Pathogenesis Of Atherosclerotic Disease Research Articles

Deficiency of transcription factor E4BP4 suppresses neointimal formation after vascular injury

Abstract Aim In addition to traditional risk factors such as hypertension, diabetes, and dyslipidemia, chronic inflammation is deeply involved in the onset and pathogenesis of atherosclerotic diseases. Furthermore, diurnal fluctuations are observed in the rupture of atherosclerotic plaques and the onset of myocardial infarction. There are still many patients for whom medical treatments such as statins and antihypertensive drugs do not respond adequately, and new treatment methods are expected. E4BP4 (also known as NFIL3) is a basic leucine zipper (bZIP)-type transcription factor associated with circadian rhythms and cell viability, and it has been reported that E4BP4 regulates inflammation. Therefore, to investigate how the circadian transcription factor E4BP4 which is involved in inflammation, we decided to examine the role of E4BP4 in neointimal formation after vascular injury. Methods and Results Using E4BP4-deficient (E4BP4−/−) and wild-type (WT) mice, we investigated neointimal formation 2 weeks after femoral artery injury induced by an external vascular cuff model. Intimal and medial area were measured, and the intima/media ratio was calculated. Systolic blood pressure was similar between groups (WT mice: 92 ± 5 mmHg [n = 5] vs. E4BP4−/− mice: 90 ± 4 mmHg [n = 5]). And there was no significant difference in baseline body weight between groups (WT mice: 22.4 ± 0.8 g [n = 5] vs. E4BP4−/− mice: 22.0 ± 1.1 g [n = 5]). The mean intimal area and the intima/media ratio of E4BP4−/− mice decreased by 86 % (WT mice: 3,683 ± 512 μm2 [n = 10] vs. E4BP4−/− mice: 521 ± 363 μm2 [n = 10]; P < 0.0001) and 97% (WT mice: 0.33 ± 0.05 vs. E4BP4−/− mice: 0.01 ± 0.03; P < 0.0001), compared with WT mice. However, we observed no significant difference in the medial area (WT mice: 11,019 ± 358 μm2 vs. E4BP4−/− mice: 11,281 ± 401 μm2; P = NS) between groups (Figure). Immunohistochemistry for NK cell (NKp46) revealed the percentage of NKp46 positive area in the adventitia of E4BP4−/− mice was significantly lower compared with WT mice at 14 days post-injury (P <0.05). Furthermore, the positive area of IL-6 (P<0.05), TNF-α (P<0.05) and IFN-γ (P<0.05) in the intima of E4BP4−/− mice tended to be much smaller than those of WT mice. Our findings indicate that E4BP4 might induce vascular inflammation following vascular injury. Conclusions Deficiency of E4BP4 reduced the inflammatory cytokines and suppressed neointimal formation after injury. We also observed a decrease in NKp46, suggesting that NK cell development is impaired by E4BP4 deficiency. The present study is the first to demonstrate that E4BP4 plays an important role in the increase of neointimal formation after injury in vivo, thus suggesting that E4BP4 inhibition may represent a useful strategy to inhibit vascular inflammation.Neointimal formation after cuff injury

Leukotrienes in the atherosclerotic cardiovascular diseases — a systematic review

Introduction: The role of inflammation in the pathogenesis of atherosclerotic diseases is strongly suggested. There are multiple studies indicating the possibility of a pathophysiological connection between atherosclerotic changes and leukotrienes (LTs) — the products of arachidonic acid metabolism. The goal of this systematic review, performed in line with the PRISMA statement, was to investigate the potential role of LTs in the pathophysiology of atherosclerotic cardiovascular diseases (CVD). Material and methods: The MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews were searched to identify the potentially eligible studies. Publications that contained information on any type of LTs identified in blood or urine were included in the review. A database search identified 2082 records. Reliable LTs identification in patients with CVD was used in 30 publications. Results: Stable and acute forms of coronary artery disease are characterized by the overproduction of different types of LTs. The level of LTB4 and LTC4 in the blood is elevated in patients with cerebral ischemia. Patients with acute and chronic peripheral artery disease have elevated levels of LTE4 in urine. Conclusions: The findings of this systematic review show that there is a clear tendency to indicate the association of cardiovascular atherosclerotic diseases with increased production of LTs. This dependency detailed characteristic remains unclear and the question on the impact of elevated leukotrienes on clinical atherosclerotic disease manifestations is still open.

The Mechanism and Role of N6-Methyladenosine (m6A) Modification in Atherosclerosis and Atherosclerotic Diseases.

N6-methyladenosine (m6A) modification is a newly discovered regulatory mechanism in eukaryotes. As one of the most common epigenetic mechanisms, m6A's role in the development of atherosclerosis (AS) and atherosclerotic diseases (AD) has also received increasing attention. Herein, we elucidate the effect of m6A on major risk factors for AS, including lipid metabolism disorders, hypertension, and hyperglycemia. We also describe how m6A methylation contributes to endothelial cell injury, macrophage response, inflammation, and smooth muscle cell response in AS and AD. Subsequently, we illustrate the m6A-mediated aberrant biological role in the pathogenesis of AS and AD, and analyze the levels of m6A methylation in peripheral blood or local tissues of AS and AD, which helps to further discuss the diagnostic and therapeutic potential of m6A regulation for AS and AD. In summary, studies on m6A methylation provide new insights into the pathophysiologic mechanisms of AS and AD, and m6A methylation could be a novel diagnostic biomarker and therapeutic target for AS and AD.

Higher levels of anti-phosphorylcholine autoantibodies in early rheumatoid arthritis indicate lower risk of incident cardiovascular events

BackgroundThe increased risk of cardiovascular events (CVE) in rheumatoid arthritis (RA) is not fully explained by traditional risk factors. Immuno-inflammatory mechanisms and autoantibodies could be involved in the pathogenesis of atherosclerotic disease. It has been suggested that anti-phosphorylcholine antibodies (anti-PC) of the IgM subclass may have atheroprotective effects. Here, we aimed to investigate the association between levels of IgM anti-PC antibodies with CVE in patients with early RA.MethodsThe study population was derived from the BARFOT early RA cohort, recruited in 1994–1999. The outcome of incident CVE (AMI, angina pectoris, coronary intervention, ischemic stroke, TIA) was tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. Sera collected at inclusion and the 2-year visit were analyzed with ELISA to determine levels of anti-PC IgM. The Kaplan-Meier estimates and Cox proportional hazards regression models were used to compare CV outcome in the groups categorized by baseline median level of IgM anti-PC.ResultsIn all, 653 patients with early RA, 68% women, mean (SD) age 54.8 (14.7) years, DAS28 5.2 (1.3), 68% seropositive, and without prevalent CVD, were included. During the follow-up of mean 11.7 years, 141 incident CVE were recorded.Baseline IgM anti-PC above median was associated with a reduction in risk of incident CVE in patients aged below 55 years at inclusion, HR 0.360 (95% CI, 0.142–0.916); in males, HR 0.558 (0.325–0.958); in patients with BMI above 30 kg/m2, HR 0.235 (0.065–0.842); and in those who did not achieve DAS28 remission at 1 year, HR 0.592 (0.379–0.924). The pattern of associations was confirmed in the models with AUC IgM anti-PC over 2 years.ConclusionProtective effects of higher levels of innate IgM anti-PC autoantibodies on CVE were detected in younger patients with RA and those at high risk of CVE: males, presence of obesity, and non-remission at 1 year.

Predictors of Platelet Mitochondria Respiration in Children – The Arkansas Active Kids Study

ObjectivesPlatelets play a critical role in the pathogenesis of atherosclerotic disease (AD). In the absence of a nucleus, platelet function and viability are largely dependent on the health of their mitochondria. The purpose of this study was to evaluate the association between common markers of cardiometabolic health in 7 to 10-year-old children and measures of platelet mitochondria function. MethodsSixty children participated in a single study visit. Fasting blood was collected, and cardiorespiratory fitness (CRF, cycle ergometer test), physical activity (PA, accelerometers), and blood pressure percentiles were determined. Routine respiration (R) was measured by high-resolution respirometry (Oxygraph-2k) before platelets were permeabilized by digitonin. Thereafter, Complex I (CI) supported respiration was assayed in the leak (L), coupled (P) and uncoupled (CIE) states. Complex IV (CIV) activity was assayed as a marker of respiratory capacity. Flux control ratios (FCR) were calculated by dividing respiratory fluxes by CIV. Multiple linear regression analyses were used to model FCRs (dependent variables) with age, sex, race, CRF, PA, Body Mass Index (BMI) percentile, HOMA2-IR, systolic (SBP-P)/diastolic blood pressure percentiles (DBP-P), triglyceride status, and Low Density Lipoprotein (LDL) status (status = high vs. normal) as dependent variables. ResultsAge, race, LDL status and the interaction between BMI percentiles with SBP-P were retained in the final regression models for R, L, P and CIE FCRs. Specifically, R and CI supported respiration in the L, P and CIE states decreased with age (P < .05), black race (P < .05), and high LDL-cholesterol status (P < .0001). To assess for the interaction between BMI and SBP-P, children were stratified as normal weight (NW) or overweight (OW = BMI ≥ 85th percentile) with high (≥90th percentile) or normal SBP. FCRs did not differ between NW groups. However, FCRs where ∼2 times higher in children with OW + high SBP compared to children with OW + normal SBP (P < 0.05). ConclusionsAge, race, LDL cholesterol status, and systolic blood pressure are determinants of platelet bioenergetics in children. SBP-P modifies the association between weight status and platelet mitochondria respiration. Funding SourcesUSDA-ARS 59-6250-4-001 and 6026-51,000-012-06S. NIH-NIGMS 5P20GM10909, NIH 8UG1OD024945, NIH-NCATS 1UL1TR003107-0.

On-line hemodiafiltration modulates atherosclerosis signaling in peripheral lymphomonocytes of hemodialysis patients

BackgroundHemodialysis patients present a dramatic increase in cardiovascular morbidity/mortality. Circulating immune cells, activated by both uremic milieu and dialysis, play a key role in the pathogenesis of dialysis-related vascular disease. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of patients treated with on-line hemodiafiltration and bicarbonate hemodialysis.MethodsThe transcriptomic profile was investigated in PBMCs isolated from eight patients on on-line hemodiafiltration and eight patients on bicarbonate hemodialysis by microarray analysis. The results were evaluated by statistical and functional pathway analysis and validated by real time PCR (qPCR) in an independent cohort of patients (on-line hemodiafiltration N = 20, bicarbonate hemodialysis n = 20).ResultsEight hundred and forty-seven genes were differentially expressed in patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. Thirty-seven functional gene networks were identified and atherosclerosis signaling was the top canonical pathway regulated by on-line hemodiafiltration. Among the genes of this pathway, on-line hemodiafiltration was associated with a reduced expression of Platelet-derived growth factor A chain (PDGF A), Clusterin, Monoamine Oxidase A, Interleukin-6 (IL-6) and Vascular Endothelial GrowthFactor C (VEGF-)C and with an increase of Apolipoprotein E. qPCR confirmed the microarray results. Platelet derived growth factor AA (PDGF-AA), IL-6 and VEGF-C serum levels were significantly lower in the on-line hemodiafiltration group. Finally, 10 patients previously on bicarbonate hemodialysis were switched to on-line hemodiafiltration and PBMCs were harvested after 6 months. The qPCR results from this perspective group confirmed the modulation of atherosclerotic genes observed in the cross-sectional analysis.ConclusionsOur data suggest that type of dialysis (on-line hemodiafiltration versus bicarbonate hemodialysis) may modulate the expression of several genes involved in the pathogenesis of atherosclerotic disease.

Endothelial activation is associated with intestinal epithelial injury, systemic inflammation and treatment regimen in children living with vertically acquired HIV-1 infection.

Premature development of cardiovascular disease in children living with HIV-1 (CLWH) may be associated with compromised gut barrier function, microbial translocation, immune activation, systemic inflammation and endothelial activation. Biomarkers of these pathways may provide insights into pathogenesis of atherosclerotic disease in CLWH. This was a cross-sectional study of CLWH enrolled in the multicentre Early Pediatric Initiation-Canadian Child Cure Cohort (EPIC4 ) who were on antiretroviral therapy (ART) with undetectable viral load. Plasma biomarkers of intestinal epithelial injury [intestinal fatty acid binding protein-1 (IFABP)], systemic inflammation [tumour necrosis factor (TNF) and interleukin-6 (IL-6)] and endothelial activation [angiopoietin-2 (Ang2), soluble vascular endothelial growth factor-1 (sVEGFR1) and soluble endoglin (sEng)] were quantified by enzyme-linked immunosorbent assay. Correlation and factor analysis of biomarkers were used to examine associations between innate immune pathways. Among 90 CLWH, 16% of Ang2, 15% of sVEGFR1 and 23% of sEng levels were elevated relative to healthy historic controls. Pairwise rank correlations between the three markers of endothelial activation were statistically significant (ρ=0.69, ρ=0.61 and ρ=0.65, P<0.001 for all correlations). An endothelial activation index, derived by factor analysis of the three endothelial biomarkers, was correlated with TNF (ρ=0.47, P<0.001), IL-6 (ρ=0.60, P<0.001) and intestinal fatty acid binding protein-1 (ρ=0.67, P<0.001). Current or past treatment with ritonavir-boosted lopinavir (LPV/r) was associated with endothelial activation (odds ratio = 5.0, 95% CI: 1.7-17, P=0.0020). Endothelial activation is prevalent in CLWH despite viral suppression with combination ART and is associated with intestinal epithelial injury, systemic inflammation and treatment with LPV/r.

Association of Thrombomodulin Gene Polymorphisms with Susceptibility to Atherosclerotic Diseases: A Meta-Analysis.

Previous studies have proved that the dysfunction of thrombomodulin (TM) plays an important role in the pathogenesis of atherosclerotic diseases. In order to reveal their inherent relationship, we conducted a meta-analysis to uncover the association between two polymorphisms -33G/A and Ala455Val (c.1418C>T) in the TM gene and atherosclerotic diseases. We carried out a systematic search in PubMed, Science Direct, BIOSIS Previews, SpringerLink, the Cochrane library, the Chinese National Knowledge Infrastructure, the Chinese Biomedical Database, the Wei Pu database, and the Wanfang Database. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were computed to show the association. We included 22 eligible studies which involved 5472 patients and 7786 controls. There were statistically significant associations between -33G/A polymorphisms in TM and the MI group under the Allele and Recessive models in Asians (G vs. A: OR = 0.67, 95%CI = 0.56-0.78, P < 0.00001; GG vs. GA+AA: OR = 0.66, 95%CI = 0.56-0.78, P < 0.00001). However, these findings of the overall and subgroups showed that Ala455Val polymorphisms did not have any relationship with atherosclerotic diseases. After Bonferroni correction, the above associations remained statistically significant. This meta-analysis provides robust evidence of association between the -33G/A polymorphism in the TM gene and the risk of myocardial infarction in Asians. The A allele may increase the incidence of MI in Asians. However, the Ala455Val variant was not associated with atherosclerotic risk. Further studies with adequate sample size are needed to verify our findings.

Blood levels of serotonin are specifically correlated with plasma lysophosphatidylserine among the glycero-lysophospholipids

BackgroundsGlycero-lysophospholipids (glycero-LPLs), which are known to exert potent biological activities, have been demonstrated to be secreted from activated platelets in vitro; however, their association with platelet activation in vivo has not been yet elucidated. In this study, we investigated the correlations between the blood levels of each glycero-LPL and serotonin, a biomarker of platelet activation, in human subjects to elucidate the involvement of platelet activation in glycero-LPLs in vivo. Methods and ResultsWe measured the plasma serotonin levels in 141 consecutive patients undergoing coronary angiography (acute coronary syndrome, n=38; stable angina pectoris, n=71; angiographically normal coronary arteries, n=32) and investigated the correlations between the plasma levels of serotonin and glycero-LPLs. The results revealed the existence of a specific and significant association between the plasma serotonin and plasma lysophosphatidylserine (LysoPS) levels. On the contrary, regular aspirin intake failed to affect the plasma LysoPS levels despite the fact that the plasma lysophosphatidic acid, lysophosphatidylethanolamine, lysophosphatidylglycerol, and lysophosphatidylinositol levels were lower in those who had taken aspirin regularly. ConclusionWe found a specific positive correlation between the blood levels of serotonin and LysoPS, a new lipid mediator. Thus, LysoPS might be specifically involved in strong platelet activation, which is associated with the release of serotonin. General SignificanceOur present results suggest the possible involvement of LysoPS in the pathogenesis of atherosclerotic diseases.

Dendritic cells: a double-edge sword in atherosclerotic inflammation.

Functional heterogeneity of dendritic cells (DCs) observed in atherosclerosis suggest for their complex and multifaced role in the pathogenesis of atherosclerotic disease. A delicate balance between anti-inflammatory and pro-inflammatory mechanisms drives atherogenesis, and local microenvironment triggers the actual involvement of DCs in atherosclerosis-associated inflammation. Responding to microenvironment stimuli, DCs contribute to atherogenesis in both ways being involved in supporting proatherogenic vascular inflammation and by suppressing inflammatory responses via induction of self-tolerogenic properties and regulatory T cells (Tregs). The local microenvironment and extrinsic stimuli influence DC phenotype and hence could control the phenotypic switch toward inflammation or tolerance.

Abstract 17312: Amyloid-β (1-40) and the Risk of Death from Cardiovascular Causes in Patients with Coronary Heart Disease

Introduction: Investigation of the clinical value of biologic pathways that are involved in pathogenesis of atherosclerotic disease is essential for identification of novel therapeutic targets and improvement of cardiovascular risk stratification. Hypothesis: To determine the clinical value of amyloid-β 1-40 (Aβ40) measurement in predicting cardiovascular (CV) mortality in patients with coronary heart disease (CHD) and arterial stiffness progression in young healthy subjects. Methods: Aβ40 was retrospectively measured in blood samples collected from three independent prospective cohorts and two case-control cohorts (total n=1464). Major adverse CV events (MACE) were assessed in the two prospective cohorts (n=877) followed for a median of 4.4 years. Arterial stiffness was evaluated at baseline and after a 5-year follow-up period (n=107) in young healthy subjects. The primary endpoint was the predictive value of Aβ40 for CV mortality and outcomes in patients with CHD. Further, the associations of Aβ40 levels with arterial stiffness progression, incident subclinical atherosclerosis and incident CHD were addressed. Results: In Cox proportional-hazards models adjusted for age, gender, glomerular filtration rate, left ventricular ejection fraction, high-sensitivity C-reactive protein and high-sensitivity troponin-T, Aβ40 was an independent predictor of CV death and MACE in patients with CHD (P&lt;0.05 for all). After multivariate adjustment, Aβ40 levels conferred a substantial enhancement of net reclassification index (continuous NRI value and 95% confidence interval: 36.7%, 12.5-60.7, P=0.001) and integrated discrimination improvement (IDI value±SE: 1.92±0.62, P&lt;0.001) of individuals at risk in the total combined CHD cohort over the best predictive model. Further cohort-based analysis revealed that Aβ40 levels were significantly and independently associated with arterial stiffness progression, incident subclinical atherosclerosis and incident CHD. Conclusions: Measuring blood levels of Aβ40 identifies patients at high risk for cardiovascular death.

Carbamylated low-density lipoprotein induces endothelial dysfunction

Cardiovascular events remain the leading cause of death in Western world. Atherosclerosis is the most common underlying complication driven by low-density lipoproteins (LDL) disturbing vascular integrity. Carbamylation of lysine residues, occurring primarily in the presence of chronic kidney disease (CKD), may affect functional properties of lipoproteins; however, its effect on endothelial function is unknown. Low-density lipoprotein from healthy donors was isolated and carbamylated. Vascular reactivity after treatment with native LDL (nLDL) or carbamylated LDL (cLDL) was examined in organ chambers for isometric tension recording using aortic rings of wild-type or lectin-like-oxidized LDL receptor-1 (LOX-1) transgenic mice. Reactive oxygen species (ROS) and nitric oxide (NO) production were determined using electron spin resonance spectroscopy. The effect of LDL-carbamyl-lysine levels on cardiovascular outcomes was determined in patients with CKD during a median follow-up of 4.7 years. Carbamylated LDL impaired endothelium-dependent relaxation to acetylcholine or calcium-ionophore A23187, but not endothelium-independent relaxation to sodium nitroprusside. In contrast, nLDL had no effect. Carbamylated LDL enhanced aortic ROS production by activating NADPH-oxidase. Carbamylated LDL stimulated endothelial NO synthase (eNOS) uncoupling at least partially by promoting S-glutathionylation of eNOS. Carbamylated LDL-induced endothelial dysfunction was enhanced in LOX-1 transgenic mice. In patients with CKD, LDL-carbamyl-lysine levels were significant predictors for cardiovascular events and all-cause mortality. Carbamylation of LDL induces endothelial dysfunction via LOX-1 activation and increased ROS production leading to eNOS uncoupling. This indicates a novel mechanism in the pathogenesis of atherosclerotic disease which may be pathogenic and prognostic in patients with CKD and high plasma levels of cLDL.

Therapie von Fettstoffwechselstörungen

Lipid disorders play an essential role in the pathogenesis of atherosclerotic diseases. An integral part of the clinical evaluation is the estimation of the individual cardiovascular risk using risk scores and patient history. Due to the long established prognostic relevance, reduction of low-density lipoproteins (LDL) using statins remains beyond doubt the central intervention both in primary and secondary prevention of atherosclerotic diseases. Indispensible components of treatment in all patients with elevated triglyceride levels are lifestyle changes contributing to a reduction of accompanying risk factors, in particular physical activity and smoking cessation.

Oxidized Haemoglobin–Driven Endothelial Dysfunction and Immune Cell Activation: Novel Therapeutic Targets for Atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by endothelial dysfunction, and in which innate and adaptive immune responses have a crucial role. Autoimmune reactions against several self molecules and modified self molecules have been identified in patients with atherosclerotic disease. Oxidative stress, increasingly reported in these patients is the major event causing protein structural modifications, thus inducing the appearance of neo/cryptic epitopes. Following intraplaque haemorrhage large amounts of cell-free haemoglobin (Hb) accumulate within atheroma, due to its impaired clearance by the haptoglobin-CD163 scavenging system. The pro-oxidative intraplaque microenvironment may induce Hb structural changes, thus generating neo/cryptic autoantigenic epitopes and rendering the oxidized self molecule as a dangerous signal for both immune and endothelial cells. In this review, we will present the most relevant information on Hb as a candidate self antigen involved in the pathogenesis of atherosclerotic disease and on its ability to trigger signals that drive endothelial dysfunction and immune cell activation. On these grounds, we will also discuss how these new paradigms may lead to novel therapeutic targets for cardiovascular diseases.

Continuous exposure to low amplitude extremely low frequency electrical fields characterizing the vascular streaming potential alters elastin accumulation in vascular smooth muscle cells

In normal development and pathology, the vascular system depends on complex interactions between cellular elements, biochemical molecules, and physical forces. The electrokinetic vascular streaming potential (EVSP) is an endogenous extremely low frequency (ELF) electrical field resulting from blood flowing past the vessel wall. While generally unrecognized, it is a ubiquitous electrical biophysical force to which the vascular tree is exposed. Extracellular matrix elastin plays a central role in normal blood vessel function and in the development of atherosclerosis. It was hypothesized that ELF fields of low amplitude would alter elastin accumulation, supporting a link between the EVSP and the biology of vascular smooth muscle cells. Neonatal rat aortic smooth muscle cell cultures were exposed chronically to electrical fields characteristic of the EVSP. Extracellular protein accumulation, DNA content, and electron microscopic (EM) evaluation were performed after 2 weeks of exposure. Stimulated cultures showed no significant change in cellular proliferation as measured by the DNA concentration. The per-DNA normalized protein in the extracellular matrix was unchanged while extracellular elastin accumulation decreased 38% on average. EM analysis showed that the stimulated cells had a 2.85-fold increase in mitochondrial number. These results support the formulation that ELF fields are a potential factor in both normal vessel biology and in the pathogenesis of atherosclerotic diseases including heart disease, stroke, and peripheral vascular disease.

Effects of preoperative homocysteine levels on postoperative outcomes and adverse events in patients undergoing on-pump cardiac surgery

Objectives: Besides the well-known risk factors for atherosclerosis and cardiovascular disorders, hyperho- mocystinemia is a recently defined factor that acts in pathogenesis of atherosclerotic diseases. It also plays role in development of end-stage renal disease. Homocysteine causes endothelial cell damage and prolifer- ation in vascular smooth muscle cells. In this study, we aimed to document the relationship between serum homocyteine levels and postoperative outcomes and occurrence of postoperative adverse events in patients undergoing on-pump cardiac surgery. Materials and Methods: Forty patients undergoing on-pump cardiac surgery were included in the study. Serum homocysteine levels were measured preoperatively. Then, patients were divided into two groups; first group included patients with homocyteine levels below 15 mmol/l and second above. Cross-clamp and car- diopulmonary bypass times, intubation times, intensive care unit and hospital length of stay and occurrence of postoperative adverse events were compared between the two groups. Results: The mean age of the patients was 57.0 ± 2.3 and mean body mass index (BMI) was 26.8 ± 4.1. There were 30 male (75%) and 10 female (25%) patients. The mean preoperative Hcy level was 18.6 ± 10.5 mmol/l. Twenty one patient (52.5%) had Hcy levels below 15 mmol/l and 19 (47.5%) had above 15 mmol/l. The preoperative demographic characteristics of the patients were comparable in two groups. Intubation times, in- tensive care unit and hospital length of stay were not different between the groups. There was not statistically significant difference between the groups when postoperative renal functions designated by serum creatinine levels and urine output, mortality, occurrence of stroke and mesenteric vascular events were compared. Conclusions: We did not observe any relationship between elevated levels of homocysteine and postopera- tive stoke, renal failure and other adverse events. We believe that further studies with increased number of patients should be performed.

Omnipresent Atherosclerotic Disease: Time to Depart From Analysis of Individual Vascular Beds

Atherosclerotic vascular disease not only remains the leading cause of death in the Western countries, but it has become the most common cause of morbidity and mortality in the low- and middle-income countries as well. Therefore, better understanding of the pathogenesis of atherosclerotic disease and its prevention are of fundamental importance. It is well known that it affects sequentially the aorta followed by coronary, carotid, peripheral, and intracerebral arteries, with some individual variability. The mechanisms of progression are similar in each of the beds, with increasing lipid accumulation in the arterial wall along with macrophages and T-cell infiltration, paucity of smooth-muscle cell proliferation and collagen deposition, and endothelial-cell dysfunction and hypercoagulability playing an important role at the time of acute manifestations of the disease. Fundamental to this inflammatory process is the presence of classic risk factors, regardless of the involved territory. Therefore, the concept of palliative treatment must be reserved for only those who have progressed beyond preventive measures.

Angiographic Features and Cardiovascular Risk Factors in Human Immunodeficiency Virus-Infected Patients With First-Time Acute Coronary Syndrome

A matched cohort study was conducted comparing patients with first-time acute coronary syndromes infected with human immunodeficiency virus (HIV) to non-HIV-infected patients with and without diabetes matched for smoking, gender, and type of acute coronary syndrome who underwent first-time coronary angiography. A total of 48 HIV-infected patients were identified from a national database. Coronary angiography showed that the HIV-infected patients had significantly fewer lesions with classification B2/C than the 2 control groups (p <0.001) but the same extent of multivessel disease. The HIV-infected patients were a decade younger than the non-HIV-infected controls and had significantly higher concentrations of total cholesterol (6.3 vs 4.8 and 4.5 mmol/L, p <0.0001), low-density lipoprotein (4.0 vs 2.9 and 2.5 mmol/L, p <0.001), and triglycerides (2.8 vs 1.0 and 1.4 mmol/L, p <0.01) compared to the nondiabetic and diabetic non-HIV-infected groups, respectively. In conclusion, HIV-infected patients with first-time acute coronary syndromes have fewer complex lesions than non-HIV-infected patients. This finding supports the idea that the pathogenesis of atherosclerotic disease in HIV patients is different from that in the general population.

OxLDL- and HSP-60 antigen-specific CD8+ T lymphocytes are detectable in the peripheral blood of patients suffering from coronary artery disease

Inflammatory and immunologic mechanisms are important for the initiation and the progression of atherosclerotic lesions. OxLDL and HSP-60 antigens are involved in the pathogenesis of atherosclerotic disease by triggering immune cells within the plaques. Through the MHC pentamer assays, we investigated the presence of OxLDL- and HSP-60-specific CD8(+) T lymphocytes in twenty HLA-A2-positive patients suffering from coronary artery disease (10 NSTEMI and 10 stable angina). Similarly, 10 age- and sex-matched healthy subjects were enrolled as controls. Biological samples were collected within 6h of admission to hospital, at 30days and at 180days. OxLDL- and HSP-60-specific CD8(+) T lymphocytes were never detectable in the peripheral blood from all the healthy controls. On the contrary, at each scheduled time point, both of these specific cells could be detected in peripheral blood from all enrolled patients. More in detail, the flow cytometric analysis of MHC-1 pentamer OxLDL-specific CD8(+) T lymphocytes revealed a sharp and significant increase at the hospital admission, within 6h from the chest pain onset, followed by an evident decline to lower levels at 30days and at 180days from the enrollment in the study. On the contrary, although MHC-1 pentamer HSP-60 CD8(+) T lymphocytes were detectable in enrolled patients, almost no variance could be detectable during the follow-up scheduled evaluations. On the whole, this finding indicates that HSP-60- and OxLDL-specific CD8(+) T lymphocytes could play a role in the maintenance or worsening of the atherosclerotic coronary disease.

Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy

The widespread use of highly active antiretroviral therapy (HAART) in HIV-infected individuals mostly in developed countries has dramatically improved their prognosis. In such advantaged regions of the world, therefore, many patients are now transitioning from middle into older age, with altered patterns of disease. While previously a rare complication of HIV infection, cerebrovascular disease (particularly that associated with atherosclerosis) is becoming relatively more important in this treated group of individuals. This review summarises the evidence regarding the shifting epidemiology of cerebrovascular diseases affecting HIV-infected individuals. While outlining the association between HIV infection and AIDS and cerebrovascular disease, as well as opportunistic diseases and HIV-associated vasculopathies, the current evidence supporting an increase in atherosclerotic disease in treated HIV-infected individuals is emphasised and a management approach to ischaemic stroke in HIV-infected individuals is presented. Evidence supporting the important role of HAART and HIV infection itself in the pathogenesis of atherosclerotic disease is discussed, together with preventative approaches to this increasingly important disease process as the population ages. Finally, a discussion regarding the significant association between cerebrovascular disease and HIV-associated neurocognitive disorder is presented, together with possible mechanisms behind this relationship.