Henrique Tria Bianco

Pharmacokinetic interactions between clopidogrel and rosuvastatin: Effects on vascular protection in subjects with coronary heart disease

Significant decrease in outcomes with statins administration in the first 24 h of an acute myocardial infarction [1–4] and reduction of myocardial injury markers after high-dose statin given few hours before percutaneous interventions [5,6] were observed. These effects of statins take place before lipid changes [7,8]. Clopidogrel, a pro-drug largely prescribed for patients undergoing stent implantation, is metabolized in the liver via cytochrome P450 (CYP2C19 and CYP3A4) to form an active metabolite that inhibits the P2Y(12) ADP platelet receptor [9,10]. Rosuvastatin is partially metabolized by CYP2C9 and CYP2C19 [11]. Functional and anatomical changes of the endothelium, an inflammatory substrate and coagulation activation participate on the pathophysiology of acute coronary syndromes [12,13]. New biomarkers, such as endothelial and platelet microparticles (EMP and PMP), endothelial progenitor cells (EPC), platelet function tests and endothelial-dependent flow-mediated dilation (FMD) have been proposed for the evaluation of vascular homeostasis [14,15]. Thus, we

Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy

It is not known whether the addition of ezetimibe to statins adds cardiovascular protection beyond the expected changes in lipid levels. Subjects with coronary heart disease were treated with four consecutive 1-week courses of therapy (T) and evaluations. The courses were: T1, 100 mg aspirin alone; T2, 100 mg aspirin and 40 mg simvastatin/10 mg ezetimibe; T3, 40 mg simvastatin/10 mg ezetimibe, and 75 mg clopidogrel (300 mg initial loading dose); T4, 75 mg clopidogrel alone. Platelet aggregation was examined in whole blood. Endothelial microparticles (CD51), platelet microparticles (CD42/CD31), and endothelial progenitor cells (CD34/CD133; CDKDR/CD133, or CD34/KDR) were quantified by flow cytometry. Endothelial function was examined by flow-mediated dilation. Comparisons between therapies revealed differences in lipids (T2 and T3<T1 and T4 for total cholesterol, LDL-C, and triglycerides; P<0.002 for all), as well as for endothelial function (T2>T1 and T4, P=0.001). Decreased platelet aggregation was observed after aspirin (arachidonic acid, T1<T3 and T4, P=0.034) and clopidogrel (adenosine, T3 and T4<T1 and T2, P<0.0001) therapy. Simvastatin/ezetimibe diphosphate did not change platelet aggregation, the amount of circulating endothelial and platelet microparticles, or endothelial progenitor cells. Cardiovascular protection following therapy with simvastatin/ezetimibe seems restricted to lipid changes and improvement of endothelial function not affecting the release of microparticles, mobilization of endothelial progenitor cells or decreased platelet aggregation.

Effects of ezetimibe on markers of synthesis and absorption of cholesterol in high-risk patients with elevated C-reactive protein

AIMS High-risk subjects with elevated C-reactive protein (CRP) are at high risk for cardiovascular events and frequently require potent statins or combined lipid-lowering therapy to achieve lipid targets and decrease inflammation. Our study aimed at evaluating the effects of three lipid-modifying therapies on LDL-cholesterol, CRP levels and markers of cholesterol absorption and synthesis. MAIN METHODS A prospective intervention study was performed in high cardiovascular risk individuals receiving atorvastatin 10mg daily for four weeks. Those with CRP≥2.0mg/L were randomized to another four-week treatment period with atorvastatin 40mg, ezetimibe 10mg or the combination of atorvastatin 40mg / ezetimibe 10mg. Lipids, markers of cholesterol absorption (campesterol and β-sitosterol), and synthesis (desmosterol), as well as CRP were quantified at baseline and end of study. KEY FINDINGS One hundred and twenty two individuals were included. Atorvastatin alone or combined with ezetimibe reduced both LDL-cholesterol and CRP (P<0.002 vs. baseline; Wilcoxon); ezetimibe did not modify CRP. Ezetimibe-based therapies reduced absorption markers and their ratios to cholesterol (P<0.0001 vs. baseline, for all; Wilcoxon), whereas atorvastatin alone increased campesterol/cholesterol and β-sitosterol/cholesterol ratios (P<0.05 vs. baseline; Wilcoxon). In addition, ezetimibe also increased desmosterol and desmosterol/cholesterol ratio (P<0.0001 vs. baseline; Wilcoxon). SIGNIFICANCE These results contribute to understanding the link between cellular cholesterol homeostasis, inflammation and lipid-modifying therapies. Our findings highlight the broader benefit of combined therapy with a potent statin and ezetimibe decreasing inflammation, and preventing increase in cholesterol biosynthesis, an effect not observed with ezetimibe alone.

I Posicionamento Brasileiro sobre Combinação de Fármacos Anti-Hipertensivos

Arterial hypertension (AH) is a highly prevalent disease, and is a major cardiovascular (CV) risk factor1; therefore, achieving blood pressure (BP) control goals as soon as possible is paramount to reduce that risk2. That means that approximately 70% of hypertensive individuals will need antihypertensive drug combination3, and up to 30% of hypertensive individuals are estimated to use four or more drugs to achieve BP control4. Thus, drug combination is currently described as an important strategy to manage AH, providing effective and safe BP reduction. Drug choice is based on effective BP reduction and CV outcomes. Despite the existence of a significant number of drugs to treat AH, their control rates are still very low, contributing to the high CV morbidity and mortality rates observed in Brazil and worldwide1,2. According to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Hypertension Optimal Treatment (HOT) Study, only 26% and 33% of the patients, respectively, could control their BP with monotherapy, while in the Losartan Intervention for Endpoints Reduction (LIFE) Study, 90% of the patients needed combined therapy for that purpose3 . Drug combination is mainly aimed at increasing antihypertensive efficacy, with fewer adverse events. It is worth noting the importance of considering therapy adherence. The pathophysiology of AH involves multiple factors and mechanisms, making its control difficult when only one drug is used, because counterregulatory mechanisms that attenuate the antihypertensive effect of the drug can occur. The association of drugs with different mechanisms of action has a greater impact on BP reduction as long as there is pharmacokinetic compatibility and no disparity of effects and properties3-5. Thus, the choice of the drugs to be combined should contemplate two aspects: synergism of the mechanisms of action and opposition to counterregulatory mechanisms triggered after the beginning of therapy with a certain drug. The desired antihypertensive efficacy is more likely to be achieved by using lower doses of the drugs involved. Thus, fewer adverse events are observed, with no loss of antihypertensive drug potency3-5. Another important aspect is that drugs should be preferably combined in a single galenic presentation, facilitating their administration, and assuring lower cost, with a consequent improvement in treatment adherence2,6.

Brazilian guidelines on prevention of cardiovascular disease in patients with diabetes: a position statement from the Brazilian Diabetes Society (SBD), the Brazilian Cardiology Society (SBC) and the Brazilian Endocrinology and Metabolism Society (SBEM)

BackgroundSince the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical risk-based approach on treatment for patients with diabetes.Main bodyThe Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy.ConclusionsDiabetes is a heterogeneous disease. Although cardiovascular risk is increased in most patients, those without risk factors or evidence of sub-clinical atherosclerosis are at a lower risk. Optimal management must rely on an approach that will cover both cardiovascular disease prevention in individuals in the highest risk as well as protection from overtreatment in those at lower risk. Thus, cardiovascular prevention strategies should be individualized according to cardiovascular risk while intensification of treatment should focus on those at higher risk.

Electrocardiogram Performance in the Diagnosis of Left Ventricular Hypertrophy in Hypertensive Patients With Left Bundle Branch Block

Background Left ventricular hypertrophy (LVH) is an important risk factor for cardiovascular events, and its detection usually begins with an electrocardiogram (ECG). Objective To evaluate the impact of complete left bundle branch block (CLBBB) in hypertensive patients in the diagnostic performance of LVH by ECG. Methods A total of 2,240 hypertensive patients were studied. All of them were submitted to an ECG and an echocardiogram (ECHO). We evaluated the most frequently used electrocardiographic criteria for LVH diagnosis: Cornell voltage, Cornell voltage product, Sokolow-Lyon voltage, Sokolow-Lyon product, RaVL, RaVL+SV3, RV6/RV5 ratio, strain pattern, left atrial enlargement, and QT interval. LVH identification pattern was the left ventricular mass index (LVMI) obtained by ECHO in all participants. Results Mean age was 11.3 years ± 58.7 years, 684 (30.5%) were male and 1,556 (69.5%) were female. In patients without CLBBB, ECG sensitivity to the presence of LVH varied between 7.6 and 40.9%, and specificity varied between 70.2% and 99.2%. In participants with CLBBB, sensitivity to LVH varied between 11.9 and 95.2%, and specificity between 6.6 and 96.6%. Among the criteria with the best performance for LVH with CLBBB, Sokolow-Lyon, for a voltage of ≥ 3,0mV, stood out with a sensitivity of 22.2% (CI 95% 15.8 - 30.8) and specificity of 88.3% (CI 95% 77.8 - 94.2). Conclusion In hypertensive patients with CLBBB, the most often used criteria for the detection of LVH with ECG showed significant decrease in performance with regards to sensitivity and specificity. In this scenario, Sokolow-Lyon criteria with voltage ≥3,0mV presented the best performance.

Antihypertensive therapy increases natural immunity response in hypertensive patients

AIMS The aim of this work was to evaluate the effects of treatment of hypertension on the autoantibodies to apolipoprotein B-derived peptides (anti-ApoB-D peptide Abs) response, inflammation markers and vascular function. MAIN METHODS Eighty-eight patients with hypertension (stage 1 or 2) were recruited and advised to receive perindopril (4mg), hydrochlorothiazide (25mg), or indapamide (1.5mg) for 12weeks in a blinded fashion. Office and 24-h ambulatory blood pressure monitoring (24h ABPM), flow-mediated dilatation (FMD), nitrate-induced dilatation (NID), titers of IgG and IgM anti-ApoB-D peptide Abs, hsCRP, and interleukins (IL-8 and IL-10) were evaluated at baseline and 12weeks after therapies. KEY FINDINGS All treatments reduced office BP, and improved FMD (P<0.05 vs. baseline). The NID was improved only in the perindopril arm (P<0.05 vs. baseline). The 24h-ABPM was reduced with perindopril and hydrochlorothiazide therapies (P<0.05 vs. baseline), but not with indapamide, and this effect was followed by increase in titers of IgM Anti-ApoB-D peptide Abs (P<0.05 vs. baseline), without modifications in titers IgG Anti-ApoB-D peptide Abs and interleukins. Multivariable regression analysis has shown that change in the titers of IgM anti-ApoB-D peptide was associated with the changes in FMD (β -0.347; P<0.05). SIGNIFICANCE These findings shed light to a possible modulator effect of the antihypertensive therapy on the natural immunity responses and vascular function.

PHARMACOKINETIC INTERACTIONS BETWEEN CLOPIDOGREL AND ROSUVASTATIN: EFFECTS ON VASCULAR PROTECTION IN SUBJECTS WITH CORONARY HEART DISEASE

Genetic polymorphisms in the hepatic cytochrome P450 (CYP2C19) affect the antiplatelet effects of clopidogrel. Rosuvastatin is partially metabolized by the same cytochrome. We hypothesized that pharmacokinetic interactions between these drugs might affect their individual responses on vascular

Behavior of Blood Pressure Variables in Children and Adolescents with Duchenne Muscular Dystrophy

BACKGROUND Duchenne muscular dystrophy is an X-chromosome-linked genetic disorder (locus Xp21). Involvement of the cardiovascular system is characterized by fibrous degeneration/replacement of myocytes with consequent ventricular hypertrophy and arterial hypertension. OBJECTIVE To assess, by using 24-hour ambulatory blood pressure monitoring, the behavior of blood pressure variables in children and adolescents with a confirmed diagnosis of Duchenne muscular dystrophy. METHODS Prospective observational cohort study, which selected 46 patients followed up on an outpatient basis, divided according to age groups. Blood pressure was classified according to the age percentile. The monitoring interpretation includes systolic and diastolic blood pressure means, systolic and diastolic blood pressure loads, and nocturnal dipping. The blood pressure means were calculated for the 24-hour, wakefulness and sleep periods. Nocturnal dipping was defined as a drop in blood pressure means during sleep greater than 10%. The significance level adopted was p < 0.05. RESULTS Nocturnal dipping for systolic blood pressure was present in 29.9% of the participants. Approximately 53% of them had attenuated nocturnal dipping, and 15%, reverse nocturnal dipping. The age groups of 9-11 years and 6-8 years had the greatest percentage of attenuation, 19.1% and 14.9%, respectively. Regarding diastolic blood pressure, nocturnal dipping was identified in 53.2% of the children, being extreme in 27.7% of those in the age group of 6-11 years. CONCLUSIONS The early diagnosis of blood pressure changes can allow the appropriate and specific therapy, aimed at increasing the life expectancy of patients with Duchenne muscular dystrophy.

Association of Multiple Genetic Variants with the Extension and Severity of Coronary Artery Disease

Background Metabolic syndrome (MS) is a condition that, when associated with ischemic heart disease and cardiovascular events, can be influenced by genetic variants and determine more severe coronary atherosclerosis. Objectives To examine the contribution of genetic polymorphisms to the extension and severity of coronary disease in subjects with MS and recent acute coronary syndrome (ACS). Methods Patients (n = 116, 68% males) aged 56 (9) years, with criteria for MS, were prospectively enrolled to the study during the hospitalization period after an ACS. Clinical and laboratory parameters, high-sensitivity C-reactive protein, thiobarbituric acid reactive substances, adiponectin, endothelial function, and the Gensini score were assessed. Polymorphisms of paraoxonase-1 (PON-1), methylenotetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (ENOS), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), apolipoprotein C3 (APOC3), lipoprotein lipase (LPL) were analysed by polymerase chain reaction (PCR) technique, followed by the identification of restriction fragment length polymorphisms (RFLP, and a genetic score was calculated. Parametric and non-parametric tests were used, as appropriate. Significance was set at p < 0.05. Results Polymorphisms of PON-1, MTHFR and ENOS were not in the Hardy-Weinberg equilibrium. The DD genotype of LPL was associated with higher severity and greater extension of coronary lesions. Genetic score tended to be higher in patients with Gensini score < P50 (13.7 ± 1.5 vs. 13.0 ± 1.6, p = 0.066), with an inverse correlation between genetic and Gensini scores (R = -0.194, p = 0.078). Conclusions The LPL polymorphism contributed to the severity of coronary disease in patients with MS and recent ACS. Combined polymorphisms were associated with the extension of coronary disease, and the lower the genetic score the more severe the disease.