45.5% of HF patients. These patients had a higher NYHA class (P < 0.001) at initial presentation and longer hospitalization (P = 0.004) than cTnI-negative patients. Nineteen deaths occurred during the study: 17 for HF and 2 for acute coronary syndrome. Finally, detectable cTnI was associated with increased mortality risk (RR 4.7; 95% CI 1.3–17.1; P = 0.021) also after adjustment for other adverse prognosis factors (age, NYHA class and presence of relapses). Our HF cTnI-positive patients had a worse clinical presentation and longer hospitalization. cTnI is a significant independent predictor of death and of longer hospitalization. It could be used for the early identification of HF patients at an increased risk of death in the long term, and of longer hospitalization. Thus, cTnI can aid decision-making and clinical management in the emergency department. A short abstract of the paper was presented at the A.C.E.P. Scientific Assembly-Research Forum in Boston U.S.A. October 2003.     

Serial analysis of troponin I levels in patients with ischemic and nonischemic dilated cardiomyopathy

BACKGROUND: Ongoing myocardial cell damage forms the basis for progression of chronic heart failure. Evidence is accumulating that progressive loss of cardiac myocytes is associated with the release of cardiac troponin I (cTnI). HYPOTHESIS: This study sought to determine whether levels of cTnI are of prognostic value for risk stratification of patients with chronic heart failure. METHODS: Release of cTnI was measured by conventional enzyme immunoassay following serum ultrafiltration in 58 consecutive patients hospitalized for chronic heart failure and 31 healthy volunteers serving as control group. Determination of serum levels was performed every 2 weeks over a time interval of 3 months. According to the results of coronary angiography, patients were divided into Group D showing normal coronary arteries (n=33, ejection fraction 27 +/- 6.1%) and Group I showing severe coronary heart disease (n=25, ejection fraction 28.8 +/- 7.8%). Survival of patients was evaluated after a mean time interval of 3 years. RESULTS: The mean cTnI serum level over all measurements was 0.66 +/- 1.8 ng/ml in patients versus 0.11 +/- 0.48 ng/ml in volunteers. At all six points of analysis, the mean cTnI serum level was significantly different (p < 0.001) between patients and volunteers. There was no significant difference between patients with and without coronary heart disease following hospital discharge, however, troponin release was significantly different between survivors and nonsurvivors (n=27) (0.56 ng/ml vs. 0.84 ng/ml; p < 0.05). CONCLUSION: Permanent cTnI release is a common finding in patients with chronic heart failure and a strong prognosticator. In this setting, coronary morphology seems to play a minor role for disease progression.     

Do cardiac troponins provide prognostic insight in hemodialysis patients?

BACKGROUND: The diagnosis of myocardial necrosis in patients with chronic renal failure is often difficult because biochemical markers of cardiac damage such as creatine kinase MB (CKMB) and cardiac troponin T (cTnT) may be spuriously elevated. Recent small studies also report unexplained elevations in cardiac troponin I (cTnI) in chronic renal failure patients undergoing hemodialysis. The relative incidence of elevated cardiac troponins in this population and their relationship to clinical events remain unknown. OBJECTIVE: To determine the incidence and prognostic significance of asymptomatic elevations of cTnT and cTnI in patients undergoing hemodialysis for chronic renal failure. DESIGN: Prospective cohort study. SETTING: University tertiary care teaching hospital. PATIENTS: One hundred thirteen patients over 21 years of age undergoing onsite hemodialysis were enrolled between December 1997 and February 1998. MEASUREMENTS: All-cause and cardiovascular mortality, hospitalization for acute myocardial infarction, unstable angina or congestive heart failure, new onset sustained arrhythmia or need for unscheduled emergency hemodialysis due to volume overload at 30 days and six months. RESULTS: The incidence of abnormal results for cTnT, cTnI and CKMB were 42%, 15% and 4%, respectively. Independent predictors of mortality at six months were median age greater than 63 years (odds ratio 14.3, 95% CI 1.5 to 130.3, P=0.019) and positive cTnT (odds ratio 13.6, 95% CI 2.5 to 73.2, P=0.002). Diabetics were more likely to have positive cTnI and cTnT results than nondiabetics (P<0.001 and P=0.023, respectively). CONCLUSIONS: cTnT is commonly elevated in patients with chronic renal failure even in the absence of acute coronary syndromes. cTnT may be an important independent prognostic marker in patients on hemodialysis for chronic renal failure. While less common, elevations of cTnI are more frequent than CKMB elevations. The basis of these cardiac troponin elevations is unclear. These findings may represent, in part, a subclinical myocardial injury, an inflammatory response to chronic renal failure or a chronically volume overloaded state.     

Prognostic use of cardiac troponin T and troponin I in patients with heart failure

BACKGROUND: Troponin T (cTnT) and troponin I (cTnI) are present in the sera of some heart failure (HF) patients and have potential importance as prognostic markers. OBJECTIVE: To prospectively evaluate the prognostic value of cTnT and cTnI in well-characterized HF patients and clarify their relationship to other clinical markers of HF severity. METHODS: cTnT and cTnI were measured in 78 HF patients (45 inpatients, 33 outpatients) who were followed up prospectively for 12 months. RESULTS: Plasma cTnT (> or =0.02 ng/mL) and cTnI (> or =0.3 ng/mL) were detected in 51% and 46% of patients, respectively. These patients were more likely to be inpatients (70% versus 45% for cTnT, 75% versus 43% for cTnI, P<0.05 for both), have a higher plasma creatinine (153 versus 119 micromol/L for cTnT; 157 versus 118 micromol/L for cTnI, P<0.05) and lower plasma sodium (134 versus 138 mmol/L for both, P<0.05). At 12 months, they were more likely to have died or undergone cardiac transplantation (41% versus 14%, P=0.01 for cTnT; 43% versus 15%, P=0.004 for cTnI). After adjustment for New York Heart Association class, plasma sodium and inpatient status, a significant association with events was still evident for both troponins. CONCLUSIONS: Both cTnT and cTnI are strongly associated with other clinical indicators of HF severity and remain independent predictors of prognosis after adjustment for these factors. These results indicate a potential role for cTnT and cTnI in the clinical management of HF patients.     

Evidence of cardiac myolysis in severe nonischemic heart failure and the potential role of increased wall strain

BACKGROUND: Myocyte death could play a role in heart failure (HF) irrespective of the presence of coronary artery disease. The study aimed to assess this hypothesis by use of the cardiac troponin I (cTnI) assay. METHODS AND RESULTS: Seventy-one patients with nonischemic HF, New York Heart Association (NYHA) class II-IV, with a normal coronary angiogram and after exclusion of myocardiopathies were evaluated in the study. The control group included 9 healthy subjects and 15 patients hospitalized for severe noncardiac dyspnea. Cardiac TnI concentrations were determined at admission with a research reagent (cTnIus) characterized by a detection limit of 0.026 ng/mL and a high analytic sensitivity of 0.002 ng/mL. cTnIus levels were more than 0.026 ng/mL in 19 HF patients, ranging between 0.027 and 0.463 ng/mL, whereas no cTnIus level was detectable in the control group. With use of a reference assay, only 2 HF patients had abnormal cTnI values. Severe HF was observed in 17 of these 19 patients, assessed by NYHA class IV or by the presence of pulmonary edema. Patients with an increased cTnIus level had a more restrictive mitral Doppler pattern (P <.001) and a more distinctive left ventricular (LV) concentric remodeling (P <.0001), whereas LV ejection fraction was similar in both HF groups. The increased cTnIus level was also associated with a LV wall strain biologic marker (ie, an increased brain natriuretic peptide plasma level) (P <.001). CONCLUSIONS: cTnI assay is a promising biochemical method for detecting cardiac myolysis in HF, independent of the presence of coronary artery disease. This subtle myolysis could be in part related to the severely increased LV wall strain.     

Leakage of cardiac troponin I in aortic valve stenosis

OBJECTIVE: Degeneration and death of cardiomyocytes contribute to the genesis of heart failure (HF) in aortic valve stenosis (AS). We studied whether the ongoing myocyte damage in AS can be detected from circulating cardiac troponin I (cTnI) concentrations. DESIGN AND SETTING: A cross-sectional cohort study in a university hospital. SUBJECTS AND METHODS: We examined 131 adult patients undergoing echocardiography and cardiac catheterization for isolated AS. Blood was sampled from the aortic root and, in a subset of 49 patients, also from the coronary sinus for the determination of cTnI using a sensitive immunoanalysis. RESULTS: Seventy-three patients (56%) had detectable aortic cTnI (> or =5 ng L(-1)) with 30 of them (23% of the total group) having cTnI above the reference limit in healthy subjects (>14 ng L(-1)). Patients with detectable cTnI had a higher prevalence of HF than those with undetectable cTnI (42% vs. 19%, P = 0.004). Plasma cTnI rose from the aorta to the coronary sinus by > or =5 ng L(-1) in 13 of 49 patients with AS (27%) versus in none of 12 control patients free of structural heart disease (P = 0.044). AS patients with transcardiac cTnI gradients > or =5 ng L(-1) had lower left ventricular (LV) ejection fractions than AS patients with gradients <5 ng L(-1) (mean +/- SD, 52 +/- 14% vs. 61 +/- 11%; P = 0.011). CONCLUSIONS: Detectable circulating cTnI is not uncommon in AS and shows a moderate association with the presence of HF. Leakage of cTnI into the coronary sinus associates with impairment of LV systolic function. Monitoring cTnI could provide a means to expose incipient clinical deterioration in AS.     

Slow skeletal troponin I gene transfer, expression, and myofilament incorporation enhances adult cardiac myocyte contractile function

The functional significance of the developmental transition from slow skeletal troponin I (ssTnI) to cardiac TnI (cTnI) isoform expression in cardiac myocytes remains unclear. We show here the effects of adenovirus-mediated ssTnI gene transfer on myofilament structure and function in adult cardiac myocytes in primary culture. Gene transfer resulted in the rapid, uniform, and nearly complete replacement of endogenous cTnI with the ssTnI isoform with no detected changes in sarcomeric ultrastructure, or in the isoforms and stoichiometry of other myofilament proteins compared with control myocytes over 7 days in primary culture. In functional studies on permeabilized single cardiac myocytes, the threshold for Ca²⁺-activated contraction was significantly lowered in adult cardiac myocytes expressing ssTnI relative to control values. The tension–Ca²⁺ relationship was unchanged from controls in primary cultures of cardiac myocytes treated with adenovirus containing the adult cardiac troponin T (TnT) or cTnI cDNAs. These results indicate that changes in Ca²⁺ activation of tension in ssTnI-expressing cardiac myocytes were isoform-specific, and not due to nonspecific functional changes resulting from overexpression of a myofilament protein. Further, Ca²⁺-activated tension development was enhanced in cardiac myocytes expressing ssTnI compared with control values under conditions mimicking the acidosis found during myocardial ischemia. These results show that ssTnI enhances contractile sensitivity to Ca²⁺ activation under physiological and acidic pH conditions in adult rat cardiac myocytes, and demonstrate the utility of adenovirus vectors for rapid and efficient genetic modification of the cardiac myofilament for structure/function studies in cardiac myocytes.     

Cardiac transgenic and gene transfer strategies converge to support an important role for troponin I in regulating relaxation in cardiac myocytes

Elucidating the relative roles of cardiac troponin I (cTnI) and phospholamban (PLN) in beta-adrenergic-mediated hastening of cardiac relaxation has been challenging and controversial. To test the hypothesis that beta-adrenergic phosphorylation of cTnI has a prominent role in accelerating cardiac myocyte relaxation performance we used transgenic (Tg) mice bearing near complete replacement of native cTnI with a beta-adrenergic phospho-mimetic of cTnI whereby tandem serine codons 23/24 were converted to aspartic acids (cTnI S23/24D). Adult cardiac myocytes were isolated and contractility determined at physiological temperature under unloaded and loaded conditions using micro-carbon fibers. At baseline, cTnI S23/24D myocytes had significantly faster relaxation times relative to controls, and isoproterenol stimulation (Iso) had only a small effect to further speed relaxation in cTnI S23/24D myocytes (delta Iso: 7.2 ms) relative to the maximum Iso effect (31.2 ms) in control. The Ca(2+) transient decay rate was similarly accelerated by Iso in Tg and nontransgenic (Ntg) myocytes. Gene transfer of cTnI S23/24D to myocytes in primary culture showed comparable findings. Gene transfer of cTnI with both serines 23/24 converted to alanines (cTnI S23/24A), or gene transfer of slow skeletal TnI, both of which lack PKA phosphorylation sites, significantly blunted Iso-mediated enhanced relaxation compared with controls. Gene transfer of wild-type cTnI had no effect on relaxation. These findings support a key role of cTnI in myocyte relaxation and highlight a direct contribution of the myofilaments in modulating the dynamics of myocardial performance.     

Chimera analysis of troponin I domains that influence Ca(2+)-activated myofilament tension in adult cardiac myocytes

The goal of this study was to investigate isoform-specific functional domains of the inhibitory troponin subunit, troponin I (TnI), as it functions within the intact myofilaments of adult cardiac myocytes. Adenovirus-mediated gene transfer was used to deliver and express a TnI chimera composed of the amino terminus of cardiac TnI (cTnI) and the carboxy terminus of slow skeletal TnI (ssTnI) in adult rat cardiac myocytes. The TnI chimera, designated N-card/slow-C TnI, was expressed and incorporated into myofilaments after gene transfer, without detectable changes in contractile protein stoichiometry or sarcomere architecture. Interestingly, force at submaximal Ca(2+) levels was markedly elevated in single permeabilized myocytes expressing the N-card/slow-C TnI chimera relative to force generated in adult myocytes expressing ssTnI or cTnI. Based on these results, a hierarchy of myofilament Ca(2+) sensitivity is emerging by use of TnI chimera analysis, with the order of sensitivity being N-card/slow-C TnI>ssTnI>cTnI. These results also strongly suggest that independent isoform-specific domains in both the amino and carboxy portions of TnI influence myofilament Ca(2+) sensitivity. In additional studies carried out under pathophysiological ionic conditions (pH 6.2), the dramatic acidosis-induced decrease in myofilament Ca(2+) sensitivity observed in myocytes expressing cTnI was blunted in myocytes expressing N-card/slow-C TnI in a manner similar to that in ssTnI-expressing myocytes. These results demonstrate that there is a pH-sensitive domain residing in the carboxy-terminal portion of TnI. The dissection of isoform-specific functional domains under physiological and acidic pH conditions demonstrates the utility of TnI chimeras for analysis of TnI function and provides important insights into the overall function of TnI within the intact myofilament of adult cardiac myocytes.