Determination of CYP2D6 *3, *4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and disease-free survival

The CYP2D6 enzyme is crucial for the metabolism of tamoxifen. The CYP2D6 gene is highly polymorphic, and individuals can be extensive, intermediate, or poor tamoxifen metabolizers. The aim of this study was to determine the frequencies of the CYP2D6 *3, *4, and *10 alleles in women with breast cancer who were treated with tamoxifen and analyze the association of enzyme activity with prognostic factors and disease-free survival. We observed a high frequency of CYP2D6 *10, with an allelic frequency of 0.14 (14.4%). The *3 allele was not present in the studied population, and *4 had an allelic frequency of 0.13 (13.8%). We conclude that patients with reduced CYP2D6 activity did not present worse tumor characteristics or decreased disease-free survival than women with normal enzyme activity, as the difference was not statistically significant. We also observed a high frequency of CYP2D6 *10, which had not been previously described in this specific population. This study is the first in north-northeastern Brazil that aimed to contribute to the knowledge of the Brazilian regional profile for CYP2D6 polymorphisms and their phenotypes. These findings add to the knowledge of the distribution of different polymorphic CYP2D6 alleles and the potential role of CYP2D6 genotyping in clinical practice prior to choosing therapeutic protocols.

Higher incidence of death in multi-vessel coronary artery disease patients associated with polymorphisms in chromosome 9p21

Background: We investigated whether 9p21 polymorphisms are associated with cardiovascular events in a group of 611 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. Methods: The participants of the MASS II were genotyped for 9p21 polymorphisms (rs10757274, rs2383206, rs10757278 and rs1333049). Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, death from cardiac causes and myocardial infarction using a Cox proportional hazards survival model. Results: We observed significant differences between patients within each polymorphism genotype group for baseline characteristics. The frequency of diabetes was lower in patients carrying GG genotype for rs10757274, rs2383206 and rs10757278 (29.4%, 32.8%, 32.0%) compared to patients carrying AA or AG genotypes (49.1% and 39.2%, p = 0.01; 52.4% and 40.1%, p = 0.01; 47.8% and 37.9%, p = 0.04; respectively). Significant differences in genotype frequencies between double and triple vessel disease patients were observed for the rs10757274, rs10757278 and rs1333049. Finally, there was a higher incidence of overall mortality in patients with the GG genotype for rs2383206 compared to patients with AA and AG genotypes (19.5%, 11.9%, 11.0%, respectively; p = 0.04). Moreover, the rs2383206 was still significantly associated with a 1.75-fold increased risk of overall mortality (p = 0.02) even after adjustment of a Cox multivariate model for age, previous myocardial infarction, diabetes, smoking and type of coronary anatomy. Conclusions: Our data are in accordance to previous evidence that chromosome 9p21 genetic variation may constitute a genetic modulator in the cardiovascular system in different scenarios. In patients with established CAD, we observed an association between the rs2383206 and higher incidence of overall mortality and death from cardiac causes in patients with multi-vessel CAD.

Cancer-related deaths among different treatment options in chronic coronary artery disease: results of a 6-year follow-up of the MASS II study

Introduction The primary end points of randomized clinical trials evaluating the outcome of therapeutic strategies for coronary artery disease (CAD) have included nonfatal acute myocardial infarction, the need for further revascularization, and overall mortality. Noncardiac causes of death may distort the interpretation of the long-term effects of coronary revascularization. Materials and methods This post-hoc analysis of the second Medicine, Angioplasty, or Surgery Study evaluates the cause of mortality of patients with multivessel CAD undergoing medical treatment, percutaneous coronary intervention, or surgical myocardial revascularization [coronary artery bypass graft surgery (CABG)] after a 6-year follow-up. Mortality was classified as cardiac and noncardiac death, and the causes of noncardiac death were reported. Results Patients were randomized into CABG and non-CABG groups (percutaneous coronary intervention plus medical treatment). No statistical differences were observed in overall mortality (P = 0.824). A significant difference in the distribution of causes of mortality was observed among the CABG and non-CABG groups (P = 0.003). In the CABG group, of the 203 randomized patients, the overall number of deaths was 34. Sixteen patients (47.1%) died of cardiac causes and 18 patients (52.9%) died of noncardiac causes. Of these, seven deaths (20.6%) were due to neoplasia. In the non-CABG group, comprising 408 patients, the overall number of deaths was 69. Fifty-three patients (77%) died of cardiac causes and 16 patients (23%) died of noncardiac causes. Only five deaths (7.2%) were due to neoplasia. Conclusion Different treatment options for multivessel coronary artery disease have similar overall mortality: CABG patients had the lowest incidence of cardiac death, but the highest incidence of noncardiac causes of death, and specifically a higher tendency toward cancer-related deaths. Coron Artery Dis 23:79-84 (C) 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Association between UCP2 A55V polymorphism and risk of cardiovascular events in patients with multi-vessel coronary arterial disease

Background UCP2 (uncoupling protein 2) plays an important role in cardiovascular diseases and recent studies have suggested that the A55V polymorphism can cause UCP2 dysfunction. The main aim was to investigate the association of A55V polymorphism with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease and preserved left ventricular function. Methods The participants of the MASS II were genotyped for the A55V polymorphism using allele-specific PCR assay. Survival curves were calculated with the Kaplan–Meier method and evaluated with the log-rank statistic. The relationship between baseline variables and the composite end-point of cardiac death, acute myocardial infarction (AMI), refractory angina requiring revascularization and cerebrovascular accident were assessed using a Cox proportional hazards survival model. Results There were no significant differences for baseline variables according genotypes. After 2 years of follow-up, dysglycemic patients harboring the VV genotype had higher occurrence of AMI (p=0.026), Death+AMI (p=0.033), new revascularization intervention (p=0.009) and combined events (p=0.037) as compared with patients carrying other genotypes. This association was not evident in normoglycemic patients. Conclusions These findings support the hypothesis that A55V polymorphism is associated with UCP2 functional alterations that increase the risk of cardiovascular events in patients with previous coronary artery disease and dysglycemia.

Mortality and safety of catheter ablation for antiarrhythmic drug-refractory ventricular tachycardia in elderly patients with coronary artery disease

As the population ages, recurrent ventricular tachycardia (VT) is increasingly encountered in elderly patients with ischemic heart disease. Radiofrequency catheter ablation is useful for reducing VT therapy in patients with an implantable defibrillator. The utility of radiofrequency catheter ablation in the elderly is not well defined.

Clinical outcomes after PCI for acute coronary syndrome in unprotected left main coronary artery disease: insights from the Swiss Acute Left Main Coronary Vessel Percutaneous Management (SALVage) study

Unprotected left main (ULM) coronary artery disease is encountered in 3%-10% of coronary angiograms and is associated with high mortality. The survival of patients with ULM disease presenting with acute coronary syndromes (ACS) depends on different variables and is lowest in those with cardiogenic shock (CS). The aim of the present study was to estimate the impact of baseline characteristics on the subsequent clinical outcome in patients treated by percutaneous coronary intervention (PCI) of ULM for ACS.

Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease

The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis.

Framingham risk score and alternatives for prediction of coronary heart disease in older adults

Background Guidelines for the prevention of coronary heart disease (CHD) recommend use of Framingham-based risk scores that were developed in white middle-aged populations. It remains unclear whether and how CHD risk prediction might be improved among older adults. We aimed to compare the prognostic performance of the Framingham risk score (FRS), directly and after recalibration, with refit functions derived from the present cohort, as well as to assess the utility of adding other routinely available risk parameters to FRS. Methods Among 2193 black and white older adults (mean age, 73.5 years) without pre-existing cardiovascular disease from the Health ABC cohort, we examined adjudicated CHD events, defined as incident myocardial infarction, CHD death, and hospitalization for angina or coronary revascularization. Results During 8-year follow-up, 351 participants experienced CHD events. The FRS poorly discriminated between persons who experienced CHD events vs. not (C-index: 0.577 in women; 0.583 in men) and underestimated absolute risk prediction by 51% in women and 8% in men. Recalibration of the FRS improved absolute risk prediction, particulary for women. For both genders, refitting these functions substantially improved absolute risk prediction, with similar discrimination to the FRS. Results did not differ between whites and blacks. The addition of lifestyle variables, waist circumference and creatinine did not improve risk prediction beyond risk factors of the FRS. Conclusions The FRS underestimates CHD risk in older adults, particularly in women, although traditional risk factors remain the best predictors of CHD. Re-estimated risk functions using these factors improve accurate estimation of absolute risk.

Subclinical hyperthyroidism and the risk of coronary heart disease and mortality

Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.

Invasive findings in patients with angina equivalent symptoms but no coronary artery disease; Results from the heart quest cohort study

The cause of angina in patients presenting at coronary angiography without significant coronary artery disease (CAD) has not been systematically assessed in a large prospective cohort. This study is aimed to identify the cause of angina in these patients.

Beneficial effect of recruitable collaterals: a 10-year follow-up study in patients with stable coronary artery disease undergoing quantitative collateral measurements

BACKGROUND: The prognostic relevance of the collateral circulation is still controversial. The goal of this study was to assess the impact on survival of quantitatively obtained, recruitable coronary collateral flow in patients with stable coronary artery disease during 10 years of follow-up. METHODS AND RESULTS: Eight-hundred forty-five individuals (age, 62+/-11 years), 106 patients without coronary artery disease and 739 patients with chronic stable coronary artery disease, underwent a total of 1053 quantitative, coronary pressure-derived collateral measurements between March 1996 and April 2006. All patients were prospectively included in a collateral flow index (CFI) database containing information on recruitable collateral flow parameters obtained during a 1-minute coronary balloon occlusion. CFI was calculated as follows: CFI = (P(occl) - CVP)/(P(ao) - CVP) where P(occl) is mean coronary occlusive pressure, P(ao) is mean aortic pressure, and CVP is central venous pressure. Patients were divided into groups with poorly developed (CFI < 0.25) or well-grown collateral vessels (CFI > or = 0.25). Follow-up information on the occurrence of all-cause mortality and major adverse cardiac events after study inclusion was collected. Cumulative 10-year survival rates in relation to all-cause deaths and cardiac deaths were 71% and 88%, respectively, in patients with low CFI and 89% and 97% in the group with high CFI (P=0.0395, P=0.0109). Through the use of Cox proportional hazards analysis, the following variables independently predicted elevated cardiac mortality: age, low CFI (as a continuous variable), and current smoking. CONCLUSIONS: A well-functioning coronary collateral circulation saves lives in patients with chronic stable coronary artery disease. Depending on the exact amount of collateral flow recruitable during a brief coronary occlusion, long-term cardiac mortality is reduced to one fourth compared with the situation without collateral supply.

Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study

OBJECTIVE: To examine by secondary analysis of the Treating to New Targets (TNT) study whether the benefits of intensive versus standard levels of lipid lowering are equally applicable to women. METHODS: A total of 10 001 patients (1902 women) with stable coronary heart disease (CHD) were randomised to double-blind treatment with atorvastatin 10 or 80 mg/day for a median follow-up of 4.9 years. RESULTS: In women and men, intensive treatment with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events compared with atorvastatin 10 mg. Among women, the relative and absolute reductions were 27% and 2.7%, respectively (hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.54 to 1.00, p = 0.049). In men, the corresponding rate reductions were 21% and 2.2% (HR = 0.79, 95% CI 0.69 to 0.91, p = 0.001). The number needed to treat value (to prevent one cardiovascular event over 4.9 years compared with patients treated with atorvastatin 10 mg) for atorvastatin 80 mg was 29 for women and 30 for men. Rates of death of non-cardiovascular origin in the atorvastatin 80 mg and atorvastatin 10 mg were 3.6% and 1.6%, respectively (p = 0.004) among women, and 2.8% and 3.1% (p = 0.47) among men. CONCLUSION: Intensive lipid-lowering treatment with atorvastatin 80 mg produced significant reductions in relative risk for major cardiovascular events compared with atorvastatin 10 mg in both women and men with stable CHD.

Longest available clinical outcomes after drug-eluting stent implantation for unprotected left main coronary artery disease: the DELFT (Drug Eluting stent for LeFT main) Registry

OBJECTIVES: The purpose of this study was to investigate the long-term safety and efficacy of percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation for unprotected left main coronary artery (ULMCA) disease. BACKGROUND: Long-term clinical outcomes after DES implantation for ULMCA disease have not yet been ascertained. METHODS: From April 2002 to April 2004, 358 consecutive patients who underwent PCI with DES implantation for de novo lesions on ULMCA were retrospectively selected and analyzed in 7 European and U.S. tertiary care centers. No patients were excluded from the analysis, and all patients had a minimum follow-up of 3 years. RESULTS: Technical success rate was 100%. Procedural success rate was 89.6%. After 3 years, major adverse cardiovascular events (MACE)-free survival in the whole population was 73.5%. According to the Academic Research Consortium definitions, cardiac death occurred in 9.2% of patients, and reinfarction, target lesion revascularization (TLR), and target vessel revascularization (TVR) occurred in 8.6%, 5.8%, and 14.2% of patients, respectively. Definite stent thrombosis occurred in 2 patients (specifically at 0 and 439 days). In elective patients, the 3-year MACE-free survival was 74.2%, with mortality, reinfarction, TLR, and TVR rates of 6.2%, 8.3%, 6.6%, and 16%, respectively. In the emergent group the 3-year MACE-free survival was 68.2%, with mortality, reinfarction, TLR, and TVR rates of 21.4%, 10%, 2.8%, and 7.1%, respectively. CONCLUSIONS: Routine DES implantation in ULMCA disease seems encouraging, with favorable long-term clinical results.