单核细胞/高密度脂蛋白比值在冠心病诊断和预测预后的研究进展

绝大部分冠心病为冠状动脉粥样硬化所致,目前认为,动脉粥样硬化是一种慢性炎性反应疾病。单核细胞和高密度脂蛋白比值(MHR)是近年新兴的一种炎性反应标志物,其获取简单,检测价格低廉,与冠心病短期和长期的心血管事件发生率及病死率相关,可作为冠心病预后的预测因素。     

New Approaches to Coronary Heart Disease

Currently available approaches for treating human coronary heart disease aim to relieve symptoms and the risk of myocardial infarction by reducing myocardial oxygen demand (drugs), preventing further disease progression (drugs), restoring coronary blood flow either pharmacologically (thrombolysis) or mechanically (angioplasty), or bypassing the stenotic lesions and obstructed coronary artery segments (surgery). Direct gene therapy, as well as gene-derived therapy, especially by angiogenic growth factors, is emerging as a potential new treatment for cardiovascular disease. After extensive experimental research on angiogenic growth factors, the first clinical studies on patients with coronary heart disease or peripheral vascular lesions are being performed. The polypeptides fibroblast growth factor (FGF) and vascular endothelial growth factor seem to be effective in initiating neovascularisation (neo-angiogenesis) in hypoxic or ischaemic tissues. The first clinical study on patients with coronary heart disease treated by local injection of FGF-1 into the compromised underperfused myocardial tissue showed a 3-fold increase of capillary density mediated by the growth factor. Angiogenic therapy of the human myocardium introduces a new modality of treatment for coronary heart disease in terms of regulation of blood vessel growth. Beyond drug therapy, angioplasty and bypass surgery, this therapy may evolve to be a fourth principle of treatment of atherosclerotic cardiovascular disease.     

Atherosclerotic lesions. Natural history, risk factors, and topography.

This article describes the development of human atherosclerosis as a framework on which to integrate and incorporate the research on thrombosis and hemostasis of participants in the 1992 College of American Pathologists Conference XXII on Hemostasis and Atherosclerotic Disease. Included are the early classic studies of the morphological features of atherosclerosis, atherosclerosis in different populations, the distribution of atherosclerotic lesions among arterial segments, the topography of atherosclerotic lesions within arterial segments, and the relationship of risk factors for coronary heart disease to the arterial lesions of atherosclerosis. Special attention is given to the development of atherosclerosis in young people, including findings from the Pathobiological Determinants of Atherosclerosis in Youth study. The data in this review provide confirmation of the development of atherosclerosis at an early age and relate atherosclerotic lesions to certain coronary heart disease risk factors. Any role of thrombosis or hemostasis in atherosclerosis must be integrated into this framework.     

Coronary atherosclerosis and interventions: Pathological sequences and restenosis

The primary cause of cardiac morbidity and mortality in developed countries is ischemic (coronary) heart disease. The incidence of this disease is virtually all due to atherosclerosis, and ischemic heart disease is also the most prevalent disease in the industrialized world, causing over 40% of all deaths in the United States and Western Europe. In Japan, the incidence of ischemic heart disease due to coronary atherosclerosis is gradually increasing as well. Compared with the classical nomenclature of atherosclerosis; that is, fatty streak, fibrous plaque and complicated lesions, the term Stary's classification has been universally accepted because it reflects the more recently acquired knowledge about the morphological and biochemical details of the processes in coronary atherosclerosis, which have been obtained by new strategies such as angioscopy, intravascular ultrasound and molecular biological methods. The term Stary's classification has been applied for the coronary atherosclerosis of patients with acute coronary syndrome at the National Cardiovascular Center, for the analysis of predisposing atherosclerosis of these patients. The recent findings regarding acute coronary syndrome resulting from a rupture of coronary atherosclerotic plaques indicate that this syndrome is probably the most important mechanism underlying the sudden onset. It has been found that the risk of plaque rupture may depend more on plaque composition than on plaque size. Plaques rich in soft extracellular lipids and macrophages are possibly more vulnerable to plaque rupture. Two of the goals of the present review are to clarify how plaque disruption occurs and to elucidate the relationship between plaque disruption and coronary risk factors in elderly Japanese patients with acute coronary syndrome. Coronary stents have been shown to be efficacious in the treatment of acute and threatened closure complicating percutaneous transluminal coronary angioplasty (PTCA) and have produced encouraging initial results in the prevention of restenosis. In the autopsy study of restenosis after PTCA, it was observed that dense caps of collagen fibers in the adventitia in the vicinity of the disrupted internal elastic laminae were present in all of the remodeling lesions. It is suggested that remodeling, which resulted in adventitial scarring, is one of the major causative factors of restenosis after PTCA. The long-term success of stenting, however, remains limited by the occurrence of late in-stent restenosis, with an incidence of 20-42% depending on the stent design and the patient population studied. Another aim of the present review is to describe the pathological mechanism of restenosis after PTCA and/or stent replacement and, consequently, the vascular remodeling that occurs around adventitial tissue after PTCA and intimal hyperplasia that is chronically irritated by a foreign body granulomatous reaction after stenting. Finally, the results of the investigation of the effect of a tissue factor pathway inhibitor on the prevention of interventional restenosis is described.     

Establishment of a rat model with diet-induced coronary atherosclerosis

Coronary atherosclerotic disease is a serious disease in humans, but no suitable animal model is available currently for further studies. We used apolipoprotein E gene knockout (ApoE KO) rats to induce hypercholesterolemia through a special high cholesterol/bile salt diet (Paigen diet), then analyzed aortic and coronary atherosclerosis lesions and the myocardial injury in order to establish a novel small animal model of coronary atherosclerosis. Plasma cholesterol of ApoE KO rats increased 7.6-fold compared with wild-type rats after 8 weeks on the Paigen diet. After 10 to 12 weeks of subsisting on the Paigen diet, ApoE KO rats developed mild aortic atherosclerosis with severe coronary atherosclerosis. Hematoxilyn and eosin staining showed that 11 out of 12 ApoE KO male rats had right coronary artery atherosclerosis, 7 of them were>70% occluded. Oil Red O (Lipid Stain), Mac2 immuno-staining and Masson’s trichrome staining demonstrated substantial amounts of lipid, macrophages and collagen fibers in coronary atherosclerosis plaques. In addition, ApoE KO male rats had severe myocardial focal lesions with cholesterol ester as the main component in the lesions. In conclusion, ApoE KO rats developed severe hypercholesterolemia, coronary atherosclerosis and myocardial cholesterol ester deposition after subsisting on the Paigen diet and can be used as a novel animal model for studies on cholesterol metabolism and coronary atherosclerotic disease.     

吸烟对女性冠心病患者冠状动脉粥样硬化的影响

心血管疾病是女性的头号死因,在美国,每分钟就有1名女性死于心血管疾病,其中绝大多数为冠心病。流行病学调查显示,在中国女性的死因排序中,心脏疾病已超过脑卒中和肿瘤,成为头号死因。多数女性甚至内科医生都认为,女性不易患冠心病,这是一个亟需纠正的误区。女性冠心病患者无论是吸烟患者或是被动吸烟患者,均会增加患者发生心血管风险事件概率,而戒烟是冠心病患者容易进行控制的危险因素,有效戒烟可以降低患者心血管风险,延长患者生命周期,保证患者生活质量。本文主要综述烟草对女性冠心病患者冠状动脉粥样硬化发生发展的影响。     

Atherosclerotic lesions in the common coronary arteries of ApoE knockout mice.

OBJECTIVE: The present study describes the distribution of atherosclerotic lesions in the coronary arteries of chow-fed 60-week-old male ApoE(-/-), 17-beta-estradiol-treated ApoE(-/-), and wild-type mice. METHODS AND RESULTS: The histologic examination of coronary arteries in 12 ApoE(-/-) and 6 wild-type mice, in contrast to the distribution of atherosclerosis in human coronary arteries, reveals that the major lesions in the mouse are located in the valve sinus, including the origins of the coronary arteries. These retrovalvular lesions either stop abruptly at the orifice of the common coronary artery or extend a short distance onto the arterial trunks. The first segment and first branch of all the major coronary arteries, the usual sites of disease in humans, are protected from disease. Although the arterial trunks and the first level branches are free of disease, we found approximately four independent lesions per heart. Independent lesions are present in the heart in smaller, intramyocardial vessels. These lesions are comprised predominantly of macrophages and proteoglycan and exhibit little extracellular lipid. In some cases, the independent lesions occlude the lumen without evidence of myocardial infarct in the surrounding tissue. CONCLUSIONS: The specificity of the localization of lesions in certain segments of the murine coronary tree suggests that fundamental properties found at different branch levels determine lesion location.     

HDL signaling and protection against coronary artery atherosclerosis in mice

Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke, important causes of morbidity and mortality across the globe. Abundant epidemiological studies demonstrate that high levels of high density lipoprotein (HDL) are associated with reduced risk of atherosclerosis and preclinical, animal model studies demonstrate that this association is causative. Understanding the molecular mechanisms underlying the protective effects of HDL will allow more strategic approaches to development of HDL based therapeutics. Recent evidence suggests that an important aspect of the ability of HDL to protect against atherosclerosis is its ability to trigger signaling responses in a variety of target cells including endothelial cells and macrophages in the vessel wall. These signaling responses require the HDL receptor, scavenger receptor class B type 1 (SR-B1), an adaptor protein (PDZK1) that binds to the cytosolic C terminus of SR-B1, Akt1 activation and (at least in endothelial cells) activation of endothelial NO synthase (eNOS). Mouse models of atherosclerosis, exemplified by apolipoprotein E or low density lipoprotein receptor gene inactivated mice (apoE or LDLR KO) develop atherosclerosis in their aortas but appear generally resistant to coronary artery atherosclerosis. On the other hand, inactivation of each of the components of HDL signaling (above) in either apoE or LDLR KO mice renders them susceptible to extensive coronary artery atherosclerosis suggesting that HDL signaling may play an important role in protection against coronary artery disease.     

Origins of human atherosclerotic plaques. The role of altered gene expression

The dramatic rise and equally dramatic fall in the mortality from coronary heart disease in the 20th century is only partly explained. This article reviews the development of our ideas concerning possible pathways other than lipids that might play a role in the development of human atherosclerosis alone or in combination with one or more of the usually considered risk factors. In some instances, such as that of cigarette smoking, the proposed concept regarding genetic alterations in vascular smooth muscle suggests a mechanism for development of at least some of the lesions. Recent studies have shown that an aberration in platelet-derived growth factor gene expression is unlikely to be a factor in proliferation of smooth-muscle cells. Aberrant expression of other oncogenes or some as yet unknown virus remain as possible explanations of some of the incidence of atherosclerosis and its consequent coronary heart disease.     

经皮冠状动脉介入治疗冠心病研究进展

近年来冠心病发生率呈不断上升趋势,严重危及人类生命健康安全。我国心脑血管疾病中冠心病发生率最高,也是导致死亡的首要疾病。经皮冠状动脉介入是临床治疗冠心病最直接有效的方法,其疗效确切,对患者创伤小。但在临床应用中存在并发症,远期心血管事件发生率高等不足。本文主要对冠心病发病机制、经皮冠状动脉介入治疗特点、治疗技术、介入路径等进行综述,为经皮冠状动脉介入治疗冠心病提供科学的参考依据。     

冠状动脉疾病患者血清APN水平变化

目的：观察在冠心病（CHD）和高血压时血清脂联素（APN）水平的变化,分析低APN血症在CHD发生发展中的可能机制。方法：采用ELISA检测血清APN含量,比较各组心血管疾病患者血清APN水平的变化。结果：①心肌梗死患者血清APN水平最低,明显低于心绞痛（P〈0.05）、高血压（P〈0.05）、动脉粥样硬化（P〈0.01）和其它疾病（P〈0.01）组;②心绞痛组明显低于其它疾病（P〈0.01）组,但与高血压、动脉粥样硬化组比较无显著性差异（P〉0.05）;③心肌梗死、心绞痛、高血压、动脉粥样硬化组患者血清APN水平均明显低于正常对照组,其它疾病组与正常对照组无明显差异（P〉0.05）。结论：CHD和高血压患者血清APN水平与其血管病变密切相关,检测患者血清APN水平有助于观察冠状动脉疾病的病情变化。     

Pathophysiological effects of radiation on atherosclerosis development and progression,and the incidence of cardiovascular complications

Radiation therapy while important in the management of several diseases, is implicated in the causation of atherosclerosis and other cardiovascular complications. Cancer and atherosclerosis go through the same stages of initiation, promotion, and complication, beginning with a mutation in a single cell. Clinical observations before the 1960s lead to the belief that the heart is relatively resistant to the doses of radiation used in radiotherapy. Subsequently, it was discovered that the heart is sensitive to radiation and many cardiac structures may be damaged by radiation exposure. A significantly higher risk of death due to ischemic heart disease has been reported for patients treated with radiation for Hodgkin's disease and breast cancer. Certain cytokines and growth factors, such as TGF-beta1 and IL-1 beta, may stimulate radiation-induced endothelial proliferation, fibroblast proliferation, collagen deposition, and fibrosis leading to advanced lesions of atherosclerosis. The treatment for radiation-induced ischemic heart disease includes conventional pharmacological therapy, balloon angioplasty, and bypass surgery. Endovascular irradiation has been shown to be effective in reducing restenosis-like response to balloon-catheter injury in animal models. Caution must be exercised when radiation therapy is combined with doxorubicin because there appears to be a synergistic toxic effect on the myocardium. Damage to endothelial cells is a central event in the pathogenesis of damage to the coronary arteries. Certain growth factors that interfere with the apoptotic pathway may provide new therapeutic strategies for reducing the risk of radiation-induced damage to the heart. Exposure to low level occupational or environmental radiation appears to pose no undue risk of atherosclerosis development or cardiovascular mortality. But, other radiation-induced processes such as the bystander effects, abscopal effects, hormesis, and individual variations in radiosensitivity may be important in certain circumstances.     

Comparison of coronary atherosclerosis in middle-aged Norwegian and Japanese men. An autopsy study

We compared the extent of lesions in the coronary arteries of autopsied middle-aged men from Oslo, Norway, with lesions in autopsied men of similar ages in Tokyo, Japan. Certain risk factors for coronary heart disease as serum cholesterol, triglycerides, and blood pressure were also available from these men in the two locations. Our comparisons reveal large differences in the extent of atherosclerosis between Oslo and Tokyo, which are reflected in the levels of the risk factors, particularly serum cholesterol levels. Our findings suggest that preventive strategies could retard the development of atherosclerosis and coronary heart disease without the economic and nutritional problems that affect technically underdeveloped societies where atherosclerosis and coronary heart disease are not prevalent.     

Coronary heart disease, hypercholesterolemia, and atherosclerosis. I. False premises

Lipid-rich caseous debris of advanced lesions stimulated interest in the role of cholesterol and lipids in atherosclerosis. Lipid-containing arterial lesions in cholesterol-overfed animals (cholesterolosis) and xanthomatous vascular lesions in subjects with familial hypercholesterolemia were then misrepresented as being atherosclerotic and led to the development of the hypercholesterolemic/lipid hypothesis. It is untenable that cholesterol, an essential multifunctional metabolite, is pathogenic at all blood levels and hypercholesterolemia is not prerequisite for human or experimental atherosclerosis. Serum cholesterol levels display a poor correlation with atherosclerosis at autopsy and with unreliable national coronary heart disease (CHD) mortality in each sex. Atherosclerosis topography and its iatrogenic production in humans and experimentally in herbivores by hemodynamic means both support a biomechanical causation and preclude causality by any circulating humoral factor. CHD, not a specific disease, is a nonspecific complication of many diseases including atherosclerosis and cannot be equated with coronary atherosclerosis due to differences in pathology and pathogenesis. Thus, extrapolations from CHD risk factors or correlations with fallacious vital statistics to atherosclerosis are invalid. It follows that the hypercholesterolemic/lipid hypothesis evolving from false premises, misuse of CHD, scientific misrepresentation, and fallacious data has no legitimate basis.     

Coronary heart disease in menopausal women: implications of primary and secondary prevention trials of hormones

In direct contrast to the observational studies, both primary and secondary prevention trials of female reproductive hormones have found no benefit for coronary heart disease (CHD). Basic science studies have elucidated several mechanisms by which estrogen may improve coronary arterial physiology and prevent pathology, but have also found mechanisms by which estrogen might increase coagulation or inflammation, or might trigger coronary events in advanced lesions. Animal studies suggest that hormones may retard early atherosclerosis, while both animal studies and human angiographic trials are conclusive that hormones do not retard progression of raised lesions. Hormone use in the primary prevention observational studies would mostly have started at the age of menopause, in women whose arteries on average would be closer to normal than those of women in the clinical trials. One hypothesis worthy of further study is that estrogen may have a beneficial effect in normal or near-normal arteries, but the opposite effect in the presence of established atherosclerosis. However, at the average age of menopause, a substantial proportion of women has raised lesions, and a smaller proportion already has advanced lesions. Also, the apparent benefit of hormone use was found in secondary prevention observational studies, i.e., in women with compromised arteries. It is likely that uncorrected biases in the observational studies lead to an overestimation of any benefit of hormone use. On the other hand, endogenous estradiol may be responsible for the later onset of coronary disease in women compared to men; if so, then the appropriate test of the estrogen hypothesis would employ transdermal estradiol in a young population of menopausal women. Hormones are not indicated for the prevention of CHD, particularly in the light of the increased risk for stroke and venous thrombosis. Their use for other indications (menopausal symptoms, osteoporosis) needs to be tempered by the risk for cardiovascular disease (CVD).     

Percutaneous transluminal coronary angioplasty of focal coronary lesions after cardiac transplantation

Summary Transplant coronary artery disease is the greatest impediment to long-term survival beyond the first year after cardiac transplantation. Transplant coronary artery disease shows a heterogeneous angiographic appearance, but focal stenoses can occur alone or at least predominate. Based on an angiographic indication 35 critical focal lesions causing narrowing by 75% or more were treated by PTCA during 23 procedures in seven patients 18–84 months after cardiac transplantation. Three patients each underwent only one procedure and four underwent repeated procedures [2, 3, 4 and 11, respectively]. Primary success was achieved without any complication in 35 of 35 lesions (100%). The mean degree of stenosis was reduced from 86±9% to 28±17% (P<0.001). The rate of restenosis was 18/29 (62%) at a mean of 4 months after angioplasty. Four patients are alive and free of adverse effects (symptoms, myocardial infarction, repeated percutaneous transluminal coronary angioplasty, retransplantation) 16±10 months after their last angioplasty. One patient underwent a successful second heart transplantation 26 months after the first angioplasty. Two patients died, 1 and 31 months after the last angioplasty. In conclusion, percutaneous transluminal coronary angioplasty can be performed safely with an excellent primary success rate in critical focal transplant coronary artery disease. The rate of restenosis is higher than in native coronary artery disease. Long-term follow-up depends on the individually variable accelerated nature of graft atherosclerosis.Abbreviations PTCA percutaneous transluminal coronary angioplasty - TxCAD transplant coronary artery disease - HTX heart transplantation - LAD left anterior decending artery - CFX circumflex artery - RCA right coronary artery     

Molecular study of human herpesvirus 6 and 8 involvement in coronary atherosclerosis and coronary instability

Several lines of evidence suggest the involvement of infectious agents in the pathogenesis of atherosclerosis. Furthermore, a correlation between infection‐driven inflammatory burden and acute manifestation of coronary artery disease has been hypothesized. The aim of this work was to assess whether human herpesvirus (HHV)‐6 and HHV‐8, two DNA viruses with a distinct tropism for endothelium and lymphocytes, may be associated with coronary instability. An age‐ and gender‐matched cross‐sectional study was undertaken in 70 patients with testing of plasma HHV‐6 and HHV‐8 DNA load in different cardiovascular clinical settings: 29 patients with acute myocardial infarction, 21 patients with stable coronary artery disease, and 20 patients without coronary and carotid artery atherosclerosis subjected to cardiac valve replacement. In all patients, HHV‐6 and HHV‐8 plasma DNA was tested by using highly sensitive, calibrated quantitative real‐time PCR assays which employ a synthetic DNA calibrator to adjust for DNA extraction and amplification efficiency. HHV‐8 viremia was undetectable in all three groups. HHV‐6 viremia was detected in a substantial fraction of the samples examined (18.6%) without significant differences among the three groups (ST segment elevation myocardial infarction: 17.2%; stable coronary artery disease: 14.3%; patients without coronary and carotid artery atherosclerosis: 25%). Furthermore, no significant differences in plasma HHV‐6 load were observed amongst the three groups of patients. These findings indicate that coronary instability is not associated specifically with active HHV‐6 or HHV‐8 infection. However, an unusually high rate of active HHV‐6 infection was documented among patients without atherosclerosis admitted to hospital with cardiac disease. J. Med. Virol. 84:1961–1966, 2012. © 2012 Wiley Periodicals, Inc.     

C-reactive protein (CRP) in the cardiovascular system

CRP (C-reactive protein) is an acute-phase reactant, the levels of which increase dramatically in response to severe bacterial infection, physical trauma, and other inflammatory conditions. CRP is found in human atherosclerotic lesions. Atherosclerosis is clearly multifactorial in origin, and chronic inflammation is an important component in its pathogenesis. Focus on inflammation is critical in research on atherosclerosis. Elevated levels of CRP have been associated with increased risk of future coronary artery disease (CAD) events. I have summarized the recent literature on CRP studies in CAD. Both coronary heart disease and dilated cardiomyopathy(DCM) result in congestive heart failure due to myocardial damage. The inflammatory state produced by myocarditis of viral or other origin may induce advanced myocardial damage, resulting in heart failure with a poor prognosis. Routine CRP measurement proved to be valuable for identifying high-risk patients with DCM and lymphocytic myocarditis. I suggest that measurement of circulating CRP would be useful for the diagnosis of and for selecting therapeutic strategies for cardiovascular disorders.     

Role of oxidative modifications in atherosclerosis

This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.