Plasma levels of Hsp70 and anti-Hsp70 antibody predict risk of acute coronary syndrome

Although immune reactions against heat shock proteins have been implicated in the pathogenesis of atherosclerosis, conflicting associations between Hsp70, anti-Hsp70 antibody and coronary heart disease (CHD) have been reported. This study assessed whether there is a significant association between extracellular human Hsp70, anti-Hsp70 antibody and acute coronary syndrome (ACS) and stable angina (SA), and examined dynamic changes in Hsp70 and anti-Hsp70 antibody levels induced by acute myocardial infarction (AMI). Plasma Hsp70 and anti-Hsp70 antibody levels in 291 patients with ACS (179 AMI, 112 unstable angina), 126 patients with SA and 417 age and sex-matched healthy subjects, and in 40 patients after admission for AMI, and on day 2, 3, and 7 after the onset of AMI were determined using enzyme-linked immunosorbent assays. Hsp70 levels were significantly higher in ACS and SA and anti-Hsp70 antibody levels were only markedly lower in ACS than controls. After adjustment for traditional CHD risk factors, increasing levels of Hsp70 were significantly associated with an increased risk and severity of ACS (P for trend < 0.001), whereas increasing levels of anti-Hsp70 antibody were associated with a decreased risk of ACS (P for trend = 0.0003). High levels of Hsp70 combined with low levels of anti-Hsp70 antibody had a joint effect on the risk of ACS (OR, 5.14, 95% CI, 3.00-8.79; P < 0.0001). In patients with AMI, Hsp70 levels decreased rapidly from days 1-7 after onset, whereas anti-Hsp70 antibody levels increased in patients with AMI. These findings suggest that higher Hsp70 levels or lower anti-Hsp70 antibody levels are independently associated with a higher risk of ACS. Higher Hsp70 levels and lower anti-Hsp70 antibody levels combine to further increase this risk.     

冠心病全基因组关联研究进展

近年来全基因组关联研究在世界范围内发展迅猛,研究者应用全基因组关联研究策略发现了一系列疾病的相关基因或变异,将疾病的基因组研究推向一个新的阶段。冠心病是一种由环境因素和遗传因素共同作用导致的复杂疾病,且是世界范围内死亡和致残的首要原因之一,世界各地的研究者应用此策略发现了候选基因关联研究未曾发现的多个冠心病相关易感区域。文章对近年来世界范围内针对冠心病的全基因组关联研究取得的重要进展进行简要总结,然后就现阶段全基因组关联研究所面临的挑战以及对未来研究的发展趋势进行分析阐述,为进一步探究冠心病的遗传机制提供指导。     

The biology and chemistry of hyperlipidemia

Coronary arterial diseases are responsible for more deaths than all other associated causes combined. Elevated serum cholesterol levels leading to atherosclerosis can cause coronary heart disease (CHD). Reduction in serum cholesterol levels reduces the risk for CHD, substantially. Medicinal chemists all around the world have been designing, synthesizing, and evaluating a variety of new bioactive molecules for lowering lipid levels. This review summarizes the disorders associated with elevation of lipids in blood and the current strategies to control them. The emphasis has been laid in particular on the new potential biological targets and the possible treatments as well as the current ongoing research status in the field of lipid lowering agents.     

Improvement in Prediction of Coronary Heart Disease Risk over Conventional Risk Factors Using SNPs Identified in Genome-Wide Association Studies

Objective

We examined whether a panel of SNPs, systematically selected from genome-wide association studies (GWAS), could improve risk prediction of coronary heart disease (CHD), over-and-above conventional risk factors. These SNPs have already demonstrated reproducible associations with CHD; here we examined their use in long-term risk prediction.

Study Design and Setting

SNPs identified from meta-analyses of GWAS of CHD were tested in 840 men and women aged 55–75 from the Edinburgh Artery Study, a prospective, population-based study with 15 years of follow-up. Cox proportional hazards models were used to evaluate the addition of SNPs to conventional risk factors in prediction of CHD risk. CHD was classified as myocardial infarction (MI), coronary intervention (angioplasty, or coronary artery bypass surgery), angina and/or unspecified ischaemic heart disease as a cause of death; additional analyses were limited to MI or coronary intervention. Model performance was assessed by changes in discrimination and net reclassification improvement (NRI).

Results

There were significant improvements with addition of 27 SNPs to conventional risk factors for prediction of CHD (NRI of 54%, P<0.001; C-index 0.671 to 0.740, P = 0.001), as well as MI or coronary intervention, (NRI of 44%, P<0.001; C-index 0.717 to 0.750, P = 0.256). ROC curves showed that addition of SNPs better improved discrimination when the sensitivity of conventional risk factors was low for prediction of MI or coronary intervention.

Conclusion

There was significant improvement in risk prediction of CHD over 15 years when SNPs identified from GWAS were added to conventional risk factors. This effect may be particularly useful for identifying individuals with a low prognostic index who are in fact at increased risk of disease than indicated by conventional risk factors alone.     

Magnified Risks From Cigarette Smoking for Coronary Prone Families in Utah

The contribution of currently accepted risk factors to the familiality of early coronary heart disease (CHD) is poorly understood. In a telephone and mail survey, risk factor and disease morbidity and mortality data were collected from 100 proband and 185 control families encompassing about 40,000 person-years of experience. Probands were white married men who had died of CHD by age 45. There was a threefold increase in CHD incidence among first-degree relatives of probands compared with control families. In all, 67% of probands had at least one first-degree relative with early CHD, and 29% had two or more first-degree relatives with early CHD compared with 8% of the control families with two or more cases of early CHD.The most striking new finding of this study is the apparently magnified liability of cigarette smoking in families prone to have early coronary heart disease. This effect was seen strongly at younger ages (under 50). Furthermore, in about a third of all families with a history of early CHD, smoking seemed to be the only risk factor contributing to the familial occurrence of the disease. The findings show a large excess absolute risk for CHD among smoking members of proband families and further suggest a possibly heritable susceptibility to the deleterious effects of smoking in many families prone to early coronary disease. Modification of coronary risk factors, especially cigarette smoking, would be of greatest benefit among members of high-risk families.     

Coronary heart disease in relation to age,sex, and the menopause.

Examination of the Registrar General''s mortality data suggested that women do not lose protection from coronary heart disease (CHD) after the menopause. Apparently, at around the age of 50 men begin to lose a factor that had previously put them at increased risk of developing CHD compared with women. Male sex hormones may be risk factors for CHD, and further studies are needed to clarify their role in the aetiology of CHD in men.     

Women and the management of acute coronary syndrome

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in both men and women in the developed countries. Despite this fact, females are still under-represented in the majority of clinical trials. At the present time, only limited evidence is available with respect to the female-specific aspects of pathogenesis, management, and outcomes in acute coronary syndrome (ACS). Women less frequently undergo coronary intervention, and a lower proportion of women receive evidence-based pharmacotherapy, compared with men. It has been shown that women benefit from an invasive approach and coronary intervention in ACS as much as men, despite their advanced age and higher rate of bleeding complications. Also, administration of beta-blockers, ACE-inhibitors, and intensive statin therapy is associated with a comparable reduction of cardiovascular event rates in women and men. On the other hand, women may profit less than men from fibrinolytic or glycoprotein IIb/IIIa inhibitor therapy. Both sexes benefit equally from aspirin therapy, whereas contradictory data are available on the efficacy of clopidogrel in women. There is an urgent need for intensive research in the development of female-specific therapeutic strategy in ACS, even though the detailed mechanisms of sex differences are still unknown.     

Cholesterol lowering and the vessel wall: new insights and future perspectives.

The basis for most acute coronary events is either rupture or fissuring of unstable atherosclerotic plaques with subsequent thrombosis leading to coronary artery occlusion. The development of atherosclerotic plaques takes several decades, but the mechanical features determining its stability and the risk of rupture can change very rapidly depending on a number of internal factors. Unstable plaques have a large lipid core, a thin overlying fibrous cap and an abundance of inflammatory cells. The most important factor determining the plaque stability is the plasma level of atherogenic LDL particles. Increased levels of these particles cause endothelial dysfunction with impaired vasodilatation capacity and prevalence of vasoconstriction, maintain inflammatory infiltration of the plaque, impair the strength of the fibrous cap and facilitate aggregation and coagulation. Effective lowering of plasma cholesterol by pharmacological and non-pharmacological means can revert most of these processes and increase the plaque's mechanical stability within several hours to days. Lipid lowering therapy can therefore decrease the risk of acute coronary events within a very short space of time. Thus a radical decrease in lipid levels, along with modification of other risk factors, may become the cornerstone for treatment of acute coronary syndromes, in addition to being an effective treatment in primary and secondary prevention of coronary heart disease (CHD).     

Trans fatty acids: effects on cardiometabolic health and implications for policy

In both developed and developing countries, trans fatty acids (TFA) are largely consumed from partially hydrogenated vegetable oils. This article focuses on TFA as a modifiable dietary risk factor for cardiovascular disease, reviewing the evidence for lipid and non-lipid effects; the relations of trans fat intake with clinical endpoints; and current policy and legislative issues. In both observational cohort studies and randomized clinical trials, TFA adversely affect lipid profiles (including raising LDL and triglyceride levels, and reducing HDL levels), systemic inflammation, and endothelial function. More limited but growing evidence suggests that TFA also exacerbate visceral adiposity and insulin resistance. These potent effects of TFA on a multitude of cardiovascular risk factors are consistent with the strong associations seen in prospective cohort studies between TFA consumption and risk of myocardial infarction and coronary heart disease (CHD) death. The documented harmful effects of TFA along with the feasibility of substituting partially hydrogenated vegetable oils with healthy alternatives indicate little reason for continued presence of industrially produced TFA in food preparation and manufacturing or in home cooking fats/oils. A comprehensive strategy to eliminate the use of industrial TFA in both developed and developing countries, including education, food labeling, and policy and legislative initiatives, would likely prevent tens of thousands of CHD events worldwide each year.     

The T29C polymorphism of the transforming growth factor-β1 (TGF-β1) gene is associated with genetic susceptibility to acute coronary syndrome in Mexican patients

Inflammation plays an essential role in the development and progression of atherosclerotic lesions, and plaque disruption. The TGF-β1 plays an important role in the anti-inflammatory process. The aim of the present study was to evaluate the role of TGF-β1 gene polymorphisms as susceptibility markers for acute coronary syndrome (ACS). Two polymorphisms (TGF-β -509T>C and TGF-β T29C) of the TGF-β gene were analyzed by 5' exonuclease TaqMan genotyping assays in a group of 426 patients with coronary acute syndrome and 551 healthy unrelated controls. A significant difference was observed in the distribution of TGF-β T29C polymorphism between ACS patients and healthy controls (P<10(-3)). According to the co-dominant model, individuals with the TGF-β 29 TT genotype have a 2.5-fold increased risk of developing ACS (P<10(-3)). Multiple logistic analysis showed that the largest risk factor for developing ACS was given by smoking habit, diabetes, hypertension, dyslipidemia, and the TGF-β1 29 TT genotype. The analysis of linkage disequilibrium showed one haplotype (TT) with increased frequency and one haplotype (CC) with decreased frequency in ACS patients when compared to healthy controls. The results suggest that TGF-β1 T29C gene polymorphism could be involved in the risk of developing ACS in Mexican individuals.     

Transforming Growth Factor Beta (TFG-β) Concentration Isoforms are Diminished in Acute Coronary Syndrome

Acute coronary syndrome (ACS) is the leading cause of death in elderly patients worldwide. Due its participation in apoptosis, fibrosis, and angiogenesis, transforming growth factor-β (TGF-β) isoforms had been categorized as risk factors for cardiovascular diseases. However, due their contradictory activities, a cardioprotective role has been suggested. The aim was to measure the plasma levels of TGF-β1, 2, and 3 proteins in patients with ACS. This was a case–control study including 225 subjects. The three activated isoforms were measured in serum using the Bio-Plex Pro TGF-β assay by means of magnetic beads; the fluorescence intensity of reporter signal was read in a Bio-Plex Magpix instrument. We observed a significant reduction of the three activated isoforms of TGF-β in patients with ACS. The three TGF-β isoforms were positively correlated with each other in moderate-to-strong manner. TGFβ-2 was inversely correlated with glucose and low-density lipoprotein (LDL)-cholesterol, whereas TGF-β3 was inversely correlated with the serum cholesterol concentration. The production of TGF-β1, TGF-β2, and TGF-β3 are decreased in the serum of patients with ACS. Further follow-up controlled studies with a larger sample size are needed, in order to test whether TGF-β isoforms could be useful as biomarkers that complement the diagnosis of ACS.     

Phytosterol plasma concentrations and coronary heart disease in the prospective Spanish EPIC cohort

Phytosterol intake with natural foods, a measure of healthy dietary choices, increases plasma levels, but increased plasma phytosterols are believed to be a coronary heart disease (CHD) risk factor. To address this paradox, we evaluated baseline risk factors, phytosterol intake, and plasma noncholesterol sterol levels in participants of a case control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) Spanish cohort who developed CHD (n = 299) and matched controls (n = 584) who remained free of CHD after a 10 year follow-up. Sitosterol-to-cholesterol ratios increased across tertiles of phytosterol intake (P = 0.026). HDL-cholesterol level increased, and adiposity measures, cholesterol/HDL ratios, and levels of glucose, triglycerides, and lathosterol, a cholesterol synthesis marker, decreased across plasma sitosterol tertiles (P < 0.02; all). Compared with controls, cases had nonsignificantly lower median levels of phytosterol intake and plasma sitosterol. The multivariable-adjusted odds ratio for CHD across the lowest to highest plasma sitosterol tertile was 0.59 (95% confidence interval, 0.36–0.97). Associations were weaker for plasma campesterol. The apolipoprotein E genotype was unrelated to CHD risk or plasma phytosterols. The data suggest that plasma sitosterol levels are associated with a lower CHD risk while being markers of a lower cardiometabolic risk in the EPIC-Spain cohort, a population with a high phytosterol intake.     

Fifty-three year follow-up of coronary heart disease versus HDL2 and other lipoproteins in Gofman's Livermore Cohort

To assess the relationships of lipoprotein mass concentrations to all-cause and coronary heart disease (CHD) mortality, we analyzed the prospective 53-year follow-up of 1,905 men measured for lipoprotein mass concentrations by analytic ultracentrifugation between 1954 and 1957. Cause of death was determined from medical records and death certificates before 1979 and from National Death Index death diagnoses thereafter. Of the 1,329 men (69.8%) who died through 2008, CHD was listed as a contributing cause of death for 409 men, including 113 deaths from premature CHD (age ≤ 65 years). When adjusted for age, the risk associated with the lowest HDL2 quartile increased 22% for all-cause (P = 0.001), 63% for total CHD (P < 10(-5)), and 117% for premature CHD mortality (P = 0.0001). When adjusted for standard risk factors (age, total cholesterol, blood pressure, BMI, smoking) and the lowest HDL3 quartile, the corresponding risk increases were 14% (P = 0.05), 38% (P = 0.004), and 62% (P = 0.02), respectively. Men with HDL3 ≤ 25(th) percentile had 28% greater total CHD risk (P = 0.03) and 71% greater premature CHD risk (P = 0.01). Higher LDL-mass concentrations increased total CHD risk by 3.8% (P < 10(-9)) and premature CHD risk by 6.1% (P < 10(-7)) per 10 mg/dl increase in concentration. Thus, low HDL2 is associated with increased CHD risk.     

Plasma lipids and lipoprotein patterns in angiographically graded atherosclerosis of the legs and in coronary heart disease.

The prevalence and type of plasma lipoprotein abnormalities were determined in 114 French-Canadian patients with angiographically proven peripheral vascular disease (PVD). The severity of atherosclerosis was positively correlated with plasma triglyceride concentration, especially in the younger patients (r = 0.29, P less than 0.05), and (not significantly) with plasma cholesterol concentration. Of the risk factors believed to predispose individuals to atherosclerosis, cigarette smoking was the most frequently found in the PVD patients (72.8%), especially among the men. Combination of two or more risk factors was the rule. Findings were compared with those in 114 patients who had undergone coronary angiography for suspected coronary heart disease (CHD). The CHD patients were, on average, younger by 10 years. Hyperlipidemia was present in 58.8% of CHD patients, compared with 43.9% of PVD patients. A far higher proportion of CHD patients showed the type II plasma lipoprotein pattern (24.6% v. 7.9%), although the type IV pattern was more common in both groups (31.6% and 28.9%, respectively). A high proportion of all patients (56.1% with PVD and 41.2% with CHD) showed a normal lipoprotein pattern on paper electrophoresis.     

The prevalence of cardiovascular disease risk factors in patients from Croatian Zagorje County treated at Department of Medicine, Zabok General Hospital from 2000 to 2006

The aim of the study was to assess the prevalence of risk factors for cardiovascular disease in patients treated for coronary heart disease (CHD) at Department of Medicine, Zabok General Hospital during the 2000-2006 period. Cardiovascular diseases are a group of diseases that occur due to arterial. The risk factors that lead to the development and occurrence of cardiovascular disease are hypertension, cigarette smoking, hyperholesterolemia, hypertriglyceridemia, diabetes mellitus and positive family history. Additional factors favoring the occurrence of cardiovascular disease include overweight, inadequate physical activity, and emotional stress. Data on all patients hospitalized and diagnosed with CHD at Department of Medicine, Zabok General Hospital during the 2000-2006 period were analyzed for the prevalence of risk factors for CHD, i.e. hypertension, cigarette smoking, hypercholesterolemia, hypertriglyceridemia, diabetes mellitus and positive family history of cardiovascular disease. Hypercholesterolemia was defined by a cholesterol level higher than 5.1 mmol/L, hypertension from history data and blood pressure measurement on admission greater than 140/90 mmHg, diabetes mellitus from history data, and hypertriglyceridemia by a triglyceride level greater than 1.7 mmol/L. Information on heredity and cigarette smoking was collected from history and a questionnaire filled out on admission. All laboratory values were determined on patient admission to the hospital. Analysis of the risk factors for CHD recorded in patients from Zagorje County during the 2000-2006 period revealed hypertension to be the most common risk factor in our patients. According to sex, CHD was found to show a male preponderance. According to age at admission, CHD predominated in the > 70 age group, which accounted for one third of all patients, followed by a comparable proportion of the 50-60 and 60-70 age groups, i.e. still active population groups. As CHD is one of the leading health threats worldwide, estimated to remain so at least by 2020, it is fully justified to invest all efforts in the study of cardiovascular disease. New research projects should be focused on the prevention and early detection of the disease, improvement of diagnosis procedures, introduction of novel therapeutic options, use of new concepts, and due survey of the measures taken. CHD poses great socioeconomic burden upon every community in industrialized societies because of the ever younger age at onset. Actions should be taken to improve awareness of the CHD risks and morbidity in the population at large, stimulating favorable lifestyle and dietary modifications, and one's own health awareness, in order to upgrade the control of risk factors for and morbidity of cardiovascular disease.     

A pilot Croatian survey of risk factor (CRO-SURF) management in patients with cardiovascular disease

A pilot survey was performed to determine the presence of known risk factors for cardiovascular disease in Croatian patients with diagnosed coronary heart disease (CHD) using a new questionnaire. The idea was to test this new and very simple questionnaire but also to compare the data collected in this pilot survey with the results of the last Croatian national survey (TASPIC-CRO V) and so to obtain the information whether secondary prevention has improved between 2003 and 2010. 122 patients with established CHD (88 men, 34 women, mean age 66.3 years) treated in Zagreb University Hospital Center were included. Data collection was based on filling the SURF questionnaire right after the clinical exam or later using review of medical records. Patients were hospitalized because of CABG (1%), PCI (8%), ACS (35%) or chronic stable angina (56%). The history of arterial hypertension had 95%patients (however, on admission mean systolic pressure was 130.1 mmHg, diastolic 76.8 mmHg), 90% had dyslipidaemia (total cholesterol <4.5 mmol/L had 43%; <4.0 mmol/L 33%; LDL-cholesterol <2.5 mmol/L 49%; <2.0 mmol/L 32%; HDL>1.2 mmol/L (women) or >1.0 mmol/L (men) had 67%), 25% had diabetes which was poorly regulated (mean HbA1c 8.2%), 18% were active smokers. After discharge only 24% performed cardiac rehabilitation. Mean body mass index of the patients was 28.3 kg/m2 (32% were obese, 72% overweight). Compared to TASPIC-CRO V there was lower usage of aspirin than recommended on discharge. This was also true for statin therapy. More patients were taking beta blockers, calcium antagonists and diuretics than 7 years ago. This pilot survey showed that CRO-SURF questionnaire is short, quick, effective and simple to use. It is a good and cost effective tool to collect data on CVD risk factors and their management. The results obtained by using it indicate that there is still a high prevalence of modifiable risk factors in Croatian patients with CHD.     

Influences of genetic variants in interleukin-15 gene and serum interleukin-15 levels on coronary heart disease

Interleukin-15 (IL-15) is a potent proinflammatory cytokine that is now considered a key component of atherosclerosis. Proinflammatory gene polymorphisms lead to variations in the production and level of the proteins. In light of these findings, we hypothesized that variations in the gene coding for IL-15 influence the risk of coronary heart disease (CHD) by modulating the IL-15 levels. To test this hypothesis, we examined 5 single nucleotide polymorphisms (SNPs) in IL-15 gene and IL-15 levels in 102 patients with acute coronary syndrome (ACS), 102 patients with chronic ischemic stable CHD and 162 healthy control subjects. This study is the first report showing the influences of IL-15 gene variants and IL-15 levels on CHD. The five single nucleotide polymorphisms (SNPs) within the IL-15 gene, G367A, C267T, A14035T, C13687A, and A10504G were carried out by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Serum IL-15 levels were significantly higher in both acute and chronic patients than in controls. Genetic variants of IL-15 gene and IL-15 levels were associated with CHD. In conclusion, our study supports the hypothesis that genetic variation in IL-15 gene and IL-15 levels influence the risk of CHD. Further studies are needed to confirm our hypothesis.