Prospective cohort studies on risk factors for cardiovascular events in systemic lupus erythematosus: a major challenge

Cardiovascular disease (CVD) has been identified as a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). The etiology of premature CVD in SLE is supposed to have many factors, including traditional coronary artery disease (CAD) risk factors, antiphospholipid antibodies, and metabolic and inflammatory factors. Despite the overwhelming interest in CVD in SLE research, prospective studies evaluating risk factors for hard endpoints (that is, cardiovascular events) are relatively scarce. The article by Gustafsson and colleagues suggests that prothrombotic factors play an important role in SLE-related CVD and that the influence of traditional CAD risk factors might be limited.     

肠道菌群及其代谢产物氧化三甲胺——冠心病治疗的新靶点

冠心病 (Coronary artery disease,CAD) 是全球发病率和死亡率最高的一种心血管疾病,冠心病和肠道菌群失调密切相关,肠道菌群可能是未来冠心病的重要诊断标志物,改善肠道菌群微环境有望成为治疗冠心病的新途径。作为肠道菌群参与合成的活性代谢产物,氧化三甲胺 (Trimethylamine-N-oxide,TMAO) 水平的升高与心血管疾病患病风险、全因死亡率的增加有关;基础研究表明TMAO可能具有促动脉粥样硬化特性;这些研究提示TMAO可作为预防和治疗冠心病的潜在靶点。文中分析了当前调控肠道菌群及其代谢产物TMAO治疗冠心病的临床及基础性研究,以期为冠心病的治疗提供帮助。     

Lack of Association Between a Common Polymorphism Near the INSIG2 Gene and BMI,Myocardial Infarction,and Cardiovascular Risk Factors

Epidemiological studies revealed an increasing prevalence of and a steep increase in obesity, a risk factor for cardiovascular disease. Because significant influence of a polymorphism, rs7566605, near the INSIG2 gene on BMI has been shown in the general population and in obesity cohorts, we hypothesized that this polymorphism might also act through an elevated BMI on the development of coronary artery disease (CAD) or myocardial infarction (MI). We pursued two strategies: First, the polymorphism rs7566605 was investigated for association with BMI, CAD/MI, and cardiovascular risk factors in a large German cohort at high risk for CAD and MI (n = 1,460 MI patients) as compared to unrelated healthy controls (n = 1,215); second, we extended our analyses on the families of MI patients and performed family‐based association testing (n = 5,390 individuals). The polymorphism rs7566605 was analyzed using TaqMan technology. No deviation from Hardy–Weinberg equilibrium could be observed, and the call rate was 98.2%. No significant associations of rs7566605 with CAD/MI, BMI, and classical cardiovascular risk factors could be detected in the full sample size or in the subgroups. A total of 6,878 individuals were investigated in a population of German MI patients and their family members. Although the number of individuals was large enough, no influence of the rs7566605 INSIG2 polymorphism was detected on BMI and CAD/MI. We therefore conclude that in our sample the SNP rs7566605 near the INSIG2 gene does not influence BMI and is not associated directly with CAD/MI or indirectly through cardiovascular risk factors.     

Managing concomitant cardiac disease and erectile dysfunction

Early studies of peak heart rates and blood pressure during coitus led physicians to believe that sexual activity represents a significant risk to patients with cardiovascular disease. Subsequent studies indicated, however, that the heart rate during coitus was no higher than the rate during unaccustomed physical exercise or associated with anger. The absolute risk of myocardial infarction (MI) in a patient with a history of MI has been found to be 10 per million per hour, and the doubling of this risk in the 2 hours following coitus has a negligible impact on annual risk. Coronary artery disease (CAD) is a powerful indicator of the presence of erectile dysfunction (ED), and the risk factors for ED are similar to those for CAD. Studies of sildenafil citrate use in patients with a history of cardiovascular disease have found sildenafil to be safe and effective, except for an absolute contraindication in the concomitant use of nitrates. Physicians should become familiar with the clinical guidelines for classifying ED patients with a history of cardiovascular disease as high risk, intermediate or indeterminate risk, and low risk. The guidelines permit physicians MIlow risk while deferring the resumption of sexual activity among higher risk patients pending further evaluation.     

Association of polymorphisms in the chemokine receptor CX3CR1 gene with coronary artery disease

Two chemokine receptor CX3CR1 gene variants, V249I and T280M, have been implicated in coronary artery diseases (CAD). Currently no consistent effect has been revealed and their role in cardiovascular disease is still conflicting. In the present study the association of CX3CR1 genotypes with CAD and myocardial infarction (MI) was investigated in the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, including 3316 individuals in whom cardiovascular disease angiographically has been defined or ruled out. Similarly to previous studies, the alleles I249 and M280 were in strong linkage disequilibrium and formed an I₂₄₉M₂₈₀ haplotype. However, there was no relationship between CX3CR1 genotypes or corresponding haplotypes and the prevalence of CAD or MI. Adjusted for classical risk factors (age, sex, hypertension, dyslipidemia, diabetes mellitus and smoking), the odds ratio (OR) of V249I for CAD was 0.95 (95% confidence interval (CI) = 0.78–1.15, p = 0.61). The OR of T280M for CAD was 0.83 (95% CI = 0.66–1.04, p = 0.11). Furthermore, CX3CR1 variants were not associated with C-reactive protein levels, age at onset of CAD, severity of CAD and MI. In conclusion, present data of LURIC do not support the hypothesis that common variants of the CX3CR1 gene are associated with the presence of CAD or MI.     

Nutritional status, genetic susceptibility, and insulin resistance--important precedents to atherosclerosis

Atherosclerosis is a progressive disease that starts early in life and is manifested clinically as coronary artery disease (CAD), cerebrovascular disease, or peripheral artery disease. CAD remains the leading cause of morbidity and mortality in Western society despite the great advances made in understanding its underlying pathophysiology. The key risk factors associated with CAD include hypercholesterolemia, hypertension, poor diet, obesity, age, male gender, smoking, and physical inactivity. Genetics also play an important role that may interact with environmental factors, including diet, nutritional status, and physiological parameters. Furthermore, certain chronic inflammatory conditions also predispose to the development of CAD. The spiraling increase in obesity rates worldwide has made it more pertinent than ever before to understand the metabolic perturbations that link over nutrition to enhanced cardiovascular risk. Great breakthroughs have been made at the pharmacological level to manage CAD; statins and aspirin have revolutionized treatment of CAD and prolonged lifespan. Nonetheless, lifestyle intervention prior to clinical presentation of CAD symptoms would negate/delay the need for chronic pharmacotherapy in at-risk individuals which in turn would relieve healthcare systems of a costly burden. Throughout this review, we debate the relative impact of nutrition versus genetics in driving CAD. We will investigate how overnutrition affects adipose tissue biology and drives IR and will discuss the subsequent implications for the cardiovascular system. Furthermore, we will discuss how lifestyle interventions including diet modification and weight loss can improve both IR and metabolic dyslipidemia that is associated with obesity. We will conclude by delving into the concept that nutritional status interacts with genetic susceptibility, such that perhaps a more personalized nutrition approach may be more effective in determining diet-related risk as well as response to nutritional interventions.     

The action of ovarian hormones in cardiovascular disease

The incidence of cardiovascular disease (CAD) differs between men and women, in part because of differences in risk factors and hormones. This sexual dimorphism means a lower incidence in atherosclerotic diseases in premenopausal women, which subsequently rises in postmenopausal women to eventually equal that of men. These observations point towards estrogen and progesterone playing a lifetime protective role against CAD in women. As exogenous estrogen and estrogen plus progesterone preparations produce significant reductions in low-density lipoprotein (LDL) cholesterol levels and significant increases in high-density lipoprotein (HDL) cholesterol, this should in theory lower the risk of CAD. However, results from oral contraceptive (OC) use and combined estrogen and progesterone hormone replacement therapy (HRT) have suggested that hormone replacement regimes do not provide cardiovascular protection. In fact, depending on the preparation and the presence or absence of genetic risk factors, an increased risk of cardiovascular diseases such as venous thrombosis, myocardial infarction (MI) and stroke have been observed. Interestingly, in the majority of studies the increase in risk was highest in the first year, after which an increase in risk was not observed, and in some studies a lower risk of CAD was evident after four or five years of exogenous hormone administration. While the debate continues about the merits of HRT, and several good reviews exist on the statistics of CAD in relation to exogenous hormones, we have decided to review the literature to piece together the physiological actions of estrogen and progesterone preparations on the individual mechanistic components leading to CAD; namely, the altered endothelium and the haemostatic balance between coagulation and fibrinolysis. We present possible mechanisms for how HRT and OCs protect against MI in the absence of cardiovascular risk factors but increase the incidence of MI in their presence. We also speculate on the roles played by hormones on the short- and long-term risks of cardiovascular disease.     

Insulin resistance, hyperglycemia, and atherosclerosis

Progress in preventing atherosclerotic coronary artery disease (CAD) has been stalled by the epidemic of type 2 diabetes. Further advances in this area demand a thorough understanding of how two major features of type 2 diabetes, insulin resistance and hyperglycemia, impact atherosclerosis. Insulin resistance is associated with systemic CAD risk factors, but increasing evidence suggests that defective insulin signaling in atherosclerotic lesional cells also plays an important role. The role of hyperglycemia in CAD associated with type 2 diabetes is less clear. Understanding the mechanisms whereby type 2 diabetes exacerbates CAD offers hope for new therapeutic strategies to prevent and treat atherosclerotic vascular disease.     

Copper,ceruloplasmin, and long-term cardiovascular and total mortality (The Ludwigshafen Risk and Cardiovascular Health Study)

Abstract

Background. Copper and its main transport protein ceruloplasmin have been suggested to promote the development of atherosclerosis. Most of the data come from experimental and animal model studies. Copper and mortality have not been simultaneously evaluated in patients undergoing coronary angiography. Methods and results. We examined whether serum copper and ceruloplasmin concentrations are associated with angiographic coronary artery disease (CAD) and mortality from all causes and cardiovascular causes in 3253 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Age and sex-adjusted hazard ratios (HR) for death from any cause were 2.23 (95% CI, 1.85–2.68) for copper and 2.63 (95% CI, 2.17–3.20) for ceruloplasmin when we compared the highest with the lowest quartiles. Corresponding hazard ratios (HR) for death from cardiovascular causes were 2.58 (95% CI, 2.05–3.25) and 3.02 (95% CI, 2.36–3.86), respectively. Further adjustments for various risk factors and clinical variables considerably attenuated these associations, which, however, were still statistically significant and the results remained consistent across subgroups. Conclusions. The elevated concentrations of both copper and ceruloplasmin are independently associated with increased risk of mortality from all causes and from cardiovascular causes.     

Emerging relations between infectious diseases and coronary artery disease and atherosclerosis

Cardiovascular disease is the leading cause of death in developed countries. The cause is multifactorial. A substantial proportion of patients with coronary artery disease (CAD) do not have traditional risk factors. Infectious diseases may play a role in these cases, or they may intensify the effect of other risk factors. The association of CAD and Chlamydia pneumoniae infection is firmly established, but causality is yet to be proven. The link with other infectious agents or conditions, such as cytomegalovirus, herpes simplex virus, Helicobacter pylori and periodontitis, is more controversial. Cytomegalovirus infection is more strongly linked than native CAD to coronary artery restenosis after angioplasty and to accelerated CAD after cardiac transplantation. However, new data on this topic are appearing in the literature almost every month. The potential for novel therapeutic management of cardiovascular disease and stroke is great if infection is proven to cause or accelerate CAD or atherosclerosis. However, physicians should not "jump the gun" and start using antibiotic therapy prematurely for CAD. The results of large randomized clinical trials in progress will help establish causality and the benefits of antimicrobial therapy in CAD.     

Will Global Transcriptome Analysis Allow the Detection of Novel Prognostic Markers in Coronary Artery Disease and Heart Failure?

Coronary artery disease (CAD) is one of the leading causes of death in the developed countries. Myocardial infarction (MI) is an acute episode of CAD that results in myocardial injury and subsequent heart failure (HF). In the acute phase of MI several risk factors for future cardiovascular events have been found. The molecular mechanisms of these disorders are still unknown, but altered gene expression may play an important role in the development and progression of cardiovascular diseases. High-throughput techniques should greatly facilitate the elucidation of the mechanisms and provide novel insights into the pathophysiology of cardiovascular diseases. In this review we focus on the perspectives of gene-expression profiling conducted on cardiac tissues and blood for the determination of novel diagnostic and prognostic markers and therapeutic targets.     

Body Mass Index and Coronary Artery Disease in African-Americans

There are limited data available concerning the influence of obesity, a major cardiovascular disease risk factor, in relationship to coronary artery disease (CAD). This is of considerable importance to African-Americans since African-Americans have one of the world's highest CAD mortality rates coupled with the fact that obesity is extremely prevalent in this population. The present study assessed the relationship between body mass index and CAD in African-Americans undergoing coronary angiography. Eight hundred sixty-six available cardiac catheterization reports between the years 1983 through 1990 were retrospectively reviewed at Howard University Hospital in Washington, D.C. CAD was prevalent in 59.6% and 41.2%, males and females, respectively. Among the males overweight and obesity were found in 22.4% and 20.9%, respectively, compared to 39.6% and 30.6% for females. An upside-down U-shaped relationship between BMI and CAD was found. The interpretation of this finding is that being overweight is associated with increased risk of CAD compared to the lean and obese.     

Small dense LDL: risk factor for coronary artery disease (CAD) and its therapeutic modulation

Pathogenesis of coronary artery disease (CAD) is multi-factorial and many risk factors are associated with development of CAD. LDL-C has been an important target for therapeutic interventions and has been extensively studied. But, various studies have indicated that estimation of LDL-C is not enough to assess the risk. Moreover, LDL particles vary in their content, density and size which have different physico-chemical properties. In this paper, the role of small dense (sd) LDL in risk assessment for CAD and its response to different therapeutic modalities available have been reviewed.     

Coronary artery disease: Are men and women created equal?

Background: Ischemic heart disease in women is a difficult issue in cardiovascular medicine, mainly because of our lack of understanding of the early-stage mechanisms and symptoms. A better and earlier understanding of the pathophysiology of coronary artery disease (CAD) in women will enable us to detect ischemic heart disease earlier and prevent adverse clinical outcomes.Objectives: The aims of this article were to describe the phenomenon of ischemic heart disease in women, increase awareness of the difference between men and women in relation to ischemic heart disease, improve our understanding of the mechanisms that cause this difference, and identify new approaches for better and earlier detection and treatment of CAD in women.Methods: We conducted a search of the PubMed database for double-blind studies on the mechanistic pathways of CAD in women published in English within the past 10 years and epidemiologic studies published since 1970. Search terms included women and coronary artery disease and ischemic heart disease in women.Results: The literature search revealed 30 peer-reviewed articles pertaining to this issue. The incidence of CAD was markedly lower in women <60 years of age than in older women. After 60 years of age, the rate of CAD increased and reached the rate seen among men by the 8th decade of life. The gender difference in atherosclerosis in the coronary tree was particularly large in patients <55 years of age and remained large at older ages. The gender difference in the coronary bed was strikingly larger than in other vascular beds. Intensive risk-factor modification had a similar effect on plaque progression in both men and women. Coronary endothelial dysfunction appeared to be related to cardiovascular morbidity and mortality in women as well as in men, and because endothelial dysfunction could be modified, it appeared that the prognosis could be improved by appropriate management. A strong association was found between body mass index (BMI) and metabolic status, but only the metabolic syndrome was associated with CAD. Physical activity was independently associated with fewer risk factors, less CAD, and fewer adverse events in women; however, obesity was not associated with these outcomes.Conclusions: Results of the identified studies suggest that reduction of risk factors is a common approach to fighting heart disease in both sexes. It appears that for women, weight and BMI are not as important as previously thought, but physical exercise and fitness are very important and can change risk factors and clinical outcomes more than any other known intervention. Data suggest that global inflammation may play an important role in women and may predict cardiovascular outcome in women much better than the traditional risk factors that have been used and proved for men.     

Detection of mtDNA with 4977 bp deletion in blood cells and atherosclerotic lesions of patients with coronary artery disease

Recent evidence suggests that somatic mutations in nuclear and mitochondrial DNA accumulated during aging, may significantly contribute to the pathogenesis of chronic-degenerative illness such as coronary artery disease (CAD). Mitochondrial DNA with 4977 bp deletion mutation (mtDNA4977) is a common type of mtDNA alteration in humans. However, little attempt has been made to detect the presence of mtDNA4977 deletion in cells and tissues of cardiovascular patients. This study investigated the presence of mtDNA4977 in blood samples of 65 cardiovascular patients and 23 atherosclerotic plaques of human coronaries with severe atherosclerosis. Moreover, the presence of the deletion has been investigated in blood cells from 22 healthy age-matched subjects. The detection of mtDNA4977 has been performed by using a nested polymerase chain reaction (PCR) protocol and normalized to wild-type mtDNA. A significant higher incidence of mtDNA4977 was observed in CAD patients with respect to healthy subjects (26.2% versus 4.5%; P=0.03). Furthermore, the relative amount of the deletion was significantly higher in the patients compared to the control group (P=0.02). The mtDNA4977 was detected in 17 of the 65 patients blood samples (26.2%) and deletion levels ranged from 0.18 to 0.46% of the total mtDNA (mean: 0.34+/-0.02%). For what concerns atherosclerotic lesions, 5 patients (21.7%) showed the deletion ranging from 0.13 to 0.45% of the total mtDNA (mean: 0.35+/-0.06%). In both samples from patients, the incidence and the relative amount of mtDNA4977 was not significantly influenced by atherogenic risk factors and clinical parameters. The obtained results may suggest that the increase of oxidative stress in cardiovascular disease may be responsible for the accumulation of mtDNA damage in coronary artery disease patients.     

Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women.

Sex steroid hormones in both males and females have been closely related to the regulation of adiposity, either through direct or indirect physiological mechanisms. Evidence also suggests a direct relationship between sex hormones and risk factors for cardiovascular disease. In the present review article, we will discuss recent studies that have examined the complex interrelationships between sex hormones, SHBG, obesity and risk factors for cardiovascular disease. Male obesity and excess abdominal adipose tissue accumulation is associated with reductions in gonadal androgen and low adrenal C19 steroid concentrations. Reduced C19 steroids are also related to an altered metabolic risk factor profile including glucose intolerance and an atherogenic dyslipidemic state. However, the concomitant visceral obese state appears as a major correlate in these associations. In women, menopause-induced estrogen deficiency and increased androgenicity are associated with increased abdominal obesity and with the concomitant alterations in the metabolic risk profile. The accelerated accretion of adipose tissue in the intra-abdominal region coincident with the onset of menopause may explain part of the increased risk of cardiovascular disease in postmenopausal women. In both men and women, plasma levels of sex hormone-binding globulin are strong correlates of obesity and risk factors for cardiovascular disease, and more importantly, the relationships between low SHBG and altered plasma lipid levels appear to be independent from the concomitant increased levels of visceral adipose tissue. SHBG concentration may, therefore, represent the most important and reliable marker of the sex hormone profile in the examination of the complex interrelation of sex steroid hormones, obesity, and cardiovascular disease risk.     

The Diagnostic Value of Clinical Symptoms in Women and Men Presenting with Chest Pain at the Emergency Department,a Prospective Cohort Study

Background

Previous studies suggested that diagnosing coronary artery disease (CAD) is more difficult in women than in men. Studies investigating the predictive value of clinical signs and symptoms and compare its combined diagnostic value between women and men are lacking.

Methodology

Data from a large multicenter prospective study was used. Patients admitted to the emergency department (ED) with chest pain but without ST-elevation were eligible. The endpoint was proven CAD, defined as a significant stenosis at angiography or the diagnosis of a non-ST-elevation myocardial infarction or cardiovascular death within six weeks after presentation at the ED. Twelve clinical symptoms and seven cardiovascular risk factors were collected. Potential predictors of CAD with a p-value <0.15 in the univariable analysis were included in a multivariable model. The diagnostic value of clinical symptoms and cardiovascular risk factors was quantified in women and men separately and areas under the curve (AUC) were compared between sexes.

Results

A total of 2433 patients were included. We excluded 102 patients (4%) with either an incomplete follow up or ST-elevation. Of the remaining 2331 patients 43% (1003) were women. CAD was present in 111 (11%) women and 278 (21%) men. In women 11 out of 12 and in men 10 out of 12 clinical symptoms were univariably associated with CAD. The AUC of symptoms alone was 0.74 (95%CI: 0.69-0.79) in women and 0.71 (95%CI: 0.68-0.75) in men and increased to respectively 0.79 (95%CI: 0.74-0.83) in women versus 0.75 (95%CI: 0.72-0.78) in men after adding cardiovascular risk factors. The AUCs of women and men were not significantly different (p-value symptoms alone: 0.45, after adding cardiovascular risk factors: 0.11).

Conclusion

The diagnostic value of clinical symptoms and cardiovascular risk factors for the diagnosis of CAD in chest pain patients presenting on the ED was high in women and men. No significant differences were found between sexes.     

Metabolic syndrome in rheumatic diseases: epidemiology,pathophysiology, and clinical implications

Subjects with metabolic syndrome–a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic–are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome provides additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity.     

超声检测心外膜脂肪组织厚度与冠心病危险因素相关性分析

目的:探讨高频超声测量冠心病患者心外膜脂肪(EAT)厚度与冠心病危险因素的相关性。方法:96例患者根据冠脉造影结果分为正常组(30例)、冠心病组(66例),用高频超声测量EAT厚度,对EAT厚度与颈动脉内中膜厚度(IMT)等冠心病危险因素进行相关性分析。结果:EAT与IMT、年龄、体质量、腰围、BMI、FPG、LDL-C、UA、CRP呈正相关(P<0.01或P<0.05),与HDL-C呈负相关(P<0.05),与身高、收缩压、舒张压、TC、TG无相关性。结论:超声测量EAT厚度对于冠心病的早期发现具有一定的预测价值。