High-Sensitivity Troponin I and Cardiovascular Events in Stable Coronary Artery Disease: Insights from a Longitudinal Outpatient Study.

Numerous studies have been published suggesting that troponin levels are related to adverse outcomes in chronic cardiac and non-cardiac conditions. Our study investigated whether troponin levels gathered from unselected blood samples taken during outpatient care are associated with adverse outcomes in a population with stable coronary artery disease. In a cohort of 949 patients with stable coronary artery disease, an average age of 67.5 ± 9.5 years, 69.5% male, 52.1% diabetics, 51.6% with previous myocardial infarction, and 57.9% with triple-vessel disease, 21.7% of patients encountered new events during an average period of monitoring of 2.07 ± 0.81 years. Troponin I/99th percentile categorized into tertiles emerged as an independent predictor of death and combined events risk (hazard ratio: 2.02 (1.13-3.60), p = 0.017; 2.30 (1.37-3.88, p = 0.002, respectively). A troponin ratio > 0.24 was able to identify 53.3% of patients at risk of death and heart failure hospitalization. In patients with stable coronary artery disease who are adherent to treatment, troponin levels are independently associated with death and heart failure hospitalization in a medium-term follow-up.

Sirtuin 1 and Vascular Function in Healthy Women and Men: A Randomized Clinical Trial Comparing the Effects of Energy Restriction and Resveratrol.

Background: Sirtuin 1 (SIRT1) has been associated with longevity and protection against cardiometabolic diseases, but little is known about how it influences human vascular function. Therefore, this study evaluated the effects of SIRT1 activation by resveratrol and energy restriction on vascular reactivity in adults. Methods: A randomized trial allocated 48 healthy adults (24 women and 24 men), aged 55 to 65 years, to resveratrol supplementation or energy restriction for 30 days. Blood lipids, glucose, insulin, C-reactive protein, noradrenaline, SIRT1 (circulating and gene expression), and flow-mediated vasodilation (FMD) and nitrate-mediated vasodilation (NMD) were measured. Results: Both interventions increased circulating SIRT1 (p < 0.001). Pre- and post-tests changes of plasma noradrenaline were significant for both groups (resveratrol: p = 0.037; energy restriction: p = 0.008). Baseline circulating SIRT1 was inversely correlated with noradrenaline (r = -0.508; p < 0.01), and post-treatment circulating SIRT1 was correlated with NMD (r = 0.433; p < 0.01). Circulating SIRT1 was a predictor of FMD in men (p = 0.045), but not in women. SIRT1 was an independent predictor of NMD (p = 0.026) only in the energy restriction group. Conclusions: Energy restriction and resveratrol increased circulating SIRT1 and reduced sympathetic activity similarly in healthy adults. SIRT1 was independently associated with NMD only in the energy restriction group.

Chronic troponin elevation assessed by myocardial T1 mapping in patients with stable coronary artery disease.

BACKGROUND: Cardiac troponin detected with sensitive assays can be chronically elevated, in the absence of unstable coronary syndromes. In patients with chronic coronary artery disease, clinically silent ischemic episodes may cause chronic troponin release. T1 mapping is a cardiovascular magnetic resonance technique useful in quantitative cardiac tissue characterization. We selected patients with anatomically and functionally normal hearts to investigate associations between chronic troponin release and myocardial tissue characteristics assessed by T1 mapping. METHODS: We investigated the relationship between cardiac troponin I concentrations and cardiovascular magnetic resonance T1 mapping parameters in patients with stable coronary artery disease enrolled in MASS V study before elective revascularization. Participants had no previous myocardial infarction, negative late gadolinium enhancement, normal left ventricular function, chamber dimensions and wall thickness. RESULTS: A total of 56 patients were analyzed in troponin tertiles: nativeT1 and extracellular volume (ECV) values (expressed as means ±â€…standard deviations) increased across tertiles: nativeT1 (1006 ±â€…27 ms vs 1016 ±â€…27 ms vs 1034 ±â€…37 ms, ptrend = 0.006) and ECV (22 ±â€…3% vs 23 ±â€…1.9% vs 25 ±â€…3%, ptrend = 0.007). Cardiac troponin I concentrations correlated with native T1(R = 0.33, P = .012) and ECV (R = 0.3, P = .025), and were independently associated with nativeT1 (P = .049) and ventricular mass index (P = .041) in multivariable analysis. CONCLUSION: In patients with chronic coronary artery disease and structurally normal hearts, troponin I concentrations correlated with T1 mapping parameters, suggesting that diffuse edema or fibrosis scattered in normal myocardium might be associated with chronic troponin release.

Cardiac Troponin I in Patients Undergoing Percutaneous and Surgical Myocardial Revascularization: Comparison of Analytical Methods.

The myocardial infarction (MI) types 4a and 5 guidelines recommend cardiac troponin (cTn) diagnostic decision limits of 5 and 10 times the 99th percentile, respectively. Different cTn kits elicit different responses, so the MI diagnosis is still challenging. The study aimed to establish the cutoff values and the accuracy of three different cTnI kits in the diagnosis of post-procedural MI. We analyzed 115 patients with multivessel stable chronic coronary artery disease; 26 underwent percutaneous coronary intervention, and 89 underwent coronary artery bypass graft. Delayed-enhancement magnetic resonance imaging was performed before and after each intervention for definitive MI diagnoses. Two contemporary and one high-sensitivity cTnI immunoassays were used. ROC curves determined the accuracy of each assay. Low accuracy was observed after applying the current guidelines recommendations. The three cTnI assays accuracies improved when adjusted by the new ROC cutoffs, reaching 82% for MI type 5 for all assays, and 78%, 88%, and 87% for MI type 4 for Siemens, Beckman, and Abbott, respectively. The ultrasensitive and contemporary tests' accuracy for MI types 4a and 5 diagnoses are equivalent when adjusted for these new cutoffs. The hs-cTnI assays had lower accuracy than contemporary tests for MI types 4a and 5 diagnoses.

The Interplay of Sirtuin-1, LDL-Cholesterol, and HDL Function: A Randomized Controlled Trial Comparing the Effects of Energy Restriction and Atorvastatin on Women with Premature Coronary Artery Disease.

INTRODUCTION: HDL function has gained prominence in the literature as there is a greater predictive capacity for risk in early coronary artery disease when compared to the traditional parameters. However, it is unclear how dietary energy restriction and atorvastatin influence HDL function. METHODS: A randomized controlled trial with 39 women with early CAD divided into three groups (n = 13): energy restriction (30% of VET), atorvastatin (80 mg), and control. Analyses of traditional biochemical markers (lipid and glucose profile), circulating Sirt-1, and HDL function (lipid composition, lipid transfer, and antioxidant capacity). RESULTS: Participants' mean age was 50.5 ± 3.8 years. Energy restriction increased Sirt-1 by 63.6 pg/mL (95%CI: 1.5-125.7; p = 0.045) and reduced BMI by 0.8 kg/m2 (95%CI: -1.349--0.273; p = 0.004) in a manner independent of other cardiometabolic factors. Atorvastatin reduced LDL-c by 40.0 mg/dL (95%CI: -69.910--10.1; p = 0.010). Increased Sirt-1 and reduced BMI were independently associated with reduced phospholipid composition of HDL (respectively, ß = -0.071; CI95%:-0.136--0.006; p = 0.033; ß = 7.486; CI95%:0.350-14.622; p = 0.040). Reduction in BMI was associated with lower HDL-free cholesterol (ß = 0.818; CI95%:0.044-1.593; p = 0.039). LDL-c reduction by statins was associated with reduced maximal lipid peroxide production rate of HDL (ß = 0.002; CI95%:0.000-0.003; p = 0.022) and total conjugated diene generation (ß = 0.001; CI95%:0.000-0.001; p = 0.029). CONCLUSION: This study showed that energy restriction and atorvastatin administration were associated with changes in lipid profile, serum Sirt-1 concentrations, and HDL function.

Sex Differences in Cardiovascular Disease Mortality in Brazil between 1996 and 2019.

BACKGROUND: cardiovascular diseases (CVD) are Brazil's leading causes of death in women and men. This study analyzed age-adjusted death rate (DRaj) trends from all causes of death (ACD), CVD, ischemic heart disease (IHD), and stroke in women and men aged 35 to 74 years from 1996 to 2019. METHODS: We analyzed DRaj trends for all causes of death (ACD), CVD, IHD, and stroke. Data were from the Ministry of Health mortality database. Joinpoint Regression Program™ performed trend analysis and adjustments in death rates. Average annual percentage change (AAPC) determined the intensity of changes. RESULTS: In women, DRaj reduced for ACD (AAPC = -1.6%); CVD (AAPC = -2.6%); IHD (AAPC = -1.9%); and stroke (AAPC = -4.6%) (p < 0.001 for all). In men, ACD reduced from 1996 to 2004 (AAPC = -0.9%; p < 0.001), from 2012 to 2019 (AAPC = -1.9%; p < 0.001), and unchanged from 2004 to 2012; CVD (AAPC = -2.1%); IHD (AAPC = -1.5%); stroke (AAPC = -4.9%) (p < 0.001 for all) reduced from 1996 to 2019. From 1996 to 2019, the male/female ratio for ACD remained unchanged. CVD increased from 1.58 to 1.83, IHD from 1.99 to 2.30, and stroke from 1.52 to 1.83. CONCLUSION: ACD, CVD, IHD, and stroke were reduced more significantly in women, and the ratio of CVD, IHD, and CVD in men and women increased more in men. Future studies will be needed to determine the main factors responsible for a better outcome in women.

Effects of Coffee on Sirtuin-1, Homocysteine, and Cholesterol of Healthy Adults: Does the Coffee Powder Matter?

Background: Coffee is one of the most popular beverages globally and contains several bioactive compounds that are relevant to human health. Many nutritional strategies modulate sirtuin-1, thereby impacting aging and cardiometabolic health. This study investigated the influence of different blended coffees on serum sirtuin-1, blood lipids, and plasma homocysteine. Methods: An eight-week randomized clinical trial that included 53 healthy adults of both sexes analyzed the effects of daily intake of 450 to 600 mL of pure Arabica or blended (Arabica + Robusta) coffee intake of filtered coffee on blood sirtuin-1, lipids, and homocysteine. Results: Both Arabica and blended coffees similarly increased serum sirtuin-1 concentration, from 0.51 to 0.58 ng/mL (p = 0.004) and from 0.40 to 0.49 ng/mL (p = 0.003), respectively, without changing plasma homocysteine, folic acid, glucose, and CRP. However, the blended coffee intake increased total cholesterol from 4.70 to 5.17 mmol/L (p < 0.001) and LDL-cholesterol from 2.98 to 3.32 mmol/L (p < 0.001), as well as HDL-c from 1.26 to 1.36 mmol/L (p < 0.001). Conclusion: Both coffee powders increased sirtuin-1 expression, but our results suggest that blended coffee had hypercholesterolemic effects which could increase cardiovascular risk. Therefore, preference should be given to Arabica coffee for the best cardiometabolic benefits of coffee.

Blood cell adhesion to arterial filters analysis by scanning electron microscopy and real-time PCR assay: observational clinical study in cardiac surgery patients.

INTRODUCTION: Arterial filter is the part of the cardiopulmonary bypass circuit where blood cells are exposed to high mechanical stress and where cellular aggregates may fasten in large quantities. The aim of this study was to analyse blood cell adhesiveness in the arterial filter through scanning electron microscopy and real-time PCR assay. METHODS: Prospective, clinical and observational study performed on 28 patients undergoing cardiac surgery with cardiopulmonary bypass. Arterial filters were analysed by scanning electron microscopy. Real-time PCR assay was performed in extracted material from the arterial filters for analysis of platelet GPIb and CD45 leucocyte gene expression. Blood coagulation was analysed during cardiopulmonary bypass. Patients were followed until hospital discharge or 28 days after surgery. RESULTS: All studied arterial filters used in the subject patients showed a degree of adhesion from blood elements at scanning electron microscopy. All studied filters were positive for platelets GPIb gene expression and 15% had CD45 leucocyte gene expression. The GPIb platelet gene expression in blood lowered at the end of cardiopulmonary bypass (p = 0.019). There was negative correlation between blood GPIb platelet gene expression and Clot SR (HEPSCREEN2 ReoRox®) (rho = 0.635; p = 0.027). The filter fields count was correlated to the D-dimer dosage (rho = 0.828; p < 0.001). CONCLUSION: There was adhesion of blood elements, especially nucleated platelets, on all arterial filters studied. Although the arterial filter worked as a safety device, that possibly prevented arterial embolisation, it may also have caused greater hyperfibrinolysis during cardiopulmonary bypass.

Comparison of Resveratrol Supplementation and Energy Restriction Effects on Sympathetic Nervous System Activity and Vascular Reactivity: A Randomized Clinical Trial.

Background: Chronic sympathetic nervous system activation is associated with endothelial dysfunction and cardiometabolic disease, which may be modulated by resveratrol (RSV) and energy restriction (ER). This study aimed to examine the effects of RSV and ER on plasma noradrenaline (NA), flow-mediated vasodilation (ed-FMD), and endothelium-independent nitrate-mediated vasodilation (ei-NMD). Methods: The study included 48 healthy adults randomized to 30-days intervention of RSV or ER. Results: Waist circumference, total cholesterol, HDL-c, LDL-c, apoA-I, and plasma NA decreased in the ER group, whilst RSV increased apoB and total cholesterol, without changing plasma NA. No effects on vascular reactivity were observed in both groups. Plasma NA change was positively correlated with total cholesterol (r = 0.443; p = 0.002), triglycerides (r = 0.438; p = 0.002), apoA-I (r = 0.467; p = 0.001), apoB (r = 0.318; p = 0.032) changes, and ei-NMD (OR = 1.294; 95%CI: 1.021-1.640). Conclusions: RSV does not improve cardiometabolic risk factors, sympathetic activity, and endothelial function. ER decreases plasma NA and waist circumference as well as improves blood lipids, but does not modify endothelial function. Finally, plasma NA was associated with ei-NMD, which could be attributed to a higher response to nitrate in patients with greater resting sympathetic vasoconstriction.

Nicotinamide attenuates streptozotocin-induced diabetes complications and increases survival rate in rats: role of autonomic nervous system.

BACKGROUND: To evaluate the effect of nicotinamide prior to streptozotocin-induced (STZ) diabetes in baroreflex sensitivity and cardiovascular autonomic modulation, and its association with hemodynamics and metabolic parameters. METHODS: Methods: Male Wistar rats were divided into control (Cont) and STZ-induced diabetes (Diab). Half of the rats from each group received a single dose of nicotinamide (100 mg/Kg) before STZ injection (Cont+NicA and Diab+NicA). All groups were followed-up for 5 weeks. RESULTS: Body weight loss of more than 40% was observed in Diab throughout the period (Diab: 271.00 ± 12.74 g; Diab+NicA: 344.62 ± 17.82). Increased glycemia was seen in Diab rats (541.28 ± 18.68 mg/dl) while Diab+NicA group had a slight decrease (440.87 ± 20.96 mg/dl). However, insulin resistance was observed only in Diab. In relation to Cont, heart rate, mean blood pressure and diastolic function were reduced when compared to Diab, together with parasympathetic modulation and baroreflex sensitivity. All of these parameters were improved in Diab+NicA when compared to Diab. Improved baroreflex sensitivity and parasympathetic modulation were correlated with glycemia, insulin resistance, and body weight mass. Additionally, Diab+NicA group increased survival rate. CONCLUSIONS: Results suggest that the association of nicotinamide in STZ-induced diabetic rats prevents most of the expected derangements mainly by preserving parasympathetic and baroreflex parameters.

Evaluation of the Long-Term Impact on Quality After the End of Pharmacist-Driven Warfarin Therapy Management in Patients With Poor Quality of Anticoagulation Therapy.

BACKGROUND: Warfarin is the most common oral anticoagulant drug, especially in low-income and emerging countries, because of the high cost of direct oral anticoagulant (DOACs), or when warfarin is the only proven therapy (mechanical prosthetic valve and kidney dysfunction). The quality of warfarin therapy is directly associated with dose management. Evidence shows that pharmaceutical care achieves a better quality of therapy with warfarin. However, there are no studies showing this intervention in a specific patient group with poor quality of anticoagulation in a long period after the end of the follow-up by a pharmacist. Thus, the aim of this study was to evaluate whether the quality of warfarin therapy driven by a pharmacist remains stable in the long term after the end of follow up with a pharmacist, in AF patients with poor quality of anticoagulation. METHODS: This is a prospective study, which evaluated about 2,620 patients and selected 262 patients with AF and poor quality of anticoagulation therapy with warfarin (TTR<50% - based on the last three values of international normalized ratio). Pharmacist-driven therapy management was performed up to 12 weeks. Data from patients were evaluated 1 year after the end of the follow-up with pharmacist. RESULTS: Comparison between mean TTR after 12 weeks of pharmaceutical care (54.1%) and mean TTR one year after the end of the pharmaceutical care (56.5%; p=0.081) did not achieve statistical difference, demonstrating that the increment of quality due to intervention of 12 weeks was maintained for 1 year after intervention. CONCLUSION: The long-term impact of pharmaceutical care was beneficial for patients with AF and poor quality of warfarin anticoagulation. This design might be an important strategy to treat a subgroup of patients without proven effectiveness of warfarin.

Prospective, case-controlled study evaluating serum concentration of sirtuin-1 and mannose-binding lectin in patients with and without periodontal and coronary artery disease.

BACKGROUND: Atherosclerosis and periodontal disease (PD) are inflammatory diseases that have been shown in studies to have a direct association. Mannose-binding lectin (MBL) is an immune system protein that binds to periodontal pathogens favoring phagocytosis. Conversely, increased serum sirtuin-1 (SIRT1) concentration reduces the inflammatory process. METHODS: This was a prospective, case-controlled study that analyzed serum concentration of biomarkers in patients with or without coronary artery disease (CAD) and PD. A total of 78 patients were evaluated: 20 healthy individuals, 18 patients with CAD, 20 patients with PD, and 20 patients with both PD and CAD. Clinical and laboratory characteristics were analyzed before and after nonsurgical treatment of PD and also at two equivalent times in patients without PD. Serum MBL and SIRT1 concentration were analyzed by enzyme-linked immunosorbent assay. RESULTS: A negative correlation was observed between changes in serum concentration of MBL and SIRT1 (r = -0.30; p = 0.006). Comparison between pre- and post-treatment of PD showed a reduction in MBL levels (886.27 ± 906.72 versus 689.94 ± 808.36; p = 0.002) and an increase in SIRT1 values (0.80 ± 1.01 versus 1.49 ± 1.55; p = 0.005) in patients with PD and without CAD. The same result was observed in patients with PD and CAD for MBL and SIRT1, respectively, of 1312.43 ± 898.21 versus 1032.90 ± 602.52 (p = 0.010) and 1.32 ± 1.0 versus 1.82 ± 1.75 (p = 0.044). CONCLUSION: PD treatment reduced MBL serum concentration and increased SIRT1 serum concentration in patients with and without CAD.

Significant association of SYNTAX score on release of cardiac biomarkers in uncomplicated post-revascularization procedures among patients with stable multivessel disease: MASS-V Study group.

This study investigated the relationship between angiographic complexities of coronary artery disease (CAD) assessed by SYNTAX Score synergy between percutaneous coronary intervention with taxus and cardiac surgery score (SYNTAX Score) and cardiac biomarker elevation after revascularization procedures.This is a post-hoc analysis of the medicine, angioplasty or surgery study V study of patients with stable CAD. High-sensitivity troponin 1 (hs-TnI) and creatinine kinase-muscle/brain (CK-MB) were assessed before and after cardiovascular procedures. Baselines SYNTAX Scores (SXScores) were calculated by blinded investigators to patient characteristics.Of the 202 patients studied, the mean SXScore was 21.25 ±â€Š9.24; 40.10 ±â€Š7.09 in the high SXScore group and 19.06 ±â€Š6.61 in low/mid SXscore group (P < .0001). Positive correlations existed between SXScore and median peaks after procedural hs-TnI (r = 0.18, P = .009) and CK-MB (r = 0.24, P = .001) levels. In patients with high SXScores (≥33), the median peaks of post-procedural hs-TnI (P = .034)and CK-MB (P = .004) levels were higher than in low/mid SXScore group (<33).The release of hs-TnI at 6 (P = .002), 12 (P = .008), and 24 hours (P = .039) was higher in high SXScore group than in low/mid SXscore group (<33) as was the release of CK-MB at 6 (P < .0001), 12 (P < .0001), 24 (P = .001), 36 (P = .007), 48 (P = .008), and 72 hours (P = .023). After multivariable analysis, high SXScore was a significant independent predictor of release of CK-MB and hs-TnI peaks higher than the median.The increase in release of cardiac biomarkers was significantly associated with the extent of atherosclerosis identified by the SYNTAX Score.

Influence of the treatment of periodontal disease in serum concentration of sirtuin 1 and mannose-binding lectin.

BACKGROUND: Increased levels of periodontal pathogens disrupt the homeostasis between the host and its microbiota and increase susceptibility to periodontal diseases. Periodontitis increases the serum concentration of mannose-binding lectin (MBL), which exacerbates local inflammatory processes. In animal studies, sirtuin 1 (SIRT1) was associated with protection against inflammation. This study analyzed the influence of non-surgical periodontal treatment on serum levels of MBL and SIRT1. METHODS: Forty patients with periodontitis and 38 periodontally healthy individuals (aged 45 to 79 years) were included. Periodontitis patients received scaling and root planing using machine driven and hand instruments. Clinical parameters, inflammatory biomarkers, MBL, and SIRT1 levels were measured at baseline and at post-treatment. RESULTS: For all patients, an inverse correlation was observed between serum concentrations of MBL and SIRT1 (r = -0.30; P = 0.006). Periodontal treatment reduced serum concentrations of MBL (1,099.35 ± 916.59 to 861.42 ± 724.82 ng/mL; P < 0.001) and C-reactive protein (6.05 ± 8.99 to 2.49 ± 2.89 mg/L; P = 0.009). By contrast, SIRT1 serum levels increased (1.06 ± 1.03 to 1.66 ± 1.64 ng/mL; P < 0.001) following periodontal treatment. CONCLUSIONS: Periodontal treatment was associated with decreased serum concentrations of MBL and CRP and increased serum levels of SIRT1. Prospective studies are needed to assess the impact of these biomarkers on pathophysiology of periodontitis.

Platelet function, coagulation and fibrinolysis in patients with previous coronary and cerebrovascular ischemic events.

OBJECTIVES: Ischemic stroke (IS) or transient ischemic attack (TIA) history is present in 4-17% of patients with coronary artery disease (CAD). This subgroup of patients is at high risk for both ischemic and bleeding events. The aim of this study was to determine the role of platelet aggregability, coagulation and endogenous fibrinolysis in patients with CAD and previous IS or TIA. METHODS: A prospective case-control study that included 140 stable CAD patients divided into two groups: the CASE group (those with a previous IS/TIA, n=70) and the CONTROL group (those without a previous IS/TIA, n=70). Platelet aggregability (VerifyNow Aspirin® and VerifyNow P2Y12®), coagulation (fibrinogen and thromboelastography by Reorox®) and endogenous fibrinolysis (D dimer and plasminogen activator inhibitor-1) were evaluated. RESULTS: Patients in the CASE group presented significantly higher systolic blood pressure levels (135.84±16.09 vs 123.68±16.11, p<0.01), significantly more previous CABG (25.71% vs 10%, p=0.015) and significantly higher calcium channel blocker usage (42.86% vs 24.29%, p=0.02) than those in the control group. In the adjusted models, low triglyceride values, low hemoglobin values and higher systolic blood pressure were significantly associated with previous IS/TIA (CASE group). Most importantly, platelet aggregability, coagulation and fibrinolysis tests were not independently associated with previous cerebrovascular ischemic events (CASE group). CONCLUSION: Platelet aggregability, coagulation and endogenous fibrinolysis showed similar results among CAD patients with and without previous IS/TIA. Therefore, it remains necessary to identify other targets to explain the higher bleeding risk presented by these patients.

Platelet function, coagulation and fibrinolysis in patients with previous coronary and cerebrovascular ischemic events

OBJECTIVES: Ischemic stroke (IS) or transient ischemic attack (TIA) history is present in 4-17% of patients with coronary artery disease (CAD). This subgroup of patients is at high risk for both ischemic and bleeding events. The aim of this study was to determine the role of platelet aggregability, coagulation and endogenous fibrinolysis in patients with CAD and previous IS or TIA. METHODS: A prospective case-control study that included 140 stable CAD patients divided into two groups: the CASE group (those with a previous IS/TIA, n=70) and the CONTROL group (those without a previous IS/TIA, n=70). Platelet aggregability (VerifyNow Aspirin® and VerifyNow P2Y12®), coagulation (fibrinogen and thromboelastography by Reorox®) and endogenous fibrinolysis (D dimer and plasminogen activator inhibitor-1) were evaluated. RESULTS: Patients in the CASE group presented significantly higher systolic blood pressure levels (135.84±16.09 vs 123.68±16.11, p<0.01), significantly more previous CABG (25.71% vs 10%, p=0.015) and significantly higher calcium channel blocker usage (42.86% vs 24.29%, p=0.02) than those in the control group. In the adjusted models, low triglyceride values, low hemoglobin values and higher systolic blood pressure were significantly associated with previous IS/TIA (CASE group). Most importantly, platelet aggregability, coagulation and fibrinolysis tests were not independently associated with previous cerebrovascular ischemic events (CASE group). CONCLUSION: Platelet aggregability, coagulation and endogenous fibrinolysis showed similar results among CAD patients with and without previous IS/TIA. Therefore, it remains necessary to identify other targets to explain the higher bleeding risk presented by these patients.

Pharmaceutical Care Increases Time in Therapeutic Range of Patients With Poor Quality of Anticoagulation With Warfarin.

Thromboembolic events are associated with high mortality and morbidity indexes. In this context, warfarin is the most widely prescribed oral anticoagulant agent for preventing and treating these events. This medication has a narrow therapeutic range and, consequently, patients usually have difficulty in achieving and maintaining stable target therapeutics. Some studies on the literature about oral anticoagulant management showed that pharmacists could improve the efficiency of anticoagulant therapy. However, the majority of these studies included general patients retrospectively. The aim of this study was to prospectively evaluate a pharmacist's warfarin management in patients with poor quality of anticoagulation therapy (Time in the Therapeutic Range- TTR < 50%). We included 268 patients with atrial fibrillation (AF) and without stable dose of warfarin (TTR < 50%, based on the last three values of International Normalized Ratio-INR). We followed them up for 12 weeks, INR values were evaluated and, when necessary, the dose adjustments were performed. During the first four visits, patient's INR was measured every 7 days. Then, if INR was within the target therapeutic range (INR: 2-3), the patient was asked to return in 30 days. However, if INR was out the therapeutic target, the patient was asked to return in 7 days. Adherence evaluation was measured through questionnaires and by counting the pills taken. Comparison between basal TTR (which was calculated based on the three last INR values before prospective phase) and TTR of 4 weeks (calculated by considering the INR tests from visits 0 to 4, in the prospective phase of the study) and basal TTR and TTR of 12 weeks (calculated based on the INR tests from visits 0 to 12, in the prospective phase of the study) revealed significant statistical differences (0.144 ± 0.010 vs. 0.382 ± 0.016; and 0.144 ± 0.010 vs. 0.543 ± 0.014, p < 0.001, respectively). We also observed that the mean TTR of 1 year before (retrospective phase) was lower than TTR value after 12 weeks of pharmacist-driven treatment (prospective phase) (0.320 ± 0.015; 0.540 ± 0.015, p < 0.001). In conclusion, pharmaceutical care was able to improve TTR values in patients with AF and poor quality of anticoagulation with warfarin.

Role of P-selectin in thromboembolic events in patients with cancer.

The objective of the present study was to evaluate the role of P-selectin in patients with cancer with suspected thromboembolic events (TEEs). Patients with cancer have a four times greater risk of developing TEEs. P-selectin is a glycoprotein that has the function of facilitating the interaction (adhesion) of leukocytes with the endothelium, or with platelets. There is a well-defined relationship between P-selectin and thrombosis; however, it is likely that the cut-off value of P-selectin for patients with cancer should be considered differently from that of the general population. In the present report, a prospective cross-sectional study was performed with patients of the Cancer Hospital of Barretos who were suspected of having TEEs. Among the 178 study participants, 167 (93.82%) were suspected of having deep vein thrombosis, while 59 of them (35.33%) were confirmed as such; and 11 (6.18%) were suspected of having pulmonary thromboembolism, while 3 of them were confirmed as such (27.69%). The mean results obtained were: P-selectin, 25.37 ng/ml; and D-dimer, 2,181.22 ng/ml. The P-selectin levels averaged 33.60 ng/ml with the confirmed TEE group compared with 20.40 ng/ml with the unconfirmed TEE group, with a standard deviation of 23.35 compared with 6.92 (P<0.001); and the level of D-dimer was 4,615.38 ng/ml compared with 977.52 ng/ml, with a standard deviation of 6,460.54 compared with 2,145.50 (P<0.001). Multiple logistic regression adjusted for distant metastases and the Eastern Cooperative Oncology Group (ECOG) score (2,3 and 4) were constructed. The cut-off value of P-selectin for patients with cancer was identified to be different from that reported in the literature for the general population, and the models using D-dimer and P-selectin therefore have been demonstrated to be a potentially useful tool to be used in a panel of tests to predict TEEs, either independently or in a prediction score.

Down-regulation of fibroblast growth factor 2 and its co-receptors heparan sulfate proteoglycans by resveratrol underlies the improvement of cardiac dysfunction in experimental diabetes.

Cardiac remodeling in diabetes involves cardiac hypertrophy and fibrosis, and fibroblast growth factor 2 (FGF2) is an important mediator of this process. Resveratrol, a polyphenolic antioxidant, reportedly promotes the improvement of cardiac dysfunction in diabetic rats. However, little information exists linking the amelioration of the cardiac function promoted by resveratrol and the expression of FGF2 and its co-receptors, heparan sulfate proteoglycans (HSPGs: Glypican-1 and Syndecan-4), in cardiac muscle of Type 2 diabetic rats. Diabetes was induced experimentally by the injection of streptozotocin and nicotinamide, and the rats were treated with resveratrol for 6 weeks. According to our results, there is an up-regulation of the expression of genes and/or proteins of Glypican-1, Syndecan-4, FGF2, peroxisome proliferator-activated receptor gamma and AMP-activated protein kinase in diabetic rats. On the other hand, resveratrol treatment promoted the attenuation of left ventricular diastolic dysfunction and the down-regulation of the expression of all proteins under study. The trigger for the changes in gene expression and protein synthesis promoted by resveratrol was the presence of diabetes. The negative modulation conducted by resveratrol on FGF2 and HSPGs expression, which are involved in cardiac remodeling, underlies the amelioration of cardiac function.

Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range - study protocol for a randomized controlled trial.

BACKGROUND: Time in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (<50%) are associated with greater risk of thromboembolic and bleeding events. Recently, we developed a pharmacogenetic-based warfarin dosing algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (<50%) from a tertiary cardiovascular hospital. METHODS/DESIGN: This study is a randomized controlled trial in patients (n = 300) with atrial fibrillation with TTR < 50%, based on the last three INR values. At the first consultation, patients will be randomized into two groups: TA group (traditional anticoagulation) and PA group (pharmacogenetic anticoagulation). For the first group, the physician will adjust the dose according to current INR value and, for the second group, a pharmacogenetic algorithm will be used. At the second, third, fourth and fifth consultations (with an interval of 7 days each) INR will be measured and, if necessary, the dose will be adjusted based on guidelines. Afterwards, patients who are INR stable will begin measuring their INR in 30 day intervals; if the patient's INR is not stable, the patient will return in 7 days for a new measurement of the INR. Outcomes measures will include the time to achieve the therapeutic target and the percentage of TTR at 4 and 12 weeks. In addition, as a secondary end-point, pharmacoeconomic analysis will be carried out. Ethical approval was granted by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School. DISCUSSION: This randomized study will include patients with low TTR and it will evaluate whether a population-specific genetic algorithm might be more effective than traditional anticoagulation for a selected group of poorly anticoagulated patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592980 . Registered on 29 October 2015.