Time-dependent changes in the plasma concentration of matrix metalloproteinase 9 after acute myocardial infarction

Matrix metalloproteinase (MMP)-2 and MMP-9 are believed to play a pathophysiologic role in acute myocardial infarction (MI). The time course of their plasma concentrations in correlation with the extent of myocardial damage is unclear. In a prospective study, 20 patients with proven acute MI underwent successful reperfusion within 6 h after the onset of symptoms. The patients were divided into two groups according to the size of their MI, i.e. large or moderate MI. Plasma concentrations of MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 were determined on admission, and after 24 h, 48 h, 1 week, 4 weeks, 3 months and 6 months. MMP-2 levels remained unchanged over time in both groups. The plasma concentration of MMP-9 was elevated on admission in patients with large MI versus moderate MI (195 +/- 190 versus 78 +/- 63 ng/ml, p < 0.01) as determined by left ventriculography, and returned to baseline (18 +/- 16 ng/ml) by 1 week after MI. TIMP-1 levels rose slowly in patients with large MI and returned to baseline at 6 months. The ratio of MMP-9 to TIMP-1 was significantly increased on admission in both groups and returned to baseline at 48 h. These data suggest that MMP-9 might play a pathophysiologic role during the early phase of acute MI.     

心肌营养素-1在心肌梗死后大鼠重塑心肌中的表达及意义

目的:研究急性心肌梗死(AMI)后左室非梗死区(LVNIZ)心肌营养素 1(CT 1)表达的动态变化与左室重塑(LVRM)的关系以及氯沙坦对 CT 1 表达的影响。方法:56 只雄性 Wistar大鼠 AMI术后 24h随机分为:AMI组及氯沙坦组,AMI组又依照术后1、3、7、14、21、28 d 6 个不同时间点分为 6 组。氯沙坦组于术后第 2天起灌胃给药 20 mg·kg-1 ·d-1,连续 4 周,另设假手术组及正常组为对照,各 8 只。采用放射免疫法测定LVNIZ血管紧张素Ⅱ(AngⅡ)含量,氯氨T法测LVNIZ胶原含量(HC),用RT PCR法检测LVNIZ CT 1mRNA表达。结果:①与正常及假手术组相比,AMI组 LVNIZ AngⅡ、HC明显升高 (P<0.05~0.01),与 LVRM相关性好(P<0.01);②LVNIZ- CT 1mRNA表达于AMI 1d即开始升高,且进行性增加,14 d达高峰,以后有所下降,28 d时仍明显高于假手术组(P<0.05~0.01);③相关分析显示 CT -1mRNA表达水平与心肌 AngⅡ、HC、LVRM 正相关(P<0.05~0.01);④与AMI 28 d组相比,氯沙坦组 LVRM明显减轻,LVNIZ AngⅡ、HC 明显下降,CT 1mRNA表达下调(P<0.05)。结论:大鼠AMI后 LVNIZ CT- 1 基因的过度表达与 LVRM发生密切相关,氯沙坦改善LVRM的机制还可能是通过影响CT 1转录实现,值得进一步研究。     

甲状腺素在判定心肌梗死预后中的意义

目的:探讨心肌梗死后甲状腺素水平与心肌梗死预后的关系。方法:测定501例心肌梗死患者甲状腺素水平,并根据游离T3(FT3)水平分为低FT3组和正常FT3组,在心肌梗死1年后随访其死亡率及主要心血管事件发生率;随机选取部分患者1年后进行甲状腺素水平随访。结果:所有患者中171例FT3水平低于正常,所占比例为34.1%。随访期间,33例患者死亡,死亡率为6.6%,Kaplan-Meyer曲线示正常FT3组1年生存率明显高于低FT3组(97.3%∶86.0%,P<0.001);正常FT3组无心血管事件发生率明显高于低FT3组(54.5%∶33.3%,P<0.001)。对部分患者甲状腺素水平随访发现,1年后低FT3组FT3水平较心肌梗死入院时更低[(2.74±0.63)pmol/L∶(3.08±0.32)pmol/L,P<0.05],而在正常FT3组FT3水平无明显改变[(4.18±0.57)pmol/L∶(4.26±0.55)pmol/L,P>0.05]。结论:心肌梗死后低FT3是心肌梗死不良预后的预测指标,同时低FT3状态可能在心肌梗死后持续存在。     

Role of oxidative stress in cardiac remodelling after myocardial infarction

Recovery from myocardial infarction is associated with a series of alterations in heart structure and function, collectively known as cardiac remodelling, which play a major role in the subsequent development of heart failure. Early remodelling involves infarct scar formation in the ischaemic zone whereas subsequent ventricular remodelling affects mainly the viable non-infarcted myocardium with especially profound alterations in the extracellular matrix. There is growing evidence for a role of oxidative stress and redox signalling in the processes underlying cardiac remodelling. Reactive oxygen species are a group of highly reactive molecules which have the potential to modulate several biological processes as well as cause tissue damage and dysfunction. Their effects can be beneficial or deleterious, depending on the concentrations produced, the site of production, and the overall redox status of the cell. Reactive oxygen species can be generated by all cardiovascular cell types. Under pathophysiological conditions, major enzymatic sources appear to be mitochondria, xanthine oxidase and the non-phagocytic NADPH oxidases. In this review, we outline the mechanisms underlying the progression of early and late cardiac remodelling with particular focus on the role of oxidative stress and the potential sources of reactive oxygen species which may be involved.     

Time-dependent predictors of primary cardiac arrest in patients with acute myocardial infarction

To understand predictors of cardiac arrest early in acute myocardial infarction (AMI), for the Thrombolytic Predictive Instrument, we developed a multivariable regression model predicting primary cardiac arrest using time-dependent variables based on a case-control study of emergency department (ED) patients with AMI: 65 cases with sudden cardiac arrest and 258 without cardiac arrest. Within the first hour of AMI symptom onset, adjusting for age, systolic blood pressure, serum potassium, and infarct size, increased risk of cardiac arrest was associated with electrocardiographic prolonged QTc interval and a greater sum of ST-segment elevation. After 1 hour, the effect of ST-segment elevation was much reduced and the effect of the QTc interval was reversed, so prolonged QTc appeared protective. Accordingly, for patients presenting 30 minutes after chest pain onset, compared with a QTc of 0.44, the risk for cardiac arrest for patients with QTc of 0.50 was more than doubled (odds ratio [OR] 2.20, 95% confidence intervals [CI] 1.17 to 4.13), whereas for those presenting after an hour, it was much lower (e.g., at 1.5 hours, OR 0.21, 95% CI 0.06 to 0.73). Patients presenting 30 minutes after chest pain onset with a sum of ST elevation of 20 mm had a threefold higher risk than patients with a sum of ST elevation of 5 mm (OR 3.37, 95% CI 1.83 to 6.20). However, if presenting 1.5 hours after chest pain onset, the risk was barely elevated (OR 1.18; 95% CI 1.09 to 1.29). Thrombolytic therapy was protective, halving the odds of cardiac arrest (OR 0.51, 95% CI 0.27 to 0.93). Thus, the relation of prolonged QTc interval and substantial ST segment elevation to cardiac arrest in AMI may be obscured because patients with these risks are more likely to die soon after AMI onset, before ED presentation, and are thereby unavailable for study. Those with prolonged QTc or substantial ST elevation who survive the initial 1.5-hour period are those less susceptible to these risks.     

甲状腺激素水平对急性心肌梗死后心力衰竭发生的预测价值

目的:探讨血清甲状腺激素水平对急性心肌梗死后心力衰竭发生的预测价值及临床意义。方法:入组2016年1月至2016年12月军事医学科学院附属医院收治的急性心肌梗死患者。完善血清甲状腺激素、血利钠肽水平及心脏超声等检验检查,1周后评估患者心功能,分析血清甲状腺激素与血利钠肽水平的相关性,评估血清甲状腺素水平预测心肌梗死后心力衰竭发生预测的敏感性与特异性。结果:共入组134例心肌梗死患者,其中44(32.8%)例患者出现符合诊断标准的心力衰竭。血清FT3、血清TT3与血利钠肽水平呈负相关(r=-0.567、-0.484)。血清FT4、血清TT4、血清TSH水平与血利钠肽无相关性。血清TT3水平对于预测其后心力衰竭发生的AUC 0.757(95%CI:0.676~0.838,P0.01),血清游离三碘甲腺原氨酸(FT3)的AUC为0.810(95%CI:0.733~0.887,P0.01)。结论:血清TT3、FT3对心肌梗死后心力衰竭的发生有预测价值,其临床价值有待更大规模的研究证实。     

N-乙酰半胱氨酸对心肌梗死心室重构的影响

目的:观察N-乙酰半胱氨酸(NAC)对急性心肌梗死(AMI)左室重构的影响.方法:比较常规治疗组(对照组)和常规治疗基础上加用NAC组(实验组)的超声指标、氨基末端脑钠肽(NT-proBNP)和严重心脏不良事件(MACE).结果:实验组术后3个月左室舒张末容积、左室收缩末容积、心室重构发生率、NT-proBNP、MACE发生率显著低于术前和对照组(P<0.05),左室球形指数和左室射血分数显著高于术前和对照组(P<0.05).结论:NAC可能通过降低NT-proBNP水平而显著改善AMI心室重构.     

The persistence of hibernating myocardium after acute myocardial infarction

Objective To establish the persistence of hibernating myocardium initiallydetected after myocardial infarction treated with thrombolysis. Methods and results Fourteen patients underwent gated positron emission tomographywith 18-fluoro-deoxyglucose and N13-ammonia at a median of 8days after first myocardial infarction. Repeat scans were performedat a median of 13 weeks post-infarction. A total of 148 (30·9%)myocardial segments showed reduced N13-ammonia uptake at thetime of the first scan compared with 154·5 (32·2%)segments at the time of repeat imaging. The median change inthe number of segments with reduced perfusion was –1·0.Initially 13 subjects had hibernating myocardium, seven patientshad large areas and six had smaller regions. Six (46·2%)subjects had repeat scans showing unchanged areas of hibernatingtissue and seven had second scans demonstrating changes in thesize of the region of hibernating myocardium. One patient hadno hibernating myocardium on either scan. Conclusions Positron emission tomography performed several months aftermyocardial infarction demonstrates significant changes in myocardialperfusion. However, a reduction in the number of segments withreduced perfusion does not always result in an improvement inmyocardial metabolism and contraction. Whilst most regions ofhibernating myocardium were still present several months afterinfarction, in only approximately half was the size of the mismatchedregion unchanged. Therefore it is not possible to predict thefate of hibernating myocardium which is present after infarction.     

急性心肌梗死后心肌炎症反应及其意义

目的：探讨急性心肌梗死后心肌是否发生炎症性损伤。方法 在体结扎Wistar大鼠冠状动脉左前降支（LAD）复制急性心肌梗死大鼠模型和假性手术大鼠对照。6周后，酶联免疫吸附试验（ELISA）检测大鼠血清抗肌球蛋白重链抗体。组织学检查心肌病理改变，免疫组织化学染色分析浸润心肌组织T淋巴细胞的表型。结果：急性心肌梗死大鼠（5／12例）血清中检测到抗肌球蛋白重链抗体，阳性率为41．7％，对照组（0／10例）均为阴性（P〈0．05）。在大鼠非梗死区心肌组织中出现散在分布的血管周围炎和间质淋巴细胞浸润，免疫组织化学染色显示心肌组织CD4^＋T细胞浸润占有显著优势。结论：急性心肌梗死后心肌组织发生了异常的炎症反应。     

Zonal expression of the thyroid hormone receptor alpha isoforms in rodent liver

Many metabolic processes occur simultaneously in the liver in different locations along the porto-central axis of the liver units. These processes are often regulated by hormones, one of which is thyroid hormone which for its action depends on the presence of the different isoforms of the thyroid hormone receptor (TR). These are encoded by two genes: c-erbA-alpha encoding TRalpha1 and TRalpha2 and their respective Delta isoforms, and c-erbA-beta which encodes TRbeta1, TRbeta2 and TRbeta3. We recently found a zonal (pericentral) expression of and a diurnal variation in the TRbeta1 isoform in rat liver. We were therefore also interested to see whether TRalpha1 and TRalpha2 expression showed similar characteristics. For this reason we raised both polyclonal and monoclonal antibodies against TRalpha1 and TRalpha2 isoforms and characterised these. Antibody specificity was tested using Western blots and immunohistochemistry in liver of TR isoform-specific knockout animals. Using these antibodies we found that the TRalpha1 and TRalpha2 isoforms are zonally expressed around the central vein in rat liver. The experiments show that the portal to central gradient of TRalpha1 is broader than that of TRbeta1. Moreover, the expression of the TRalpha2 protein showed a diurnal variation with a peak in the afternoon when the animals are least active whereas no such variation was found for the TRalpha1 protein.From our data it appears that both the TRalpha1 and TRalpha2 isoforms show a zonal distribution in liver. This finding, together with the observed diurnal rhythm, has major implications for interpreting and timing experiments concerning the TR and its downstream actions in liver.     

心肌梗死区存活心肌对糖尿病急性心肌梗死患者PCI术后心功能的影响(英文)

目的:探讨糖尿病急性心肌梗死经皮冠状动脉介入治疗(PCI)术后患者心肌梗死区存活心肌对左室重构及左心功能的影响。方法:208例2型糖尿病并急性心肌梗死PCI术后的患者接受静息状态下18-氟脱氧葡萄糖正电子发射断层扫描术(18F-FDG PET)心肌代谢显像与99m锝-甲氧基异丁基异腈单光子发射型计算机断层成像术(99Tcm-MIBI SPECT)心肌灌注显像,根据心肌梗死区有无存活心肌,分为有心肌存活组(115例,灌注-代谢不匹配)和无心肌存活组(93例,灌注一代谢匹配)。检测两组PCI术前、术后超声心动图各指标,观察心肌梗死区心肌存活状态对于左室重构以及心功能的影响。结果:心肌梗死12个月后有存活心肌组左室射血分数(LVEF)显著高于无存活心肌组[(46.7±6.98)%比(44.1±7.12)%],左室舒张末期内径(LVEDd)[(53.17±4.77)mm比(55.46±4.75)mm],左房内径[(35.89±12.08)mm比(39.25±11.31)mm]显著小于无存活心肌组,P均<0.05。舒张期二尖瓣血流速度峰值的比值12个月后两组无显著差异(P>0.05)。结论:于2型糖尿病合并急性心肌梗死的患者,心肌梗死区有存活心肌患者较无心肌存活患者,LVEF明显改善,左室舒张末期内径显著缩小。     

Decreased expression of Na+/H+ exchanger isoform 1 (NHE1) in non-infarcted myocardium after acute myocardial infarction

Although cardiac NHE1 is activated during myocardial ischemia and reperfusion injury, little is known about changes in expression in non-infarcted myocardium after acute myocardial infarction (AMI). The purpose of this study was to examine left ventricular function and region dependent NHE1 expression after myocardial infarction. Therefore, we produced two AMI models in rats, a small infarction model which was continuously ligated at the branches of the left coronary artery, and an extensive infarction model continuously ligated at the root of the artery. We examined NHE1 mRNA expression using RNase protection assay and protein levels using Western blot analysis in non-infarcted myocardium during the 24 hour period after AMI. The level of NHE1 mRNA and protein expression in the whole heart including the infarcted myocardium did not change after a small infarction. On the other hand, in the case of an extensive infarction, the levels of NHE1 mRNA and protein expression decreased significantly by 21.5% (P<0.05) and by 22.0% (P<0.05), respectively, in non-infarcted myocardium. Left ventricular systolic pressure (LVSP) decreased significantly by 13% and 38% with the branch and root ligation, respectively. However, left ventricular end-diastolic pressure (LVEDP) only increased with the root ligation. These results indicate that NHE1 expression decreased in response to extensive myocardial infarction only in non-infarcted myocardium. The present study may be important in furthering the understanding of NHE1 in myocardial infarction and suggests that decreased expression of NHE1 in non-infarcted myocardium may decrease the extent of cardiac cell injury.     

Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca²⁺ transport protein, such as sarcoplasmic reticulum Ca²⁺(SR-Ca²⁺)-ATPase, Na⁺-Ca²⁺ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca ²⁺ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ration of E wave to A wave velocity. Expression of myocardial α-skeletal actin, β-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca²⁺-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na⁺-Ca²⁺ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling. Received: 9 August 1999, Returned for revision: 16 September 1999, Revision received: 5 January 2000, Accepted: 26 January 2000     

Change in serum thyroid hormone levels in patients with acute myocardial infarction

It has been reported that there is a decrease in the serum concentration of thyroid hormones in non-thyroidal illness. In the present study we made serial measurements of serum concentration of thyroid hormones [triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), reverse triiodothyronine (rT3)], thyroid stimulating hormone (TSH) and thyroxine binding globulin (TBG) in 10 patients with acute myocardial infarction (AMI, Grade I, according to the classification of Killip & Forrester) during 14 days after onset. In the early phase of AMI, serum T3, T4, FT3 and FT4 levels decreased while rT3 increased. TSH and TBG levels, however, were unchanged. In the patients with a high peak creatine phosphokinase activity (greater than or equal to 400 mU/ml), the decrease in thyroid hormone and increase in serum rT3 levels were greater than in patients with a low peak value (less than 400 mU/ml), suggesting a correlation between severity of AMI and changes in serum thyroid hormone levels. Especially, serum FT3 levels fell below the lower limit of controls within 14 days, with the lowest levels and the rT3 peak on the third day after onset. These data suggest that in AMI peripheral conversion of T4 favours rT3 production and that low levels of serum FT3 and T3 protect the infarcted heart muscle against thyroid hormone action.     

Losartan preserves integrity of cardiac gap junctions and PGC-1 alpha gene expression and prevents cellular apoptosis in remote area of left ventricular myocardium following acute myocardial infarction

This study tests the hypothesis that peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha) and the integrity of gap junctions (GJs) were suppressed and the number of apoptotic bodies was increased in remote viable areas of left ventricle following acute myocardial infarction (AMI), which can be reversed by losartan therapy. Open chest surgery was consecutively performed on 32 adult male Sprague-Dawley rats. These rats were classified into 4 groups (n = 8/each group): group I, AMI (by ligation of left coronary artery (LCA) without treatment); group II, AMI with losartan 20 mg/kg/day; group III, sham control (without LAD ligation); and group IV, sham control with losartan 20 mg/kg/day. Echocardiography was performed on day 1 prior to AMI and on day 14 just before the rats were to be sacrificed for cellular and molecular studies. The results showed that mRNA expression of PGC-1alpha, integrated area (microm(2)) of clustered connexin43 (Cx43) spots, and Cx43 GJs were substantially down-regulated and the number of apoptotic bodies was markedly increased in nontreated AMI rats compared with healthy control and losartan-treated AMI rats on day 14 following AMI (all values of P < 0.001). Additionally, day 14 left ventricular (LV) ejection fraction was significantly lower in nontreated AMI rats than in healthy control and losartan-treated AMI rats (all values of P < 0.0001). Down-regulation of GJs and PGC-1alpha gene expression and cellular death were frequently observed in remote viable areas of LV following AMI. Losartan therapy reversed the adverse effects of AMI and preserved LV function.     

Long-term thyroid hormone administration reshapes left ventricular chamber and improves cardiac function after myocardial infarction in rats

Thyroid hormone (TH) is critical for tissue differentiation at early stages of development, induces physiological hypertrophy and regulates the expression of important contractile proteins such as myosin heavy chain (MHC) isoform and calcium cycling proteins. Furthermore, TH seems to control the response to stress by regulating important cardioprotective molecules such as heat shock proteins (HSPs). Thus, the present study investigated whether TH administration immediately after acute myocardial infarction can favourably remodel the post-infarcted myocardium. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI, n=10), while SHAM-operated animals served as controls (SHAM, n = 8). TH was administered for 13 weeks (AMI-THYR, n = 9). Cardiac contractile function and left ventricular (LV) chamber remodelling was assessed by serial echocardiography and in Langendorff heart preparations. AMI significantly reduced LV ejection fraction (EF%); 30.0 (s.e.m, 2.3) Vs. 73.8 (1.8) in SHAM, P < 0.05. In addition, +dp/dt and -dp/dt (in mmHg/s) were 4,051 (343) and 2,333 (118) respectively for SHAM Vs. 2,102 (290) and 1,368 (181) for AMI, P < 0.05. With TH treatment, EF% was increased to 49.5 (2.7) in AMI-THYR, P < 0.05, while +dp/dt and -dp/dt (in mmHg/s) were 3,708 (231) and 2,035 (95) for AMI-THYR, P < 0.05 Vs. AMI. A marked elevation of the expression of beta-MHC and a reduced ratio of SERCA/Phospholamban were found in viable myocardium of AMI hearts, which was prevented by TH. Furthermore, heat shock protein 70 myocardial content was decreased in AMI hearts and was significantly increased after TH treatment. An ellipsoidal reshaping of LV chamber was observed with TH; cardiac sphericity index, (ratio of long/short axis, SI), was 1.98 (0.03) for SHAM, 1.52 (0.05) for AMI and 1.72(0.02) for AMI-THYR, P < 0.05. In conclusion, long-term TH administration immediately after AMI results in sustained improvement of cardiac haemodynamics.     

Nonfatal cardiac events and recurrent infarction in the year after acute myocardial infarction

The occurrence and importance of nonfatal cardiac events in the year after an acute myocardial infarction were studied in 866 patients who were enrolled by nine hospitals with a broad geographic distribution. The extensive clinical data acquired on each patient included special tests, such as radionuclide-determined ejection fraction, 24 hour ambulatory electrocardiogram and a low level exercise tolerance test. Recurrent events were frequent in the first 5 months, and certain events were significant indicators of a poor prognosis. An ejection fraction less than 40% and angina after discharge from the coronary care unit predicted patients at high risk of rehospitalization. Recurrent infarction was similarly predicted by angina, but not by any features of an exercise test. This study demonstrates the considerable morbidity that occurs after an acute myocardial infarction and its relation to and role in subsequent mortality.