Endothelial dysfunction in coronary heart disease.
McGorisk G M,Treasure C B
Current opinion in cardiology
Atherosclerosis is a chronic disease characterized by the focal accumulation of plaque (leukocytes, macrophages, smooth muscle cells, lipids, and extracellular matrix) in the vessel wall that ultimately leads to obstruction of the lumen through gradual progression, plaque rupture with intraluminal thrombosis, or both. The "vulnerable" plaque is smaller in size, richer in lipids, and more infiltrated with macrophages than the stable fibromuscular lesion. Therefore, lowering the lipid or macrophage pools stored in the plaque may stabilize the plaque and reduce the risk for plaque rupture. Indeed, cholesterol-lowering trials have yielded a significant reduction in acute cardiac events. Antithrombotic therapy may further prevent acute coronary syndromes by altering the consequences of plaque rupture. However, we need to address the earlier stages of atherosclerosis, namely, endothelial dysfunction. Current hypotheses concerning its pathogenesis focus on vascular endothelial injury, the oxidation of low-density lipoprotein and its effects on the endothelium, which set off a cascade or responses involving the complex interaction of growth factors and cytokines leading to increased oxidative stress, increased free radical formation, destruction of nitric oxide, endothelial dysfunction, increased platelet aggregation, thrombosis, inflammation, plaque formation, proteolysis, plaque fissure, and rupture.
Markers of chronic infection and inflammation. Are they important in cases with chronic coronary heart disease.
Kaftan H A,Kaftan O,Kiliç M
Japanese heart journal
The human cytomegalovirus plays a causal role in atherosclerosis etiology, but it is discussed as controversial. We conducted a case control study to investigate whether previous infection with cytomegalovirus is associated with coronary heart disease and markers of systemic inflammation, because systemic inflammation may play a role in atherosclerosis too. We also studied the correlation between anti-cytomegalovirus antibody titer and coronary artery disease. The study involved 150 cases (45 females, mean age +/- SD is 58.73 +/- 7.68 years) with a documented coronary heart disease and 160 healthy volunteers (50 females, mean age +/- SD is 57.82 +/- 7.68, p > 0.05). Cytomegalovirus serology was performed to determine the presence of specific IgG antibodies and titers of the anti-cytomegalovirus IgG antibodies. In addition, C-Reactive protein levels were determined for each case. The prevalence of specific antibodies to cytomegalovirus was 57.30% for the patients and 56% for the controls (p = 0.39). But higher levels of anti-cytomegalovirus IgG antibody titer (> 1/800) were seen in the patient group (28.6% versus 10%, p = 0.0000). Mean value of C-reactive protein was higher in the patient group (2.99 +/- 0.92 mg/l versus 1.79 +/- 0.51 mg/l, p = 0.0000), and there was a linar correlation with the high antibody titers and the level of C-reactive protein (r = 0.35, p = 0.0000) These findings support that not the seropositivity of the population but rather the titer of anti-cytomegalovirus antibody and the levels of C-reactive protein could predict patients with a high risk of coronary heart disease.
Inflammation markers and coronary heart disease.
Tracy R P
Current opinion in lipidology
Evidence supports the position that the chronic atherothrombotic process is intimately associated with what has classically been called 'inflammation'. Proteins that are part of the acute phase response (e.g. fibrinogen, C-reactive protein) are sensitive markers of low-level inflammation, and in population studies, inflammation marker levels at the upper end of the healthy reference range are associated with the presence of subclinical atherothrombotic disease (e.g. carotid wall thickness) and, prospectively, with future cardiovascular disease events. While there are plausible mechanisms for most of these markers, it remains to be demonstrated whether the markers actually participate in cardiovascular disease, or simply reflect the underlying disease process. This point is important, since marker-specific interventions might be useful if the former position is correct. Recent work suggests that inflammation markers may represent different aspects of the atherothrombotic process at different points in the natural history of the disease. This has implications for the interpretation of marker levels and the timing of the future events that they predict.
Inflammatory markers in men with angiographically documented coronary heart disease.
Rifai N,Joubran R,Yu H,Asmi M,Jouma M
BACKGROUND:Recent evidence suggests that atherosclerosis is a chronic inflammatory process. In this study, we examined several markers of inflammation in men with coronary heart disease (CHD) and appropriate controls. METHODS:The concentrations of C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6), and soluble intracellular adhesion molecule (sICAM-1) were examined in 100 men with angiographically documented CHD and 100 age-, gender-, and smoking-matched controls with no history of CHD. We assessed the association of these markers with severity of disease as indicated by >50% obstruction in one vessel (n = 30), two vessels (n = 39), or three vessels (n = 31). RESULTS:Significant increases were noted in serum CRP (median for cases vs controls, 3.4 vs 1.5 mg/L; P <0.0001), SAA (5.9 vs 3.7 mg/L; P <0.005), and IL-6 (2.3 vs 1.7 ng/L; P <0. 013) in patients with CHD compared with controls. These differences remained significant after correction for age, smoking, hypertension, diabetes, and lipid and homocysteine concentrations. Plasma sICAM-1 was not significantly different between the two groups (335 vs 339 microg/L). No significant correlation was seen between these markers and the severity of coronary disease. CONCLUSIONS:Concentrations of CRP, SAA, and IL-6 were increased in patients with CHD but failed to correlate with severity of coronary disease. These markers might reflect the diffuse atherosclerotic process in the vascular system rather than the degree of localized obstruction from coronary lesions.
Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?
Yudkin J S,Kumari M,Humphries S E,Mohamed-Ali V
There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions.
Relation of inflammation to vascular function in patients with coronary heart disease.
Sinisalo J,Paronen J,Mattila K J,Syrjälä M,Alfthan G,Palosuo T,Nieminen M S,Vaarala O
Endothelium plays a pivotal role in the regulation of vascular relaxation. Inflammation may in turn induce endothelial dysfunction and thus increase the risk of atherothrombosis. We investigated 31 men with angiographically verified coronary heart disease, aged 57. 7+/-5.3 years, in regard to endothelium-dependent, acetylcholine-induced, and to endothelium-independent, sodium nitroprusside-induced vasodilatation in the forearm vasculature by strain-gauge plethysmography. Logistic regression analysis served to determine the relation between forearm vascular function and the inflammatory factors measured, concentration of C-reactive protein, subtypes of peripheral blood T-lymphocytes, and other factors potentially affecting endothelial function (lipoprotein and glucose levels). Concentration of C-reactive protein was an independent determinant of endothelium-dependent vascular function (P<0.001 for low dose acetylcholine, P=0.01 for high dose acetylcholine). Other determinants of endothelium-dependent vascular dysfunction were CD8-lymphocytes expressing ICAM-1 (P=0.001), antibodies to oxidized low-density lipoprotein (P<0.001), and body weight (P=0.007). The present data showed an association between inflammatory risk factors linked to atherothrombosis and endothelial dysfunction in coronary heart disease patients. It is possible that endothelial dysfunction in coronary heart disease patients is related to the chronic inflammation or infection coexisting with atherosclerosis.
Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group.
Packard C J,O'Reilly D S,Caslake M J,McMahon A D,Ford I,Cooney J,Macphee C H,Suckling K E,Krishna M,Wilkinson F E,Rumley A,Lowe G D
The New England journal of medicine
BACKGROUND:Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events. METHODS:A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-associated phospholipase A2, C-reactive protein, and fibrinogen levels, and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles. RESULTS:Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile. CONCLUSIONS:Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.
White blood cell count: an independent predictor of coronary heart disease mortality among a national cohort.
Brown D W,Giles W H,Croft J B
Journal of clinical epidemiology
An association between elevated white blood cell (WBC) count and coronary heart disease (CHD) mortality has been previously observed. However, the relationship between WBC count and CHD mortality independent of cigarette smoking and the possible interaction between WBC count and smoking remains unclear. We examined the association between WBC count and CHD mortality with Cox regression analyses of data from 8914 adults, aged 30-75, in the NHANES II Mortality Study (1976-1992). Covariates included age, sex, race, education, physical activity, smoking status, hypertensive status, total serum cholesterol, body mass index, hematocrit, and history of cardiovascular disease, stroke, and diabetes. During 17 follow-up years, there were 548 deaths from CHD (ICD-9 410-414) and 782 deaths from diseases of the heart (ICD-9 390-398, 402, 404, 410-414, 415-417, 420-429). Mean WBC count (x10(9) cells/L) was greater among persons who died from CHD (7.6 vs 7.2, P <.001). Compared to persons with a WBC count <6.1, persons with a WBC count > 7.6 were at increased risk of death from CHD (relative risk = 1.4, 95% confidence interval = 1.1-1.8) after adjustment for smoking status and other CVD risk factors. Similar results were observed among nonsmokers (RR = 1.4, 95% CI = 0.9-2.0). These results suggest that higher WBC counts are a predictor of CHD mortality independent of the effects of smoking and other traditional CVD risk factors, which may indicate a role for inflammation in the pathogenesis of CHD. Additional studies are needed to determine whether interventions to decrease inflammation can reduce the risk for CHD associated with elevated WBC.
The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men.
Humphries S E,Luong L A,Ogg M S,Hawe E,Miller G J
European heart journal
AIMS:Inflammation is a key component of coronary heart disease, and genes coding for cytokines are candidates for predisposing to coronary heart disease risk. We have examined the effect of two polymorphisms (-174G>C and -572G>C) in the promoter of the interleukin-6 (IL-6) gene on risk of coronary heart disease, and on intermediate risk traits including fibrinogen and systolic blood pressure, in 2751 middle-aged healthy U.K. men. RESULTS:The -174C allele (frequency 0.43, 95% CI 0.42-0.44) was not associated with significant effects on fibrinogen levels, but was associated with a significantly (P=0.007) higher systolic blood pressure (mean mmHg (95% CI): GG=135.5 (134.3-136.7); GC=137.9 (136.9-138.9); CC= 138.0 (136.3-139.8)). This effect was of similar magnitude in smokers and non-smokers, and was greater in men in the top two tertiles of body mass index (>24.86 kg x m(-2)) than in those in the bottom tertile. Compared to those with the genotype GG, men carrying the -174C allele had a relative risk of coronary heart disease of 1.54 (95% CI 1.0-2.23, P=0.048) and this effect was greatest in smokers (compared to GG non-smokers, RR 2.66, CI 1.64-4.32). These effects remained statistically significant after adjusting for classical risk factors including blood pressure (P=0.04). The -572C allele (frequency 0.05, 0.04-0.06) was not associated with a significant effect on blood pressure, fibrinogen or relative risk of coronary heart disease. In a subset of the genotyped men (n=494), carriers of the -174C allele had higher levels of C-reactive protein than non-carriers. CONCLUSIONS:These data confirm the importance of the inflammatory system in the development of coronary heart disease. They suggest that, at least in part, the effect of the IL-6 -174G>C polymorphism on blood pressure is likely to be operating through inflammatory mechanisms, but the genotype effect on coronary heart disease risk is largely unexplained by its effect on blood pressure. The molecular mechanisms whereby genetically determined differences in plasma levels of IL-6 are having these effects remain to be determined.
Increased levels of markers of vascular inflammation in patients with coronary heart disease.
Schumacher A,Seljeflot I,Sommervoll L,Christensen B,Otterstad J E,Arnesen H
Scandinavian journal of clinical and laboratory investigation
Elevated levels of soluble cell adhesion molecules (sCAMs), inflammatory cytokines and C-reactive protein (CRP) have been associated with atherosclerotic disease states. The aim of the present study was to evaluate whether circulating levels of vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), E- and P-selectin were significantly elevated in patients with coronary heart disease (CHD) compared with healthy controls, and to study possible associations between these sCAMs, tumour necrosis factor alpha (TNFalpha). interleukin-6 (IL-6), CRP and major CHD risk factors. The study included 193 patients in various stages of CHD and 193 matched controls. To evaluate any possible influence of acute phase reaction, reinvestigation was performed after 6 months. After adjustment for major CHD risk factors, sVCAM-1, sICAM-1, P-selectin, IL-6 and CRP remained significantly elevated in the CHD patients (p for all <0.001). In multivariate analysis sVCAM-1 was predicted by age (p=0.015), sICAM-1 by smoking (p<0.001) and total cholesterol (p=0.026), E-selectin by body mass index (BMI) (p=0.004) and P-selectin by male gender (p=0.015). TNFalpha significantly predicted sICAM-1 and E-selectin levels, while IL-6 predicted CRP but none of the sCAMs measured. This might indicate that TNFalpha, but not IL-6, plays a major role in the regulation of sCAM levels in vivo.
[Genes and coronary heart disease].
Revista espanola de cardiologia
The causes of atherosclerotic cardiovascular disease have been intensely scrutinized for the last few decades. Since the classic risk factors have been found to be incomplete predictors of the disease, additional risk factors based on molecular genetics are now being sought. Polymorphisms are gene variations that have only modest effects on the function of coded proteins or enzymes. However, they are common and may be risk factors in the presence of environmental risk factors (cholesterol, stress, tobacco). Recent advances in molecular biology have made it possible to detect numerous polymorphisms that might have a detrimental effect on vascular biology, suggesting the hypothesis that multiple polymorphisms in the presence of environmental factors could act synergistically in the pathogenesis of atherosclerosis and coronary heart disease, which are typically polygenic and multifactorial diseases. In this review, the current status of our knowledge of polymorphisms and mutations potentially implicated in the mechanisms of coronary artery disease is discussed. Genotype/phenotype, gene-gene, and gene-environmental interactions related to lipid metabolism, the renin-angiotensin-aldosterone and adrenergic systems, insulin resistance, oxidative stress and endothelial function, inflammation and thrombosis are analyzed. Individual coronary risk might be related to the presence of a critical accumulation detrimental polymorphisms.
A polymorphism in the promoter of the tumor necrosis factor-alpha gene (-308) is associated with coronary heart disease in type 2 diabetic patients.
Vendrell Joan,Fernandez-Real José Manuel,Gutierrez Cristina,Zamora Alberto,Simon Inmaculada,Bardaji Alfredo,Ricart Wifredo,Richart Cristobal
BACKGROUND:Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine in the inflammation process of atherosclerosis. Through its effects on lipid metabolism, insulin resistance and endothelial function, it might be involved in coronary heart disease (CHD). A biallelic polymorphism within the promoter of TNF-alpha locus at the position -308 has been reported to be associated with TNF production. We have studied the association of this polymorphism with CHD in a Mediterranean non-diabetic and type 2 diabetic population. METHODS:Three hundred and forty one CHD patients (106 with type 2 diabetes), 207 healthy matched control subjects and 135 type 2 diabetic patients without CHD were evaluated. A single nucleotide polymorphism at the promoter TNF-alpha (-308) was analyzed by RFLP-PCR. RESULTS:TNF-alpha (-308) genotype and allele frequencies for A carriers were higher in CHD patients than those observed in the control group (32.3 vs. 23.2%, P=0.03; and 18.8 vs. 12.1%, P=0.0047; respectively) independently of other risk factors. Genotypic analysis revealed that CHD patients with type 2 DM displayed a greater prevalence of the -308 TNF-alpha A allele (40.6%) than controls (23.2%) or CHD patients without type 2 DM (28.5%) (P=0.0056). The odds ratio for CHD in type 2 diabetic patients in presence of -308 TNF-alpha A allele was 2.86 (CI 95%: 1.55-5.32). This difference was observed mainly in diabetic women for the A allele carriers (OR: 4.29; CI 95%: 1.6-11.76). CONCLUSIONS:These results suggest that -308 TNF-alpha gene polymorphism may contribute to CHD risk in patients with type 2 diabetes and it could constitute an useful predictive marker for CHD in type 2 diabetic women.
Leukocytes and coronary heart disease.
Hoffman Michael,Blum Arnon,Baruch Roni,Kaplan Eli,Benjamin Moshe
Inflammation has been demonstrated to be an important risk factor for the development of cardiovascular events. Patients with elevated white blood cell counts have been shown to be in a higher risk of developing acute myocardial infarction and acute coronary and vascular events. We review the clinical data of high white blood cell counts and the prognosis, and demonstrate several possible mechanisms. It is possible that measuring white blood cell count and subpopulations could be used for a better way of risk stratification of patients admitted with acute vascular events.
[Related inflammation markers among different types of coronary heart disease].
Luo Ying,Xie Xiu-Mei,Liu Hui-Xia
Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences
OBJECTIVE:To study the relationship between levels of activity of NF-kappaB p65, plasma soluble inter-cellular adhesion molecule-1, C-reactive protein on plaque stability, and different types of coronary heart disease. METHODS:We measured the levels of plasma soluble inter-cellular adhesion molecule-1 and C-reactive protein by enzyme-linked immunosorbant assay and the activity of NF-kappaB p65 in peripheral blood lymocytes immunohistochemically. RESULTS:Compared with the stable angina and the control group, the baseline activity of NF-kappaB p65, sICAM-1 and C-reactive protein was significantly elevated in the acute myocardial infarction and the unstable angina (P <0.01). After 3 month follow-up, the levels of activity of NF-kappaB p65 and sICAM-1 were unchanged (P > 0.05). In all groups, C-reactive proteins were lowered at the review (P <0.01). CONCLUSION:The levels of activity of NF-kappaB p65, sICAM-1 and C-reactive protein are related to the plaque stability among different types of coronary heart disease. NF-kappaB p65, and sICAM-1 are not affected by the acute event. These plasma markers may be important risk factors for the development of the acute coronary syndrome.
Low-grade inflammation may play a role in the etiology of the metabolic syndrome in patients with coronary heart disease: the HIFMECH study.
Yudkin J S,Juhan-Vague I,Hawe E,Humphries S E,di Minno G,Margaglione M,Tremoli E,Kooistra T,Morange P E,Lundman P,Mohamed-Ali V,Hamsten A,
Metabolism: clinical and experimental
Risk of coronary heart disease has been related to insulin resistance, but the mechanism for this is incompletely understood. Variables attributed to insulin resistance are associated with low-grade inflammation. A case-control study was performed of 469 male myocardial infarction (MI) survivors aged < 60 years and 575 control subjects recruited from centers in northern and southern Europe. Principal factor analysis was used to explore correlations between insulin resistance and inflammatory variables. Three factors resulted: (a) "Metabolic Syndrome" (insulin/proinsulin/ triglyceride/body mass index [BMI]); (b) "Inflammation" (fibrinogen/C-reactive protein [CRP]/interleukin-6 [IL-6]); and (c) "Blood Pressure" (systolic and diastolic blood pressure). The "Metabolic Syndrome" factor was related to the "Inflammation" factor (largely independently of obesity), the "Blood Pressure" factor, smoking, and south location (all P < or = .0002). There were significant relationships between all 3 factors and case status (P < or = .0002). Markers of low-grade inflammation are strongly related to metabolic syndrome variables independently of obesity. This raises the possibility that links between insulin resistance and cardiovascular disease could, in part, represent common consequences of low-grade inflammation.
Interleukin-6, fibrin D-dimer, and coagulation factors VII and XIIa in prediction of coronary heart disease.
Lowe Gordon D O,Rumley Ann,McMahon Alex D,Ford Ian,O'Reilly Denis St J,Packard Christopher J,
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Activated inflammation and activated blood coagulation are believed to increase the risk of coronary thrombosis and are related. We therefore compared plasma IL-6 (a key cytokine in the inflammatory process), fibrin D-dimer (a marker of fibrin turnover), and coagulation factors VII and XIIa (initiators of extrinsic and intrinsic blood coagulation, respectively) as predictors of coronary risk in the West of Scotland Coronary Prevention Study of pravastatin in men with hypercholesterolemia. METHODS AND RESULTS:485 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or revascularization) were matched for age and smoking status with 934 controls. Baseline IL-6 and D-dimer were strong univariate predictors of coronary risk (relative risk in the highest quintile approximately twice that in the lowest quintile) and were associated with each other and with C-reactive protein. On multivariate analyses, D-dimer retained a significant association with coronary risk (relative risk, 1.86; 95% CI, 1.24 to 2.80), whereas IL-6 (1.47; 0.95 to 2.28) and C-reactive protein (1.33; 0.85 to 2.08) did not. Neither factor VII nor factor XIIa antigens were predictors of coronary events. CONCLUSIONS:Fibrin D-dimer may be a stronger predictor of coronary risk than inflammatory markers, perhaps through its ability to stimulate monocyte release of IL-6.
Oxidized LDL and coronary heart disease.
During inflammation, several cell types synthesize and secrete phospholipase A2 that catalyses lipid oxidation in LDL. Myeloperoxidase, a haeme protein secreted by activated phagocytes, oxidizes L-tyrosine to a tyrosyl radical that is a physiological catalyst for the initiation of lipid oxidation in LDL. Lipid oxidation results in the generation of aldehydes that substitute lysine residues in the apolipoprotein B-100 moiety. Lipid together with protein oxidation in LDL results in the generation of oxidized LDL. We, among others, have demonstrated an association between coronary heart disease (CHD) and increased plasma levels of oxidized LDL. Recently, we have demonstrated a higher prevalence of elevated oxidized LDL in persons with high-calculated CHD risk prior to events. The odds of having elevated oxidized LDL for persons with high-calculated CHD risk prior to events were even higher than for persons with diagnosed CHD. A likely explanation is that once CHD has been diagnosed the patients are more treated with a statin that appears to decrease oxidized LDL even beyond its cholesterol-lowering effect. We have identified several metabolic syndrome components (high triglycerides, low HDL-cholesterol, glucose intolerance and diabetes) that independently of LDL-cholesterol, predicted high levels of oxidized LDL. Finally, elevated oxidized LDL predicted myocardial infarction in the Health ABC cohort consisting of well-functioning elderly people, even after adjusting for age, gender, race, smoking, and the metabolic syndrome.
Leukocyte count and coronary heart disease: implications for risk assessment.
Madjid Mohammad,Awan Imran,Willerson James T,Casscells S Ward
Journal of the American College of Cardiology
Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count is a marker of inflammation that is widely available in clinical practice. This paper reviews the available epidemiologic evidence for a relationship between the leukocyte count and coronary heart disease (CHD). Numerous epidemiologic and clinical studies have shown leukocytosis to be an independent predictor of future cardiovascular events, both in healthy individuals free of CHD at baseline and in patients with stable angina, unstable angina, or a history of myocardial infarction. This relationship has been observed in prospective and retrospective cohort studies, as well as in case-control studies. It is strong, consistent, temporal, dose-dependent, and biologically plausible. The relationship persists after adjustment for multiple CHD risk factors, including smoking. Elevated differential cell counts, including eosinophil, neutrophil, and monocyte counts, also predict the future incidence of CHD. Leukocytosis affects CHD through multiple pathologic mechanisms that mediate inflammation, cause proteolytic and oxidative damage to the endothelial cells, plug the microvasculature, induce hypercoagulability, and promote infarct expansion. In summary, leukocytosis has been consistently shown to be an independent risk factor and prognostic indicator of future cardiovascular outcomes, regardless of disease status. The leukocyte count is inexpensive, reliable, easy to interpret, and ordered routinely in inpatient and outpatient settings. However, its diagnostic and prognostic utility in CHD is widely unappreciated. Further studies are needed to assess the true impact of leukocytosis on CHD, compare it with other inflammatory markers such as C-reactive protein and lipoprotein phospholipase A(2) levels, and promote its use in CHD prediction.
White blood cell count predicts reduction in coronary heart disease mortality with pravastatin.
Stewart Ralph A H,White Harvey D,Kirby Adrienne C,Heritier Stephane R,Simes R John,Nestel Paul J,West Malcolm J,Colquhoun David M,Tonkin Andrew M,
BACKGROUND:Elevated serum inflammatory marker levels are associated with a greater long-term risk of cardiovascular events. Because 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) may have an antiinflammatory action, it has been suggested that patients with elevated inflammatory marker levels may have a greater reduction in cardiovascular risk with statin treatment. METHODS AND RESULTS:We evaluated the association between the white blood cell count (WBC) and coronary heart disease mortality during a mean follow-up of 6.0 years in the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) Study, a clinical trial comparing pravastatin (40 mg/d) with a placebo in 9014 stable patients with previous myocardial infarction or unstable angina. An increase in baseline WBC was associated with greater coronary heart disease mortality in patients randomized to placebo (hazard ratio for 1x10(9)/L increase in WBC, 1.18; 95% CI, 1.12 to 1.25; P<0.001) but not pravastatin (hazard ratio, 1.02; 95% CI, 0.96 to 1.09; P=0.56; P for interaction=0.004). The numbers of coronary heart disease deaths prevented per 1000 patients treated with pravastatin were 0, 9, 30, and 38 for baseline WBC quartiles of <5.9, 6.0 to 6.9, 7.0 to 8.1, and >8.2x10(9)/L, respectively. WBC was a stronger predictor of this treatment benefit than the ratio of total to high-density lipoprotein cholesterol and a global measure of cardiac risk. There was also a greater reduction (P=0.052) in the combined incidence of cardiovascular mortality, nonfatal myocardial infarction, and stroke with pravastatin as baseline WBC increased (by quartile: 3, 41, 61, and 60 events prevented per 1000 patients treated, respectively). CONCLUSIONS:These data support the hypothesis that individuals with evidence of inflammation may obtain a greater benefit from statin therapy.
Coronary heart disease and polymorphisms in genes affecting lipid metabolism and inflammation.
Current atherosclerosis reports
Several biologic systems contribute to the pathophysiology of atherosclerosis and its complications, and within each of these systems many genes have been explored to establish the possible implication of their variability in coronary heart disease (CHD) risk. This report is focused on recent results pertaining to lipid and inflammatory genes, their variability, and their relationship with intermediate phenotypes and CHD. For both systems, there is no evidence at the present time that testing genetic polymorphisms might be of any benefit to the patient, for the diagnosis or prognosis of CHD, or for tailoring drug prescription. Understanding the genetics of complex traits like CHD will require a system approach that allows a modeling of the interaction among genes as well as between genetic and nongenetic sources of variation.
Systemic low-grade inflammation and risk of coronary heart disease: results from the MONICA/KORA Augsburg cohort studies.
Koenig W,Meisinger C,Baumert J,Khuseyinova N,Löwel H
Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))
Atherosclerosis is characterised by a non-specific local inflammatory process accompanied by a systemic response. A number of prospective studies in initially healthy subjects and in patients with manifest atherosclerosis have now convincingly demonstrated a strong and independent association between even slightly elevated concentrations of various systemic markers of inflammation (plasma viscosity, C-reactive protein [CRP], and other acute phase reactants) and a number of cardiovascular endpoints. Presently, CRP, the classical acute phase protein, seems to be the marker of choice for the clinical situation. Initial evidence suggests that measurement of CRP adds to global risk assessment based on the Framingham risk score. The recent AHA/CDC consensus report recommends the measurement of CRP in asymptomatic subjects at intermediate risk for future coronary events (10-year risk of 10-20 %) and in selected patients after an acute coronary syndrome. Whether CRP shall alter treatment strategies in subjects without clinically manifest atherosclerosis is presently being tested in a large randomised clinical trial. In addition, recent research has suggested that CRP may not only be a risk marker, but may be directly involved in the pathogenesis of atherothrombosis. However, there are other emerging biomarkers. Lipoprotein-associated phospholipase A (2) (Lp-PLA (2)), an enzyme produced by monocytes/macrophages, T-cells and mast cells was found to generate proinflammatory and proatherogenic molecules from oxidised LDL. We tested the association of these new biomarkers with traditional risk factors and their ability to predict incident coronary events, using the MONICA/KORA database.
White blood cell count and the incidence of ischemic stroke in coronary heart disease patients.
Koren-Morag Nira,Tanne David,Goldbourt Uri
The American journal of medicine
PURPOSE:White blood cell (WBC) count is a marker of inflammation and has been associated with the development of cardiovascular disease. We investigated the relationship between WBC counts and the incidence of ischemic cerebrovascular disease in a large cohort of patients with pre-existing atherothrombotic disease and defined blood lipid boundaries. SUBJECTS AND METHODS:We followed up patients with documented coronary heart disease for 4.8 to 8.1 years. An extensive medical evaluation, conducted at baseline, included assessment of vascular risk factors and measures of blood lipids. Among 5435 patients with WBC counts, free of stroke, 295 developed an ischemic cerebrovascular disease (fatal and nonfatal). After review of available medical records, 186 of these cases had ischemic stroke or TIA. RESULTS:Higher WBC counts were associated with increased risk for ischemic cerebrovascular disease. Age-adjusted hazard ratio (HR) was 1.55 with 95% confidence interval (CI) 1.16-2.07, upper WBC tertile compared with the lowest. Adjusting for clinical covariates, WBC count remained an independent predictor for ischemic cerebrovascular disease (HR = 1.39; 95% CI 1.03-1.87, upper WBC tertile compared with the lowest). A similar trend appeared for the endpoint of ischemic stroke/transient ischemic attack (TIA). Further adjustment for plasma fibrinogen did not change the association materially (HR = 1.32; 95% CI 1.01-1.80; upper tertile of WBC compared with lowest). CONCLUSIONS:These findings support the role of WBC count as a simple inexpensive and readily available marker for risk stratification of ischemic cerebrovascular disease among patients with pre-existing atherothrombotic disease and defined blood lipid boundaries.
Interleukin 6 -174 g/c promoter polymorphism and risk of coronary heart disease: results from the rotterdam study and a meta-analysis.
Sie Mark P S,Sayed-Tabatabaei Fakhredin A,Oei Hok-Hay S,Uitterlinden André G,Pols Hubert A P,Hofman Albert,van Duijn Cornelia M,Witteman Jacqueline C M
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Interleukin (IL) 6 has many inflammatory functions, and the IL-6 -174 G/C promoter polymorphism appears to influence IL-6 levels. Findings of previous studies on the relation between this polymorphism and risk of cardiovascular diseases are inconsistent. We investigated this polymorphism in relation to risk of coronary heart disease (CHD) in a population-based study and meta-analysis. METHODS AND RESULTS:Participants (6434) of the Rotterdam Study were genotyped. Analyses on the relation between genotype and CHD were performed using Cox proportional hazards tests, and the association between genotype and plasma levels of IL-6 and C-reactive protein was investigated. All of the analyses were adjusted for age, sex, and common cardiovascular risk factors. A meta-analysis was performed, using a random effects model. No association between genotype and risk of CHD was observed. The polymorphism was not associated with IL-6 levels, but the C-allele was associated with higher C-reactive protein levels (P<0.01). Our meta-analysis did not show a significant association between the genotype and risk of CHD. CONCLUSIONS:We conclude that the polymorphism is not a suitable genetic marker for increased risk of CHD in subjects > or =55 years of age.
Vascular and fibrinolytic effects of intra-arterial tumour necrosis factor-alpha in patients with coronary heart disease.
Robinson Simon D,Dawson Pamela,Ludlam Christopher A,Boon Nicholas A,Newby David E
Clinical science (London, England : 1979)
Elevated plasma t-PA (tissue plasminogen activator) and serum CRP (C-reactive protein) concentrations are associated with an adverse cardiovascular risk. In the present study, we investigated whether acute local inflammation causes vascular dysfunction and influences t-PA release in patients with stable coronary heart disease. Serum CRP, plasma t-PA and PAI-1 (plasminogen activator inhibitor type 1) concentrations were determined in 95 patients with stable coronary heart disease. A representative subpopulation of 12 male patients received an intra-brachial infusion of TNF-alpha (tumour necrosis factor-alpha) and saline placebo using a randomized double-blind cross-over study design. Forearm blood flow and plasma fibrinolytic and inflammatory variables were measured. Serum CRP concentrations correlated with plasma t-PA concentrations (r=0.37, P<0.001) and t-PA/PAI-1 ratio (r=-0.21, P<0.05). Intra-arterial TNF-alpha caused a rise in t-PA concentrations (P<0.001) without affecting blood flow or PAI-1 concentrations. TNF-alpha pretreatment impaired acetylcholine- and sodium nitroprusside-induced vasodilatation (P<0.001 for both) whilst doubling bradykinin-induced t-PA release (P=0.006). In patients with stable coronary heart disease, plasma fibrinolytic factors correlate with a systemic inflammatory marker and local vascular inflammation directly impairs vasomotor function whilst enhancing endothelial t-PA release. We suggest that the adverse prognosis associated with elevated plasma t-PA concentrations relates to the underlying causative association with vascular inflammation and injury.
Local inflammation, endothelial dysfunction and fibrinolysis in coronary heart disease.
Lowe Gordon D O
Clinical science (London, England : 1979)
Prospective epidemiological studies have shown associations of circulating inflammatory markers with risk of CHD (coronary heart disease); however, these associations are modest after adjustment for confounding by established risk factors, and do not add significantly to the predictive value of current clinical risk scores. In contrast, experimental human studies of local arterial inflammation, such as the brachial artery infusion of TNF-alpha (tumour necrosis factor-alpha) model reported in this issue of Clinical Science by Robinson and co-workers, are of value in elucidating the pathophysiology of atherothrombosis.
Vascular stem cells: a new concept in the pathogenesis of atherosclerosis and interventions for coronary heart disease.
Geng Yong-Jian,Yang Yue-Jin,Casscells S Ward,Willerson James T
Vascular stem cells are undifferentiated, oligopotent progenitor cells that are capable of giving rise to mature, functional cells in the vascular wall. Several types of vascular progenitor cells have been identified and characterized from embryonic and adult tissues, including progenitors with the potential to differentiate into endothelial and smooth muscle cells. The progenitors for endothelial and smooth muscle cells reside in atherosclerotic or restenotic lesions and circulate in the bloodstream. These stem cells may malfunction under the influence of the risk factors for atherosclerosis, as well as by medical interventions. The biological activities of these stem cells contribute to the regeneration, repair and remodeling of arterial walls injured by atherosclerosis. Hypercholesterolemia, inflammation, mechanical stress and genetic defects may interact in regulating the vascular stem cell response to atherogenic stimulation. Stem cell production, potency, growth and differentiation may decline as people age. Clarifying the cellular and molecular pathways that govern stem cell growth, differentiation and apoptosis should help clinical scientists to understand the pathogenesis of atherosclerosis and to develop novel therapeutic strategies for coronary heart disease. Recent clinical trials demonstrate encouraging outcomes of stem cell therapies.
[Association of the polymorphism of macrophage migration inhibitory factor gene with coronary heart disease in Chinese population].
Shan Zhi-xin,Fu Yong-heng,Yu Xi-yong,Deng Chun-yu,Tan Hong-hong,Lin Qiu-xiong,Yu Hui-min,Lin Shu-guang
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics
OBJECTIVE:Inflammation is involved in the process of coronary heart disease (CHD). Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine which can inhibit the random migration of macrophages and concentrate macrophages at the inflammatory site, and is thought to play an important role in cell mediated immunity. The present study is to investigate the association of the -173 G/C polymorphism of MIF gene with the outcome of the CHD. METHODS:One hundred and thirty-eight patients with coronary angiography (CAG) proved CHD were studied, and 163 healthy matched controls in Guangdong were studied. Patients and controls were genotyped for a single nucleotide polymorphism in the 5'-flanking region at position -173 of the MIF gene, using PCR-RFLP analysis, followed by DNA sequencing identification. RESULTS:Only MIF -173G/G and MIF -173G/C genotypes were detected in CHD patients and controls. The MIF -173 G allele was detected in 0.966 of normal controls and 0.917 of patients, while MIF -173 C allele was detected in 0.034 of normal controls and 0.083 of patients. Individuals possessing a MIF-173*C genotype have an increased risk of CHD (16.7% versus 6.8%) (OR: 2.764, 95% CI: 1.295-5.899; P= 0.007). CONCLUSION:These results suggest that MIF -173G /C polymorphism was associated with CHD in Chinese population, the MIF -173C allele might be a risk factor for CHD in Chinese Han nationality.
Cardiovascular metabolic syndrome - an interplay of, obesity, inflammation, diabetes and coronary heart disease.
Rana J S,Nieuwdorp M,Jukema J W,Kastelein J J P
Diabetes, obesity & metabolism
Cardiovascular disease is currently one of the biggest causes of morbidity and mortality facing humanity. Such a paradigm shift of disease pattern over the last century has only worsened due to the alarming global prevalence of obesity and type 2 diabetes. In recent years there is increasing focus on inflammation as one of the key players in the patho-physiology of these disorders. In addition to these overt risk factors new research is unraveling the significance of a constellation of early metabolic abnormalities that include weight gain, insulin resistance, prehypertension and a specific pattern of dyslipidaemia. There exists a complex interrelationship of these various metabolic disorders and their effect on cardiovascular system. Simplified explanation can be that inflammation increases insulin resistance, which in turn leads to obesity while perpetuating diabetes, high blood pressure, prothrombotic state and dyslipidaemia. While inflammation and insulin resistance have direct adverse effects on cardiac muscle, these metabolic abnormalities as a whole cause causes cardiovascular complications; warranting a multi pronged therapeutic and preventive approach for the 'Cardiovascular Metabolic Syndrome' as an entity.
Coagulation factor VII and inflammatory markers in patients with coronary heart disease.
Ekström Mattias,Silveira Angela,Bennermo Marie,Eriksson Per,Tornvall Per
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis
To further elucidate the connection between inflammation and factor VII (FVII) taking genetic variation in the FVII locus into account, we have examined 387 patients after myocardial infarction and 387 age-matched and sex-matched healthy control individuals. Circulating levels of C-reactive protein, FVII antigen (FVIIag), activated FVII (FVIIa), fibrinogen and interleukin-6 were analysed and all subjects were genotyped for the Arg353Gln polymorphism in the FVII locus. Plasma concentrations of C-reactive protein, fibrinogen, and interleukin-6 were higher among patients than control individuals. FVIIag was lower in the patient group, but for FVIIa there was no difference between the two groups. Among the inflammatory markers, only C-reactive protein indicated a weak nonlinear association with FVII. No significant difference in frequency of the Gln allele was observed between patients and control individuals but the presence of the Gln allele was associated with lower plasma levels of FVIIag and FVIIa in both groups. The low-grade chronic inflammation seen 3 months after myocardial infarction is not of major importance for the variation in plasma concentration of FVII. The presence of the Gln allele in the Arg353Gln polymorphism in the FVII locus did not differ between patients and control individuals but was associated with lower plasma levels of FVIIag and FVIIa that could have a protective effect against myocardial infarction. To further elucidate these facts, a prospective study should be performed to reduce the risk of a possible selection bias due to coronary heart disease death seen in retrospective case-control studies.
Association of sICAM-1 and MCP-1 with coronary artery calcification in families enriched for coronary heart disease or hypertension: the NHLBI Family Heart Study.
Tang Weihong,Pankow James S,Carr J Jeffrey,Tracy Russell P,Bielinski Suzette J,North Kari E,Hopkins Paul N,Kraja Aldi T,Arnett Donna K
BMC cardiovascular disorders
BACKGROUND:Data accumulated from mouse studies and in vitro studies of human arteries support the notion that soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play important roles in the inflammation process involved in atherosclerosis. However, at the population level, the utility of sICAM-1 and MCP-1 as biomarkers for subclinical atherosclerosis is less clear. In the follow-up exam of the NHLBI Family Heart Study, we evaluated whether plasma levels of sICAM-1 and MCP-1 were associated with coronary artery calcification (CAC), a measure of the burden of coronary atherosclerosis. METHODS:CAC was measured using the Agatston score with multidetector computed tomography. Information on CAC and MCP-1 was obtained in 2246 whites and 470 African Americans (mean age 55 years) without a history of coronary heart disease (CHD). Information on sICAM-1 was obtained for white participants only. RESULTS:In whites, after adjustment for age and gender, the odds ratios (ORs) of CAC (CAC > 0) associated with the second, third, fourth, and fifth quintiles of sICAM-1 compared to the first quintile were 1.22 (95% confidence interval [CI]: 0.91-1.63), 1.15 (0.84-1.58), 1.49 (1.09-2.05), and 1.72 (1.26-2.36) (p = 0.0005 for trend test), respectively. The corresponding ORs for the second to fifth quintiles of MCP-1 were 1.26 (0.92-1.73), 0.99 (0.73-1.34), 1.42 (1.03-1.96), and 2.00 (1.43-2.79) (p < 0.0001 for trend test), respectively. In multivariable analysis that additionally adjusted for other CHD risk factors, the association of CAC with sICAM-1 and MCP-1 was attenuated and no longer statistically significant. In African Americans, the age and gender-adjusted ORs of CAC associated with the second and third tertiles of MCP-1 compared to the first tertile were 1.16 (0.64-2.08) and 1.25 (0.70-2.23) (p = 0.44 for trend test), respectively. This result did not change materially after additional adjustment for other CHD risk factors. Test of race interaction showed that the magnitude of association between MCP-1 and CAC did not differ significantly between African Americans and whites. Similar results were obtained when CAC > or = 10 was analyzed as an outcome for both MCP-1 and sICAM-1. CONCLUSION:This study suggests that sICAM-1 and MCP-1 are biomarkers of coronary atherosclerotic burden and their association with CAC was mainly driven by established CHD risk factors.
[Influence of gene polymorphisms in adhesion molecules and inflammation mediators as risk factors for coronary heart disease and myocardial infarction--an overview].
Grsković Branka,Pasalić Daria,Ferencak Goran,Stavljenić-Rukavina Ana
Acta medica Croatica : casopis Hravatske akademije medicinskih znanosti
Cardiovascular diseases are influenced by inheritance and environmental factors. There is a growing number of genetic variants, which may be included in the genesis and development of coronary artery disease (CAD). CAD or ischemic heart disease is a set of clinical symptoms caused by inadequate transport of oxygen because of changes in coronary circulation leading to myocardial ischemia. The most common cause of CAD is atherosclerosis of coronary arteries, which primarily narrows or occludes the lumen of coronary arteries or stimulates thrombosis. In this review, the role of the most important polymorphisms in adhesion molecules, intracellular adhesion molecule-1, integrins alpha2beta1 and beta3, E-selectin as well as of inflammation mediators, tumor necrosis factors alpha and beta, in the development of CAD risk and myocardial infarction is discussed. A review of different genotyping results provides an insight into the mechanisms responsible for the disease risk and helps detect the key sets of predictive markers that are clinically informative.
Relationship between markers of activated coagulation, their correlation with inflammation, and association with coronary heart disease (NPHSII).
Miller G J,Ireland H A,Cooper J A,Bauer K A,Morrissey J H,Humphries S E,Esnouf M P
Journal of thrombosis and haemostasis : JTH
OBJECTIVE:To determine whether activation of coagulation increases in parallel with inflammation and whether coagulation activation markers (CAMs) are independently associated with coronary heart disease (CHD), in the prospective study, NPHSII. METHODS:Surveillance of 2997 men between 50 and 63 years yielded 314 first CHD events during 36507 person-years of observation. The plasma levels of activated factor XII (FXIIa), the peptides released upon activation of factor X (FXpep) and factor IX (FIXpep), activated factor VII (FVIIa), prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FpA) served as indices of activity along the coagulation pathway. C reactive protein (CRP) provided a marker of inflammatory activity. RESULTS:While borderline or significant correlations were identified for each CAM with inflammation, as determined by CRP levels, these did not reach as high a numerical value as was shown for fibrinogen with CRP. FVIIa and FIXpep possessed independent associations with CHD: a one SD increase in adjusted FIXpep and FVIIa level was associated with a relative hazard of 1.20 (95% CI 1.00-1.43) and 0.70 (CI 0.58-0.86), respectively, using a group including all CHD events, compared with 'no-event'. CONCLUSIONS:Inflammation has significant but minimal impact upon CAMs of the extrinsic coagulation pathway. Reduced FVIIa and increased FIXpep levels were found to be significant, independent, predictors of CHD.
Analysis of potential predictors of depression among coronary heart disease risk factors including heart rate variability, markers of inflammation, and endothelial function.
Pizzi Carmine,Manzoli Lamberto,Mancini Stefano,Costa Grazia Maria
European heart journal
AIMS:We investigated the relationship between autonomic nervous system balance, systemic immune activation, endothelial dysfunction, and depression in patients free of coronary heart disease (CHD) with increased CHD risk. METHODS AND RESULTS:Depression status (Beck Depression Inventory, BDI), selected CHD risk factors, inflammation markers, measures of heart rate variability (HRV), and indices of endothelial function (flow-mediated dilation, FMD) were evaluated in 415 subjects free of CHD, diabetes mellitus, and other life-threatening conditions, with at least two CHD risk factors among the following: older age, male gender, current smoking, hypertension, and dislipidaemia. Overall, 51.7% of the participants were males, aged 57.6 +/- 8.8 years on average (minimum 30, maximum 70). Almost half were hypertensive, 43.9% were dyslipidemic, 30.4% current smokers, and 23.1% showed a depressive symptomatology (BDI > or = 10). Logistic regression showed that, as compared with non-depressed individuals and after adjustment for age, gender, and hypertension, depressive subjects were significantly more likely to be smokers, to have higher total cholesterol, higher C-reactive protein, and Interleukin-6. In addition, depressed subjects were more likely to have altered HRV and their FMD was severely impaired (adjusted odds ratio of 1% increase = 0.72; 95% CI: 0.61-0.86). CONCLUSION:Our data indicate an independent association between depression and impaired HRV, systemic inflammatory, and endothelial function. These mechanisms play a role not only in the complication of advanced forms of disease, but also promote and/or accelerate the early disease and connect depression and CHD.
Macrophage migration inhibitory factor (MIF) and risk for coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.
Herder Christian,Illig Thomas,Baumert Jens,Müller Martina,Klopp Norman,Khuseyinova Natalie,Meisinger Christa,Martin Stephan,Thorand Barbara,Koenig Wolfgang
OBJECTIVE:Macrophage migration inhibitory factor (MIF), a central cytokine of the innate immunity, has been reported to contribute to the development of cardiovascular disease. MIF is expressed in atherosclerotic lesions in humans, and gene deletion and antibody inhibition studies in animal models indicated that MIF may be cause rather than consequence of atherosclerosis. We sought to assess the triangular association between MIF genotypes, circulating MIF levels and risk for incident coronary heart disease (CHD) in the large, prospective, population-based MONICA/KORA case-cohort study (Augsburg, Southern Germany). METHODS:MIF genotypes, haplotypes and serum concentrations were determined in 363 individuals with incident CHD and 1908 individuals without CHD during follow-up (mean follow-up time 10.3 years). RESULTS:Circulating MIF concentrations were not associated with the risk for CHD. In women, carriers of the minor alleles rs755622C and rs2070766G had a higher risk for incident CHD, and a haplotype that contained these two minor alleles was significantly associated with increased risk for CHD (HR 2.44, 95%CI 1.30-4.59). CONCLUSION:The lack of association between serum levels and incident CHD indicates that MIF may not be a novel biomarker for CHD risk. However, the association of a haplotype containing the rs755622C allele, which has been reported before to increase the susceptibility for various other proinflammatory conditions, with CHD points towards a role for MIF in local vascular inflammation and atherogenesis.
[Obesity and coronary heart disease: the mechanism of atherogenic impact].
Micić Dragan,Polovina Snezana
The epidemic of obesity and overweight leads to many diseases including cardiovascular disease. Having an influence on function and heart structure, obesity and overweight are in connection with coronary heart disease, heart failure and sudden heart death. Cardiomyopathy in obesity (adipositas cordis) appears due to accumulation of adipose tissue between the heart muscle fibers and degeneration of myocites. The degeneration of myocardial could be due to lipotoxicity of free fatty acids in adipose tissue. The left ventricle hypertrophy, diastolic dysfunction, increasing blood volume, ejection fraction lead to heart failure. Obesity is low inflammation state with increased adipocitokine production from truncal adipose tissue which causes endothelial dysfunction and insulin resistance. Adipocitokines include leptin, adiponectin, resistin, visfatin, RBP 4 (retinol binding protein), angiotenzinogen, TNF alpha (tumor necrosis factor), PAI 1 (plazminogen activator inhibitor), fatty acids, sex steroids and different growth factors. Adipocitokines act synergistically or competitively with insulin, that explaining their impact on insulin resistance. Inflammatory citokines from adipose tissue could have influence on blood vessels endothelial function without their increase in plasma concentrations.
Markers of inflammation and risk of coronary heart disease.
Sarwar Nadeem,Thompson Alexander J,Di Angelantonio Emanuele
Cardiovascular disease is the leading cause of global mortality, with coronary heart disease (CHD) its major manifestation. Although inflammation, the body's response to noxious stimuli, is implicated in several stages of CHD development, the relevance of circulating levels of markers of inflammation to CHD risk remains uncertain. This review summarizes available epidemiological evidence for four emerging inflammatory markers implicated in CHD (fibrinogen, C-reactive protein, lipoprotein-associated phospholipase A2 and interleukin-6); considers their likely utility in cardiovascular risk prediction; and outlines areas of outstanding uncertainty.
Effects of pravastatin on the function of dendritic cells in patients with coronary heart disease.
Li Xiang,Liu Cheng,Cui Jian,Dong Min,Peng Cheng-Hai,Li Qing-Song,Cheng Jia-Li,Jiang Shu-Lin,Tian Ye
Basic & clinical pharmacology & toxicology
The aim of the study was to investigate the functional profile of dendritic cells in patients with coronary heart disease and the effects of pravastatin on this. Forty-eight patients with coronary heart disease were divided into three groups: 16 treated with pravastatin 10 mg/day, 16 treated with pravastatin 20 mg/day and 16 not treated with pravastatin. Dendritic cells from 48 patients with coronary heart disease (before and 4 weeks after the treatment) and 16 healthy individuals were derived from peripheral blood. CD86 of dendritic cells was assessed by flow cytometry. Immunostimulatory capacity of dendritic cells was measured by mixed lymphocyte reaction. The levels of cytokines in the medium of mixed lymphocyte reaction were analysed. Blood lipids and high-sensitivity C-reactive protein were measured. Compared to normal group, more CD86+ dendritic cells were expressed in coronary heart disease and greater immunostimulatory capacity of dendritic cells in coronary heart disease was demonstrated. T lymphocytes in coronary heart disease in mixed lymphocyte reaction secreted higher levels of pro-inflammation cytokines and lower levels of anti-inflammation cytokines. CD86 expression significantly correlated with C-reactive protein, but did not correlate with low-density lipoprotein cholesterol. Both dosages of pravastatin markedly inhibited the function of dendritic cells and lowered C-reactive protein, which is independent of plasma cholesterol lowering. The anti-inflammatory effect of pravastatin showed no obvious difference between the two dosage groups. In conclusion, dendritic cells were activated in coronary heart disease and dendritic cell-mediated immune mechanisms may be involved in the pathogenesis of coronary heart disease. Pravastatin can inhibit dendritic cell activation, which is independent of plasma cholesterol lowering. Pravastatin in different doses showed no apparent differences in the inhibition of dendritic cell functions.
The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA).
Ding Jingzhong,Hsu Fang-Chi,Harris Tamara B,Liu Yongmei,Kritchevsky Stephen B,Szklo Moyses,Ouyang Pamela,Espeland Mark A,Lohman Kurt K,Criqui Michael H,Allison Matthew,Bluemke David A,Carr J Jeffrey
The American journal of clinical nutrition
BACKGROUND:Pericardial fat (ie, fat around the heart) may have a direct role in the atherosclerotic process in coronary arteries through local release of inflammation-related cytokines. Cross-sectional studies suggest that pericardial fat is positively associated with coronary artery disease independent of total body fat. OBJECTIVE:We investigated whether pericardial fat predicts future coronary heart disease events. DESIGN:We conducted a case-cohort study in 998 individuals, who were randomly selected from 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants and 147 MESA participants (26 from those 998 individuals) who developed incident coronary heart disease from 2000 to 2005. The volume of pericardial fat was determined from cardiac computed tomography at baseline. RESULTS:The age range of the subjects was 45-84 y (42% men, 45% white, 10% Asian American, 22% African American, and 23% Hispanic). Pericardial fat was positively correlated with both body mass index (correlation coefficient = 0.45, P < 0.0001) and waist circumference (correlation coefficient = 0.57, P < 0.0001). In unadjusted analyses, pericardial fat (relative hazard per 1-SD increment: 1.33; 95% CI: 1.15, 1.54), but not body mass index (1.00; 0.84, 1.18), was associated with the risk of coronary heart disease. Waist circumference (1.14; 0.97, 1.34; P = 0.1) was marginally associated with the risk of coronary heart disease. The relation between pericardial fat and coronary heart disease remained significant after further adjustment for body mass index and other cardiovascular disease risk factors (1.26; 1.01, 1.59). The relation did not differ by sex. CONCLUSION:Pericardial fat predicts incident coronary heart disease independent of conventional risk factors, including body mass index.
Relation of obesity to heart failure hospitalization and cardiovascular events in persons with stable coronary heart disease (from the Heart and Soul Study).
Spies Christian,Farzaneh-Far Ramin,Na Beeya,Kanaya Alka,Schiller Nelson B,Whooley Mary A
The American journal of cardiology
Obesity is an independent risk factor for recurrent events among patients with established coronary heart disease (CHD). The goal of the present study was to identify potential mechanisms underlying this association. We measured the waist-to-hip ratio and body mass index in 979 outpatients with stable CHD and followed them for a mean of 4.9 years. We used proportional hazards models to evaluate the extent to which the association of obesity with subsequent heart failure (HF) hospitalization or cardiovascular (CV) events (myocardial infarction, stroke, or CHD death) was explained by baseline co-morbidities, cardiac disease severity, inflammation, insulin resistance, neurohormones and adipokines. Of the 979 participants, 128 (13%) were hospitalized for HF and 152 (16%) developed a CV event. Each standard deviation (SD) increase in the waist-to-hip ratio was associated with a 30% increased risk of HF hospitalization (unadjusted hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.1 to 1.6). This association was not attenuated after adjustment for potential mediators (HR 1.6, 95% CI 1.2 to 2.1). Likewise, each SD increase in the waist-to-hip ratio was associated with a 20% greater risk of CV events (unadjusted HR 1.2, 95% CI 1.0 to 1.4), and this remained unchanged after adjustment for potential mediators (adjusted HR 1.3, 95% CI 1.0 to 1.5). The body mass index was not associated with the risk of HF or CV events. In conclusion, abdominal obesity is an independent predictor of HF hospitalization and recurrent CV events in patients with stable CHD. This association does not appear to be mediated by co-morbid conditions, cardiac disease severity, insulin resistance, inflammation, neurohormones, or adipokines.
Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease.
de Mello V D F,Lankinen M,Schwab U,Kolehmainen M,Lehto S,Seppänen-Laakso T,Oresic M,Pulkkinen L,Uusitupa M,Erkkilä A T
AIMS/HYPOTHESIS:Ceramides and IL-6 have a role in immune-inflammatory responses and cardiovascular diseases, and are suggested to be involved in insulin and glucose metabolism. We sought to assess the associations of circulating levels of IL-6, TNF-alpha and high-sensitivity C reactive protein (hsCRP), which are inflammatory markers related to insulin resistance (IR), with the plasma lipid metabolites ceramides and diacylglycerols (DAG) in patients with CHD. METHODS:Cross-sectional analyses were carried out on data from 33 patients with CHD. Serum levels of the inflammatory markers and plasma lipid metabolites (lipidomics approach performed by ultra-performance liquid chromatography coupled to electrospray ionisation MS) were measured at the same time point as insulin resistance (IR) (HOMA-IR index). RESULTS:Serum circulating levels of IL-6 were strongly correlated with plasma ceramide concentrations (r = 0.59, p < 0.001). Adjustments for serum TNF-alpha or hsCRP levels, smoking, BMI, age, sex or HOMA-IR did not change the results (p < 0.001). After adjustments for the effect of serum inflammatory markers (TNF-alpha or hsCRP), HOMA-IR and BMI the correlation between plasma DAG and serum IL-6 (r = 0.33) was also significant (p < 0.03). In a linear regression model, circulating levels of both ceramides and TNF-alpha had a significant independent influence on circulating levels of IL-6, altogether accounting for 41% of its variation (p < 0.001). CONCLUSIONS/INTERPRETATION:Our results strongly suggest that the link between ceramides, IR and inflammation is related to the inflammatory marker IL-6. Ceramides may contribute to the induction of inflammation involved in IR states that frequently coexist with CHD.
[Research of pro-/anti-inflammatory cytokines in the study of coronary heart disease].
Wu Min,Wang Jie
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine
The study of the relationship between inflammation, inflammatory cytokines and coronary heart disease (CHD) has become a hot spot. The disequilibrium of pro- and anti-inflammation cytokines tempts the attention abroad and domestically, and this provides a new way to prevent and treat CHD in Chinese medicine. This paper discussed the research progress of pro- and anti-inflammatory cytokines in the study of CHD.
Markers of atherosclerosis and inflammation for prediction of coronary heart disease in older adults.
Rodondi Nicolas,Marques-Vidal Pedro,Butler Javed,Sutton-Tyrrell Kim,Cornuz Jacques,Satterfield Suzanne,Harris Tamara,Bauer Douglas C,Ferrucci Luigi,Vittinghoff Eric,Newman Anne B,
American journal of epidemiology
Although both inflammatory and atherosclerosis markers have been associated with coronary heart disease (CHD) risk, data directly comparing their predictive value are limited. The authors compared the value of 2 atherosclerosis markers (ankle-arm index (AAI) and aortic pulse wave velocity (aPWV)) and 3 inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)) in predicting CHD events. Among 2,191 adults aged 70-79 years at baseline (1997-1998) from the Health, Aging, and Body Composition Study cohort, the authors examined adjudicated incident myocardial infarction or CHD death ("hard" events) and "hard" events plus hospitalization for angina or coronary revascularization (total CHD events). During 8 years of follow-up between 1997-1998 and June 2007, 351 participants developed total CHD events (197 "hard" events). IL-6 (highest quartile vs. lowest: hazard ratio = 1.82, 95% confidence interval: 1.33, 2.49; P-trend < 0.001) and AAI (AAI < or = 0.9 vs. AAI 1.01-1.30: hazard ratio = 1.57, 95% confidence interval: 1.14, 2.18) predicted CHD events above traditional risk factors and modestly improved global measures of predictive accuracy. CRP, TNF-alpha, and aPWV had weaker associations. IL-6 and AAI accurately reclassified 6.6% and 3.3% of participants, respectively (P's < or = 0.05). Results were similar for "hard" CHD, with higher reclassification rates for AAI. IL-6 and AAI are associated with future CHD events beyond traditional risk factors and modestly improve risk prediction in older adults.
Inflammatory biomarkers and coronary heart disease: from bench to bedside and back.
Biasillo Gina,Leo Milena,Della Bona Roberta,Biasucci Luigi Marzio
Internal and emergency medicine
Inflammation plays a pivotal role in all stages of atherosclerosis from endothelial dysfunction and plaque formation to plaque destabilization and disruption. Inflammatory biomarkers, originally studied to better understand the pathophysiology of atherosclerosis, have generated increasing interest among clinicians, because of their utility in the challenging problems of diagnosis and risk assessment of patients with suspected or proved coronary heart disease. Moreover, in fascinating perspective, they could be used as therapeutic target, counteracting initiation, progression, and development of complications of atherosclerosis. In this review, we will provide an overview of the more promising inflammatory biomarkers, focusing on their utility and limitations in the clinical setting.
VEGF and IL-4 gene variability and its association with the risk of coronary heart disease in north Indian population.
Sobti R C,Maithil Nishi,Thakur Hitender,Sharma Yashpaul,Talwar K K
Molecular and cellular biochemistry
Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that has been shown to play a significant role in neovascularization during inflammation in atherosclerotic plaques, formation of collateral vessels to an area of ischemic myocardium and neovascularization at the edges of a myocardial infarction during its repair. Interleukin-4 (IL-4) has important role in immune cell chemotaxis, formation of endothelial cell adhesion molecules and has numerous anti-inflammatory effects which prevent the complications of atherosclerosis, the primary cause of coronary heart disease (CHD). In this study, we have analyzed the effect of 1154 A/G polymorphism of VEGF and 70 bp VNTR polymorphism of intron 3 in IL-4 genes in coronary heart disease (CHD) patients (n = 300) and their age matched controls (n = 300). To analyze polymorphic alleles, ARMS-PCR and RFLP techniques were used. Multiple logistic regression analysis was carried out with statistical software. GG genotype was associated with a decreased risk of development of CHD (OR 0.22, 95% CI 0.12-0.38, P < 0.001). However, A allele showed an increased risk whereas G allele decreased the risk of CHD with diabetes mellitus, hypertension, chronic mental stress and positive familial history of myocardial infarction (MI)/CHD. GG genotype was found to have protective effect with alcohol intake (OR 0.34, 95% CI 0.14-0.82, P < 0.01) and central obesity (OR 0.15, 95% CI 0.04-0.56, P < 0.001). GG genotype of VEGF has also shown significant association with IL-4 (P2P2 and P1P2) genotypes.
Inflammatory markers in coronary heart disease.
Madjid Mohammad,Willerson James T
British medical bulletin
INTRODUCTION:Inflammation plays a key role in the development of atherosclerosis and coronary heart disease (CHD). SOURCES OF DATA:Peer-reviewed studies published in English-language journals were reviewed with a focus on C-reactive protein (CRP) and lipoprotein-associated phospholipase A(2) (Lp-PLA2). AREAS OF AGREEMENT:Elevated levels of serum CRP and Lp-PLA2 are associated with an increased risk of incident CHD events in both primary and secondary prevention studies across a wide range of age, gender and ethnic groups. AREAS OF CONTROVERSY:The utility of inflammatory markers in predicting CHD risk when added to traditional risk factors is under debate. They are most useful in subjects in the intermediate-risk category. GROWING POINTS:Treatment with a statin in subjects with elevated CRP but without hyperlipidemia can reduce the risk of CHD. AREAS TIMELY FOR DEVELOPING RESEARCH:Extensive research is under way to identify additional novel serum markers with higher specificity for coronary artery plaque inflammation. Specific inhibitors against vascular inflammation in combination with medications to lower low-density lipoprotein cholesterol, i.e. statins, may help prevent cardiovascular events in the future.
Atherosclerotic coronary heart disease-epidemiology, classification and management.
Negi Smita,Anand Aashish
Cardiovascular & hematological disorders drug targets
Atherosclerotic coronary heart disease (CHD) is a major health problem worldwide. Epidemiological studies have identified the role of several modifiable and non-modifiable risk factors in the pathogenesis of CHD. Aggressive risk modification has led to a significant improvement in the morbidity and mortality from CHD. However, there is a growing need to identify better modalities of risk prediction in CHD. Many of these newer risk markers, currently under evaluation, are based on the newer concept that atherosclerosis is more than merely a problem of lipid imbalance. There has been a recent shift in the paradigm towards inflammation and oxidative stress as the key drivers in the pathophysiology of atherosclerosis and its complications. Further understanding of this complex interplay of lipid and inflammatory factors is likely to pave way to a better understanding of this disease and its myriad complications.
[Laboratory diagnosis of atherosclerotic plaque damage in patients with coronary heart disease: PAPP-A (a review of literature)].
Shevchenko A O,Slesareva Iu S,Shevchenko O P
Klinicheskaia laboratornaia diagnostika
Vascular inflammation is a major pathogenetic factor for the progression of an atherosclerotic process and for the development of destructive plaque changes. Now an active search is under way for markers to diagnose acute coronary syndrome at the early stage of development. The paper discusses the role of markers of inflammation and endogenous destruction in the development of atherosclerotic plaque instability. Pregnancy-associated plasma protein A (PAPP-A) is its most promising marker. It may be used to stratify the risk of cardiovascular complications in coronary heart disease and to assess their prognosis.
The NFKB1 ATTG ins/del polymorphism and risk of coronary heart disease in three independent populations.
Vogel Ulla,Jensen Majken K,Due Karen Margrete,Rimm Eric B,Wallin Håkan,Nielsen Michael R S,Pedersen Anne-Pernille T,Tjønneland Anne,Overvad Kim
AIM:Inflammation is a risk factor for coronary heart disease (CHD). A common deletion-allele in the promoter region of NFKB1 results in lower protein levels of the NF-κB p50 subunit. Recent evidence suggests that the NF-κB p50 dimer has anti-inflammatory effects. We aimed to investigate the association of the functional ATTG NFKB1 insertion/deletion variant with risk of CHD in three independent prospective studies of generally healthy men and women. METHODS AND RESULTS:The NFKB1 ins/del polymorphism was genotyped in studies of CHD nested within the Diet, Cancer and Health (DCH) study, the Health Professionals Follow-up (HPFS) and the Nurses' Health (NHS) studies, totaling 1008, 428 and 439 cases, respectively. The minor allele frequency in the combined sample was 0.38 among controls. In a pooled analysis, the relative risk (RR) among heterozygous men and women was 1.22 (95% CI: 1.07-1.40), compared to the most common ins/ins genotype. The RR among homozygotes was 1.20 (95% CI: 0.94-1.53). There was no evidence of an allele-dosage effect, and in a dominant model the RR among del-allele carriers was 1.22 (95% CI: 1.07-1.39). The risk was similar in women and men (RR was 1.20 in women and 1.23 in men, respectively). The NFKB1 variant was not associated with plasma lipid levels, but del-carriers had lower levels of C-reactive protein. CONCLUSIONS:The NFKB1 promoter variant, previously shown to cause partial depletion of NF-κB p50, was associated with a higher risk of CHD in three independent prospective studies of generally healthy Caucasians.
Expression of inflammatory and apoptosis factors following coronary stent implantation in coronary heart disease patients.
Liu Li-Li,Lin Li-Rong,Lu Cheng-Xiang,Fu Jian-Guo,Chao Peng-Li,Jin Hong-Wei,Zhang Zhong-Ying,Yang Tian-Ci
We investigated the changes in characteristics of neutrophil CD11b, monocyte CD11b, platelet CD62P, endothelin (ET), and neutrophil CD178 in patients with coronary heart disease (CHD) before and after primary coronary stenting. A total of 41 patients with CHD who underwent coronary stenting and 40 control subjects were enrolled in the study. In CHD patients, peripheral blood samples were taken 24 h before and 30 min, 24 h, and 72 h after successful coronary stenting. All markers were significantly elevated in patients with CHD compared with controls (P<0.05). Time-course studies revealed that the expressions of neutrophil CD11b, monocyte CD11b, platelet CD62P, and ET were lower at 30 min post-operation (PO) compared with that at 24 h before operation (BO) (P<0.05). All levels significantly increased from 30 min PO to 24 h PO (P<0.05) and decreased thereafter until 72 h PO (P>0.05). Time course changes in neutrophil CD11b levels after coronary stenting were significantly higher in patients with unstable angina pectoris than in patients with stable angina pectoris (P<0.05). CD11b levels were related to CD62P in patients with CHD (P<0.05). Neutrophil CD11b and monocyte CD11b levels were significantly increased in patients with CHD who underwent coronary stenting compared with controls (P<0.05). Results show that CD11b levels increased, meanwhile, the levels of CD62P and ET increased in CHD patients after coronary stenting. In addition, neutrophil CD178 levels of apoptosis factor in patients, which is important for regression of inflammation, remained high for a period of time after coronary stenting.
Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.
,Sarwar Nadeem,Butterworth Adam S,Freitag Daniel F,Gregson John,Willeit Peter,Gorman Donal N,Gao Pei,Saleheen Danish,Rendon Augusto,Nelson Christopher P,Braund Peter S,Hall Alistair S,Chasman Daniel I,Tybjærg-Hansen Anne,Chambers John C,Benjamin Emelia J,Franks Paul W,Clarke Robert,Wilde Arthur A M,Trip Mieke D,Steri Maristella,Witteman Jacqueline C M,Qi Lu,van der Schoot C Ellen,de Faire Ulf,Erdmann Jeanette,Stringham Heather M,Koenig Wolfgang,Rader Daniel J,Melzer David,Reich David,Psaty Bruce M,Kleber Marcus E,Panagiotakos Demosthenes B,Willeit Johann,Wennberg Patrik,Woodward Mark,Adamovic Svetlana,Rimm Eric B,Meade Tom W,Gillum Richard F,Shaffer Jonathan A,Hofman Albert,Onat Altan,Sundström Johan,Wassertheil-Smoller Sylvia,Mellström Dan,Gallacher John,Cushman Mary,Tracy Russell P,Kauhanen Jussi,Karlsson Magnus,Salonen Jukka T,Wilhelmsen Lars,Amouyel Philippe,Cantin Bernard,Best Lyle G,Ben-Shlomo Yoav,Manson JoAnn E,Davey-Smith George,de Bakker Paul I W,O'Donnell Christopher J,Wilson James F,Wilson Anthony G,Assimes Themistocles L,Jansson John-Olov,Ohlsson Claes,Tivesten Åsa,Ljunggren Östen,Reilly Muredach P,Hamsten Anders,Ingelsson Erik,Cambien Francois,Hung Joseph,Thomas G Neil,Boehnke Michael,Schunkert Heribert,Asselbergs Folkert W,Kastelein John J P,Gudnason Vilmundur,Salomaa Veikko,Harris Tamara B,Kooner Jaspal S,Allin Kristine H,Nordestgaard Børge G,Hopewell Jemma C,Goodall Alison H,Ridker Paul M,Hólm Hilma,Watkins Hugh,Ouwehand Willem H,Samani Nilesh J,Kaptoge Stephen,Di Angelantonio Emanuele,Harari Olivier,Danesh John
Lancet (London, England)
BACKGROUND:Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. METHODS:In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. FINDINGS:The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. INTERPRETATION:Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. FUNDING:British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial.
Lüscher Thomas F,Taddei Stefano,Kaski Juan-Carlos,Jukema J Wouter,Kallend David,Münzel Thomas,Kastelein John J P,Deanfield John E,
European heart journal
AIMS:High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538). METHODS AND RESULTS:Patients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively and did not change significantly from placebo after 12 and 36 weeks (P = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all P < 0.0001), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group (P = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA(2) mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo). CONCLUSION:The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function.
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.
,Swerdlow Daniel I,Holmes Michael V,Kuchenbaecker Karoline B,Engmann Jorgen E L,Shah Tina,Sofat Reecha,Guo Yiran,Chung Christina,Peasey Anne,Pfister Roman,Mooijaart Simon P,Ireland Helen A,Leusink Maarten,Langenberg Claudia,Li Ka Wah,Palmen Jutta,Howard Philip,Cooper Jackie A,Drenos Fotios,Hardy John,Nalls Michael A,Li Yun Rose,Lowe Gordon,Stewart Marlene,Bielinski Suzette J,Peto Julian,Timpson Nicholas J,Gallacher John,Dunlop Malcolm,Houlston Richard,Tomlinson Ian,Tzoulaki Ioanna,Luan Jian'an,Boer Jolanda M A,Forouhi Nita G,Onland-Moret N Charlotte,van der Schouw Yvonne T,Schnabel Renate B,Hubacek Jaroslav A,Kubinova Ruzena,Baceviciene Migle,Tamosiunas Abdonas,Pajak Andrzej,Topor-Madry Roman,Malyutina Sofia,Baldassarre Damiano,Sennblad Bengt,Tremoli Elena,de Faire Ulf,Ferrucci Luigi,Bandenelli Stefania,Tanaka Toshiko,Meschia James F,Singleton Andrew,Navis Gerjan,Mateo Leach Irene,Bakker Stephan J L,Gansevoort Ron T,Ford Ian,Epstein Stephen E,Burnett Mary Susan,Devaney Joe M,Jukema J Wouter,Westendorp Rudi G J,Jan de Borst Gert,van der Graaf Yolanda,de Jong Pim A,Mailand-van der Zee Anke-Hilse,Klungel Olaf H,de Boer Anthonius,Doevendans Pieter A,Stephens Jeffrey W,Eaton Charles B,Robinson Jennifer G,Manson JoAnn E,Fowkes F Gerry,Frayling Timonthy M,Price Jackie F,Whincup Peter H,Morris Richard W,Lawlor Debbie A,Smith George Davey,Ben-Shlomo Yoav,Redline Susan,Lange Leslie A,Kumari Meena,Wareham Nick J,Verschuren W M Monique,Benjamin Emelia J,Whittaker John C,Hamsten Anders,Dudbridge Frank,Delaney J A Chris,Wong Andrew,Kuh Diana,Hardy Rebecca,Castillo Berta Almoguera,Connolly John J,van der Harst Pim,Brunner Eric J,Marmot Michael G,Wassel Christina L,Humphries Steve E,Talmud Philippa J,Kivimaki Mika,Asselbergs Folkert W,Voevoda Mikhail,Bobak Martin,Pikhart Hynek,Wilson James G,Hakonarson Hakon,Reiner Alex P,Keating Brendan J,Sattar Naveed,Hingorani Aroon D,Casas Juan Pablo
Lancet (London, England)
BACKGROUND:A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. METHODS:Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. FINDINGS:In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)). INTERPRETATION:On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. FUNDING:UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.
The Effect of Sodium Tanshinone IIA Sulfate and Simvastatin on Elevated Serum Levels of Inflammatory Markers in Patients with Coronary Heart Disease: A Study Protocol for a Randomized Controlled Trial.
Shang Qinghua,Wang Hanjay,Li Siming,Xu Hao
Evidence-based complementary and alternative medicine : eCAM
UNLABELLED:Background. Coronary heart disease (CHD) due to atherosclerotic inflammation remains a significant threat to global health despite the success of the lipid-lowering, anti-inflammatory statins. Tanshinone IIA, a potent anti-inflammatory compound derived from Traditional Chinese Medicine (TCM), may be able to supplement statins by further reducing levels of circulating inflammatory markers correlated to cardiovascular risk. Here, we present the protocol of a randomized controlled trial (RCT) that will investigate the synergistic effect of sodium tanshinone IIA sulfate and simvastatin on reducing elevated inflammatory markers in patients with CHD. PARTICIPANTS:Seventy-two inpatients with confirmed CHD, elevated serum high-sensitivity C-reactive protein (Hs-CRP) level, and a TCM diagnosis of blood stasis syndrome will be enrolled and randomized 1 : 1 into the control or experimental group. Intervention. All subjects will receive a standard Western therapy including 20 mg simvastatin orally once per evening. Patients in the experimental group will additionally receive a daily 80 mg dose of sodium tanshinone IIA sulfate intravenously, diluted into 250 mL 0.9% NaCl solution. The treatment period will be 14 days. Outcomes. Primary outcome parameter: serum Hs-CRP level. Secondary outcome parameters: other circulating inflammatory markers (including IL-6, TNF α , VCAM-1, CD40, sCD40L, MCP-1, and MMP-9), improvement in symptoms of angina and blood stasis syndrome, and safety. This trial is registered with ChiCTR-TRC-12002361.
[The role of necrosis and inflammation markers in prognostication of acute coronary heart disease].
Shalenkova M A,Mukhametova E T,Mikhailova Z D
With the incessant growth of cardiovascular mortality, mainly due to myocardial infarction makes prognostication of acute coronary syndrome a principal goal of clinical practice. Biochemical markers (creatine phosphokinase-MB and troponins) are extensively used for diagnostics and prediction of acute coronary heart syndrome (ACS). However, drawbacks of necrosis markers necessitate the search for new ones identifiable at early stages of atherosclerotic plaque instability. Lately atherosclerosis has been considered as an immuno-inflammatory reaction involving cytokines, chemokines, C-reactive protein, natriuretic peptide, and tumor necrosis factor-alpha. Their prognostic value has been demonstrated in many clinical studies, but these data are contradictory and need to be confirmed.
[Methods for the correction of dysregulated erythropoesis in coronary heart disease].
Makarova N A
AIM--to develop pathogenetic methods for the correction of dysregulated erythropoesis in coronary heart disease (CHD). 20 patients with myocardial Q-infarction and 52 ones with chronic CHD. 26 patients of the CHD group suffered anemia. Ten volunteers without signs of cardiovascular pathology served as controls. Characteristics of peripheral blood and iron metabolism, serum levels of inflammation markers and erythropoietin (EPO) were measured. In most CHD patients elevated levels of TNF-alpha inhibited hepatic synthesis of EPO. Low hepcidin production was associated with increased EPO levels and low iron content in blood. Anemia developing in CHD patients may cause not only inflammation but also depletion of iron reserves. Correction of dysregulated erythropoesis in coronary heart in CHD must be performed with due regard for the above mechanisms on an individual basis.
A decrease in the percentage of circulating mDC precursors in patients with coronary heart disease: a relation to the severity and extent of coronary artery lesions?
Wen Jin,Wen Yan,Zhiliang Li,Lingling Chen,Longxing Cao,Ming Wang,Qiang Fu
Heart and vessels
Inflammation plays a pivotal role in coronary heart disease. Dendritic cells (DCs) are principal players in inflammation and atherosclerosis. Although the percentage of circulating DC precursors in coronary heart disease have been investigated, circulating myeloid DC (mDC) and plasmacytoid DC (pDC) precursors have not been extensively studied, particularly in relation to the severity of coronary artery lesions in patients with coronary heart disease. In this study, we recruited controls (n = 29), patients with stable angina pectoris (SAP, n = 30), patients with unstable angina pectoris (UAP, n = 56), and patients with acute myocardial infarction (AMI, n = 50). The severity and extent of coronary artery lesions was evaluated by Gensini score, following coronary angiograms. The percentage of circulating mDC and pDC precursors was determined by fluorescence-activated cell sorting (FACS). Plasma levels of MCP-1 and MMP-9, which correlate with atherosclerosis and DC migration, were also measured. The percentage of circulating mDC precursors was reduced in patients with AMI and UAP compared with control and SAP patients, respectively (p < 0.01 for AMI vs. SAP and Control, p < 0.05 for UAP vs. SAP and Control). The percentage of circulating pDC precursors was not significant changed. The levels of plasma MMP-9 and MCP-1 and Genisi score were all increased in patients with AMI and UAP, compared to control and SAP patients, respectively (p < 0.01 for AMI vs. SAP and control, p < 0.05 for UAP vs. SAP and control). Overall, the percentage of circulating mDC precursors was negatively correlated with MCP-1 (p < 0.001), MMP-9 (p < 0.001) and Genisi scores (p < 0.001). Genisi scores were positively correlated with the levels of MCP-1 (p < 0.001) and MMP-9 (p < 0.001). Our study suggested that the percentage of circulating mDC precursors is negatively correlated with the severity and extent of coronary artery lesions in patients with coronary heart disease.
Circulating microparticles in patients with coronary heart disease and its correlation with interleukin-6 and C-reactive protein.
Cui Ying,Zheng Lihui,Jiang Ming,Jia Ru,Zhang Xiao,Quan Qishan,Du Guiqin,Shen Dongjin,Zhao Xiaodan,Sun Wenying,Xu Hongwei,Huang Lijuan
Molecular biology reports
Microparticles (MPs) are vesicles released from activated or apoptotic cells. MP derive from various cells, most notably platelets, but also leucocytes, lymphocytes, erythrocytes, and endothelial cells. The aim of this study was to investigate endothelial MP (EMP), platelet MP (PMP), lymphocyte MP and monocyte MP and TF-positive MPs (TF+ MPs) in patients with coronary heart disease (CHD), and to evaluate the correlation of these MPs with Interleukin-6 (IL-6) and C-reactive protein (CRP). Different cell-derived MPs and TF+ MPs were analyzed by flow cytometry in 40 patients with myocardial infarction (MI), 30 unstable angina (UA), 20 stable angina (SA) and 20 healthy individuals, and IL-6 and CRP were determined by ELISA and special protein analyzer, respectively. Compared with SA and control, EMP and PMP was significantly elevated in MI and UA (P < 0.001), and TF+ MPs was significantly elevated in MI and UA (P < 0.001). EMP and PMP correlated with IL-6 (r = 0.822, P < 0.001 and r = 0.567, P < 0.001; respectively) or CRP level (r = 0.597, P < 0.001 and r = 0.66, P < 0.001; respectively). Different cell-derived MPs in CHD may indicate the different pathophysiological changes in vessels, and MPs may both participate in the development of thrombosis and enhance the vascular inflammation.
Potential benefits of weight loss in coronary heart disease.
Ades Philip A,Savage Patrick D
Progress in cardiovascular diseases
The prevalence of overweight, obesity and insulin resistance in patients with coronary heart disease (CHD) exceeds that of the general population. Obesity is associated with a constellation of coronary risk factors that predispose to the development and progression of CHD. Intentional weight loss, accomplished through behavioral weight loss and exercise, improves insulin sensitivity and associated cardio-metabolic risk factors such as lipid measures, blood pressure, measures of inflammation and vascular function both in healthy individuals and patients with CHD. Additionally, physical fitness, physical function and quality of life all improve. There is evidence that intentional weight loss prevents the onset of CHD in high risk overweight individuals. While weight loss associated improvements in insulin resistance, fitness and related risk factors strongly supports favorable prognostic effects in individuals with established CHD, further study is needed to determine if long-term clinical outcomes are improved.
Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis.
Kaptoge Stephen,Seshasai Sreenivasa Rao Kondapally,Gao Pei,Freitag Daniel F,Butterworth Adam S,Borglykke Anders,Di Angelantonio Emanuele,Gudnason Vilmundur,Rumley Ann,Lowe Gordon D O,Jørgensen Torben,Danesh John
European heart journal
AIMS:Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta-analysis of prospective studies. METHODS AND RESULTS:Interleukin-6 (IL-6), IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and tumour necrosis factor-α (TNF-α) were measured at baseline in a case-cohort study of 1514 participants and 833 incident CHD events within population-based prospective cohorts at the Danish Research Centre for Prevention and Health. Age- and sex-adjusted hazard ratios (HRs) for CHD per 1-SD higher log-transformed baseline levels were: 1.37 (95% CI: 1.21-1.54) for IL-6, 1.26 (1.11-1.44) for IL-18, 1.30 (1.16-1.46) for MMP-9, 1.01 (0.89-1.15) for sCD40L, and 1.13 (1.01-1.27) for TNF-α. Multivariable adjustment for conventional vascular risk factors attenuated the HRs to: 1.26 (1.08-1.46) for IL-6, 1.12 (0.95-1.31) for IL-18, 1.21 (1.05-1.39) for MMP-9, 0.93 (0.78-1.11) for sCD40L, and 1.14 (1.00-1.31) for TNF-α. In meta-analysis of up to 29 population-based prospective studies, adjusted relative risks for non-fatal MI or CHD death per 1-SD higher levels were: 1.25 (1.19-1.32) for IL-6; 1.13 (1.05-1.20) for IL-18; 1.07 (0.97-1.19) for MMP-9; 1.07 (0.95-1.21) for sCD40L; and 1.17 (1.09-1.25) for TNF-α. CONCLUSIONS:Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner. The findings lend support to the inflammation hypothesis in vascular disease, but further studies are needed to assess causality.
Genetic and environmental influences on the prospective correlation between systemic inflammation and coronary heart disease death in male twins.
Wu Sheng-Hui,Neale Michael C,Acton Anthony J,Considine Robert V,Krasnow Ruth E,Reed Terry,Dai Jun
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Because of lack of evidence, we aimed to examine to what degree low-grade systemic inflammation and coronary heart disease (CHD) death shared common genetic and environmental substrates. APPROACH AND RESULTS:From the 41-year prospective National Heart, Lung, and Blood Institute Twin Study, we included 950 middle-aged male twins at baseline (1969-1973). Low-grade systemic inflammation was measured with plasma levels of interleukin-6 (IL-6) and C-reactive protein. Univariate and bivariate structural equation models were used, adjusted for a risk score for CHD death. The score-adjusted heritability was 19% for IL-6, 27% for C-reactive protein, and 22% for CHD death. The positive phenotypic correlation of IL-6 with CHD death (radjusted=0.27; 95% confidence interval [CI], 0.08-0.43) was driven by additive genetic factors (contribution [relative contribution], 0.30 [111%]) but attenuated by unique environment (-0.03 [-11%]). The genetic correlation between IL-6 and CHD death was 0.74 (95% CI, 0.21-1.00), whereas the unique environmental correlation was -0.05 (95% CI, -0.35 to 0.25). The proportion of genetic variance for CHD death shared with that for IL-6 was 74%. The phenotypic correlation of C-reactive protein with CHD death (radjusted=0.10; 95% CI, -0.02 to 0.22) was explained by additive genetic factors (0.20 [149%]) but was attenuated by the unique environment (-0.09 [-49%]). The genetic correlation of C-reactive protein with CHD death was 0.63 (95% CI, -0.07 to 1.00), whereas the unique environmental correlation was -0.07 (95% CI, -0.29 to 0.17). CONCLUSIONS:Low-grade systemic inflammation, measured by IL-6, and long-term CHD death share moderate genetic substrates that augment both traits.
Glycemia and cognitive function in metabolic syndrome and coronary heart disease.
Avadhani Radhika,Fowler Kristen,Barbato Corinne,Thomas Sherine,Wong Winnie,Paul Camille,Aksakal Mehmet,Hauser Thomas H,Weinger Katie,Goldfine Allison B
The American journal of medicine
OBJECTIVE:Higher hemoglobin A1c (HbA1c) is associated with lower cognitive function in type 2 diabetes. To determine whether associations persist at lower levels of dysglycemia in patients who have established cardiovascular disease, cognitive performance was assessed in the Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD) trial. METHODS:The age-adjusted relationships between HbA1c and cognitive performance measured by the Mini-Mental State Examination, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Trail Making Test, and Categorical Verbal Fluency were assessed in 226 men with metabolic syndrome and established stable coronary artery disease. RESULTS:Of the participants, 61.5% had normoglycemia, 20.8% had impaired fasting glucose, and 17.7% had type 2 diabetes. HbA1c was associated with cognitive function tests of Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Trail Making Test, and Categorical Verbal Fluency (all P < .02), but not the Mini-Mental State Examination. In an age-adjusted model, a 1% (11 mmol/mol) higher HbA1c value was associated with a 5.9 lower Digit Symbol Substitution Test score (95% confidence interval [CI], -9.58 to -2.21; P < .0001); a 2.44 lower Rey Auditory Verbal Learning Test score (95% CI, -4.00 to -0.87; P < .0001); a 15.6 higher Trail Making Test score (95% CI, 5.73 to 25.6; P < .0001); and a 3.71 lower Categorical Verbal Fluency score (95% CI, -6.41 to -1.01; P < .02). In a multivariate model adjusting for age, education, and cardiovascular covariates, HbA1c remained associated with cognitive function tests of Rey Auditory Verbal Learning Test (R(2) = 0.27, P < .0001), Trail Making Test (R(2) = 0.18, P < .0001), and Categorical Verbal Fluency (R(2) = 0.20, P < .0001), although association with the Digit Symbol Substitution Test was reduced. CONCLUSIONS:Higher HbA1c is associated with lower cognitive function performance scores across multiple domain tests in men with metabolic syndrome and coronary artery disease. Future studies may demonstrate whether glucose lowering within the normative range improves cognitive health.
Novel coronary heart disease risk factors at 60-64 years and life course socioeconomic position: the 1946 British birth cohort.
Jones Rebecca,Hardy Rebecca,Sattar Naveed,Deanfield John E,Hughes Alun,Kuh Diana,Murray Emily T,Whincup Peter H,Thomas Claudia,
Social disadvantage across the life course is associated with a greater risk of coronary heart disease (CHD) and with established CHD risk factors, but less is known about whether novel CHD risk factors show the same patterns. The Medical Research Council National Survey of Health and Development was used to investigate associations between occupational socioeconomic position during childhood, early adulthood and middle age and markers of inflammation (C-reactive protein, interleukin-6), endothelial function (E-selectin, tissue-plasminogen activator), adipocyte function (leptin, adiponectin) and pancreatic beta cell function (proinsulin) measured at 60-64 years. Life course models representing sensitive periods, accumulation of risk and social mobility were compared with a saturated model to ascertain the nature of the relationship between social class across the life course and each of these novel CHD risk factors. For interleukin-6 and leptin, low childhood socioeconomic position alone was associated with high risk factor levels at 60-64 years, while for C-reactive protein and proinsulin, cumulative effects of low socioeconomic position in both childhood and early adulthood were associated with higher (adverse) risk factor levels at 60-64 years. No associations were observed between socioeconomic position at any life period with either endothelial marker or adiponectin. Associations for C-reactive protein, interleukin-6, leptin and proinsulin were reduced considerably by adjustment for body mass index and, to a lesser extent, cigarette smoking. In conclusion, socioeconomic position in early life is an important determinant of several novel CHD risk factors. Body mass index may be an important mediator of these relationships.
The Link Between Inflammatory Disorders and Coronary Heart Disease: a Look at Recent Studies and Novel Drugs in Development.
Teague H,Mehta Nehal N
Current atherosclerosis reports
Inflammation is a critical component in the development of coronary heart disease (CHD), specifically in the process of atherogenesis. Human translational and preclinical studies have demonstrated that inflammation contributes to the development, sustainment, and progression of atherosclerosis, and epidemiological studies demonstrate that human diseases associated with increased systemic inflammation increase the risk of CHD-related events. Therefore, over the last decade, multiple clinical studies were designed to target the inflammatory cascade in order to reduce the risk of CHD and to identify which populations may benefit from these preventative treatment strategies. This review briefly summarizes inflammation as a risk factor in atherosclerosis, human disease states associated with accelerated atherosclerosis, and current treatment strategies for CHD targeting the inflammatory cascade.
Effect of DanQi Pill on PPARα, lipid disorders and arachidonic acid pathway in rat model of coronary heart disease.
Chang Hong,Wang Qiyan,Shi Tianjiao,Huo Kuiyuan,Li Chun,Zhang Qian,Wang Guoli,Wang Yuanyuan,Tang Binghua,Wang Wei,Wang Yong
BMC complementary and alternative medicine
BACKGROUND:Danqi pill (DQP) is one of the most widely prescribed formulas and has been shown to have remarkable protective effect on coronary heart disease (CHD). However, its regulatory effects on lipid metabolism disorders haven't been comprehensively studied so far. We aimed to explore the effects of DQP on Peroxisome Proliferator activated receptors α (PPARα), lipid uptake-transportation-metabolism pathway and arachidonic acid (AA)-mediated inflammation pathway in rats with CHD. METHODS:80 Sprague-Dawley (SD) Rats were randomly divided into sham group, model group, positive control group and DQP group. Rat model of CHD was induced by ligation of left ventricle anterior descending artery and fed with high fat diet in all but the sham group. Rats in sham group only underwent thoracotomy. After surgery, rats in the positive control and DQP group received daily treatments of pravastatin and DQP respectively. At 28 days after surgery, rats were sacrificed and plasma lipids were evaluated by plasma biochemical detection. Western blot and PCR were applied to evaluate the expressions of PPARα, proteins involved in lipid metabolism and AA pathways. RESULTS:Twenty eight days after surgery, dyslipidemia developed in CHD model rats, as illustrated by elevated plasma lipid levels. Expressions of apolipoprotein A-I (ApoA-I), cluster of differentiation 36 (CD36) and fatty acid binding protein (FABP) in the heart tissues of model group were down-regulated compared with those in sham group. Expressions of carnitine palmitoyl transferase I (CPT-1A) and lipoproteinlipase (LPL) were also reduced significantly. In addition, levels of phospholipase A2 (PLA2) and cyclooxygenase 2 (COX-2) were up-regulated. Expressions of Nuclear factor-κB (NF- κB) and signal transducer and activator of transcription 3 (STAT3) also increased. Furthermore, Expression of PPARα decreased in the model group. DQP significantly up-regulated expressions of ApoA-I and FABP, as well as the expressions of CPT-1A and CD36. In addition, DQP down-regulated expressions of PLA2, COX-2 and NF-κB in inflammation pathway. Levels of STAT3 and LPL were not affected by DQP treatment. In particular, DQP up-regulated PPARα level significantly. CONCLUSIONS:DQP could effectively regulate lipid uptake-transportation-metabolism process in CHD model rats, and the effect is achieved mainly by activating ApoA-I-CD36-CPT-1A molecules. Interestingly, DQP can up-regulate expression of PPARα significantly. The anti-inflammatory effect of DQP is partly exerted by inhibiting expressions of PLA2-COX2 -NF-κB pathway.
Lipoprotein-Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease.
Wallentin Lars,Held Claes,Armstrong Paul W,Cannon Christopher P,Davies Richard Y,Granger Christopher B,Hagström Emil,Harrington Robert A,Hochman Judith S,Koenig Wolfgang,Krug-Gourley Sue,Mohler Emile R,Siegbahn Agneta,Tarka Elizabeth,Steg Philippe Gabriel,Stewart Ralph A H,Weiss Robert,Östlund Ollie,White Harvey D,
Journal of the American Heart Association
BACKGROUND:We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. METHODS AND RESULTS:Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1-204.2 μmol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes. CONCLUSIONS:Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
Inflammatory biomarkers of coronary heart disease.
Li Hongyu,Sun Kai,Zhao Ruiping,Hu Jiang,Hao Zhiru,Wang Fei,Lu Yaojun,Liu Fu,Zhang Yong
Frontiers in bioscience (Landmark edition)
Coronary heart disease (CHD), characterized by inflammation and accumulation of plaques mainly comprised of lipids, calcium and inflammatory cells in the walls of coronary arteries. CHD is exacerbated by specific cardiovascular risk factors, such as obesity, diabetes mellitus, and hypertension. The current review focuses on the critical role of traditional inflammatory biomarkers, including interleukin-6, C-reactive protein (CRP), complement, CD40 and myeloperoxidase (MPO), in the pathogenesis of CHD.
Interleukin-18, matrix metalloproteinase-22 and -29 are independent risk factors of human coronary heart disease.
Jin Dong-Yi,Liu Cong-Lin,Tang Jun-Nan,Zhu Zhao-Zhong,Xuan Xue-Xi,Zhu Xiao-Dan,Wang Yun-Zhe,Zhang Tian-Xia,Shen De-Liang,Wang Xiao-Fang,Shi Guo-Ping,Zhang Jin-Ying
Journal of Zhejiang University. Science. B
BACKGROUND:Coronary heart disease (CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase (MMP)-22 and -29 and pro-inflammatory cytokine interleukin-18 (IL18) are present in human hearts. IL18 may regulate MMP-22 and -29 expression, which may correlate with CHD progression. METHODS AND RESULTS:Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and -29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18 (odds ratio (OR)=1.131, P=0.007), MMP-22 (OR=1.213, P=0.040), and MMP-29 (OR=1.198, P=0.033) were independent risk factors of CHD. Pearson's correlation test showed that IL18 (coefficient (r)=0.214, P=0.045; r=0.246, P=0.031) and MMP-22 (r=0.273, P=0.006; r=0.286, P=0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson's correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein (hs-CRP) (r=0.167, P=0.023), and MMP-29 levels correlated negatively with triglyceride (r=-0.169, P=0.018). Spearman's correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22 (r=0.845, P<0.001) and MMP-29 (r=0.548, P<0.001). CONCLUSIONS:Our observations suggest that IL18, MMP-22 and -29 serve as biomarkers and independent risk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and -29 levels in these patients.
Psychological Stress, Inflammation, and Coronary Heart Disease.
Wirtz Petra H,von Känel Roland
Current cardiology reports
PURPOSE OF REVIEW:In this review, we summarize evidence on the risk factor psychological stress in the context of coronary heart disease (CHD) in humans and explore the role of inflammation as a potential underlying mechanism. RECENT FINDINGS:While chronic stress increases the risk of incident CHD and poor cardiovascular prognosis, acute emotional stress can trigger acute CHD events in vulnerable patients. Evidence supporting a potential role for inflammation as a promising biological mechanism comes from population-based studies showing associations between chronic stress and increased inflammation. Similarly, experimental studies demonstrate acute stress-induced increases in inflammatory markers and suggest modulatory potential for pharmacological and biobehavioral interventions. So far, studies investigating patients with cardiovascular disease are few and the full sequence of events from stress to inflammation to CHD remains to be established. Psychological stress is an independent CHD risk factor associated with increased inflammation. Although promising, causality needs to be further explored.
CXCR2 Inhibition - a novel approach to treating CoronAry heart DiseAse (CICADA): study protocol for a randomised controlled trial.
Joseph Jubin P,Reyes Eliana,Guzman Josephine,O'Doherty Jim,McConkey Hannah,Arri Satpal,Kakkar Rahul,Beckley Nicholas,Douiri Abdel,Barrington Sally F,Redwood Simon R,Ferro Albert
BACKGROUND:There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Patients with lower neutrophil counts following acute coronary syndromes tend to have a greater coronary flow reserve, which is a strong predictor of long-term cardiovascular health. But so far, no data are available regarding the impact of neutrophil inhibition on cardiovascular clinical or surrogate endpoints. Therefore, the aim of this study is to investigate the effects of AZD5069, a cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibitor, on coronary flow reserve and coronary structure and function in patients with coronary artery disease. METHODS/DESIGN:Ninety subjects with coronary artery disease undergoing percutaneous coronary intervention will be included in this investigator-driven, randomised, placebo-controlled, double-blind, phase IIa, single-centre study. Participants will be randomised to receive either AZD5069 (40 mg) administered orally twice daily or placebo for 24 weeks. Change in coronary flow reserve as determined by N-ammonia positron emission tomography-computed tomography will be the primary outcome. Change in the inflammatory component of coronary plaque structure and the backward expansion wave, an invasive coronary physiological measure of diastolic function, will be assessed as secondary outcomes. DISCUSSION:Cardiovascular surrogate parameters, such as coronary flow reserve, may provide insights into the potential mechanisms of the cardiovascular effects of CXCR2 inhibitors. Currently, ongoing trials do not specifically focus on neutrophil function as a target of intervention, and we therefore believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease. TRIAL REGISTRATION:EudraCT, 2016-000775-24 . Registered on 22 July 2016. International Standard Randomised Controlled Trial Number, ISRCTN48328178 . Registered on 25 February 2016.
Inflammatory Biomarkers Interleukin-6 and C-Reactive Protein and Outcomes in Stable Coronary Heart Disease: Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial.
Held Claes,White Harvey D,Stewart Ralph A H,Budaj Andrzej,Cannon Christopher P,Hochman Judith S,Koenig Wolfgang,Siegbahn Agneta,Steg Philippe Gabriel,Soffer Joseph,Weaver W Douglas,Östlund Ollie,Wallentin Lars,
Journal of the American Heart Association
BACKGROUND:Evaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population. METHODS AND RESULTS:Overall, 15 828 patients with coronary heart disease in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were 2.1 (interquartile range, 1.4-3.2) ng/L and 1.3 (interquartile range, 0.6-3.1) mg/L, respectively. Associations between continuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers. IL-6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.30-1.97; <0.0001); cardiovascular death (HR, 2.15; 95% CI, 1.53-3.04; <0.0001); myocardial infarction (HR, 1.53; 95% CI, 1.14-2.04; <0.05); all-cause mortality (HR, 2.11; 95% CI, 1.62-2.76; <0.0001); and risk of hospitalization for heart failure (HR, 2.28; 95% CI, 1.34-3.89; <0.001). Cancer death was doubled in the highest IL-6 quartile group (HR, 2.34; 95% CI, 1.20-4.53; <0.05). High-sensitivity C-reactive protein was associated with both cardiovascular and non-cardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments. CONCLUSIONS:IL-6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL-6 might reflect a pathophysiological process involved in the development of these events. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00799903.
Flaxseed Oil Supplementation Improve Gene Expression Levels of PPAR-γ, LP(a), IL-1 and TNF-α in Type 2 Diabetic Patients with Coronary Heart Disease.
Hashemzadeh Ali Akbar,Nasoohi Nikoo,Raygan Fariba,Aghadavod Esmat,Akbari Elmira,Taghizadeh Mohsen,Memarzadeh Mohammad Reza,Asemi Zatollah
This study was carried out to determine the effects of flaxseed oil administration on gene expression levels related to insulin, lipid and inflammation in overweight diabetic patients with coronary heart disease (CHD). This randomized double-blind, placebo-controlled trial was conducted among 60 diabetic patients with CHD. Subjects were randomly allocated into two groups to intake either 1000 mg n-3 fatty acid from flaxseed oil containing 400 mg α-Linolenic acid [ALA (18:3n-3)] (n = 30) or placebo (n = 30) twice a day for 12 weeks. Gene expression related to insulin, lipid and inflammation were quantified in peripheral blood mononuclear cells (PBMC) of diabetic patients with CHD with RT-PCR method. Results of RT-PCR demonstrated that after the 12-week intervention, compared with the placebo, flaxseed oil supplementation could up-regulate gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.02) in PBMC of diabetic patients with CHD. In addition, compared with the placebo, taking flaxseed oil supplements down-regulated gene expression levels of lipoprotein(a) [LP(a)] (P = 0.001), interleukin-1 (IL-1) (P = 0.001) and tumor necrosis factor alpha (TNF-α) (P = 0.02) in PBMC of diabetic patients with CHD. We did not observe any significant effect of flaxseed oil supplementation on gene expression levels of low-density lipoprotein receptor (LDLR), IL-8 and transforming growth factor beta (TGF-β) in PBMC of diabetic patients with CHD. Overall, flaxseed oil supplementation for 12 weeks in diabetic patients with CHD significantly improved gene expression levels of PPAR-γ, LP(a), IL-1 and TNF-α, but did not influence LDLR, IL-8 and TGF-β.
Inflammatory biomarkers of coronary heart disease.
Li Hongyu,Sun Kai,Zhao Ruiping,Hu Jiang,Hao Zhiru,Wang Fei,Lu Yaojun,Liu Fu,Zhang Yong
Frontiers in bioscience (Scholar edition)
Coronary heart disease (CHD) is one of the leading causes of death worldwide. CHD is characterized by formation of arterial plaques which are mainly comprised of lipids, calcium and inflammatory cells. These plaques narrow the lumen of coronary arteries leading to episodic or persistent angina. Rupture of these plaques leads to the formation of thrombus, which as a result of cessation of blood flow, causes myocardial infarct and death. CHD is exacerbated by risk factors including obesity, diabetes mellitus, and hypertension. Diagnosis is established by the level of blood cholesterol, triglycerides and lipoproteins Inflammation is considered significant in the pathogenesis of CHD and for this reason, severity and prognosis of CHD is assessed by the levels of inflammatory biomarkers, including interleukin-6, C-reactive protein (CRP), complement, CD40 and myeloperoxidase (MPO).
[Prospects of buccal epithelium application for noninvasive diagnosis of coronary heart disease in people of different age.]
Bunin V A,Karpasova E A,Kozhevnikova E O,Linkova N S,Kozlov K L,Paltseva E M
Advances in gerontology = Uspekhi gerontologii
Cardiovascular diseases caused by atherosclerosis, in many countries of the world are one of the most important social and economic problems due to the high morbidity and mortality rate of the working population. Recently, the immunological theory of atherosclerosis and coronary heart disease (CHD) has been actively developed, and the search for markers of inflammation characterizing immuno- and atherogenesis has been conducted. Buccal epithelium (BE) can be used as biological material for in vivo molecular-cellular studies, allowing to diagnose CHD by inflammation markers. The purpose of the work was a comparative study of the expression of IL-1β, IL-6, IL-10, MCP-1 and GDF-15 in BE in patients of different ages with CHD and without cardiovascular disease. The material of BE in healthy donors and patients with 2nd stage CHD was divided into groups according to age classification of the WHO: the 1st - middle-aged people (45-59 years) and the 2nd - elderly people (60-74 years). Control material was obtained from people of middle and old age without cardiovascular disease. According to the immunocytochemical study, the area of IL-1β expression in BE is 3 times higher in middle-aged people with CHD, and in 4,4 times higher in elderly people compared to healthy individuals of the same age group. The area of IL-6 expression in middle-aged and elderly people with CHD was in 7,9 and 7,4 times higher, respectively, than in the control group. In middle-aged and elderly patients with CHD, IL-10 expression was in 1,6 and 2,8 times higher, respectively, compared to healthy donors of the same age group. The expression of MCP-1 in BE of middle-aged and elderly people in normal and ischemic heart disease did not differ. GDF-15 expression is in 6,8 and 6,6 times higher in middle-aged and elderly people with CHD than in healthy people of the same age. The findings showed that the expression of the cytokines IL-1β, IL-6, IL-10 and GDF-15 increase in BE in patients with CHD of middle-aged and elderly people compared with persons of the same age group without cardiovascular disease. Thus, BE can serve as an informative material for noninvasive molecular diagnosis of CHD in people of different ages.
The effect of hydroxy safflower yellow A on coronary heart disease through Bcl-2/Bax and PPAR-γ.
Zhou Dayan,Qu Zongjie,Wang Hao,Su Yong,Wang Yazhu,Zhang Weiwei,Wang Zhe,Xu Qiang
Experimental and therapeutic medicine
The aim of the present study was to investigate the effect of hydroxy safflower yellow A (HSYA) on coronary heart disease through assessing the expression of B-cell lymphoma 2 (Bcl-2)/Bcl-2-like protein 4 (Bax) and peroxisome proliferator-activated receptor (PPAR)-γ. Coronary heart disease was induced in male Bama miniature swines via thoracoscope to serve as an animal model. Coronary heart disease swine were lavaged with 20 or 40 mg/kg HSYA. The mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-10, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected using reverse transcription-quantitative polymerase chain reaction. The protein expression of Bcl-2, Bax, PPAR-γ, phosphorylation of Janus kinase (JAK)2 and phosphorylation of signal transducer and activator of transcription (STAT)3 were detected using western blot analysis. Treatment with HSYA significantly suppressed the mRNA levels of IL-1β (P<0.01), IL-6 (P<0.01), TNF-α (P<0.01), COX-2 (P<0.01) and iNOS (P<0.01), and significantly increased IL-10 mRNA level in the coronary heart disease model (P<0.01). Furthermore, HSYA treatment significantly decreased the Bcl-2/Bax ratio (P<0.01) in the coronary heart disease model group, and enhanced the phosphorylation of JAK2/STAT3 pathway (P<0.01). However, HSYA had no significant effect on the expression of PPAR-γ protein. The results of the present study suggest that HSYA is able to weaken coronary heart disease via inflammation, Bcl-2/Bax and the PPAR-γ signaling pathway.
Effects of telmisartan on vascular endothelial function, inflammation and insulin resistance in patients with coronary heart disease and diabetes mellitus.
Chen Tao,Xing Jieyong,Liu Yanshao
Experimental and therapeutic medicine
The aim of the present study was to investigate the effects of telmisartan on vascular endothelial functions, inflammatory factors and insulin resistance of coronary heart disease patients complicated with diabetes mellitus. In total, 80 coronary heart disease patients complicated with type 2 diabetes mellitus, admitted and treated in the Zhangqiu Hospital from January 2016 to March 2017 were enrolled in the study. Each patient was randomly assigned to an observation (n=40) or a control group (n=40) using a random number table. Conventional symptomatic and supporting therapies were administered to all the patients in the two groups for 12 consecutive weeks, while additional telmisartan was given only to patients in the observation group. Markers of glucose metabolism, vascular endothelial function and inflammation were determined before and after intervention, to compare averages between groups. Results showed the levels of fasting blood glucose and blood glucose in the observation group were significantly lower than those in the control group (p<0.05) after 4 weeks of treatment. The levels of HOMA-IR in the observation group were clearly improved compared to those in the control group during the same period (p<0.05). After the intervention, the levels of FINS and HOMA-IR in the observation group improved significantly more compared with those in the control group (p<0.05), while the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP) were much lower than those in the control group (p<0.05). Furthermore, at the 4th, 8th and 12th week after starting the treatment, the vascular endothelin (ET) levels in the observation group were significantly lower than those in the control group (p<0.05). In addition, the brachial artery diameters in the basal state were significantly larger than those in the control group (p<0.05) for the same time-points. Coronary heart disease patients complicated with diabetes mellitus whose treatment includes telmisartan can better regulate their blood glucose, reduce the insulin resistance and body inflammatory responses and improve their vascular endothelial functions.
Gamma-glutamyl transferase and the risk of atherosclerosis and coronary heart disease.
Ndrepepa Gjin,Colleran Roisin,Kastrati Adnan
Clinica chimica acta; international journal of clinical chemistry
Gamma-glutamyl transferase (GGT) is a ubiquitous cell surface enzyme that cleaves extracellular glutathione (G-SH) or other gamma-glutamyl compounds. GGT serves to increase the availability of amino acids, primarily cysteine, for intracellular G-SH synthesis and plays a crucial role in maintaining G-SH homeostasis and defense against oxidative stress in organisms. Measurement of circulating GGT activity is widely used for the diagnosis of liver and obstructive biliary diseases and as an indicator of alcohol consumption. Epidemiological studies suggest an association between elevated GGT activity level and a risk of incident coronary heart disease (CHD) or CHD-related mortality. Elevated GGT activity level is associated with a plethora of cardio-metabolic risk factors, including traditional cardiovascular risk factors, metabolic syndrome, systemic inflammation, oxidative stress burden and various comorbidities that incur a negative impact on patient risk profile and prognosis. Experimental studies and studies of human atherosclerotic plaques have revealed not only the presence of catalytically active GGT in atherosclerotic plaques, but also a correlation between GGT activity and indices of plaque instability, suggesting direct involvement in the pathophysiology of atherosclerosis and related clinical events via promotion of pro-oxidant reactions by the enzyme. However, it remains unknown whether GGT plays a direct role in the pathophysiology of atherosclerosis and CHD or is merely a correlate of coexisting cardiovascular risk factors. The exact molecular mechanisms of GGT participation in atherosclerosis or CHD and assessment of GGT-lowering therapies, as well as their impact on clinical outcomes, remain to be investigated in longitudinal studies.
Lipoprotein-associated Phospholipase A2 and Coronary Heart Disease.
Sofogianni Areti,Alkagiet Stelina,Tziomalos Konstantinos
Current pharmaceutical design
In the last decades, the role of inflammation in the pathogenesis of atherosclerosis has been the topic of intense research. Several markers of inflammation have shown predictive value for first and recurrent coronary events in patients without and with established Coronary Heart Disease (CHD). Among these markers, lipoprotein- associated phospholipase A2 (Lp-PLA2) has recently received considerable attention. In the present review, the potential role of Lp-PLA2 as a marker of CHD risk and as a therapeutic target is discussed. Elevated Lp- PLA2 mass and activity appears to be associated with increased risk for CHD, both in the general population and in patients with established CHD. However, it is unclear whether the measurement of Lp-PLA2 improves risk discrimination when incorporated in models that include traditional cardiovascular risk factors. Moreover, the lack of effect on CHD events of darapladib, a potent, selective Lp-PLA2 inhibitor, in two large, randomized, placebo-controlled trials and the mostly negative findings of genetic association studies suggest that Lp-PLA2 is unlikely to represent a causal factor in atherogenesis. Therefore, it is doubtful whether Lp-PLA2 will constitute a therapeutic target for the prevention of CHD.
[Prospective analysis of lipid profile parameters and markers of vascular inflammatory response with prognosis of undesirable coronary events in patients with coronary heart disease after angioplasty with stenting.]
Petelina T I,Musikhina N A,Gapon L I,Gorbatenko E A,Dyachkov S M,Sharoyan Yu A,Zueva E V
Klinicheskaia laboratornaia diagnostika
The study of the causes of the development of vascular coronary complications after angioplasty with stenting using the evaluation of biochemical parameters in the dynamic observation of patients with IHD with significant coronary stenosis determines the relevance of the study. To analyze the parameters of lipid spectrum and markers of vascular inflammatory reaction in patients with IHD, in groups with stable angina and episode of unstable angina after angioplasty with stenting, to trace the dynamics of biochemical parameters and to reveal the predictors of undesirable coronary events. Patients with IHD with significant coronary stenosis of the arteries (SCS, n = 95) after coronary angiography at the point of maximum increase in the level of markers of the inflammatory reaction (3 months after angioplasty) are divided into 2 groups - patients with persistent stable angina pectoris (SA, n = 77) until the end of the study and patients with developed postvascularization episode of unstable angina (UA, n = 18). The dynamics of observation of biochemical parameters recorded the absence of normalization of the atherogenic spectrum of the lipid profile and the prolonged nature of the vascular inflammatory response to the end point of observation after angioplasty.The method of binary logistic regression revealed that in the general group of patients with IHD, an increase in the level of low density lipoprotein cholesterol by 1 mmol / L significantly increases the probability of significant coronary stenosis in men and raises the risk of UA after angioplasty by 7.38 times. It was found that patients with UA at the initial stage have a significantly higher risk of coronary blood flow instability in the post-vascularization period due to an elevated level of homocysteine. A set of biochemical markers for predicting the significance of coronary stenosis and development of undesirable vascular coronary events after angioplasty in patients with IHD has been identified: male sex, elevated LDL cholesterol and hyperhomocysteinemia.
Analysis of changes in intestinal flora and intravascular inflammation and coronary heart disease in obese patients.
Li Xv,Li Chuantao
Experimental and therapeutic medicine
Changes in intestinal flora in obese patients and intravascular C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and coronary heart disease (CHD) were analyzed. A total of 75 cases of obese patients were divided into obesity (OB) alone (n=40) and OB with CHD group (n=35). There was no statistically significant difference in age, sex, pre-existing basic diabetes, history of hypertension, and body mass index (P>0.05). Results showed that total bacterial load of CHD was obviously higher than that of OB group. The uric acid decomposed by intestinal flora (IFUA) and blood uric acid levels in CHD were higher than those in OB group, but the fecal uric acid level was lower than that of OB group (P<0.05). Levels of inflammatory factors in CHD, were significantly higher than those in OB group (P<0.05). Correlation analyses showed that the intestinal flora total load and CRP were positively correlated (r=0.793, P<0.001). Intestinal flora and Gensini score were also positively related to total load (r=0.893, P=0.893). Furthermore, CRP and Gensini score were positively related (r=0.796, P<0.796). IFUA and Gensini score were positively related to (r=0.647, P<0.001). Over-reaction in the flammation system in obese patients may lead to intestinal flora disorder, disturbance and also increased levels of IFUA and inflammatory factors.
Dioscin protects against coronary heart disease by reducing oxidative stress and inflammation via Sirt1/Nrf2 and p38 MAPK pathways.
Yang Bo,Xu Bin,Zhao Hua,Wang Ya-Bin,Zhang Jian,Li Chuan-Wei,Wu Qing,Cao Yu-Kang,Li Yang,Cao Feng
Molecular medicine reports
Cardiovascular diseases are common diseases in Sweden as in most countries. In 2016, 25,700 persons suffered from coronary heart disease (CHD) and 25% of these died within 28 days. The present study investigated whether dioscin may exert protective effects against CHD‑induced heart apoptosis, oxidative stress and inflammation in a pig model and the potential underlying mechanisms. Adult pigs were used to establish a CHD model group and 80 mg/kg dioscin was administered for 4 weeks. Histological analysis and measurement of serum levels of heart injury markers demonstrated that 80 mg/kg dioscin markedly alleviated CHD, while left ventricular ejection fraction and left ventricular systolic internal diameter measurements indicated that 80 mg/kg dioscin also increased heart function in the CHD pig model. Furthermore, western blotting demonstrated that 80 mg/kg dioscin significantly reduced protein levels of apoptosis markers in the heart of CHD model pigs, including Bcl‑2‑associated X and caspase‑3, potentially via the suppression of poly (ADP‑ribose) polymerase 1 (PARP)/p53 expression. Additionally, the results of ELISA and western blotting demonstrated that 80 mg/kg dioscin may reduce oxidative stress and inflammation in CHD model pigs through the promotion of sirtuin 1 (Sirt1)/nuclear factor erythroid 2‑related factor 2 (Nrf2) protein expression and the suppression of PARP/p53 and p38 mitogen‑activated protein kinase (MAPK) expression. The results of the current study indicate that dioscin may protect against CHD by regulating oxidative stress and inflammation via Sirt1/Nrf2 and p38 MAPK pathways.
Catechin Attenuates Coronary Heart Disease in a Rat Model by Inhibiting Inflammation.
Tu Su,Xiao Feng,Min Xiaoyan,Chen Huiping,Fan Xiaochun,Cao Kejiang
Accumulating evidence has established that systemic inflammation is an important pathophysiologic factor of coronary heart disease (CHD). In this study, we investigated whether catechin exerts anti-inflammatory function in CHD rats. CHD model of rats was established by high-fat diet feeding and pituitrin injection. The successful building of CHD model was confirmed using blood liquid biochemical analyzer. Additionally, the effects of catechin on CHD parameters and several inflammatory signaling were investigated. The levels of total cholesterol, high-density lipoprotein, low-density lipoprotein cholesterin, triglyceride and blood glucose were all significantly elevated in CHD rats compared to them in control rats, suggesting the successful establishment of CHD model. Administration of catechin attenuated CHD by reversing the levels of creatine kinase, creatine kinase-MB, lactate dehydrogenase, cardiac troponin (cTnT), ventricular ejection fraction (LVEF) and systolic internal diameter (LVIDs). Additionally, several inflammatory biomarkers or cytokines such as C-reactive protein, lipoprotein-associated phospholipase A2 (Lp-PLA2), interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were inhibited by catechin. In contrast to nuclear factor-kappa beta (NF-κB), several proteins involved in inflammation such as farnesoid X receptor, signal transducers and activators of transcription (STAT)-3 and protein kinase B (PKB/Akt) were all activated by catechin. Catechin could be used as a promising treatment for CHD based on its role in suppressing inflammation and balancing STAT-3 signaling.
Influence of visceral obesity on the secretion of adipokines with epicardial adipocytes in patients with coronary heart disease.
Gruzdeva O V,Borodkina A D,Akbasheva O E,Dileva Yu A,Antonova L V,Matveeva V G,Uchasova E G,Ivanov S V,Belik E V,Fanaskova E V,Karetnikova V N,Kokov A N,Barbarash O L
AIM:To study adipokine-cytokine profile of epicardial adipocytes (EAT) and subcutaneous adipose tissue (SAT) in conjunction with the area of visceral adipose tissue (VAT), biochemical and clinical characteristics of patients with coronary heart disease. MATERIALS AND METHODS:Examined 84 patients (70 men and 14 women) with coronary artery disease. In fact the presence of visceral obesity (VO) the patients were divided into two groups. Patients VO the sampling of adipocytes of EAT and SAT, with subsequent cultivation and evaluation of adipokine and provospalitelna activity. Carried out the determination of carbohydrate and lipid metabolism, adipokine and pro-inflammatory status in the blood serum. RESULTS:It was found that adipokine-cytokine profile of adipocytes of EAT and SAT differ. Adipocytes art of the disease on the background characterized by an increase IL-1, TNF-α, leptin-adiponectin relationships and a decrease in the content of protective factors: adiponectin and anti-inflammatory cytokine IL-10. While the SAT adipocytes was characterized by a decrease in the concentration of soluble receptor for leptin and the more pronounced leptinresistance, and the increase in proinflammatory cytokines was offset by the increase in the concentration of IL-10. The presence associated with multi-vessel coronary bed lesion, multifocal atherosclerosis, insulin resistance, atherogenic dyslipidemia, an imbalance of adipokines and markers of inflammation. So the value of the square VAT determined higher concentrations of leptin, TNF-α in adipocytes and serum, lipid and carbohydrate metabolism and a lower content of soluble receptor for leptin. CONCLUSION:Thus, the disease on the background of the status of the adipocytes of EAT characterized as a "metabolic inflammation", and may indicate the direct involvement of adipocytes in the pathogenesis of coronary artery disease, due to the formation of adipokine imbalance and the activation of proinflammatory reactions.
Vitamin D Deficiency Harms Patients with Coronary Heart Disease by Enhancing Inflammation.
Liu Yongxing,Peng Wanzhong,Li Ya,Wang Bingxun,Yu Jiancai,Xu Zesheng
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND Vitamin D (VD) deficiency and local inflammation of plaque are potential new risk factors and prevention goals for coronary heart disease (CHD). MATERIAL AND METHODS This study included 135 CHD patients and 45 chest tightness or chest pain patients (control group). Basic clinical data and serum 25-OH-VD, TNF-α, IL-6, IL-8, and IL-1β of the 2 groups were compared by SPSS 25.0. A CHD rat model was used to explore the potential molecular mechanisms. RESULTS The serum 25-OH-VD level in the control group was significantly higher compared to the CHD group, and decreased with the worsening of the CHD condition. Logistic regression found that serum 25-OH-VD was a protective factor in the occurrence of CHD. In CHD patients, the level of serum 25-OH-VD had a negative correlation with serum TNF-α (r=-0.651, P<0.001), IL-6 (r=-0.457, P<0.001), IL-8 (r=-0.755, P<0.001), and IL-1β (r=-0.628, P<0.001). In animal experiments, VD deficiency enhanced the level of serum TC, TG, and LDL-C. VD deficiency could increase the inflammatory response by upregulating the expression of p65 protein and reducing SIRT1 protein expression in heart tissue, thereby inducing or aggravating the state of CHD. CONCLUSIONS Serum 25-OH-VD was a protective factor in the occurrence of CHD, and VD deficiency could induce or aggravate the state of CHD by enhancing inflammation through the NF-κB pathway.
Effect of rosuvastatin on vascular endothelial functions and inflammatory factors of patients with type 2 diabetes mellitus and coronary heart disease.
Ma Gang,Bi Shuting
Experimental and therapeutic medicine
Effects of rosuvastatin on vascular endothelial functions and inflammatory factors of patients with type 2 diabetes mellitus and coronary heart disease were investigated. Eighty patients with type 2 diabetes mellitus and coronary heart disease, who were admitted and treated in Center hospital of Zibo from January 2016 to January 2017, were selected and divided into observation group (n=40) and control group (n=40) by the random number table; symptomatic and supporting therapy, including use of metformin, captopril, asprin and levocarnitine, was used in control group while rosuvastatin was adopted in observation group in addition to the symptomatic and supporting therapy. Patients in both groups were treated for a treatment cycle, namely, 3 consecutive months. After that, indexes related to blood lipid, diabetes mellitus and vascular endothelial activity, as well as variations in inflammation-associated cytokines, before and after intervention were compared; the correlation of changes in total cholesterol (TC) with those in fasting insulin (FINS), high-sensitivity C-reactive protein (hs-CRP) and endothelin-1 (ET-1), respectively, was analyzed. Among the blood lipid indexes of the patients, the levels of TC, triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) after intervention were significantly lower than those before intervention (P<0.05), while the post-intervention level of high-density lipoprotein cholesterol (HDL-C) was higher than that before intervention (P<0.05). Compared with those before intervention, the level of FINS after intervention was remarkably higher (P<0.05), while the homeostasis model assessment of insulin resistance (HOMA-IR) level after intervention was significantly lower (P<0.05). After intervention, the levels of hs-CRP and tumor necrosis factor-α (TNF-α) in the patients were obviously decreased compared with those before intervention (P<0.05). Compared with that before intervention, the ET-1 level was decreased (P<0.05), while the nitric oxide (NO) level was elevated after intervention (P<0.05). The TC level was negatively correlated with FINS level (P<0.05) but positively correlated with the levels of hs-CRP (P<0.05) and ET-1 (P<0.05). For patients with type 2 diabetes mellitus and coronary heart disease, treatment with rosuvastatin can effectively lower the level of blood lipid and regulate insulin functions; moreover, potent decrease in blood lipid level has great significance in improving the vascular endothelial functions and reducing inflammatory response levels.
Decoy receptor-3 regulates inflammation and apoptosis via PI3K/AKT signaling pathway in coronary heart disease.
Chen Xinjing,Wang Rehua,Chen Wei,Lai Li,Li Zhiliang
Experimental and therapeutic medicine
Coronary heart disease is a disease characterized by coronary artery atherosclerosis lesions caused by vascular cavity stenosis, occlusion, myocardial ischemia, hypoxia or necrosis. Previous studies have demonstrated that decoy receptor-3 (DCR-3) can act as a pleiotropic immunomodulation for enhancing angiogenesis, which may be associated with the progression of coronary heart disease. In the present study, ELISA assay was used to investigate the plasma concentration level of DCR-3 in patients with coronary heart disease. The mRNA and protein level of DCR-3 in myocardial cells were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The role and molecular mechanism of DCR-3 was also evaluated in myocardial cells in mice with coronary heart disease. The role of small interfering RNA that targeted phosphoinositide 3-kinase (PI3K) in DCR-3 mediated apoptosis was confirmed by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling and immunofluorescence. C57BL/6 mice with coronary heart disease were used to evaluate the efficacy of DCR-3 on inflammation and apoptosis. The data indicated that plasma concentration level of DCR-3 was downregulated in mice with coronary heart disease and that DCR-3 administration improved symptoms of coronary heart disease and prolonged survival of mice with coronary heart disease. In addition, it was demonstrated that DCR-3 treatment suppressed the inflammatory response and apoptosis of myocardial cells. Circulating DCR-3 concentration levels may be identified as a predictor of coronary heart disease and prognosis of coronary heart disease. Notably, it was also demonstrated that DCR-3 inhibited inflammatory factor expression levels by regulation of the PI3K/protein kinase B (AKT) signaling pathway. Taken together, these results indicate that increasing circulating DCR-3 plasma concentration is associated with degree of coronary heart disease, suggesting that DCR-3 may be a promising drug for the treatment of coronary heart disease via regulating inflammation and apoptosis through the PI3K/AKT signaling pathway.
Oxidative Stress Status and Liver Markers in Coronary Heart Disease.
Reports of biochemistry & molecular biology
BACKGROUND:Oxidative stress plays an important role in the development of atherosclerosis. An association exists between the alterations of liver markers and the risk of coronary heart disease (CHD). This study was designed to investigate the status of oxidative stress and liver markers in patients with CHD. METHODS:This study included 50 CHD patients and 50 healthy volunteers. Serum activities of glutathione peroxidase (GPX), catalase (CAT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), and fasting blood sugar (FBS) concentrations were measured. The Unpaired Student's t-test was used to analyze the data. RESULTS:Serum GSH level and CAT and GPX activities were significantly greater in healthy controls than in CHD patients. Serum MDA, NO, and FBS levels and GGT, ALT, ALP activities were significantly greater in CHD patients than in healthy controls. Serum AST activity was greater in CHD patients than in controls, but the difference was not statistically significant. CONCLUSION:Our results indicate that CHD is related to oxidative stress, lipid peroxidation, inflammation, and elevated liver enzyme activity. CHD is a deadly disease that requires appropriate medical care. Antioxidant treatment might inhibit disease progression.
Anti-inflammatory and antioxidative effects of Dan-Lou tablets in the treatment of coronary heart disease revealed by metabolomics integrated with molecular mechanism studies.
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL EVIDENCE:The Dan-Lou tablet (DLT), a well-known Chinese prescription, has definitive clinical efficacy in the treatment of precordial discomfort and pain caused by coronary heart disease (CHD). However, the pharmacological mechanism of DLT in the treatment of CHD has not been clearly elucidated and needs to be further explored. AIM OF THE STUDY:We aimed to identify relevant biological pathways by assessing changes in biomarkers in response to DLT intervention in CHD to reveal the potential biological mechanism of DLT treatment for CHD. MATERIALS AND METHODS:The major chemical components in DLT were qualitatively analyzed using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and a model of CHD in rats was subsequently established with a high-fat diet and left anterior coronary artery ligation (LADCA) followed by DLT intervention. Next, the metabolic profile of rat serum samples was analyzed using nontargeted metabolomics, wherein changes in the metabolites in serum samples before and after DLT administration were measured by PLS-DA, and two pathways of DLT treatment for CHD were predicted. Finally, predicted metabolomic pathways were verified by detecting and analyzing tissues from the rat model, revealing the mechanism of DLT in the treatment of CHD. RESULTS:Forty-five major chemical components were identified by the chemical characterization of DLT. In terms of metabolism, 17 biomarkers of CHD in rats were identified. Among these biomarkers, linoleic acid, γ-linolenic acid and lysophosphatidylcholines (LPCs) were found to play an important role in energy metabolism and glycerophospholipid metabolism. Protein analysis revealed that EGFR phosphorylation was inhibited in CHD rats after DLT treatment, which lowered the expression of TNF-α, IL-6 and MMP9, decreased the expression levels of ox-LDL and MDA, and increased the expression of SOD. CONCLUSION:The mechanism of DLT in the treatment of CHD involves inhibiting the expression of EGFR and the activation of the MAPK signaling pathway by regulating glycerophospholipid metabolism (LPCs) and energy metabolism (linoleic acid and γ-linolenic acid). Therefore, inflammation-related (TNF-α, IL-6, MMP9) and oxidative stress-related (ox-LDL, MDA, SOD) indicators are affected, leading to the regulation of the oxidative stress state and anti-inflammatory effects.
Uncovering the protective mechanism of Huoxue Anxin Recipe against coronary heart disease by network analysis and experimental validation.
Wang Jie,Zhang Yun,Liu Yong-Mei,Yang Xiao-Chen,Chen Yin-Ying,Wu Guang-Jun,He Xuan-Hui,Duan Lian,Dong Yan,Ma Ru-Feng
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Coronary heart disease (CHD) is a leading cause of death and disability worldwide. Huoxue Anxin Recipe (HAR) is a novel Chinese Herbal Medicine formula of that has been used to treat CHD for several decades. Our previous study found that HAR had anti-oxidative effects, and could promote myocardial angiogenesis and improve cardiac function following myocardial infarction (MI) in rats. However, the active compounds, potential targets, and biological processes related to HAR have not been systematically investigated. Here, network pharmacology and experimental validation were used to study the protective mechanisms of HAR against CHD. We identified 124 active components, 124 verified targets, and 111 predictive targets. A total of 1192 genes related to CHD were identified by cDNA microarray and database analysis. A total of 47 putative targets of HAR against CHD were identified, including 32 verified targets and 15 predictive targets. ClueGo enrichment analysis identified 49 biological processes involved in the anti-CHD effects of HAR. Among them, the negative regulation of blood coagulation and regulation of collagen biosynthetic process were experimentally validated. After constructing a protein-protein interaction network and clustering with MECODE and ClusterONE, 162 key proteins (from ClueGo and clustering) were used to construct an internal interaction network. Complement C3 (C3), Fibrinogen alpha (FGA), Fibrinogen gamma (FGG), interleukin-6 (IL6), and Apolipoprotein A1 (APOA1) were the top 5 hub proteins identified by cytoHubber analysis. HAR limited the concentrations of C3, FGA, FGG, and IL6 and increased APOA1 levels. The results indicated that HAR could down-regulate blood coagulation, regulate collagen biosynthesis, inhibit peroxidation and inflammation injury, and promote cholesterol efflux. HAR could be a potential source of novel and effective drugs for CHD.
Interleukin‑37 is increased in peripheral blood mononuclear cells of coronary heart disease patients and inhibits the inflammatory reaction.
Li Huimin,Shen Chen,Chen Bingni,Du Jing,Peng Bin,Wang Wei,Chi Fanwu,Dong Xiaoqiang,Huang Zhong,Yang Chao
Molecular medicine reports
It has been universally acknowledged that interleukin‑37 (IL‑37) has an immunosuppressive effect on various inflammatory disorders. However, whether IL‑37 participates in the acute inflammation associated with coronary heart disease (CHD) has not yet been clarified. In the present study, the association between the serum levels of IL‑37 and the clinical indexes of CHD were analysed. In addition, the anti‑inflammatory effects of IL‑37 on peripheral blood mononuclear cells (PBMCs) were studied in CHD patients. PBMCs from 46 healthy controls (HCs) and 92 CHD patients were cultured in vitro and stimulated using the recombinant IL‑37 protein. The protein levels, as well as the mRNA expression of inflammatory cytokines (TNF‑α, IL‑1β, IL‑6, and IL‑17) were analysed by enzyme‑linked immunosorbent assay (ELISA) and real‑time polymerase chain reaction (RT‑PCR). Spearman's correlation test was performed to examine the association between the serum level of IL‑37 and the levels of pro‑inflammatory cytokines, certain clinical indexes, and disease activity during CHD. Compared to the HCs, the CHD patients, especially those with acute myocardial infarction, exhibited higher levels of IL‑37 in their PBMCs and sera. Serum levels of IL‑37 were associated with the levels of IL‑17, IL‑6, and TNF‑α, and clinical indexes such as the left ventricular ejection fraction (LVEF), amino‑N‑terminal pro‑plasma brain natriuretic peptide (NT‑proBNP) levels, and cardiac troponin T (cTnT) levels in CHD patients. Compared to the HC group, the production of inflammatory cytokines such as IL‑17, IL‑6, TNF‑α, and IL‑1β increased in the PBMCs of CHD patients and significantly decreased after the stimulation of the cells with recombinant IL‑37. The IL‑37 levels in CHD patients were high, and were correlated with the levels of CHD‑related pro‑inflammatory cytokines and disease activity. Notably, the expression of CHD‑related pro‑inflammatory cytokines in the PBMCs of CHD patients decreased following the stimulation of the cells with recombinant IL‑37, indicating that IL‑37 exerts anti‑inflammatory effects during CHD.
Inflammation-Related MicroRNAs Are Associated with Plaque Stability Calculated by IVUS in Coronary Heart Disease Patients.
Journal of interventional cardiology
OBJECTIVES:This study aimed to investigate the association between inflammation-related microRNAs (miR-21, 146a, 155) and the plaque stability in coronary artery disease patients. METHODS:The expression of miR-21, 146a, and 155 was measured by real-time PCR in 310 consecutive patients. The level of hs-CRP, IL-6, and IL-8 was measured by ELISA. The plaque stability of coronary stenotic lesions was evaluated with intravascular ultrasound (IVUS). RESULTS:(1) The levels of hs-CRP, IL-6, and IL-8 were significantly increased in the UAP and AMI groups compared with the CPS group ( < 0.01). (2) The expression of miR-21 and miR-146a in peripheral blood mononuclear cells (PBMCs) and plasma was significantly higher in CAD patients compared with non-CAD patients, whereas the miR-155 expression in PBMCs and plasma was significantly lower in patients with CAD. (3) The miR-21 expression in PBMCs was higher in UAP and AMI groups compared with CPS group. The miR-146a expression in PBMCs was higher in SAP, UAP, and AMI groups than in CPS group. Although the level of miR-155 in PBMCs was lower in SAP, UAP, and AMI groups than in CPS group. The expression patterns of miR-21, miR-146a, and miR-155 in plasma were consistent with those of PBMCs. (4) The expressions of miR-21 and miR-146a in PBMCs and plasma were significantly higher in the vulnerable plaque group than those in stable plaque group. While miR-155 in PBMCs and plasma was significantly lower in vulnerable plaque group compared with stable plaque group. (5) The levels of miR-21 and miR-146a in PBMCs and plasma were significantly higher in soft plaque group than in fibrous plaque group and calcified plaque group. However, miR-155 in PBMCs and plasma was significantly lower in soft plaque group. CONCLUSIONS:The expression of miR-21 and miR-146a are associated with the plaque stability in coronary stenotic lesions, whereas miR-155 expression is inversely associated with the plaque stability.
The Association Between Sortilin and Inflammation in Patients with Coronary Heart Disease.
Journal of inflammation research
PURPOSE:Inflammation is a key contributor to coronary heart disease (CHD). Sortilin is a sorting receptor and has been identified as a critical regulator of inflammatory response. Therefore, our study aimed to determine the link between circulating sortilin levels, proinflammatory cytokine levels, and the occurrence of CHD. PATIENTS AND METHODS:Our study included 227 CHD patients and 101 matched healthy individuals. Circulating serum levels of sortilin and proinflammatory cytokines, including IL-1β, IL-6 and TNF-α, were assessed by a double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA). Linear regression and correlation analyses were used to estimate the associations between sortilin and proinflammatory cytokines. Moreover, six single-nucleotide polymorphisms (SNPs) spanning the sortilin and SORL1 genes were genotyped. RESULTS:Elevated levels of sortilin (P=0.027) and proinflammatory cytokines IL-1β (P=0.013), IL-6 (P=0.000) and TNF-α (P=0.010) were observed in CHD patients compared to those in healthy controls. Furthermore, sortilin levels were significantly positively correlated with IL-1β (r=0.252, P=0.0001), IL-6 (r=0.250, P=0.0001) and TNF-α (r=0.180, P=0.0064) levels. Notably, sortilin polymorphisms were revealed to be associated with the occurrence of CHD and varying sortilin levels. Subjects with the rs599839 AA risk genotype for CHD had significantly higher sortilin levels than those with the GG and GA genotypes (P=0.000); the same tendency was also observed in the levels of the proinflammatory cytokines IL-1β (P=0.003) and TNF-α (P=0.000). Similarly, GG carriers of rs464218 with increased sortilin levels were found to be at increased risk for CHD (P=0.014). The levels of IL-1β (P=0.025) and IL-6 (P=0.015) were also increased in these patients. CONCLUSION:Our findings reveal that high sortilin levels may interact with inflammatory response to contribute to the occurrence of CHD. Considering that our clinical evidence suggests for the first time that sortilin involves in inflammatory response in CHD, the mechanistic role of sortilin in the progression of CHD deserves detailed investigation.
Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts.
Olson Nels C,Sitlani Colleen M,Doyle Margaret F,Huber Sally A,Landay Alan L,Tracy Russell P,Psaty Bruce M,Delaney Joseph A
BACKGROUND AND AIMS:Cell-mediated immunity is implicated in atherosclerosis. We evaluated whether innate and adaptive immune cell subsets in peripheral blood are risk factors for coronary heart disease. METHODS:A nested case-cohort study (n = 2155) was performed within the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Cases of incident myocardial infarction (MI) and incident angina (n = 880 total cases) were compared with a cohort random sample (n = 1275). Immune cell phenotypes (n = 34, including CD14 monocytes, natural killer cells, γδ T cells, CD4, CD8 and CD19 lymphocyte subsets) were measured from cryopreserved cells by flow cytometry. Cox proportional hazards models with adjustment for cardiovascular disease risk factors were used to evaluate associations of cell phenotypes with incident MI and a composite phenotype of incident MI or incident angina (MI-angina) over a median 9.3 years of follow-up. Th1, Th2, Th17, T regulatory (CD4CD25CD127), naive (CD4CD45RA), memory (CD4CD45RO), and CD4CD28 cells were specified as primary hypotheses. In secondary analyses, 27 additional cell phenotypes were investigated. RESULTS:After correction for multiple testing, there were no statistically significant associations of CD4 naive, memory, CD28, or T helper cell subsets with MI or MI-angina in MESA, CHS, or combined-cohort meta analyses. Null associations were also observed for monocyte subsets, natural killer cells, γδ T cells, CD19 B cell and differentiated CD4 and CD8 cell subsets. CONCLUSIONS:The proportions of peripheral blood monocyte and lymphocyte subsets are not strongly related to the future occurrence of MI or angina in adults free of autoimmune disease.
Prediction of Residual Risk by Ceramide-Phospholipid Score in Patients With Stable Coronary Heart Disease on Optimal Medical Therapy.
Hilvo Mika,Wallentin Lars,Ghukasyan Lakic Tatevik,Held Claes,Kauhanen Dimple,Jylhä Antti,Lindbäck Johan,Siegbahn Agneta,Granger Christopher B,Koenig Wolfgang,Stewart Ralph A H,White Harvey,Laaksonen Reijo,
Journal of the American Heart Association
Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide- and phospholipid-based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography-mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein-associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow-up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25-1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35-1.59) for cardiovascular death, 1.32 (95% CI, 1.16-1.49) for stroke, 1.23 (95% CI, 1.14-1.33) for myocardial infarction, and 1.56 (95% CI, 1.39-1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation (<0.001, >0.2) with inflammatory markers high-sensitivity C-reactive protein, interleukin 6, the heart failure marker N-terminal pro-B-type natriuretic peptide, and low-density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
Andrographolide protects against endothelial dysfunction and inflammatory response in rats with coronary heart disease by regulating PPAR and NF-κB signaling pathways.
Shu Jia,Huang Ruizhen,Tian Ying,Liu Yanru,Zhu Rui,Shi Gang
Annals of palliative medicine
BACKGROUND:Andrographolide (Andro) is an active compound extracted from Andrographis, which has protective anti-inflammatory effects. But, its pathological role in coronary heart disease (CHD) is unclear, the aim of this study is to investigate the therapeutic effect of Andro in CHD and explore its potential mechanism. METHODS:Here, we established a mouse model of CHD, and rats were randomly divided into 5 groups (n=10): sham, Andro (50 mg/kg), CHD, CHD + Andro (10 mg/kg), and CHD + Andro (50 mg/kg). HE staining was employed to evaluate the pathological changes of myocardial injury cardiac injury. The serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), highdensity lipoprotein cholesterol (HDL-C), nitric oxide (NO), TXA2, ET-1, and prostaglandin I2 (PGI2) were detected by ELISA assay. Myocardial inflammation and the interaction between Andro and PPAR-α/NF-κB axis was measured using western blot. RESULTS:Compared with CHD groups, Andro preserved cardiac injury and decreased the levels of TC, TG, and LDL-C while increasing the level of HDL-C. In addition, Andro also reduced the levels of TNF-α, MCP-1, hs-CRP and IL-1β by shifting the macrophage phenotype and attenuated the endothelial dysfunction by increasing the serum levels of ET-1 and TAX2 and decreasing the levels of NO and PGI2 in mice. Furthermore, Andro impeded cardiac apoptosis and inhibited the activation of PPARα and NF-κB proteins. CONCLUSIONS:Andro may represent a medicinal approach for assessing and treating CHD.
Pharmacological Network Reveals the Active Mechanism of Qi-Replenishing, Spleen-Strengthening, Phlegm-Dispelling, and Blood-Nourishing Fufang on Coronary Heart Disease.
Zhang Fan,Liu Yue,Zheng Sicheng,Dang Boyi,Wang Jianan,Zhang Zhe
Evidence-based complementary and alternative medicine : eCAM
This study aimed to investigate the potential targets and pathways of qi-replenishing, spleen-strengthening, phlegm-dispelling, and blood-nourishing Fufang in the treatment of coronary heart disease (CHD). The composition of Fufang was identified, followed by screening of the active components using ADME. The targets of active components were predicted and screened based on the TCMSP and BATMAN databases and were cross-validated using the CTD database and DisGeNET. A functional enrichment analysis was performed using the ClueGO + CluePedia plugins and clusterProfiler in the R package. The protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape. Finally, a pharmacological network was constructed. A total of 27 overlapping targets were obtained after cross-validation. ALB, IL-6, and TNF were the hub genes in the PPI network. The pharmacological network included 59 nodes and 189 relation pairs. Among the 59 nodes, there were 2 herbal medicine nodes ( and ), 8 chemical component nodes (magnesium lithospermate B, neocryptotanshinone II, heteratisine, daphneolone, tanshinone IIA, tanshinone IIB, soyasapogenol B, and astragaloside II), 27 target protein nodes (such as ALB, TNF, IL-6, NFKB1, APOA1, APOA2, CYP1A1, and CYP1A2), and 22 pathway nodes (such as the toll-like receptor signaling pathway, IL-17 signaling pathway, and TNF signaling pathway). Therefore, we found that the genes TNF, IL-6, NFKB1, ALB, CYP1A1, CYP1A2, APOA1, and APOA2 might be important targets of the key active compounds neocryptotanshinone II and astragaloside II. These genes targeted by the key active compounds might regulate inflammation-related pathways and the level of albumin and cholesterol in CHD.
Expression of Genes Encoding Nuclear Factors PPARγ, LXRβ, and RORα in Epicardial and Subcutaneous Adipose Tissues in Patients with Coronary Heart Disease.
Panteleeva A A,Razgildina N D,Pobozheva I A,Polyakova E A,Dracheva K V,Belyaeva O D,Berkovich O A,Baranova E I,Pchelina S N,Miroshnikova V V
Bulletin of experimental biology and medicine
The nuclear factors PPARγ, RORα, and LXRβ are involved in transcriptional control of adipogenesis and implicated in glucose and lipid metabolism. In adipose tissues, they regulate inflammation. This study focuses on expression of the PPARG, RORA, and LXRβ (NR1H2) genes in epicardial and subcutaneous adipose tissues in patients with coronary heart disease as well as with concomitant abdominal obesity. In patients with coronary heart disease and abdominal obesity, PPARG mRNA level in subcutaneous adipose tissue was reduced in comparison with control group. In patients with total coronary occlusions, LXRβ mRNA level in epicardial adipose tissue was reduced, and it positively correlated with plasma HDL cholesterol. Thus, in cases of concomitant abdominal obesity and chronic total coronary occlusions, coronary heart disease is characterized by down-regulated expression of the genes of various transcriptional adipogenesis-regulating factors in adipose tissue.
Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.
Wallentin Lars,Eriksson Niclas,Olszowka Maciej,Grammer Tanja B,Hagström Emil,Held Claes,Kleber Marcus E,Koenig Wolfgang,März Winfried,Stewart Ralph A H,White Harvey D,Åberg Mikael,Siegbahn Agneta
BACKGROUND:Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. METHODS AND FINDINGS:The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events. CONCLUSIONS:Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. TRIAL REGISTRATION:ClinicalTrials.gov NCT00799903.
Puerarin alleviates coronary heart disease via suppressing inflammation in a rat model.
Zhao Liangping,Wang Li,Zhang Daimin,Chen Yuqi,Jin Fulu
BACKGROUND:Puerarin shows inhibitory effects on inflammation in chronic heart failure (CHF), but its efficacy in coronary heart disease (CHD) remained vague. METHODS:Rat CHD model was constructed, and serum parameters were determined using a blood liquid biochemical analyzer. Also, contents of creatine kinase (CK), creatine kinase MB isoenzyme (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin (cTnT) were measured using colorimetry. Histological examination was conducted with Hematoxylin-Eosin (H&E) staining, and cardiac function was assessed by Echocardiography. Cell apoptosis was detected using Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Relative expressions were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot as needed. RESULTS:In CHD rats, the levels of TC, LDL and TG and the expressions of matrix metalloproteinase-9 (MMP-9), CD40 ligand (CD40L), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were increased while HDL level was decreased, accompanied with inflammatory cell infiltration and cardiac malfunction. Also, the contents of CK, CK-MB, LDH and cTnT, the percentage of apoptotic cells, the expressions of Bcl-2 associated X protein (Bax), cleaved Caspase-3, TNF-α, Interleukin-β (IL-β), IL-6 and Lipoprotein-associated Phospholipase A2 (Lp-PLA2) expressions and the levels of oxidized-(ox-)LDL and malondialdehyde (MDA) were upregulated, while the level of super oxidase dismutase (SOD) and the expressions of B cell lymphoma-2 (Bcl-2) and vascular endothelial growth factor (VEGF) were downregulated. However, Puerarin ameliorated the effects of CHD model construction, suppressed nuclear factor-(NF-)κB expression, and enhanced the expressions of Farnesoid X Receptor (FXR), phosphorylated-AKT (p-AKT) and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3). CONCLUSION:Puerarin alleviated CHD in rats via inhibiting inflammation, providing possible method for CHD treatment.
The traditional Chinese medicine formula Fufang-Zhenzhu-Tiaozhi protects myocardia from injury in diabetic minipigs with coronary heart disease.
Song Lixia,Zhang Dongxing,Guo Caijuan,Gu Zhanhui,Wang Lexun,Yao Yu Si,Wang Hong,Zeng Zhihuan,Wang Weixuan,Yang Yiqi,Bei Weijian,Rong Xianglu,Guo Jiao
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
BACKGROUND AND PURPOSE:Diabetes mellitus (DM) is a major risk factor for coronary heart disease (CHD). Previous research has reported that the Fufang-Zhenzhu-Tiaozhi (FTZ) formula has obvious effects on the treatment of dyslipidemia and hyperglycemia. In the present study, we intended to establish a convenient DM-CHD model in minipigs and investigated the protective effect of FTZ against myocardial injury and its mechanism. METHODS:The DM-CHD model was established by a high-fat/high-sucrose/high-cholesterol diet (HFSCD) combined with balloon injury in the coronary artery. Subsequently, sixteen Wuzhishan minipigs were assigned to three groups: control group, model group, and FTZ group. The model group and FTZ group were given a HFSCD, while the control group was given a normal diet (ND). FTZ was given with meals in the FTZ group. During this time, biochemical parameters, such as total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL-C), and fasting blood glucose (FBG), were measured by using testing kits. Insulin (INS) was determined by ELISA, and the homeostasis model assessment index of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance levels. After FTZ administration, the plasma levels of lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB), and cardiac troponin I (cTnI) were measured by using ELISA kits to evaluate myocardial injury. Coronary artery stenosis was analyzed by angiographic and HE staining. Myocardial ischemia was assayed with electrocardiogram (ECG). Moreover, cytokines, including interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), and tumor necrosis factor-alpha (TNF-α), were measured by ELISA kits to assess inflammation. The myocardial tissue was collected, and the pathological morphology was observed by transmission electron microscopy (TEM), HE staining, and Masson staining. Western blots were used to detect the expression of PI3K, AKT, p-AKT, p-NF-κB, and NF-κB. RESULTS:A DM-CHD model in minipigs with glucose-lipid metabolism disorder, coronary artery incrassation and myocardial damage was successfully established through balloon injury in the coronary artery combined with HFSCD. FTZ effectively inhibited coronary artery incrassation and protected the myocardium against injury in DM-CHD minipigs. FTZ decreased proinflammatory cytokine levels and upregulated the protein expression of the PI3K/Akt pathway in the myocardium. CONCLUSIONS:A novel DM-CHD model in minipigs was successfully established through balloon injury in the coronary artery combined with HFSCD. FTZ has a protective effect against myocardial injury in DM-CHD by inhibiting inflammation and activating the PI3K/AKT signaling pathway.
High triglyceride to HDL cholesterol ratio is associated with increased coronary heart disease among White but not Black adults.
American journal of preventive cardiology
OBJECTIVE:Black adults are less likely than White adults to present with adverse lipid profiles and more likely to present with low-grade inflammation. The impact of race on the association between atherogenic lipid profiles, inflammation, and coronary heart disease (CHD) is unknown. METHODS:We evaluated the association between high levels (>50th percentile) of high-sensitivity C-reactive protein (hsCRP) and of triglycerides to high density lipoprotein ratio (TG/HDL-C) and CHD events by race in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort with 30,239 Black and White participants aged 45 and older. RESULTS:Participants with both high hsCRP and high TG/HDL-C had highest rates of CHD (HR 1.84; 95% CI: 1.48, 2.29 vs HR 1.52; 95% CI: 1.19, 1.94 in White vs Black participants respectively). Whereas isolated high hsCRP was associated with increased CHD risk in both races (HR 1.68; 95% CI: 1.31, 2.15 and HR 1.43; 95% CI: 1.13, 1.81 for White and Black participants respectively), isolated high TG/HDL was associated with increased CHD risk only in White participants (HR 1.44; 95% CI: 1.15, 1.79 vs HR 1.01; 95% CI: 0.74, 1.38). Further, the effects of high hsCRP and high TG/HDL-C were additive, with inflammation being the driving variable for the association in both races. CONCLUSION:In both races, higher inflammation combined with adverse lipid profile is associated with greater CHD risk. Therefore, inflammation increases CHD risk in both races whereas dyslipidemia alone is associated with a greater risk in White but not in Black adults. hsCRP testing should be a standard feature of CHD risk assessment, particularly in Black patients.
The Role of the VEGF Family in Coronary Heart Disease.
Zhou Yan,Zhu Xueping,Cui Hanming,Shi Jingjing,Yuan Guozhen,Shi Shuai,Hu Yuanhui
Frontiers in cardiovascular medicine
The vascular endothelial growth factor (VEGF) family, the regulator of blood and lymphatic vessels, is mostly investigated in the tumor and ophthalmic field. However, the functions it enjoys can also interfere with the development of atherosclerosis (AS) and further diseases like coronary heart disease (CHD). The source, regulating mechanisms including upregulation and downregulation, target cells/tissues, and known functions about VEGF-A, VEGF-B, VEGF-C, and VEGF-D are covered in the review. VEGF-A can regulate angiogenesis, vascular permeability, and inflammation by binding with VEGFR-1 and VEGFR-2. VEGF-B can regulate angiogenesis, redox, and apoptosis by binding with VEGFR-1. VEGF-C can regulate inflammation, lymphangiogenesis, angiogenesis, apoptosis, and fibrogenesis by binding with VEGFR-2 and VEGFR-3. VEGF-D can regulate lymphangiogenesis, angiogenesis, fibrogenesis, and apoptosis by binding with VEGFR-2 and VEGFR-3. These functions present great potential of applying the VEGF family for treating CHD. For instance, angiogenesis can compensate for hypoxia and ischemia by growing novel blood vessels. Lymphangiogenesis can degrade inflammation by providing exits for accumulated inflammatory cytokines. Anti-apoptosis can protect myocardium from impairment after myocardial infarction (MI). Fibrogenesis can promote myocardial fibrosis after MI to benefit cardiac recovery. In addition, all these factors have been confirmed to keep a link with lipid metabolism, the research about which is still in the early stage and exact mechanisms are relatively obscure. Because few reviews have been published about the summarized role of the VEGF family for treating CHD, the aim of this review article is to present an overview of the available evidence supporting it and give hints for further research.
Anti-inflammatory Therapies for Coronary Heart Disease: A Systematic Review and Meta-Analysis.
Wang Haiming,Jiang Min,Li Xin,Zhao Yunzhang,Shao Junjie,Liu Zifan,Lin Lejian,Xu Qiang,Wang Lin,Lu Xuechun,Zhang Haomin,Chen Yundai,Zhang Ran
Frontiers in cardiovascular medicine
Anti-inflammatory therapy has been proposed as a promising treatment for coronary heart disease (CHD) that could reduce residual inflammation risk (RIR) and therefore major adverse cardiovascular events. We implemented a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the clinical benefits of anti-inflammatory agents in patients with CHD based on secondary cardiovascular prevention. We systemically searched the PubMed, Embase, and Cochrane Library databases for RCTs (published between Jan 1, 1950, and June 1, 2021; no language restrictions) that focused on anti-inflammatory therapy for coronary heart disease. Our primary end points of interest were a composite of all-cause death, recurrent myocardial infarction and stroke. We processed pooled data using a random-effects model. Of 1497 selected studies, 18 studies with 67,449 participants met our inclusion criteria and were included in the present meta-analysis. Comparing anti-inflammatory agents with placebo, there was no significant decrease in risk of primary end points, secondary end points, all-cause mortality, cardiac mortality, recurrent myocardial infarction, stroke or revascularization. Further subgroup analysis indicated that anti-inflammatory agents led to a significant reduction in secondary end points (OR 0.87, CI 0.77-0.99; = 0.03), recurrent myocardial infarction (OR 0.86, CI 0.78-0.95; = 0.003) and revascularization (OR 0.81, CI 0.70-0.92; = 0.001) in patients with stable CHD compared with placebo. Moreover, stable CHD patients had a lower propensity for recurrent myocardial infarction than acute coronary syndrome (ACS) patients when using anti-inflammatory agents ( = 0.03). The colchicine subgroup analysis showed that colchicine yielded a promising reduction in the primary end points (OR 0.81, CI 0.70-0.95; = 0.009) compared with placebo. Anti-inflammatory agents were associated with a higher risk of infection (OR 1.13, CI 1.03-1.23; = 0.007) and negligible effects on cancers (OR 0.98, CI 0.90-1.06; = 0.61). Anti-inflammatory agents appear to have beneficial effects in reducing the risk of recurrent myocardial infarction in patients with stable CHD, albeit at the cost of increased infection. Notably, colchicine demonstrates a promising cardioprotective effect with a lower incidence of major cardiovascular events and thus is a potential therapeutic strategy for stable CHD patients. PROSPERO, identifier CRD42021245514.
Efficacy and safety of coronary stent intervention for coronary heart disease and its impact on short-term and long-term prognosis.
Zhang Ning,Wei Duhui
American journal of translational research
OBJECTIVE:To investigate the effect of coronary stent intervention on the efficacy, safety, and short-term and long-term prognosis of patients with coronary heart disease (CHD). METHODS:From March 2016 to November 2017, 60 cases of CHD patients receiving coronary stent interventiontherapy (research group) and 42 cases of patients receiving conventional drug therapy (control group) in our hospital were recruited as research objects. The clinical efficacy, safety and prognosis in the two groups were compared, and the levels of matrix metalloproteinase-9 (MMP-9) and interleukin-33 (IL-33) in the two groups were measured before and after treatment. RESULTS:The clinical efficacy and prognostic quality of life of patients in the research group were higher than those in the control group (<0.050), and the serum levels of MMP-9 and IL-33 in the research group were higher than those in the control group after treatment (<0.050). CONCLUSION:Compared with drug therapy alone, coronary stent intervention therapy has better clinical efficacy and short-term and long-term prognosis in treating CHD, but it is easy to promote inflammatory reaction after surgery. Therefore, attention should be paid to the control of inflammation before and after treatment.
Anti-inflammatory activity of the Tongmai Yangxin pill in the treatment of coronary heart disease is associated with estrogen receptor and NF-κB signaling pathway.
Fan Yadong,Liu Jianwei,Miao Jing,Zhang Xiaoyu,Yan Yiqi,Bai Liding,Chang Jun,Wang Ying,Wang Li,Bian Yuhong,Zhou Huifang
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:The Tongmai Yangxin Pill (TMYX) is a patented traditional Chinese medicine originating from two classic prescriptions, Zhigancao Decoction and Shenmai Yin, which composed of 11 Chinese medicinal herbs: Rehmannia glutinosa (Gaertn.) DC., Spatholobus suberectus Dunn, Ophiopogon japonicus (Thunb.) Ker Gawl., Glycyrrhiza uralensis Fisch., Polygonum multiflorum Thunb., Equus asinus L., Schisandra chinensis (Turcz.) Baill., Codonopsis pilosula (Franch.) Nannf., Chinemys reevesii (Gray), Ziziphus jujuba Mill. and Cinnamomum cassia (L.) J.Presl (Committee of the Pharmacopoeia of PR China, 2015). TMYX has marketed in China for the treatment of chest pain, palpitation, angina, irregular heartbeat and coronary heart disease (CHD) for several decades. Previous studies have confirmed that TMYX can treat CHD by reducing inflammation, but the underlying pharmacological mechanism remains unclear. AIM OF THE STUDY:This study aimed to declare the underlying pharmacological mechanism of anti-inflammatory activity of TMYX in the treatment of CHD via clinical trial, microarray study, bioinformatics analysis and the vitro assays. MATERIALS AND METHODS:Eight CHD patients' serum biochemical indices including coagulation function, lipid metabolism, endothelial injury, metalloprotease, adhesion molecule, inflammatory mediator and homocysteine were measured to investigate the reduction of CHD risk by TMYX oral administration (40 pills/time, 2 times/day) for eight weeks. The expression profile chips and Ingenuity Pathway Analysis (IPA) were assessed to reveal the global transcriptional response and predict related functions, diseases and canonical pathways. The in vitro anti-inflammatory actions of TMYX were evaluated using oxidized low-density lipoprotein (100 μg/mL) induced murine RAW264.7 macrophage with an ethanol extract from TMYX (EETMYX) (25-100 μg/mL). RESULTS:TMYX treatment showed reduced levels of apolipoprotein B, endothelin 1, nuclear factor κB (NF-κB) and homocysteine in CHD patients. In contrast, the treatment increased the ratio of apolipoprotein A/apolipoprotein B. EETMYX restored cell morphology and suppressed the lipid deposition of the induced foam cells. EETMYX exerted anti-inflammatory effects by raising the mRNA and protein expression of Estrogen receptor 1 (ESR1), blocking the reduction of IκBa level and the phosphorylation of IKKα/β, IκBα and NF-κB p65, accompanied by inhibiting MCP-1, TNF-α and IL-6 production, which were consistent with bioinformatics predictions. CONCLUSION:TMYX treatment improved the biochemical indices in CHD patients. EETMYX effectively attenuated macrophage foam cell formation and exhibited anti-inflammatory activity is associated with regulating ESR1 and NF-κB signaling pathway activity.
The relation of circulating cell division cycle 42 expression with Th1, Th2, and Th17 cells, adhesion molecules, and biochemical indexes in coronary heart disease patients.
Irish journal of medical science
BACKGROUND:Cell division cycle 42 (CDC42) regulates macrophage polarization, vascular inflammation, atherosclerosis progression, and modifies differentiation of T helper (Th) cells, while its potential as a biomarker in coronary heart disease (CHD) patients is still lacking. This study aimed to evaluate CDC42 expression, its correlation with Th1, Th2, and Th17 cells, adhesion molecules, and biochemical indexes in CHD patients. METHODS:One hundred two CHD patients and 50 controls were enrolled. CDC42 expression in peripheral blood mononuclear cells was assessed by reverse transcription quantitative polymerase chain reaction in all participants. In CHD patients, Th1, Th2, and Th17 cells were detected by flow cytometric analysis; meanwhile, serum levels of inflammatory cytokines and adhesion molecules were detected by enzyme-linked immunosorbent assay. RESULTS:CDC42 was lower in CHD patients (median (interquartile range (IQR)) = 0.431 (0.304-0.722)) than in controls (median (IQR) = 0.985 (0.572-1.760)) (p < 0.001). CDC42 was positively associated with Th2 cells (p = 0.016) and interleukin (IL)-10 (p = 0.034), but negatively correlated with Th17 cells (p < 0.001) and IL-17A (p < 0.001) in CHD patients. However, no association was found in CDC42 with Th1 cells (p = 0.199) or interferon-γ (p = 0.367) in CHD patients. Besides, CDC42 was negatively correlated with vascular cell adhesion molecule-1 (p = 0.013) and intercellular cell adhesion molecule-1 (p = 0.001) in CHD patients. Additionally, CDC42 negatively associated with C-reactive protein (p < 0.001), Gensini score (p < 0.001), total cholesterol (p = 0.039), and low-density lipoprotein cholesterol (p = 0.014), but not with other biochemical indexes (p > 0.05) in CHD patients. CONCLUSION:CDC42 correlates with Th2 cells, Th17 cells, and adhesion molecules, also reflects inflammation, coronary stenosis degree, and cholesterol level in CHD patients.
Exploring the Therapeutic Mechanisms of Huzhang-Shanzha Herb Pair against Coronary Heart Disease by Network Pharmacology and Molecular Docking.
Evidence-based complementary and alternative medicine : eCAM
BACKGROUND:Coronary heart disease (CHD) seriously affects human health, and its pathogenesis is closely related to atherosclerosis. The Huzhang (the root of )-Shanzha (the fruit of sp.), a classic herb pair, has been widely used for the treatment of CHD. In recent years, Huzhang-Shanzha herb pair (HSHP) was found to have a wide range of effects in CHD; however, its therapeutic specific mechanisms remain to be further explored. The aim of this study was to elucidate the molecular mechanism of HSHP in the treatment of CHD using a network pharmacology analysis approach. METHODS:The Batman-TCM database was used to explore bioactive compounds and corresponding targets of HSHP. CHD disease targets were extracted from Genecards, OMIM, PharmGkb, TTD, and DrugBank databases. Then, the protein-protein interaction (PPI) network was constructed using the STRING web platform and Cytoscape software. GO functional and KEGG pathway enrichment analyses were carried out on the Metascape web platform. Finally, molecular docking of the active components was assessed to verify the potential targets of HSHP to treat CHD by the AutoDock Vina and PyMOL software. RESULTS:Totally, 243 active components and 2459 corresponding targets of LDP were screened out. Eighty-five common targets of HSHP and CHD were identified. The results of the network analysis showed that resveratrol, anthranone, emodin, and ursolic acid could be defined as four therapeutic components. TNF, ESR1, NFКB1, PPARG, INS, TP53, NFКBIA, AR, PIK3R1, PIK3CA, PTGS2, and NR3C1 might be the 12 key targets. These targets were mainly involved in the regulation of biological processes, such as inflammatory responses and lipid metabolism. Enrichment analysis showed that the identified genes were mainly involved in fluid shear force, insulin resistance (IR), inflammation, and lipid metabolism pathways to contribute to CHD. This suggests that resveratrol, anthranone, emodin, and ursolic acid from HSHP can be the main therapeutic components of atherosclerosis. CONCLUSION:Using network pharmacology, we provide new clues on the potential mechanism of action of HSHP in the treatment of CHD, which may be closely related to the fluid shear force, lipid metabolism, and inflammatory response.
Systemic immune-inflammation index predicts the severity of coronary stenosis in patients with coronary heart disease.
Liu Yehong,Ye Ting,Chen Liang,Jin Tianhui,Sheng Ying,Wu Gangyong,Zong Gangjun
Coronary artery disease
BACKGROUND:Coronary atherosclerosis is a systemic chronic inflammatory disease with variable occurrence and progression. Some laboratory parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) level, are used to evaluate the degree of inflammation and the severity of coronary artery disease (CAD). The neutrophil*platelet/lymphocyte is a novel systemic immune-inflammation index (SII), and its relationship with the development and severity of CAD is unclear. OBJECTIVE:To investigate the association between the SII and the severity of CAD. METHODS:Three-hundred and ninety-five patients who underwent coronary angiography were enrolled; among whom, 285 patients were included in the CAD group and 110 patients were included in the non-CAD group according to the WHO guidelines. Patients with CAD were further divided according to the Gensini score into the severe coronary stenosis group and the mild coronary stenosis group. The SII was calculated using the following formula: neutrophil*platelet/lymphocyte. RESULTS:When the cutoff value of the SII was set at 439.44, the predictive power of CAD was the highest, with a sensitivity and specificity of 64.6 and 68.2%, respectively. When the cutoff value of the SII was set at 652.83, the predictive power of severe coronary stenosis was the highest, with a sensitivity and specificity of 71.0 and 86.0%, respectively. The area under the curve of the SII in predicting severe coronary stenosis was greater than that of the NLR, PLR and CRP level. CONCLUSION:The SII is an independent risk factor for the occurrence and severity of CAD.
IL-34 and coronary heart disease complicated with diabetes mellitus.
Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences
Coronary heart disease and diabetes mellitus are closely related to chronic low-grade inflammation. Interleukin-34 (IL-34) is a new member of the interleukin family discovered in recent years. It is involved in the pathophysiological process of mononuclear phagocyte system mainly via binding to colony stimulating factor-1 receptor, and it is closely related to inflammatory and autoimmune diseases. IL-34 is highly expressed in patients with coronary heart disease or diabetes mellitus. IL-34 induces atherosclerosis and insulin resistance through multiple pro-inflammatory actions, ultimately leading to the occurrence and development of coronary heart disease, type 2 diabetes, and their comorbidities.
Chronic inflammatory diseases and coronary heart disease: Insights from cardiovascular CT.
Patel Nidhi H,Dey Amit K,Sorokin Alexander V,Teklu Meron,Petrole Rylee,Zhou Wunan,Mehta Nehal N
Journal of cardiovascular computed tomography
Epidemiological and clinical studies have demonstrated a consistent relationship between increased systemic inflammation and increased risk of cardiovascular events. In chronic inflammatory states, traditional risk factors only partially account for the development of coronary artery disease (CAD) but underestimate total cardiovascular risk likely due to the residual risk of inflammation. Computed coronary tomography angiography (CCTA) may aid in risk stratification by noninvasively capturing early CAD, identifying high risk plaque morphology and quantifying plaque at baseline and in response to treatment. In this review, we focus on reviewing studies on subclinical atherosclerosis by CCTA in individuals with chronic inflammatory conditions including rheumatoid arthritis (RA), systemic lupus erythematous (SLE), human immunodeficiency virus (HIV) infection and psoriasis. We start with a brief review on the role of inflammation in atherosclerosis, highlight the utility of using CCTA to delineate vessel wall and plaque characteristics and discuss combining CCTA with laboratory studies and emerging technologies to complement traditional risk stratification in chronic inflammatory states.