PAPP-A: a possible pathogenic link to the instability of atherosclerotic plaque

The rupture of coronary atherosclerotic plaque and subsequent thrombus formation are major events underlying acute coronary syndromes (ACS). Pregnancy associated plasma protein A (PAPP-A) is a member of the metzincin superfamily of metalloproteinases originally identified in the serum of pregnant women. Recent studies indicate that ACS is associated with elevated serum concentrations of PAPP-A. PAPP-A level is not only a marker of plaque instability favoring the progression to myocardial infarction, but is indicative of a poor prognosis even after the occurrence of an acute ischemic event caused by plaque instability. Why PAPP-A expression in unstable plaques is high is a puzzling problem. We hypothesized that PAPP-A is a possible cause of the instability of atherosclerotic plaque which plays a role in ACS. Studies found that PAPP-A was abundantly expressed in both eroded and ruptured plaques, but was only minimally expressed in stable plaques. Other studies have also demonstrated that patients with hyperechoic or isoechoic carotid plaques exhibit significantly higher PAPP-A levels than those with hypoechoic early carotid lesions. If the hypothesis is confirmed, administration of PAPP-A monoclonal antibodies may be used to eliminate the pathogen. It will be a new target point to treat ACS.     

Plasma brain natriuretic peptide levels in coronary heart disease with preserved systolic function

We evaluated the circulating levels of brain natriuretic peptide (BNP) in stable angina, unstable angina, and myocardial infarction relating hormone levels to extension of coronary disease and number of vessels involved after angiographic examination. We studied 86 patients consecutively undergoing angiographic coronary examination and echocardiographic evaluation for coronary heart disease. These included 15 control subjects (group 0), 21 with stable angina (group I), 26 with unstable angina (group II), and 24 with non-Q myocardial infarction (group III). Patients with heart failure, a history of myocardial infarction, or recent myocardial damage with electrocardiographic S-T elevation were excluded. BNP levels in patients with unstable angina and myocardial infarction were significantly increased with respect to the group with stable angina (P<0.01). There were no differences between the groups with unstable angina and myocardial infarction. Analysis of peptide levels in relation to the number of involved vessels demonstrated a significant increase in patients with three-vessel disease compared with subjects with one or two vessels involved (P<0.03); among subjects with mono-vessel disease, patients with left descendent anterior stenosis had a more-marked BNP elevation than subjects with stenosis in other regions (P<0.01). Hence, BNP levels appear to be elevated in coronary disease, especially in acute coronary syndromes, even in the absence of systolic dysfunction. BNP levels also seem to be related to the severity of coronary atherosclerosis and number of vessels involved. BNP could prove a novel marker for risk stratification, not only in heart failure but also in coronary heart disease.     

基质金属蛋白酶1与冠状动脉粥样硬化斑块破裂的关系

目的 探讨冠状动脉粥样硬化斑块破裂与基质金属蛋白酶１（ＭＭＰ－１）的关系,以及不稳定斑块中ＭＭＰ－１的来源。方法 收集２０例死于急性心肌梗死、１０例有不稳定心绞痛史,以及１２例有稳定心绞痛史的尸体解剖病例共４２例,从冠状动脉各分支取材,常规病理检查、部分节段行ＭＭＰ－１、平滑肌肌动蛋白、ＣＤ６８、ＣＤ４５ＲＯ和ＣＤ２０洒色。结果 在急性心肌梗死及不稳定心绞痛病例中,均见有斑块破裂伴血栓形成,而在稳     

稳定性,不稳定性心绞痛及急性心肌梗死病人冠状动脉病变的？…

比较稳定型心绞痛、不稳定型心绞痛及急性心肌梗死病人冠状动病变的组织学差异,以阐明其发生的病理学机制。方法选天临床诊明确的ＳＡ、ＵＡ及ＡＭＩ病人死后的尸检收脏标本,对其冠状动脉取材并做组织学及免疫组织化学观察。     

Plasma brain natriuretic peptide levels in coronary heart disease with preserved systolic function

Abstract. We evaluated the circulating levels of brain natriuretic peptide (BNP) in stable angina, unstable angina, and myocardial infarction relating hormone levels to extension of coronary disease and number of vessels involved after angiographic examination. We studied 86 patients consecutively undergoing angiographic coronary examination and echocardiographic evaluation for coronary heart disease. These included 15 control subjects (group 0), 21 with stable angina (group I), 26 with unstable angina (group II), and 24 with non-Q myocardial infarction (group III). Patients with heart failure, a history of myocardial infarction, or recent myocardial damage with electrocardiographic S-T elevation were excluded. BNP levels in patients with unstable angina and myocardial infarction were significantly increased with respect to the group with stable angina (P<0.01). There were no differences between the groups with unstable angina and myocardial infarction. Analysis of peptide levels in relation to the number of involved vessels demonstrated a significant increase in patients with three-vessel disease compared with subjects with one or two vessels involved (P<0.03); among subjects with mono-vessel disease, patients with left descendent anterior stenosis had a moremarked BNP elevation than subjects with stenosis in other regions (P<0.01). Hence, BNP levels appear to be elevated in coronary disease, especially in acute coronary syndromes, even in the absence of systolic dysfunction. BNP levels also seem to be related to the severity of coronary atherosclerosis and number of vessels involved. BNP could prove a novel marker for risk stratification, not only in heart failure but also in coronary heart disease.     

Major types of unstable atherosclerotic plaques and their distribution in coronary arteries in acute myocardial infarction

A pathomorphological investigation of unstable atherosclerotic plaques and their distribution in coronary arteries were studied on successive (5 mm) transverse sections of autopsy material from 60 patients with acute myocardial infarction (AMI). Two morphological types of such plaques were distinguished: lipid one (70%) and dystrophic-necrotic (30%). Unstable plaques in AMI are spread. Numerous unstable plaques were more frequently observed in AMI with preceding unstable angina pectoris but single plaques were found in cases with absence of coronary anamnesis. There were no significant age, sex and risk factor differences between cases with multiple and single atherosclerotic plaques.     

Plasma osteopontin levels are elevated in non-ST-segment elevation acute coronary syndromes

BACKGROUND: The regions of ruptured atherosclerotic plaques have numerous macrophages. Osteopontin that modulates macrophage function has been shown in atherosclerotic plaques. We aimed to study the plasma levels of osteopontin in patients with unstable angina or non-ST-seg ment elevation myocardial infarction (NSTEMI) and the rela tionship between osteopontin and the extent of the coronary artery disease (CAD). METHODS: We studied 65 patients with unstable angina or NSTEMI, 25 patients with stable angina and 18 patients as the control group. The extent of coronary artery stenosis was determined by the number of vessels with >50% stenosis. Plasma osteopontin concentrations were measured from the blood samples that were drawn immediately after admission to the emergency department in unstable angina/NSTEMI patients and before the coronary angiograph in the stable angina and control groups. RESULTS: The plasma osteopontin concentration was (495 118 ng/ml) significantly higher in the patients with unstable angina/NSTEMI compared to the stable angina group (319 106 ng/ml) and control group (125+/-54 ng/ml) (p=0.0001 The plasma osteopontin levels were lower in the patients with stable angina pectoris who had one-vessel disease compared to those with two-vessel disease (p=0.01). How ever, in the unstable angina/NSTEMI group, the plasma osteopontin levels were statistically not different among the patients with one-vessel, and two-vessel and three-vessel disease (p=NS). There was no correlation between the plasma osteopontin levels and the extent of coronary stenosis. CONCLUSIONS: The plasma osteopontin levels are elevatedin patients with unstable angina/NSTEMI, but there appears to be no correlation with the extent of CAD. These results ma suggest that osteopontin may have a role in the pathobiology of ACS.     

Multiple complex coronary plaques in patients with acute myocardial infarction

BACKGROUND: Acute myocardial infarction is believed to be caused by rupture of an unstable coronary-artery plaque that appears as a single lesion on angiography. However, plaque instability might be caused by pathophysiologic processes, such as inflammation, that exert adverse effects throughout the coronary vasculature and that therefore result in multiple unstable lesions. METHODS: To document the presence of multiple unstable plaques in patients with acute myocardial infarction and determine their influence on outcome, we analyzed angiograms from 253 patients for complex coronary plaques characterized by thrombus, ulceration, plaque irregularity, and impaired flow. RESULTS: Single complex coronary plaques were identified in 153 patients (60.5 percent) and multiple complex plaques in the other 100 patients (39.5 percent). As compared with patients with single complex plaques, those with multiple complex plaques were less likely to undergo primary angioplasty (86.0 percent vs. 94.8 percent, P = 0.03) and more commonly required urgent bypass surgery (27.0 percent vs. 5.2 percent, P < or = 0.001). During the year after myocardial infarction, the presence of multiple complex plaques was associated with an increased incidence of recurrent acute coronary syndromes (19.0 percent vs. 2.6 percent, P < or = 0.001); repeated angioplasty (32.0 percent vs. 12.4 percent, P < or = 0.001), particularly of non-infarct-related lesions (17.0 percent vs. 4.6 percent, P < or = 0.001); and coronary-artery bypass graft surgery (35.0 percent vs. 11.1 percent, P < or = 0.001). CONCLUSIONS: Patients with acute myocardial infarction may harbor multiple complex coronary plaques that are associated with adverse clinical outcomes. Plaque instability may be due to a widespread process throughout the coronary vessels, which may have implications for the management of acute ischemic heart disease.     

IL-18、IL-10和IL-6与急性冠状动脉综合征的关系研究

目的：研究白细胞介素（IL）-18、IL-10和IL-6血清浓度与急性冠状动脉综合征之间的关系。方法： 采用酶联免疫吸附法（ELISA）和放射免疫法检测62例冠心病患者（急性心肌梗死17例、不稳定性心绞痛30例、稳定性心绞痛15例）和20例正常健康者血清IL-18、IL-10和IL-6水平，并比较上述指标水平之间的相关关系。 结果： 血清IL-18、IL-6水平在急性心肌梗死（AMI）组和不稳定性心绞痛（UAP）组显著高于稳定性心绞痛（SAP）组和对照组(P＜0.05, P＜0.01)；AMI组和UAP组血清IL-10水平明显低于SAP组和对照组（P＜0.01）。血清IL-18和IL-6水平与血清IL-10水平呈显著负相关（r＝－0.827, P＜0.01; r＝－0.231, P＜0.05)； 血清IL-6水平与IL-18水平相关性不明显（r＝0.119, P＞0.05）。 结论： 急性冠状动脉综合征患者血清IL-18、IL-6水平明显升高而IL-10水平显著降低；IL-18、IL-6与IL-10的平衡失调可能是促进斑块不稳定的重要因素。     

Coronarographic and pathomorphological characteristics of unstable atherosclerotic plaques in acute coronary syndromes

The proximal segments of the main coronary vessels are the most often localization of “soft” unstable atherosclerotic plaques. The maximum number of plaques developed in the anterior descending branch of the left coronary artery. Pathognomonic relationship was found between the type of these plaques (with ulceration, rupture, thrombosis) and certain acute coronary syndrome. It was shown that the criteria of the plaque instability correlated with clinical manifestations of coronary syndromes. The bases and effects of “pathological” vascularization of unstable atherosclerotic plaques on the angioarchitectonics and hemodynamics of the heart were determined. Dissociation between myocardial vascularization degree and myocardial blood supply index was detected, which underlies the development of “unstable” myocardium in patients with acute coronary syndromes. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 8, pp. 229–235, August, 2007     

Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes.

BACKGROUND. Disruption of an atherosclerotic plaque in a coronary artery followed by the formation of a thrombus is believed to be the cause of both unstable angina and acute myocardial infarction. Although thrombolytic therapy is efficacious in patients with acute myocardial infarction, for unknown reasons it is far less effective in patients with unstable angina. We postulated that there might be differences in the composition of the coronary-artery thrombi in unstable angina and acute myocardial infarction. METHODS. To investigate the appearance of coronary-artery thrombi, we performed percutaneous transluminal coronary angioscopy in 15 patients with unstable angina and 16 with acute myocardial infarction. Angioscopy was performed within 48 hours after an episode of pain at rest in the patients with unstable angina and within 8 hours of onset in those with acute myocardial infarction. RESULTS. Angioscopy revealed coronary thrombi in all but two patients (one in each group). Of the 29 patients with thrombi, those with unstable angina were frequently observed to have grayish-white thrombi (10 of 14, 71 percent), but none were seen in the 15 patients with acute myocardial infarction (P less than 0.01). By contrast, reddish thrombi were observed in all 15 patients with acute myocardial infarction who had thrombi, but in only 4 of the 14 patients with unstable angina and thrombi (P less than 0.01). As assessed by coronary angiography, occlusive thrombi occurred frequently in patients with acute myocardial infarction (13 of 16 patients) but were not seen in any of the 15 patients with unstable angina (P less than 0.01). CONCLUSIONS. Coronary-artery thrombi play an important part in the pathogenesis of unstable angina and acute myocardial infarction. However, the appearance of the thrombi is different in the two conditions, possibly reflecting differences in the composition of age of the thrombi or the presence or absence of blood flow in the artery. This difference may account for the contrasting results of thrombolytic therapy.     

Pro-inflammatory/anti-inflammatory cytokine imbalance in acute coronary syndromes

Abstract The aim of this study was to evaluate the presence of an imbalance between proinflammatory and anti-inflammatory mediators in patients affected by acute coronary syndromes (ACS). We considered two groups of 26 and 28 patients with acute myocardial infarction (AMI) and unstable angina (UA) respectively, compared with a group of 30 patients with stable angina and 30 healthy volunteers. We evaluated the production in cultured and stimulated lymphomonocytes of interferon (IFN)γ and tumour necrosis factor (TNF)α, which are well known to possess proinflammatory effects, and of interleukin (IL)10, which has been shown to have a protective anti-inflammatory activity. We also assessed the clinical characteristics of groups and, particularly, we evaluated the circulating levels of C-reactive protein (hs-CRP). We found a significant increase of IFNγ and TNFα production (P<0.01) and a significant decrease of IL10 production (P<0.05) in cultures of lymphomonocytes taken from patients with AMI and UA compared with SA patients and controls. No significant changes where found between AMI and UA patients and SA patients and controls. Circulating levels of hs-CRP were significantly increased (P<0.01) in patients with ACS compared with the other control groups. Our data showed an increased production of proinflammatory mediators in ACS that may be detectable both in circulating blood and in cell cultures where it is possible to evaluate in a better way the functional state of cells; this finding was associated with a reduced production of the antiinflammatory cytokine IL10. In conclusion, a relevant imbalance is present in ACS and this fact could contribute to plaque instability and clinical manifestations.     

APN、CD62P、hs-CRP在冠心病病程发展中的作用

目的:探讨在冠状动脉粥样硬化发展中脂联素(adipomectin,APN)、CD62P、hs-CRP的作用.方法:检测60例稳定型心绞痛患者(stable angina pectoris,SAP组)、58例不稳定型心绞痛(unstable angina pectoris,SAP组),50例急性心肌梗死患者(AMI组)及...     

CHD患者血清可溶性CD40L检测的临床意义

目的:探讨冠心病(CHD)患者血清可溶性CD40L(sCD40L)水平变化的临床意义.方法:应用酶联免疫吸附法(ELISA)对入选的90例CHD患者[急性心梗(AMI)患者28例,不稳定型心绞痛(UAP)患者35例,稳定型心绞痛(SAP)患者27例]的外周血sCD40L进行检测,并与30例正常对照者血清sCD40L的浓...     

IMA、hs-CRP、BNP联合检测对急性冠脉综合征的临床意义

目的 探讨缺血修饰蛋白(IMA)、超敏C反应蛋白(hs-CRP)、B型钠酸肽(BNP)对于急性冠状动脉综合征(ACS)的早期诊断及预后评价的意义.方法 选择90例患者分成三组,其中急性心肌梗死( AMI)组30例、不稳定型心绞痛(UAP)组30例、稳定型心绞痛(SAP)组30例,对照组选取同期我院体检未发现心血管疾病者...     

Coronary angioscopy in patients with unstable angina pectoris

To visualize intracoronary lesions in patients with different clinical expressions of coronary disease, we performed coronary angioscopy during coronary-artery bypass surgery in 10 patients with unstable angina and 10 patients with stable coronary disease. We examined a total of 32 vessels, using flexible fiberoptic angioscopes. Twenty-two vessels had no acute intimal lesion; three had complex plaques, six had thrombi, and one had both. Coronary angiography correctly identified the absence of complex plaque and thrombus in 22 vessels, but it detected only one of four complex plaques and one of seven thrombi. On angioscopy, none of the 17 arteries in the patients with stable coronary disease had either a complex plaque or thrombus. In the "offending" arteries of the patients with unstable angina, all three patients with accelerated angina had complex plaques and all seven with angina at rest had thrombi. We conclude that angioscopy frequently reveals complex plaques or thrombi not detected by coronary angiography. Our observations suggest that anginal syndromes that are refractory to medical treatment can be caused by unstable pathologic processes in the intima. Ulceration of plaques may increase the frequency and severity of effort angina, and the subsequent development of partially occlusive thrombi may cause unstable rest angina.     

The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes

BACKGROUND: Brain (B-type) natriuretic peptide is a neurohormone synthesized predominantly in ventricular myocardium. Although the circulating level of this neurohormone has been shown to provide independent prognostic information in patients with transmural myocardial infarction, few data are available for patients with acute coronary syndromes in the absence of ST-segment elevation. METHODS: We measured B-type natriuretic peptide in plasma specimens obtained a mean (+/-SD) of 40+/-20 hours after the onset of ischemic symptoms in 2525 patients from the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction 16 study. RESULTS: The base-line level of B-type natriuretic peptide was correlated with the risk of death, heart failure, and myocardial infarction at 30 days and 10 months. The unadjusted rate of death increased in a stepwise fashion among patients in increasing quartiles of base-line B-type natriuretic peptide levels (P< 0.001). This association remained significant in subgroups of patients who had myocardial infarction with ST-segment elevation (P=0.02), patients who had myocardial infarction without ST-segment elevation (P<0.001), and patients who had unstable angina (P<0.001). After adjustment for independent predictors of the long-term risk of death, the odds ratios for death at 10 months in the second, third, and fourth quartiles of B-type natriuretic peptide were 3.8 (95 percent confidence interval, 1.1 to 13.3), 4.0 (95 percent confidence interval, 1.2 to 13.7), and 5.8 (95 percent confidence interval, 1.7 to 19.7). The level of B-type natriuretic peptide was also associated with the risk of new or recurrent myocardial infarction (P=0.01) and new or worsening heart failure (P<0.001) at 10 months. CONCLUSIONS: A single measurement of B-type natriuretic peptide, obtained in the first few days after the onset of ischemic symptoms, provides powerful information for use in risk stratification across the spectrum of acute coronary syndromes. This finding suggests that cardiac neurohormonal activation may be a unifying feature among patients at high risk for death after acute coronary syndromes.     

Blood Levels of Inflammatory and Destructive Biomarkers in Coronary Atherosclerosis of Different Severity

In male patients with coronary atherosclerosis without acute coronary syndrome, the levels of inflammatory-destructive biomarkers of atherosclerotic plaque instability depended on the severity and dissemination of coronary atherosclerosis. The highest levels of C-reactive protein and matrix metalloproteinase 3 were found in men with atherosclerotic involvement of all three main coronary arteries, primarily their middle and distal segments, and in men with predominance of low-grade stenoses (<50%) of coronary arteries in areas of atherosclerotic plaques.     

Inflammation markers in acute coronary syndrome

Inflammation is a component of atherosclerotic plaque, but it is also a possible pathogenetic factor of acute coronary event responsible for coronary instability. Inflammatory markers are considered as new risk factors for atherosclerosis. Among others (C-reactive protein (CRP) is the best known marker of inflammatory response which is most frequently found in patients with acute myocardial infarction preceded by a period of instability. High values of inflammatory markers indicate poor prognosis after acute myocardial infarction. Therapy may lower the inflammatory component and the risk of coronary disease. Specific response of inflammatory marker during diagnostic and percutaneous coronary interventions indicates more severe coronary disease.     

Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease

Coronary-artery thrombosis may be important in the pathogenesis of unstable angina at rest. To study this possibility, we measured the serum concentrations of fibrin-related antigen, D dimer (the principal breakdown fragment of fibrin), and fibrin monomer (an intermediate product of fibrin formation) in the serum of five groups of subjects. These included 10 healthy controls, 10 controls with noncardiac pain, and three groups of 10 patients each with chronic stable angina, unstable angina at rest, or acute myocardial infarction. The concentration of fibrin-related antigen (normal range, 48 to 184 ng per milliliter) was normal in the control patients with noncardiac pain (63 to 202 ng per milliliter) and in patients with chronic stable angina (95 to 186), but it was increased in patients with unstable angina (401 to 2507) or acute myocardial infarction (470 to 1930) (P less than 0.001). D dimer concentrations in patients with unstable angina (178.3 to 310.6 ng per milliliter) or acute myocardial infarction (103.9 to 321.6) were higher than those in patients with chronic stable angina (28.6 to 52.1), in controls with noncardiac pain (44.7 to 53.1), and in healthy controls (40.4 to 50.3) (P less than 0.001). Concentrations of fibrin monomer were highest in patients with acute myocardial infarction (247.5 to 571.3 ng per milliliter) (P less than 0.001), intermediate in those with unstable angina (54.7 to 241.7) (P less than 0.001), and normal (normal range, 14.5 to 19.8 ng per milliliter) in controls with noncardiac pain (12.0 to 18.4). and patients with chronic stable angina (10.7 to 17.6). These findings suggest the presence of an active thrombotic process in patients with unstable angina at rest or acute myocardial infarction. The data do not prove that the coronary arteries were the site of the thrombotic process, but the observations are consistent with the hypothesis that thrombus formation may have an important role in the pathogenesis of these conditions.