Sex-based differences in outcomes with bivalirudin or unfractionated heparin for transcatheter aortic valve replacement: Results from the BRAVO-3 randomized trial.

BACKGROUND: Women comprise almost 50% of patients undergoing transcatheter aortic valve replacement (TAVR) and previous studies have indicated higher rates of procedural complications and bleeding in women compared to men. It is unknown whether men and women demonstrate a differential response to bivalirudin versus unfractionated heparin (UFH) in TAVR. We sought to evaluate outcomes by sex and type of anticoagulant from the Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement (BRAVO-3) trial of transfemoral TAVR. METHODS: BRAVO-3 was a randomized multicenter trial comparing transfemoral TAVR with bivalirudin versus UFH (31 centers, n = 802). The primary endpoint was 48 h major bleeding defined as Bleeding Academic Research Consortium (BARC) type ≥3b. Major adverse cardiovascular events (MACE) were a composite of 30-day death, myocardial infarction, or stroke. Net adverse cardiovascular events (NACE) were a composite of BARC ≥3b bleeding or 30-day MACE. We examined the outcomes in men and women. RESULTS: The total cohort included 49% women (n = 391, 195 received bivalirudin and 196 UFH) and 51% men (n = 411, 209 received bivalirudin and 202 UFH). Women were older than men with fewer comorbidities including coronary artery disease, atrial fibrillation, diabetes but similar EuroSCORE I. Women received smaller sheath and device sizes compared with men without differences in the use of vascular closure devices. At 48-hr post-TAVR there was no difference in bleeding or vascular complications in women compared to men. The use of bivalirudin did not result in significantly lower bleeding at 48 hr or 30-days compared to UFH. CONCLUSIONS: There was no difference in early outcomes with bivalirudin versus UFH in men or women undergoing contemporary TAVR. © 2016 Wiley Periodicals, Inc.

Bivalirudin use in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Insights from the prospective, multi-centre EUROVISION registry.

BACKGROUND: The effectiveness of bivalirudin in patients undergoing percutaneous coronary intervention for acute myocardial infarction has been tested in clinical trials, but its use in a real-world scenario has never been reported. METHODS: From the total number of patients enrolled in the EUROVISION registry, 678 subjects affected by ST-elevation myocardial infarction were selected and included in the analysis. Posology and usage patterns of bivalirudin, as evaluated by dose and time of drug bolus and infusion administered, were evaluated. The 30-day outcome has been assessed by efficacy and safety endpoints. RESULTS: All patients received an initial intravenous bolus of bivalirudin (0.70±0.25 mg/kg) followed by an infusion (1.58±0.47 mg/kg/h; duration: 60 [30, 107] min) in 99.3% of cases. An additional bolus (0.49±0.06 mg/kg) was administered in 9.3% of patients. Bivalirudin infusion was prolonged after procedure in 62.2%. Death occurred in 2.1% of patients, non-fatal myocardial reinfarction in 0.3%, unplanned revascularization in 0.6% and non-fatal stroke in 0.4%. Acute stent thrombosis was not observed. Major bleeding occurred in 1.5% of patients. CONCLUSIONS: Bivalirudin usage in the setting of primary PCI provided excellent results in terms of 30-day outcome even in a real-world population.

The association between apolipoprotein E gene polymorphisms and essential hypertension: a meta-analysis of 45 studies including 13,940 cases and 16,364 controls.

The apolipoprotein E single-nucleotide polymorphisms are among the potential candidate genes that may serve as modulators in susceptibility to essential hypertension. In an effort to clarify earlier inconclusive results, we performed a meta-analysis of population-based case-control genetic association studies. Random-effects methods were applied on summary data in order to combine the results of the individual studies. We identified in total 45 studies, including 13 940 hypertensive cases and 16 364 controls. The contrast of E4 carriers versus non-carriers yielded an overall odds ratio (OR) of 1.16 (95% confidence interval (CI): 1.02, 1.31), whereas the contrast of E4 allele versus the others in a subtotal of 6617 cases and 7330 controls, yielded an OR of 1.39 (95% CI: 1.12, 1.72). There was moderate evidence of publication bias in both contrasts, which was eliminated after excluding studies not in Hardy-Weinberg equilibrium. Subgroup analyses revealed that significant estimates arose from studies on Asian populations, as opposed to the Caucasian ones. Furthermore, no evidence of publication bias was demonstrated in the comparisons within this subgroup. Our results are consistent with recent meta-analyses but show that the association is weaker than that has been previously demonstrated. Further studies are needed in order to fully address questions about the etiological mechanism of the particular association, as well as to study the effect in populations of African descent.

Apolipoprotein E polymorphisms and type 2 diabetes: a meta-analysis of 30 studies including 5423 cases and 8197 controls.

Type 2 diabetes mellitus (T2DM) is a highly complicated metabolic disorder for which there is worldwide effort for the identification of susceptibility genes. Polymorphisms of the Apolipoprotein E (ApoE) gene are associated with plasma lipid and lipoprotein levels and influence cardiovascular risk. Since insulin resistance is known to be strongly associated with metabolic dyslipidemia, ApoE polymorphisms have been implicated in predisposition to diabetes but the results of the individual studies were inconclusive. We present here a meta-analysis of population-based case-control genetic-association studies relating ApoE polymorphisms and T2DM. We included in the analysis 30 studies, which reported data of ApoE genotypes in 5423 T2DM patients and 8197 healthy unrelated controls. Multivariate and univariate methods suggest a significant role played by the E2 allele, since carriers of the E2 allele were at elevated risk for T2DM (Odds Ratio=1.18, 95% CI: 1.02, 1.35). There was no evidence for publication bias or other small-study related bias or significant heterogeneity in the analyses. Cumulative meta-analysis revealed no trend of the effect estimates over time and influential analysis excluded the possibility of a single influential study. E2 allele of ApoE seems to be a moderate risk factor for T2DM. Meta-regression analysis provided some weak evidence that the risk conferred by E2 allele is mediated through altering serum lipid levels (Total Cholesterol, LDL and HDL). Further studies are needed in order to elucidate the metabolic mechanism of this association as well as to study its effects on larger populations.

Expression of FAS adjacent to fibrotic foci in the failing human heart is not associated with increased apoptosis.

Fibrosis in the heart may result from loss of myocytes, which are replaced by collagens. Apoptosis is now known to contribute to myocyte loss in the failing human heart. The mechanisms underlying the induction of cardiomyocyte apoptosis, and thus the expansion of fibrotic foci in the failing heart, are poorly understood. We hypothesized that viable heart cells adjacent to fibrotic foci might become "predisposed" to apoptosis by expression of the receptor FAS (APO1, CD95). We therefore studied the spatial relationship of FAS expression and fibrosis in patients with heart failure. Left ventricular biopsies were obtained from seven patients undergoing coronary artery bypass grafting. All patients had reduced ejection fraction but varied in New York Heart Association class score at the time of surgery. Heart cell apoptosis, fibrosis, and FAS expression were studied by propidium iodide and in situ end labeling (ISEL) of DNA, Picrosirius red staining, and immunohistochemistry. All patient samples exhibited, albeit to varying degrees, apoptosis detected by ISEL, chromatin condensation, and nuclear fragmentation. In all samples, fibrosis (collagen) was evident both perivascular and in isolated regions of scarring. Regardless of the extent of fibrosis or detectable apoptosis, FAS expression was observed in regions immediately adjacent to the fibrosis, but not in regions distal to fibrosis, nor in fibrotic areas devoid of nuclei. Expression of FAS was found adjacent to both perivascular and diffuse fibrosis, and ISEL-positive nuclei were found within cells reacting positively with anti-FAS antibodies. However, ISEL-positive nuclei were no more abundant in FAS-positive regions (67.6 +/- 5.8% of total nuclei) than in FAS-negative areas (69.5 +/- 9.8%). We conclude that expression of FAS occurs in remaining heart cells adjacent to fibrosis of either perivascular or presumed reparative origin. Although this phenomenon could contribute to the expansion of fibrotic foci, FAS-induced apoptosis in the failing heart may not be more prevalent than apoptosis initiated by other signaling mechanisms.

Non-invasive evaluation of coronary reserve. Assessment of coronary reserve in patients with coronary artery disease by transesophageal-Doppler echocardiography.

We assessed coronary flow reserve using transesophageal Doppler echocardiography in patients with coronary artery disease. The study included 33 coronary artery disease patients who were undergoing coronary arteriography. The blood flow velocities of the left anterior descending artery before and after intravenous infusion (0.56 mg/min for 4 min) of dipyridamole were recorded using transesophageal Doppler echocardiography. Fourteen normal healthy individuals, matched for age, served as a control group. The index of coronary flow reserve, i.e. the ratio of dipyridamole to baseline maximum diastolic velocity, was calculated. Maximal coronary flow reserve in coronary artery disease patients was significantly lower than in the control group (1.4+/-0.2 vs. 2.8+/-0.3, P<0.001). The coronary artery disease patients were classified into three groups: Group A included 10 patients with <50% left anterior descending artery stenosis; Group B included seven patients with 50-69% left anterior descending artery stenosis; 16 patients with >70% left anterior descending artery stenosis constituted Group C. The maximum coronary flow reserve was significantly different for A vs. B and A vs. C. (A, 1.77+/-0.18; B, 1.51+/-0.1; C, 1.28+/-0.24). A strong and significant correlation was found between the maximum coronary flow reserve and the degree of proximal left anterior descending artery stenosis (r=0.78, P<0.001). Coronary artery disease patients without left anterior descending artery stenosis on the arteriogram exhibited lower maximum coronary flow reserve compared to the control subjects (1.78+/-0.19 vs. 2.8+/-0.3, P=0.000).

Coronary microcirculation evaluation with transesophageal echocardiography Doppler in type II diabetics.

Evaluation of coronary microvascular function can be obtained through coronary flow reserve measurements. The aim of this study was to evaluate the coronary microvascular function by using transesophageal-Doppler echocardiographic assessment of coronary flow reserve. The study included 32 normotensive patients with type II diabetes mellitus (group A) of short duration (6.1+/-3.8 years) aged 55.4+/-9.4 years and 14 healthy volunteers matched for age, gender and BMI (group B). No patients had clinical evidence of coronary artery disease and all of them produced a negative recent stress ECG test. Excluded from the study were patients with anemia, left ventricular hypertrophy, arrhythmia, congenital, or acquired structural heart disease. All subjects underwent transesophageal-Doppler echocardiography. Satisfactory coronary blood flow velocity recordings could be obtained from the initial segment of the left anterior descending coronary artery in healthy volunteers and in 27 patients at baseline and 2 min after dipyridamole infusion (0.56 mg/kg, for 4 min). In the remaining 5 patients no satisfactory recordings were available. The indexes of coronary flow reserve, i.e. the ratios of dipyridamole over basal maximum and mean diastolic velocities were calculated. Dipyridamole/rest maximal coronary reserve (Table 3) was 1.946+/-0.743, while this ratio for the mean diastolic velocity was 1.969+/-0.805 in group A. The respective values for group B, were 2.811+/-0.345 (P=0.000 vs. group A) and 2.914+/-0.303 (P=0.000 vs. group A). Thus, the increase in coronary flow reserve although present in both groups, it was more impressive in the normal group. Multiple regression logistic analysis of: age, sex, smoking, glucosylated hemoglobin, duration of diabetes and type of therapy, did not show any correlation of these parameters with the above ratios. This study shows that coronary flow reserve, as measured with transesophageal echocardiography-Doppler, is severely impaired in normotensive patients with type II diabetes, with relatively short duration of the disease.

Stress echocardiography using adenosine combined with nitroglycerin-dobutamine in the detection of viable myocardium in patients with previous myocardial infarction.

The aim of this study was to assess the value of adenosine (A) and the combination of nitroglycerin (N) with dobutamine (D) stress echocardiography (SE) in the identification of viable myocardium. The clinical and electrocardiographic (ECG) effects of both tests were also evaluated. Fifty-two coronary artery disease patients, aged 56.4 +/- 8 years, with left ventricular dysfunction due to a previous myocardial infarction (mean ejection fraction: 49 +/- 8%) were included in the study. Cardiac catheterization was performed in all patients before A (140 micrograms/kg/minute for five minutes) and the combination of N with D (5-10 micrograms/kg/minute) stress echocardiography. On the echocardiogram, the left ventricle was divided into 16 segments and wall motion was graded semiquantitatively from 1 (normal) to 4 (dyskinesia). The echocardiographic index was also estimated. A segment was considered viable during A infusion when resting asynergy showed deterioration of one grade or more. In contrast, segmental viability was considered to be present during the combination of N with D infusion when resting asynergy showed improvement of one grade or more. A thallium 201 single photon emission computed tomography (SPECT) with reinjection was performed as reference standard for the identification of viable myocardium. Stress echocardiography during infusion of A was associated with short-duration angina attacks in 3 (5.8%) patients and transient complete atrioventricular (AV) block in 1 (1.9%), whereas during the combination of N with D infusion, 6 (11.5%) patients experienced ventricular bigeminy lasting for a short period. ST segment elevation greater than 1 mm was recorded in those leads having a Q wave, in 19 (36.5%) patients. In 10 of these 19 (52.6%), viable myocardium was present in SPECT, as it was in 33 patients (63.5%) having no ST segment elevation (P = NS). Of a total of 832 segments that were graded during A-SE, 276 exhibited resting asynergy and the remaining 556 had normal motion and thickening at rest. The echocardiographic index during A infusion increased from 1.52 +/- 0.22 to 1.71 +/- 0.24 (P < 0.001), whereas during D and N infusion it decreased from 1.53 +/- 0.31 to 1.30 +/- 0.42 (P < 0.001). With SPECT considered as the gold standard for the identification of viable myocardium, sensitivity, specificity, and positive and negative predictive values of A-SE in detecting viable myocardium were 54%, 86%, 65% and 80%, respectively. The respective values for the combination of nitroglycerin with D-SE were 91%, 89%, 78%, and 96%, respectively. Stress echocardiography during A, and the combination of N with D, constitute safe methods in the identification of viable myocardium. The detection of ST segment elevation in the ECG leads with a Q wave during the combined infusion of nitroglycerin and dobutamine is not related to the presence of viable myocardial tissue. The A-SE provide moderate diagnostic accuracy, while the combination of N with D during SE is much superior in detecting viable myocardium.