The crosstalk between bone metabolism, lncRNAs, microRNAs and mRNAs in coronary artery calcification.

The association between Coronary Artery Calcification (CAC) and osteoporosis has been reported but not fully understood. Therefore, using an original bioinformatic framework we analyzed transcriptomic profiles of 20 elderly women with high CAC score and 31 age- and sex-matching controls from São Paulo Ageing & Health study (SPAH). We integrated differentially expressed microRNA (miRNA) and long-noncoding RNA (lncRNA) interactions with coding genes associated with CAC, in the context of bone-metabolism genes mined from literature. Top non-coding regulators of bone metabolism in CAC included miRNA 497-5p/195 and 106a-5p, and lncRNA FAM197Y7. Top non-coding RNAs revealed significant interplay between genes regulating bone metabolism, vascularization-related processes, chromatin organization, prostaglandin and calcium co-signaling. Prostaglandin E2 receptor 3 (PTGER3), Fibroblasts Growth Factor Receptor 1 (FGFR1), and One Cut Homeobox 2 (ONECUT2) were identified as the most susceptible to regulation by the top non-coding RNAs. This study provides a flexible transcriptomic framework including non-coding regulation for biomarker-related studies.

Five-year follow-up of a randomized comparison between off-pump and on-pump stable multivessel coronary artery bypass grafting. The MASS III Trial.

BACKGROUND: Coronary artery bypass graft surgery with cardiopulmonary bypass is a safe, routine procedure. Nevertheless, significant morbidity remains, mostly because of the body's response to the nonphysiological nature of cardiopulmonary bypass. Few data are available on the effects of off-pump coronary artery bypass graft surgery (OPCAB) on cardiac events and long-term clinical outcomes. METHODS AND RESULTS: In a single-center randomized trial, 308 patients undergoing coronary artery bypass graft surgery were randomly assigned: 155 to OPCAB and 153 to on-pump CAB (ONCAB). Primary composite end points were death, myocardial infarction, further revascularization (surgery or angioplasty), or stroke. After 5-year follow-up, the primary composite end point was not different between groups (hazard ratio 0.71, 95% CI 0.41 to 1.22; P=0.21). A statistical difference was found between OPCAB and ONCAB groups in the duration of surgery (240±65 versus 300±87.5 minutes; P<0.001), in the length of ICU stay (19.5±17.8 versus 43±17.0 hours; P<0.001), time to extubation (4.6±6.8 versus 9.3±5.7 hours; P<0.001), hospital stay (6±2 versus 9±2 days; P<0.001), higher incidence of atrial fibrillation (35 versus 4% of patients; P<0.001), and blood requirements (31 versus 61% of patients; P<0.001), respectively. The number of grafts per patient was higher in the ONCAB than the OPCAB group (2.97 versus 2.49 grafts/patient; P<0.001). CONCLUSIONS: No difference was found between groups in the primary composite end point at 5-years follow-up. Although OPCAB surgery was related to a lower number of grafts and higher episodes of atrial fibrillation, it had no significant implications related to long-term outcomes. Clinical Trial Registration-URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66068876.

The impact of race/ethnicity on baseline characteristics and the burden of coronary atherosclerosis in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.

OBJECTIVES: We aimed to test the impact of race/ethnicity on coronary artery disease (CAD) after adjusting for baseline risk factors. BACKGROUND: Whether race/ethnicity remains an important determinant of the burden of CAD even among patients with long-standing type 2 diabetes (diabetes mellitus) and established CAD is unknown. METHODS: Analysis of baseline data from the BARI 2D trial (January 1, 2001, to March 31, 2005) was performed. Myocardial jeopardy index (MJI) was evaluated by a blinded core angiographic laboratory. Multivariate regression analysis was performed to determine the independent association of race/ethnicity on the burden of CAD after adjusting for baseline risk factors. Data were collected from US and Canadian academic and community hospitals. The baseline analysis was performed on patients with long-standing diabetes and documented CAD with no prior revascularization at study entry (n = 1,331). The main outcome measure was MJI, which represents the percentage of myocardium jeopardized by significant lesions (≥50%). The secondary outcome measure was ≥2 lesions with ≥50% stenosis. RESULTS: Risk factors varied significantly among racial/ethnic groups. Blacks were significantly more likely to be women, have no health insurance, be current smokers, have higher body mass index, have hypertension, have a longer duration of diabetes, a higher hemoglobin A(1c) level, and were more likely to be taking insulin. Their mean total, low-density lipid, and high-density lipid cholesterol levels were higher, whereas their triglycerides were lower than others. After controlling for baseline risk factors, blacks had a significantly lower burden of CAD; the adjusted MJI was 5.43 U lower (95% CI -9.13 to -1.72), and the adjusted number of lesions was 0.53 fewer (95% CI -0.88 to -0.18) in blacks compared to whites. CONCLUSIONS: In the BARI 2D trial, self-reported race/ethnicity is associated with important differences in baseline risk factors and is a powerful predictor of the burden of CAD adjusting for such baseline differences. These findings may help direct medical intervention and resources and further investigation into the basis of racial/ethnic differences in CAD burden.

Transcriptomic analysis of elderly women with low muscle mass: association with immune system pathway.

Despite the well-established association of gene expression deregulation with low muscle mass (LMM), the associated biological mechanisms remain unclear. Transcriptomic studies are capable to identify key mediators in complex diseases. We aimed to identify relevant mediators and biological mechanisms associated with age-related LMM. LMM-associated genes were detected by logistic regression using microarray data of 20 elderly women with LMM and 20 age and race-matched controls extracted from our SPAH Study (GSE152073). We performed weighted gene co-expression analysis (WGCNA) that correlated the identified gene modules with laboratorial characteristics. Gene enrichment analysis was performed and an LMM predictive model was constructed using Support Vector Machine (SVM). Overall, 821 discriminating transcripts clusters were identified (|beta coefficient| >1; p-value <0.01). From this list, 45 predictors of LMM were detected by SVM and validated with 0.7 of accuracy. Our results revealed that the well-described association of inflammation, immunity and metabolic alterations is also relevant at transcriptomic level. WGCNA highlighted a correlation of genes modules involved in immunity pathways with vitamin D level (R = 0.63, p = 0.004) and the Agatston score (R = 0.51, p = 0.02). Our study generated a predicted regulatory network and revealed significant metabolic pathways related to aging processes, showing key mediators that warrant further investigation.

Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial.

CONTEXT: Perioperative red blood cell transfusion is commonly used to address anemia, an independent risk factor for morbidity and mortality after cardiac operations; however, evidence regarding optimal blood transfusion practice in patients undergoing cardiac surgery is lacking. OBJECTIVE: To define whether a restrictive perioperative red blood cell transfusion strategy is as safe as a liberal strategy in patients undergoing elective cardiac surgery. DESIGN, SETTING, AND PATIENTS: The Transfusion Requirements After Cardiac Surgery (TRACS) study, a prospective, randomized, controlled clinical noninferiority trial conducted between February 2009 and February 2010 in an intensive care unit at a university hospital cardiac surgery referral center in Brazil. Consecutive adult patients (n = 502) who underwent cardiac surgery with cardiopulmonary bypass were eligible; analysis was by intention-to-treat. INTERVENTION: Patients were randomly assigned to a liberal strategy of blood transfusion (to maintain a hematocrit ≥30%) or to a restrictive strategy (hematocrit ≥24%). MAIN OUTCOME MEASURE: Composite end point of 30-day all-cause mortality and severe morbidity (cardiogenic shock, acute respiratory distress syndrome, or acute renal injury requiring dialysis or hemofiltration) occurring during the hospital stay. The noninferiority margin was predefined at -8% (ie, 8% minimal clinically important increase in occurrence of the composite end point). RESULTS: Hemoglobin concentrations were maintained at a mean of 10.5 g/dL (95% confidence interval [CI], 10.4-10.6) in the liberal-strategy group and 9.1 g/dL (95% CI, 9.0-9.2) in the restrictive-strategy group (P < .001). A total of 198 of 253 patients (78%) in the liberal-strategy group and 118 of 249 (47%) in the restrictive-strategy group received a blood transfusion (P < .001). Occurrence of the primary end point was similar between groups (10% liberal vs 11% restrictive; between-group difference, 1% [95% CI, -6% to 4%]; P = .85). Independent of transfusion strategy, the number of transfused red blood cell units was an independent risk factor for clinical complications or death at 30 days (hazard ratio for each additional unit transfused, 1.2 [95% CI, 1.1-1.4]; P = .002). CONCLUSION: Among patients undergoing cardiac surgery, the use of a restrictive perioperative transfusion strategy compared with a more liberal strategy resulted in noninferior rates of the combined outcome of 30-day all-cause mortality and severe morbidity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01021631.

Overexpression of SNTG2, TRAF3IP2, and ITGA6 transcripts is associated with osteoporotic vertebral fracture in elderly women from community.

BACKGROUND: Vertebral fractures (VFs) are the most common clinical manifestation of osteoporosis associated with high morbimortality. A personal/familiar history of fractures increases the risk of fractures. The purpose of this study is to identify possible molecular markers associated with osteoporotic VFs in elderly women from community. METHODS: Transcriptomic analysis using Affymetrix HTA2 microarray was performed using whole blood samples of 240 subjects from a population-based survey (Sao Paulo Ageing & Health [SPAH] study). Only elderly women with osteoporosis diagnosis by densitometry were analyzed, and divided in two groups: VF: women with osteoporosis and VFs versus no vertebral fracture (NVF): women with osteoporosis and NVFs. They were matched for age, chronic disease, medication use, and bone mineral density (BMD). The logistic regression model adjusted for age was applied for transcriptome data analysis. SYBR green-based quantitative polymerase chain reaction (qPCR) was used to validate the most significant expression changes obtained in the microarray experiment. RESULTS: Microarray analysis identified 142 differentially expressed genes (DEGs, p < .01), 57 upregulated and 85 downregulated, compared VF versus NVF groups. The DEG with the greatest expression difference was the Gamma2-Syntrophin (SNTG2) (ß = 31.88, p = .005). Validation by qPCR confirmed increased expression in VF group of Syntrophin (SNTG2, fold change = 2.79, p = .009), TRAF3 Interacting Protein2 (TRAF3IP2, fold change = 2.79, p = .020), and Integrin Subunit Alpha 6 (ITGA6, fold change = 2.86, p = .038). CONCLUSION: Our data identified and validated the association of SNTG2 (608715), TRAF3IP2 (607043), and ITGA6 (147556) with osteoporotic VF in elderly women, independently of BMD. These results suggest that these transcripts have potential clinical significance and may help to explain the molecular mechanisms and biological functions of vertebral fracture.

Association of moderate/severe vertebral fractures with reduced trabecular volumetric bone density in older women and reduced areal femoral neck bone density in older men from the community: A cross-sectional study (SPAH).

BACKGROUND: Many vertebral fractures (VF) occur in individuals classified by DXA as being at low risk of fragility fractures. The aim of this study was to verify the association between VF and peripheral bone microarchitecture and strength parameters (SP) using, in addition to DXA, high-resolution peripheral quantitative computed tomography (HR-pQCT) and axial bone microarchitecture using the trabecular bone score (TBS). STUDY DESIGN: Cross-sectional study of 276 community-dwelling subjects aged ≥65 years from the SPAH study cohort. METHODS: Lateral DXA scans of the spine were analyzed to assess VF. HR-pQCT was performed at the radius and tibia. TBS was determined using DXA. RESULTS: VF was observed in 42.6% of women and 28% of men. At the tibia, women with moderate/severe VF had lower volumetric bone density (vBMD), trabecular number (Tb.N), and SP, and higher trabecular separation (Tb.Sp); and men with VF had lower Tb.N and SP, and higher Tb.Sp. At the radius, women with moderate/severe VF had lower vBMD, trabecular and cortical thickness and SP; and men with VF had lower trabecular vBMD and SP. No associations between TBS and VF were observed in either gender. Logistic regression analysis revealed that trabecular vBMD at the tibia in women (OR:0.980, 95%CI:0.963-0.997, p = 0.022) and femoral neck aBMD in men (OR:0.445, 95%CI:0.212-0.935, p = 0.033) were independently associated with VF. CONCLUSION: HR-pQCT images detected differences in bone microstructure in older women with VF independent of aBMD and TBS by DXA, and HR-pQCT could be a useful tool to assess fracture risk. In men, femoral neck aBMD was associated with VF, and DXA continues to be an important tool for predicting VF.

Impact of metabolic syndrome on the outcome of patients with stable coronary artery disease: 2-year follow-up of the MASS II study.

OBJECTIVE: We characterized the impact of the metabolic syndrome (MetS) and its components on cardiovascular adverse events in patients with symptomatic chronic multivessel coronary artery disease, which have been followed prospectively for 2 years. METHODS: Patients enrolled in the MASS II study were evaluated for each component of the MetS, as well as the full syndrome. RESULTS: The criteria for MetS were fulfilled in 52% of patients. The presence of MetS (P<0.05), glucose intolerance (P=0.007), and diabetes (P=0.04) was associated with an increased mortality in our studied population. Moreover, despite a clear tendency for each of its components to increase the mortality risk, only the presence of the MetS significantly increased the risk of mortality among nondiabetic study participants in a multivariate model (P=0.03, relative risk 3.5, 95% confidence interval 1.1-6). Finally, MetS was still associated with increased mortality even after adjustment for diabetes status. These results indicate a strong and consistent relationship of the MetS with mortality in patients with stable coronary artery disease. CONCLUSION: Although glucose homeostasis seems to be the major force driving the increased risk of MetS, the operational diagnosis of MetS still has information for stratifying patients when diabetes information is taken into account.

Dynamic regulation of MTHFR mRNA expression and C677T genotype modulate mortality in coronary artery disease patients after revascularization.

INTRODUCTION: A large body of evidence links plasma homocysteine (Hcy) concentrations and cardiovascular disease. A common MTHFR polymorphism (C677T) leads to a variant with reduced activity and associated with increased Hcy levels. Coronary surgery precipitates a significant and sustained increase in the blood concentrations of Hcy and elevated levels of plasma Hcy have been associated to saphenous vein (SV) graft disease after CABG. However, the effects of MTHFR genotypes in the incidence of cardiovascular events after CABG have not been investigated prospectively. Here, we investigate whether MTHFR gene variants are associated with an increased cardiovascular risk in individuals submitted to CABG. We also propose a molecular mechanism to explain our findings. METHODS: We performed MTHFR C677T genotypes in 558 patients with two or three vessel-disease and normal left ventricular function prospectively followed in the MASS II Trial, a randomized study to compare treatments for multivessel CAD and preserved left ventricle function. Follow-up time was 5 years. Survival curves were calculated with the Kaplan-Meier method, and evaluated with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, myocardial infarction and refractory angina using a Cox proportional hazards survival model. Finally, using an ex-vivo organ culture we have reproduced the arterialization of SV implants by culturing human SV either under venous hemodynamic condition (flow: 5 mL/min; no pressure) or arterial hemodynamic condition (flow: 50 mL/min; pressure: 80 mm Hg) for 1 day. MTHFR gene expression was quantified by real time RT-PCR in 15 SV from different individuals in both experimental conditions. RESULTS: There were no significant differences among individuals within each genotype group for baseline clinical characteristics. A statistically significant association between the TT genotype, associated with increased serum levels of Hcy, and cardiovascular mortality after 5 years was verified (p=0.007) in individuals submitted to CABG surgery. In addition, MTHFR TT genotype was still significantly associated with a 4.4 fold increased risk in cardiovascular outcomes (p=0.01) even after adjustment of a Cox multivariate model for age, sex, hypertension, diabetes, LDL, HDL, triglycerides, and number of diseased vessels in this population. Finally, a significant reduction in MTHFR gene expression was demonstrated in human SV when submitted to an arterial hemodynamic condition (p=0.02). CONCLUSIONS: There is a dynamic regulation of MTHFR gene expression during the arterialization process of human saphenous vein grafts resulting in lower levels of gene expression when in an arterial hemodynamic condition. In addition, the C677T MTHFR functional variant is associated with a worse outcome in individuals submitted to CABG. Taken together, these data suggest an important role of Hcy metabolism in individuals after CABG.

[State-of-the-art in the treatment of chronic coronariopathy in diabetic patients: evidences and controversies based in clinical trials]. / Estado atual do tratamento da coronariopatia crônica em pacientes diabéticos: evidências e controvérsias baseadas em ensaios clínicos.

Diabetes mellitus is a powerful risk factor for coronary artery disease. Diabetics demonstrate accelerated coronary atherosclerosis and worst prognosis following cardiac events. Although myocardial revascularization procedures result in more effective relieve of symptoms in patients with known coronary artery disease, there is no substantial evidence that this strategy improves outcome, except for specific situations. In addition, the benefit of myocardial revascularization is attenuated by the presence of metabolic abnormalities related to insulin resistance and other significant co-morbidities in diabetic patients. New advances recently developed for the clinical treatment of diabetes, as well as surgical and percutaneous approaches of myocardial revascularization, such as drug-eluting stents, seem to be promising therapeutical strategies for diabetic patients. Most importantly, treatment of type 2 diabetics with chronic coronary artery disease should consider the multifactorial pathogenesis of the disease and combine aggressive control of glycemic levels, strict management of all conventional risk factors, and lifestyle modification. The metabolic effects of insulin sensitizers over cardiovascular disease and mortality are under discussion. Ongoing clinical multicenter trials will probably define the real impact of new therapeutic modalities over the prognosis of diabetic patients.

Rac-dependent monocyte chemoattractant protein-1 production is induced by nutrient deprivation.

Under ischemic conditions, the vessel wall recruits inflammatory cells. Human aortic endothelial cells (HAECs) exposed to hypoxia followed by reoxygenation produce monocyte chemoattractant protein-1 (MCP-1); however, most experiments have been performed in the presence of nutrient deprivation (ND). We hypothesized that ND rather than hypoxia mediates endothelial MCP-1 production during ischemia, and that the small GTP-binding protein Rac1 and reactive oxygen species (ROS) are involved in this process. ND was generated by shifting HAECs from 10% to 1% FBS. Superoxide production by HAECs was increased 6 to 24 hours after ND, peaking at 18 hours. MCP-1 production was increased over a similar time frame, but peaked later at 24 hours. These effects were blocked by treatment with antioxidants such as superoxide dismutase mimetic and N-acetylcysteine (NAC), or NADPH oxidase inhibitors, DPI and gp91ds-tat. Superoxide and MCP-1 production were enhanced by RacV12 (constitutively active) in the absence of ND, and were inhibited by RacN17 (dominant-negative) adenoviral transduction under ND, suggesting that the small G-protein Rac1 is required. In conclusion, ND, an important component of ischemia, is sufficient to induce MCP-1 production by HAECs, and such production requires a functional Rac1, redox-dependent pathway.

Association between platelet P2Y12 haplotype and risk of cardiovascular events in chronic coronary disease.

INTRODUCTION: A positive association was recently described between P2Y12 platelet receptor H1 and H2 haplotypes and peripheral artery disease. We tested the described P2Y12 receptor haplotypes in a group of patients with coronary artery disease. STUDY DESIGN AND METHODS: The P2Y12 platelet receptor H1 and H2 haplotypes was tested in a group of 540 patients enrolled in the Medical, Angioplasty, or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease (CAD) and preserved left ventricular function. After a 3-year follow-up period, the incidence of the composite end point of cardiac death, myocardial infarction, and refractory angina requiring revascularization was determined in the H1/H1, H1/H2 and H2/H2 haplotype groups. We used Student's t-test and the chi-square test to analyze the differences among groups and Kaplan-Meier method to calculate survival curves. Risk was assessed with the use of a Cox proportional-hazards model. RESULTS: The frequency of haplotypes among studied patients were 410 (75.9%) H1/H1, 119 (22.0%) H1/H2 and 11 (2.1%) H2/H2. The baseline clinical characteristics, mean clinical follow-up time and received treatment of each genotype group were similar. We did not disclose any association between haplotype groups regarding the incidence of any of the studied cardiovascular end-points. CONCLUSION: This is the first report studying the association of P2Y12 platelet receptor H1 and H2 haplotype and cardiovascular events. Our findings do not provide evidence for a strong association between H1/H1 and H1/H2 haplotypes and a increased risk of cardiovascular events in a population with CAD. Future works should address the role of the H2/H2 haplotype as a genetic marker for cardiovascular events.

Mac-1 and Fas activities are concurrently required for execution of smooth muscle cell death by M-CSF-stimulated macrophages.

OBJECTIVE: We have previously shown that macrophage colony stimulating factor (M-CSF), a potent survival and mitogenic factor for monocytes/macrophages (MM), enables MM to induce vascular smooth muscle cell (VSMC) apoptosis. The killing requires the binding of MM to VSMC via Mac-1 (CD11b/CD18) on MM and intracellular adhesion molecule-1 (ICAM-1) on VSMC. We hypothesized that, in addition to Mac-1 binding, the killing process requires the activation of the Fas-death receptor pathway, which can be blocked at the level of Fas-Fas ligand interaction. METHODS AND RESULTS: Human peripheral blood monocytes and VSMC were isolated and cultured as previously described. Soluble Fas (sFas) was overexpressed in VSMC by transduction using adenovirus specifying soluble Fas (Ad3hsFas). M-CSF markedly increased the expression of ICAM-1 in VSMC, resulting in enhanced clustering of MM on the surface of VSMC (>/=3 MM per VSMC). MM, but not VSMC, expressed Fas-ligand (FasL), and VSMC apoptosis was inhibited by secretion of sFas by VSMC upon Ad3sFas transduction. CONCLUSIONS: MM and M-CSF-induced VSMC killing requires MM binding to VSMC mediated by Mac-1 and ICAM-1, and Fas-FasL interaction.

Effect of glycoprotein IIIa PlA2 polymorphism on outcome of patients with stable coronary artery disease and effect of smoking.

A polymorphism of glycoprotein IIb/IIIa has been associated with myocardial infarction and restenosis after percutaneous coronary intervention. The influence on outcome and the interaction of the Pl(A1) genotype with classic risk factors for coronary artery disease (CAD) were characterized in patients with chronic CAD followed prospectively for 3 years. Pl(A1) genotypes were assessed in 592 patients enrolled in the Medical, Angioplasty, or Surgery Study II, a randomized trial comparing treatments for patients with CAD and preserved left ventricular function. The incidence of the composite end point of cardiac death, myocardial infarction, and refractory angina requiring revascularization were determined in each genotype group. Risk was assessed with the Cox proportional-hazards model. The clinical characteristics and treatment of each genotype were similar. Although the composite end point tended to be more common in patients with the Pl(A2) allele, only smokers with the Pl(A2) allele had a significantly increased incidence of the composite end point (p = 0.01). Moreover, a 2.2-fold increased risk was apparent in smokers with the Pl(A2) allele (p = 0.03). Thus, taken together, these data provide support for the interaction effect between smoking and the Pl(A1) gene variant. Smokers with the Pl(A2) polymorphism of platelet glycoprotein IIIa are at greater risk for subsequent cardiac events in stable coronary disease.

Genetic variants of diabetes risk and incident cardiovascular events in chronic coronary artery disease.

OBJECTIVE: To determine whether information from genetic risk variants for diabetes is associated with cardiovascular events incidence. METHODS: From the about 30 known genes associated with diabetes, we genotyped single-nucleotide polymorphisms at the 10 loci most associated with type-2 diabetes in 425 subjects from the MASS-II Study, a randomized study in patients with multi-vessel coronary artery disease. The combined genetic information was evaluated by number of risk alleles for diabetes. Performance of genetic models relative to major cardiovascular events incidence was analyzed through Kaplan-Meier curve comparison and Cox Hazard Models and the discriminatory ability of models was assessed for cardiovascular events by calculating the area under the ROC curve. RESULTS: Genetic information was able to predict 5-year incidence of major cardiovascular events and overall-mortality in non-diabetic individuals, even after adjustment for potential confounders including fasting glycemia. Non-diabetic individuals with high genetic risk had a similar incidence of events then diabetic individuals (cumulative hazard of 33.0 versus 35.1% of diabetic subjects). The addition of combined genetic information to clinical predictors significantly improved the AUC for cardiovascular events incidence (AUC = 0.641 versus 0.610). CONCLUSIONS: Combined information of genetic variants for diabetes risk is associated to major cardiovascular events incidence, including overall mortality, in non-diabetic individuals with coronary artery disease. CLINICAL TRIAL REGISTRATION INFORMATION: Medicine, Angioplasty, or Surgery Study (MASS II). Unique identifier: ISRCTN66068876 URL.

Association between ADAMTS13 polymorphisms and risk of cardiovascular events in chronic coronary disease.

INTRODUCTION: Association between ADAMTS13 levels and cardiovascular events has been described recently. However, no genetic study of ADAMTS13 in coronary patients has been described. MATERIALS AND METHODS: Based on related populations frequencies and functional studies, we tested three ADAMTS13 polymorphisms: C1342G (Q448E), C1852G (P618A) and C2699T (A900V) in a group of 560 patients enrolled in the Medical, Angioplasty, or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease (CAD) and preserved left ventricular function. The incidence of the 5-year end-points of death and death from cardiac causes, myocardial infarction, refractory angina requiring revascularization and cerebrovascular accident was determined for each polymorphim's allele, genotype and haplotype. Risk was assessed with the use of logistic regression and Cox proportional-hazards model and multivariable adjustment was employed for possible confounders. RESULTS: Clinical characteristics and received treatment of each genotype group were similar at baseline. In an adjusted model for cardiovascular risk variables, we were able to observe a significant association between ADAMTS13 900V variant and an increased risk of death (OR: 1,92 CI: 1,14-3,23, p=0,015) or death from cardiac cause (OR:2,67, CI: 1,59-4,49, p=0,0009). No association between events and ADAMTS13 Q448E or P618A was observed. CONCLUSIONS: This first report studying the association between ADAMTS13 genotypes and cardiovascular events provides evidence for the association between ADAMTS13 900V variant and an increased risk of death in a population with multi-vessel CAD.

Reduced expression of systemic proinflammatory and myocardial biomarkers after off-pump versus on-pump coronary artery bypass surgery: a prospective randomized study.

BACKGROUND: The effects of off-pump (OffPCABG) and on-pump (OnPCABG) coronary artery bypass grafting (CABG) on myocardium and inflammation are unclear. OBJECTIVE: Compare the inflammatory response and myocardial injury from patients (pts) submitted to OffPCABG with those that undergo OnPCABG. METHODS: Patients with normal left ventricular function were assigned to OffPCABG (n = 40) and OnPCABG (n = 41). Blood samples were collected before and 24 hours after surgery for determination of creatine kinase (CK)-MB (CK-MB), troponin I (cTnI), interleukin (IL)-6, IL-8, P-selectin, intercellular adhesion molecule (ICAM)-1 and C-reactive protein (CRP). Mortalities were registered at 12 months. RESULTS: Preoperative CK-MB and cTnI levels were 3.1 +/- 0.6 IU and 1.2 +/- 0.5 ng/mL for OffPCABG and 3.0 +/- 0.5 IU and 1.0 +/- 0.2 ng/mL for OnPCABG pts. Postoperative CK-MB and cTnI levels were 13.9 +/- 6.5 IU and 19.0 +/- 9.0 ng/mL for OffPCABG vs 29.5 +/- 11.0 IU and 31.5 +/- 10.1 ng/mL for OnPCABG (P < .01). OffPCABG and OnPCABG pts had similar preoperative IL-6 (10 +/- 7 and 9 +/- 13 pg/mL), IL-8 (19 +/- 7 and 17 +/- 7 pg/mL), soluble P-selectin (70 +/- 21 and 76 +/- 23 pg/mL), soluble ICAM-1 (117 +/- 50 and 127 +/- 52 ng/mL), and CRP (0.09 +/- 0.05 and 0.11 +/- 0.07 mg/L). At 24 hours, for OffPCABG and OnPCABG: IL-6 was 37 +/- 38 and 42 +/- 41 g/mL; IL-8, 33 +/- 31 and 60 +/- 15 pg/mL; soluble P-selectin, 99 +/- 26 and 172 +/- 30 pg/mL; soluble ICAM-1, 227 +/- 47 and 236 +/- 87 ng/mL; and CRP, 10 +/- 11 and 14 +/- 13 mg/L (P < .01 vs preoperation; P < .01 vs OffPCABG). Increased 24-hour postoperative CRP levels was the only marker to have significant positive correlations with events and occurred just for the OnPCABG pts. In-hospital and 1-year mortalities for the OnPCABG and OffPCABG pts were 2.0% and 2.2% (P = .1) and 2.7% and 4.7% (P = .06), respectively. CONCLUSIONS: Thus, the absence of CPB during CABG preserves better the myocardium and attenuates inflammation-however, without improving survival.

Hemostatic changes and clinical sequelae after on-pump compared with off-pump coronary artery bypass surgery: a prospective randomized study.

OBJECTIVE: To delineate the effects of extracorporeal bypass on biomarkers of hemostasis, fibrinolysis, and inflammation and clinical sequelae. METHODS: Patients were assigned prospectively and randomly to either on-pump (n=41) or off-pump (n=51) coronary bypass surgery. The concentrations of C-reactive protein, fibrinogen, D-dimer, and plasminogen activator inhibitor type-1 in blood were quantified before and after (1 and 24 h) surgery. Similar surgical and anesthetic procedures were used for both groups. Clinical events were assessed during initial hospitalization and at the end of 1 year. RESULTS: The concentrations of plasminogen activator inhibitor type-1 and D-dimer were greater compared with preoperative values 1 and 24 h after surgery in both groups, but their concentrations increased to a greater extent 24 h after surgery in the on-pump group (P<0.01). The concentration of C-reactive protein did not change appreciably immediately after surgery in either group but increased in a parallel manner 24 h after either on-pump or off-pump surgery (P<0.01). Bypass surgery in the on-pump group was associated with greater blood loss during surgery and more bleeding after surgery (P< or =0.01). The incidence of all other complications was similar in the two groups. CONCLUSION: On-pump surgery was associated with biochemical evidence of a prothrombotic state early after surgery but no greater incidence of thrombotic events was observed. The prothrombotic state might be a consequence of extracorporeal bypass, compensation in response to more bleeding, or both in patients undergoing on-pump surgery.