Abstract 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.
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 A1c 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.
Abstract 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.
The MASS III Trial is a large project from a single institution, The Heart Institute of the University of Sao Paulo, Brazil (InCor), enrolling patients with coronary artery disease and preserved ...ventricular function. The aim of the MASS III Trial is to compare medical effectiveness, cerebral injury, quality of life, and the cost-effectiveness of coronary surgery with and without of cardiopulmonary bypass in patients with multivessel coronary disease referred for both strategies. The primary endpoint should be a composite of cardiovascular mortality, cerebrovascular accident, nonfatal myocardial infarction, and refractory angina requiring revascularization. The secondary end points in this trial include noncardiac mortality, presence and severity of angina, quality of life based on the SF-36 Questionnaire, and cost-effectiveness at discharge and at 5-year follow-up. In this scenario, we will analyze the cost of the initial procedure, hospital length of stay, resource utilization, repeat hospitalization, and repeat revascularization events during the follow-up. Exercise capacity will be assessed at 6-months, 12-months, and the end of follow-up. A neurocognitive evaluation will be assessed in a subset of subjects using the Brain Resource Center computerized neurocognitive battery. Furthermore, magnetic resonance imaging will be made to detect any cerebral injury before and after procedures in patients who undergo coronary artery surgery with and without cardiopulmonary bypass.
Clinical Trial registration information ISRCTN59539154 Off-pump vs. on-pump surgery in patients with Stable CAD MASS III.
ABSTRACT—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.
OBJECTIVETo delineate the effects of extracorporeal bypass on biomarkers of hemostasis, fibrinolysis, and inflammation and clinical sequelae.
METHODSPatients 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.
RESULTSThe 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≤0.01). The incidence of all other complications was similar in the two groups.
CONCLUSIONOn-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.
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.
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.
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.
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.
Surgical techniques of myocardial revascularization without the use of extracorporeal circulation (ECC) have raised hopes of attaining operative results with less systemic damage, lower occurrence of ...clinical complications and shorter hospital stay duration, generating expectations of lower hospital costs.
To evaluate the hospital costs in patients submitted to myocardial revascularization with and without ECC and in those with stable multiarterial coronary disease with preserved ventricular function.
The hospital costs were based on the existing governmental reimbursement. The costs included that of ortheses and prostheses and clinical complications. The time and costs of ICU stay and hospital stay duration were considered.
Between January 2002 and August 2006, 131 patients were randomized to surgery with ECC (SECC), whereas 128 were randomized to surgery without ECC (WECC). The basal characteristics were similar for both groups. The costs of surgical complications were significantly lower (p < 0.001) in patients from the WECC when compared to the SECC group (606.00 +/- 525.00 vs. 945.90 +/- 440.00), as well as ICU costs: 432.20 +/- 391.70 vs. 717.70 +/- 257.70, respectively. The duration of the operating room stay were 4.9 +/- 1.1 h vs. 3.9 +/- 1.0 h, p < 0.001; at the ICU it was 48.2 +/- 17.2 h vs. 29.2 +/- 26.1h) (p < 0.001), with intubation time of 9.2 +/- 4.5 h vs. 6.4 +/- 5.1h, p < 0.001 for patients from the group with and without ECC, respectively.
The present study allowed us to conclude that the myocardial revascularization surgery without extracorporeal circulation results in the decrease of operational costs and duration of the stay in each section related to the surgical treatment.
OBJECTIVEWe 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.
METHODSPatients enrolled in the MASS II study were evaluated for each component of the MetS, as well as the full syndrome.
RESULTSThe 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.
CONCLUSIONAlthough 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.
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