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The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women had 62% and 59% higher S-metoprolol AUC0-[infinity] and 26% and 71% lower CL/F, respectively, compared to men with the same phenotype (all Ps < .05 women compared to men). These differences dissipated on body weight (WT) correction. Women (especially PMs) experienced greater negative chronotropic effects of metoprolol than men (P < .0001 women compared to men). Diphenhydramine coadministration increased S-metoprolol AUC by 84% in EM women and 45% in EM men (P < .009 women compared to men). In the diphenhydramine arm, sex differences in pharmacokinetics persisted even after WT correction, resulting in greater negative chronotropic effects in women (all Ps < .05 women compared to men). Metoprolol dose should be adjusted for body weight, particularly in women. Coadministration of a CYP2D6 inhibitor such as diphenhydramine, by a patient at similar doses in the 2 sexes, could result in a greater inhibition of clearance of CYP2D6 substrates with a resulting higher risk of pronounced pharmacological and adverse effects in women compared to men. [ABSTRACT FROM AUTHOR]

Objective: The accuracy of E/E' ratio has not been validated in atrial fibrillation (AF). The objective of this study is to compare the accuracy of the E/E' ratio averaged over a sample of 10 cardiac cycles and E/E' ratio obtained in the cycle with the longest RR interval for the estimation of wedge pressure in patients with AF using a simultaneous pulmonary artery occlusive pressure measured with a Swan-Ganz catheter. Design: Twenty-four consecutive patients with AF with a Swan-Ganz catheter were recruited in this study. The majority of patients (92%) were in the early postoperative phase of cardiac surgery. Results: The best sensitivity and specificity was reached with E/E' ratio in the medial position using the one-beat method; E/E' ratio >/=16 with one beat predicts a wedge pressure >15 mmHg with a sensitivity and specificity of 91% and 85%, respectively. Conclusions: Measuring E/E' ratio using the one-beat method is a simple and clinically accurate way to estimate wedge pressure in patients with AF. [ABSTRACT FROM AUTHOR]

Objectives: We sought to determine the impact of valve prosthesis-patient mismatch (PPM) on pulmonary arterial (PA) pressure after mitral valve replacement (MVR). Background: Pulmonary arterial hypertension is a serious complication of mitral valve disease, and it is a major risk factor for poor outcome after MVR. We hypothesized that valve PPM might be a determinant of PA hypertension after MVR. Methods: Systolic PA pressure was measured by Doppler echocardiography in 56 patients with normally functioning mitral prosthetic valves. Mitral valve effective orifice area (EOA) was determined by the continuity equation and indexed for body surface area. Results: Thirty patients (54%) had PA hypertension defined as systolic PA pressure >40 mm Hg, whereas 40 patients (71%) had PPM defined as an indexed EOA < or =1.2 cm(2)/m(2). There was a significant correlation (r = 0.64) between systolic PA pressure and indexed EOA. The average systolic PA pressure and prevalence of PA hypertension were 34 +/- 8 mm Hg and 19% in patients with no PPM versus 46 +/- 8 mm Hg and 68% in patients with PPM (p < 0.001). In multivariate analysis, the indexed EOA was by far the strongest predictor of systolic PA pressure. Conclusions: Persistent PA hypertension is frequent after MVR and strongly associated with the presence of PPM. The clinical implications of these findings are important given that PPM can largely be avoided by using a simple prospective strategy at the time of operation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the effect of systemic arterial hypertension on the indices of aortic stenosis (AS) severity. METHODS: A severe supravalvar AS was created in 24 pigs. The maximum and mean pressure gradients across the stenosis were measured by Doppler echocardiography and by catheterisation. Both echocardiography and catheter data were used to calculate stenosis effective orifice area, energy loss coefficient, and peak systolic left ventricular wall stress. Measurements were taken both at normal aortic pressures and during hypertension induced by banding of the distal thoracic aorta in 14 pigs and by intravenous administration of phenylephrine in 10 pigs. RESULTS: During hypertension, systemic arterial resistance downstream from the stenosis increased greatly (all animals: 71 (40)%), whereas total systemic arterial compliance decreased significantly (-38 (21)%). Hypertension resulted in a moderate increase in effective orifice area (29 (14)%) and energy loss coefficient (25 (17)%) and substantial decreases in catheter gradients (maximum: -40 (20)%; mean: -43 (20)%; peak to peak: -70 (23)%) and Doppler gradients (maximum: -35 (17)%; mean: -37 (16)%). In multivariate analysis, peak to peak gradient was significantly (p < 0.001) related to the energy loss coefficient, mean flow rate, and arterial compliance, whereas maximum and mean catheter gradients were related only to the energy loss coefficient and flow rate. Of major importance, maximum systolic left ventricular wall stress increased greatly during hypertension (43 (23)%). CONCLUSIONS: The severity of AS may be partially masked by the presence of coexisting hypertension. The markers of AS severity should thus be interpreted with caution in hypertensive patients and be re-evaluated when the patient is in a normotensive state. [ABSTRACT FROM AUTHOR]

Objectives: This study examined the effect of aspirin on the risk of embolic events in infective endocarditis (IE).Background: Embolism is a major complication of IE, and studies in animal models have shown that platelet inhibition with aspirin can lead to more rapid vegetation resolution and a lower rate of embolic events.Methods: We conducted a randomized, double-blinded, placebo-controlled trial of aspirin treatment (325 mg/day) for four weeks in patients with IE to test the hypothesis that the addition of aspirin would reduce the incidence of clinical systemic embolic events. Patients with perivalvular abscess were excluded. Serial cerebral computed tomograms and transesophageal echocardiograms were obtained in a subset of patients.Results: During the four-year study period, 115 patients were enrolled: 60 assigned to aspirin and 55 assigned to placebo. Embolic events occurred in 17 patients (28.3%) on aspirin and 11 patients (20.0%) on placebo, with an odds ratio (OR) of 1.62 (95% confidence interval [CI] 0.68 to 3.86, p = 0.29). There was a trend toward a higher incidence of bleeding in the patients taking aspirin versus placebo (OR 1.92, 95% CI 0.76 to 4.86, p = 0.075). Development of new intracranial lesions was similar in both groups. Aspirin had no effect on vegetation resolution and valvular dysfunction.Conclusions: In endocarditis patients already receiving antibiotic treatment, the addition of aspirin does not appear to reduce the risk of embolic events and is likely associated with an increased risk of bleeding. Aspirin is not indicated in the early management of patients with IE. [ABSTRACT FROM AUTHOR]

Twenty-six patients with severe pure mitral stenosis underwent Doppler echocardiographic examination and cardiac catheterization within the same day before the realization of mitral valve balloon valvuloplasty. Net atrioventricular compliance estimated by Doppler echocardiography from the ratio of mitral valve effective orifice area and E-wave downslope was a major independent determinant of left atrial and pulmonary arterial pressures measured by catheterization. [ABSTRACT FROM AUTHOR]

Objective: This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS)., Methods: Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1-4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild-moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (V peak ), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a)., Results: Immunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised V peak (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised V peak (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a)., Conclusion: ApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild-moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death., Trial Registration: NCT00800800., Competing Interests: Competing interests: J-PD has served as a speaker for Abbott Laboratories, AstraZeneca, Solvay Pharma, GlaxoSmithKline, and Pfizer Canada, Inc.; has received research funding from Eli Lilly Canada; and has served on the advisory boards of Novartis, Theratechnologies, Torrent Pharmaceuticals Ltd., and Sanofi-Aventis. PM has a patent application on the use of Lp-PLA2 inhibitors in the treatment of AS. BA has received research funding from Ionis Pharmaceuticals, Merck and Pfizer. ST and JLW are co-inventors and receive royalties from patents owned by UCSD on oxidation-specific antibodies and of biomarkers related to oxidised lipoproteins and are co-founders of Oxitope, Inc. ST is a consultant to Boston Heart Diagnostics, a co-founder of Oxitope, Inc. and has a dual appointment at UCSD and Ionis Pharmaceuticals. JLW is a consultant to Ionis Pharmaceuticals and a co-founder of Oxitope, Inc., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The objective of this study was to determine the prognostic value of combined measures of B-type natriuretic peptide (BNP) and high-sensitivity cardiac troponin T (hsTnT) in patients with low-flow, low-gradient aortic stenosis (LF-LG AS) who had either a preserved or reduced left ventricular ejection fraction (LVEF)., Background: An elevated BNP level is associated with increased risk of mortality in patients with LF-LG AS. The incremental prognostic value of hsTnT in these patients is unknown., Methods: Ninety-eight patients (74 ± 10 years; 75% men) with LF-LG AS (LVEF <50% and/or stroke volume index <35 ml/m 2 , mean gradient <40 mm Hg, indexed aortic valve area <0.6 cm 2 /m 2 ) who were prospectively enrolled in the TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study were included. The cohort was divided into 3 groups according to BNP and hsTnT levels: group A: BNP <550 pg/ml and hsTnT <15 ng/l; group B: BNP ≥550 pg/ml or hsTnT ≥15 ng/l; and group C: BNP ≥550 pg/ml and hsTnT ≥15 ng/l. The primary endpoint was all-cause mortality., Results: Twenty-seven patients (27%) were in group A, 39 (40%) were in group B, and 32 (33%) were in group C. During a median follow-up of 2.8 years, 43 patients died. Two-year mortality was higher in group C (41 ± 9%) than in group B (23 ± 7%) and group A (5 ± 4%) (p = 0.002). In group B, there was no significant difference in 2-year mortality rates between the subgroup with hsTnT ≥15 ng/l (n = 29) and the subgroup with BNP ≥550 pg/ml (n = 10) (26 ± 9% vs. 11 ± 10%, respectively; p = 0.21). In multivariable analysis adjusted for age, type of treatment (aortic valve replacement vs. conservative therapy), coronary artery disease, and LVEF, being in group C remained independently associated with an increased risk of mortality (hazard ratio [HR]: 4.25; p = 0.023), and group B tended to have higher mortality (HR: 3.63; p = 0.058) compared with group A., Conclusions: This study demonstrated the usefulness of combined measures of BNP and hsTnT to enhance risk stratification in patients with LF-LG AS. Patients with elevation of both BNP and hsTnT had a markedly increased risk of mortality. (Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis [TOPAS]; NCT01835028)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies reported that middle-aged patients with atherogenic lipoprotein-lipid profile exhibit faster progression of aortic valve stenosis (AS). The ratio of apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) reflects the balance between atherogenic and anti-atherogenic lipoproteins. The aim of this study was to examine the association between apoB/apoA-I ratio and AS hemodynamic progression and to determine whether this association varies according to age., Methods and Results: A total of 159 patients (66±13 years, 73% men) with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. Hemodynamic progression of AS was determined by the change in peak aortic jet velocity (V peak ) measured by Doppler-echocardiography between baseline and 2-year follow-up. Patients in the top tertile of apoB/apoA-I ratio (≥0.62) had a faster progression rate of AS compared with those in the bottom/mid tertiles (V peak progression: 0.30 [0.09-0.49] versus 0.16 [0.01-0.36] m/s, P =0.02). There was a significant interaction ( P =0.007) between apoB/apoA-I ratio and age. Among younger patients (ie, aged <70 years; median value of the cohort), those in the top tertile of apoB/apoA-I ratio had a 3.4-fold faster AS progression compared with those in the bottom/mid tertiles (V peak progression: 0.34 [0.13-0.69] versus 0.10 [-0.03-0.31] m/s, P =0.002), whereas there was no significant difference between tertiles in the subgroup of older patients ( P =0.83). After comprehensive adjustment, higher apoB/apoA-I ratio was significantly associated with faster AS progression in the subset of younger patients (all, standardized β≥0.36; P ≤0.01)., Conclusions: Higher apoB/apoA-I ratio is significantly associated with faster hemodynamic progression of AS in the younger patients. These findings suggest that atherogenic lipid factors may play a crucial role in the pathogenesis of AS in younger patients, but may be are less important in older patients., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01679431., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Aims: The objective of this study was to examine the association between the different patterns of left ventricular (LV) remodelling/hypertrophy on all-cause and cardiovascular mortality in patients with aortic stenosis (AS)., Methods and Results: In total, 747 consecutive patients (69 ± 14 years, 57% men) with AS and preserved LV ejection fraction were included in this study. According to LV mass index and relative wall thickness, patients were classified into four LV patterns: normal, concentric remodelling (CR), concentric hypertrophy (CH), and eccentric hypertrophy (EH). One hundred and sixteen patients (15%) had normal pattern, 66 (9%) had EH, 169 (23%) had CR, and 396 (53%) had CH. During a median follow-up of 6.4 years, 339 patients died (242 from cardiovascular causes). CH was associated with higher risk of all-cause mortality compared with the three other LV patterns (all P < 0.05). After multivariable adjustment, CH remained associated with higher risk of mortality (HR = 1.27, 95% CI 1.01-1.61, P = 0.046). There was a significant interaction (P < 0.05) between sex and CH with regards to the impact on mortality: CH was associated with worse outcome in women (P = 0.0001) but not in men (P = 0.22). In multivariable analysis, CH remained associated with higher risk of worse outcome in women (HR = 1.56, 95% CI 1.08-2.24, P = 0.018)., Conclusions: This study shows that CH was independently associated with increased risk of mortality in AS patients with preserved ejection fraction. This association was observed in women but not in men. The pattern of LV remodelling/hypertrophy should be integrated in the risk stratification process in patients with AS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background: The timing of mitral valve surgery in asymptomatic patients with primary mitral regurgitation (MR) is controversial. We hypothesized that the forward left ventricular (LV) ejection fraction (LVEF; ie, LV outflow tract stroke volume divided by LV end-diastolic volume) is superior to the total LVEF to predict outcomes in MR. The objective of this study was to examine the association between echocardiographic parameters of MR severity and LV function and outcomes in patients with MR., Methods and Results: The clinical and Doppler-echocardiographic data of 278 patients with ≥mild MR and no class I indication of mitral valve surgery at baseline were retrospectively analyzed. The primary study end point was the composite of mitral valve surgery or death. During a mean follow-up of 5.4±3.2 years, there were 147 (53%) events: 96 (35%) MV surgeries and 66 (24%) deaths. Total LVEF and global longitudinal strain were not associated with the occurrence of events, whereas forward LVEF ( P <0.0001) and LV end-systolic diameter ( P =0.0003) were. After adjustment for age, sex, MR severity, Charlson probability, coronary artery disease, and atrial fibrillation, forward LVEF remained independently associated with the occurrence of events (adjusted hazard ratio: 1.09, [95% confidence interval]: 1.02-1.17 per 5% decrease; P =0.01), whereas LV end-systolic diameter was not ( P =0.48)., Conclusions: The results of this study suggest that the forward LVEF may be superior to the total LVEF and LV end-systolic diameter to predict outcomes in patients with primary MR. This simple and easily measurable parameter may be useful to improve risk stratification and select the best timing for intervention in patients with primary MR., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background and Aims: Elevated levels of lipoprotein(a) [Lp(a)] and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) predict the progression of pre-existing mild-to-moderate calcific aortic valve stenosis (CAVS). Whether indirect markers of oxidation-specific epitopes (OSE) are also predictive is not known. The association between IgG and IgM autoantibodies and malondialdehyde-modified low density lipoprotein (MDA-LDL) and IgG and IgM apolipoprotein B immune complexes (apoB-IC), and the hemodynamic progression rate of CAVS was determined in the ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin, NCT00800800) trial., Methods: Plasma levels of IgG and IgM MDA-LDL and apoB-IC were measured in 220 patients with mild-to-moderate CAVS from the ASTRONOMER trial. The endpoint of this study was the progression rate of CAVS, measured by the annualized increase in peak aortic jet velocity (V peak ) over a median follow-up of 3.5 [2.9-4.5] years., Results: There was no difference in the progression rate of CAVS across tertiles of IgG and IgM MDA-LDL and apoB-IC levels (all p > 0.05). After multivariable analysis, no marker reached significance level to predict faster CAVS progression or need for aortic valve replacement (all p > 0.05). There was no interaction between the OSE antibody titers and plasma levels of Lp(a) or OxPL-apoB, as well as age, with regards to the progression rate of CAVS., Conclusions: Autoantibody titers to MDA-LDL and apoB-IC, which are an indirect measurement of OSE, unlike direct measurements of OxPL-apoB or their major lipoprotein carrier Lp(a), do not predict the progression of CAVS or need for AVR., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: Hypertension is highly prevalent in patients with aortic stenosis (AS) and is associated with worse outcomes. The current prospective study assessed the impact of systolic hypertension (SHPT) on the progression of aortic valve calcification (AVC) measured by multidetector computed tomography (MDCT) in patients with AS., Methods and Results: The present analysis includes the first series of 101 patients with AS prospectively recruited in the PROGRESSA study. Patients underwent comprehensive Doppler echocardiography and MDCT exams at baseline and after 2-year follow-up. AVC and coronary artery calcification (CAC) were measured using the Agatston method. Patients with SHPT at baseline (i.e. systolic blood pressure ≥140 mmHg; n = 37, 37%) had faster 2-year AVC progression compared with those without SHPT (i.e. systolic blood pressure <140 mmHg) (AVC median [25th percentile-75th percentile]: +370 [126-824] vs. +157 [58-303] AU; P = 0.007, respectively). Similar results were obtained with the analysis of AVC progression divided by the cross-sectional area of the aortic annulus (AVC density : +96 [34-218] vs. +45 [14-82] AU/cm 2 , P = 0.01, respectively). In multivariable analysis, SHPT remained significantly associated with faster progression of AVC or AVC density (all P = 0.001). There was no significant difference between groups with respect to progression of CAC (+39 [3-199] vs. +41 [0-156] AU, P = 0.88)., Conclusion: This prospective study shows for the first time that SHPT is associated with faster AVC progression but not with CAC progression in AS patients. These findings provide further support for the elaboration of randomized clinical trials to assess the efficacy of antihypertensive medication to slow the stenosis progression in patients with AS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objective: To evaluate the effect of age and aortic valve anatomy (tricuspid (TAV) vs bicuspid (BAV) aortic valve) on the relationship between the aortic valve calcification (AVC) and the haemodynamic parameters of aortic stenosis (AS) severity., Methods: Two hundred patients with AS and preserved left ventricular ejection fraction were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study and underwent a comprehensive Doppler echocardiography and multidetector CT (MDCT). Mean transvalvular gradient (MG) measured by Doppler echocardiography was used to assess AS haemodynamic severity and AVC was evaluated by MDCT using the Agatston method and indexed to the left ventricular outflow tract area to obtain AVC density (AVCd). All analyses were adjusted for sex., Results: Thirty-nine patients had a BAV and 161 a TAV. Median age was 51 and 72 years for BAV and TAV patients, respectively. There was a modest correlation between MG and AVCd (ρ=0.51, p<0.0001) in the whole cohort. After dichotomisation for valve anatomy, there was a good correlation between AVCd and MG in the TAV group (ρ=0.61, p<0.0001) but weak correlation in the BAV group (ρ=0.32, p=0.046). In the TAV group, the strength of the AVCd-MG correlation was similar in younger (<72 years old; ρ=0.59, p<0.0001) versus older (≥72 years old; ρ=0.61, p<0.0001) patients. In the BAV group, there was no correlation between AVCd and MG in younger patients (<51 years old; ρ=0.12, p=0.65), whereas there was a good correlation in older patients (≥51 years old; ρ=0.55, p=0.009). AVCd (p=0.005) and age (p=0.02) were both independent determinants of MG in BAV patients while AVCd (p<0.0001) was the only independent determinant of MG in TAV patients., Conclusions: In patients with TAV as well as in older patients with BAV, AVCd appears to be the main factor significantly associated with the haemodynamic severity of AS and so it may be used to corroborate AS severity in case of uncertain or discordant findings at echocardiography. However, among younger patients with BAV, some may have a haemodynamically significant stenosis with minimal AVCd. The results of MDCT AVCd should thus be interpreted cautiously in this subset of patients., Trial Registration Number: NCT01679431; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)