BackgroundSignificant (moderate or greater) mitral regurgitation (MR) could augment the hemodynamic effects of aortic valvular diseasein patients with bicuspid aortic valve (BAV), imposing a... Show moreBackgroundSignificant (moderate or greater) mitral regurgitation (MR) could augment the hemodynamic effects of aortic valvular diseasein patients with bicuspid aortic valve (BAV), imposing a greater hemodynamic burden on the left ventricle and atrium, possibly culminating in a faster onset of left ventricular dilation and/or symptoms. The aim of this study was to determine the prevalence and prognostic implications of significant MR in patients with BAV.MethodsIn this large, multicenter, international registry, a total of 2,932 patients (mean age, 48 ± 18 years; 71% men) with BAV were identified. All patients were evaluated for the presence of significant primary or secondary MR by transthoracic echocardiography and were followed up for the end points of all-cause mortality and event-free survival.ResultsOverall, 147 patients (5.0%) had significant primary (1.5%) or secondary (3.5%) MR. Significant MR was associated with all-cause mortality (hazard ratio [HR], 2.80; 95% CI, 1.91-4.11; P < .001) and reduced event-free survival (HR, 1.97; 95% CI, 1.58-2.46; P < .001) on univariable analysis. MR was not associated with all-cause mortality (adjusted HR, 1.33; 95% CI, 0.85-2.07; P = .21) or event-free survival (adjusted HR, 1.10; 95% CI, 0.85-1.42; P = .49) after multivariable adjustment. However, sensitivity analyses demonstrated that significant MR not due to aortic valve disease retained an independent association with mortality (adjusted HR, 1.81; 95% CI, 1.04-3.15; P = .037). Subgroup analyses demonstrated an independent association between significant MR and all-cause mortality for individuals with significant aortic regurgitation (HR, 2.037; 95% CI, 1.025-4.049; P = .042), although this association was not observed for subgroups with significant aortic stenosis or without significant aortic valve dysfunction.ConclusionsSignificant MR is uncommon in patients with BAV. Following adjustment for important confounding variables, significant MR was not associated with adverse prognosis in this large study of patients with BAV, except for the patient subgroup with moderate to severe aortic regurgitation. In addition, significant MR not due to aortic valve disease demonstrated an independent association with all-cause mortality. Show less
BACKGROUND: The prognostic impact of left ventricular ejection fraction (LVEF) in patients with bicuspid aortic valve (BAV) disease has not been previously studied. & nbsp; OBJECTIVES: The... Show moreBACKGROUND: The prognostic impact of left ventricular ejection fraction (LVEF) in patients with bicuspid aortic valve (BAV) disease has not been previously studied. & nbsp; OBJECTIVES: The purpose of this study was to determine the prognostic impact of LVEF in BAV patients according to the type of aortic valve dysfunction. & nbsp; METHODS: We retrospectively analyzed the data collected in 2,672 patients included in an international registry of patients with BAV. Patients were classified according to the type of aortic valve dysfunction: isolated aortic stenosis (AS) (n = 749), isolated aortic regurgitation (AR) (n = 554), mixed aortic valve disease (MAVD) (n = 190), or no significant aortic valve dysfunction (n =1,179; excluded from this analysis). The study population was divided according to LVEF strata to investigate its impact on clinical outcomes. & nbsp; RESULTS: The risk of all-cause mortality and the composite endpoint of aortic valve replacement or repair (AVR) and all-cause mortality increased when LVEF was < 60% in the whole cohort as well as in the AS and AR groups, and when LVEF was < 55% in MAVD group. In multivariable analysis, LVEF strata were significantly associated with increased rate of mortality (LVEF 50%-59%: HR: 1.83 [95% CI: 1.09-3.07]; P = 0.022; LVEF 30%-49%: HR: 1.97 [95% CI: 1.13-3.41]; P = 0.016; LVEF < 30%: HR: 4.20 [95% CI: 2.01-8.75]; P < 0.001; vs LVEF 60%-70%, reference group). & nbsp; CONCLUSIONS: In BAV patients, the risk of adverse clinical outcomes increases significantly when the LVEF is < 60%. These findings suggest that LVEF cutoff values proposed in the guidelines to indicate intervention should be raised from 50% to 60% in AS or AR and 55% in MAVD. (J Am Coll Cardiol 2022;80:1071 & ndash;1084) (c) 2022 by the American College of Cardiology Foundation. Show less
Shitut, S.S.; Shen, M.; Claushuis, B.; Derks, R.J.E.; Giera, M.; Rozen, D.E.; ... ; Kros, A. 2022
Background: Sex-specific thresholds of computed tomography (CT)-derived aortic valve calcification (AVC) or AVC density (AVCd) to identify severe aortic stenosis (AS) have been established in... Show moreBackground: Sex-specific thresholds of computed tomography (CT)-derived aortic valve calcification (AVC) or AVC density (AVCd) to identify severe aortic stenosis (AS) have been established in populations that consisted mainly of Caucasians with a tricuspid aortic valve. The objective of this study was to evaluate the accuracy (i.e., sensitivity and specificity) of previously established thresholds to identify severe AS in patients with bicuspid aortic valve (BAV) and according to ethnicity: Caucasian vs. Asian. Methods: We built a multicenter registry of echocardiographic and CT data collected in BAV patients with at least mild AS and preserved left ventricular ejection fraction from 7 different centers. Anatomic severity of AS obtained by CT-derived AVC and AVCd was compared to hemodynamic severity of AS obtained by echocardiography. Results: Among 485 BAV patients (60% men, 73% Asians), the best thresholds of AVC and AVCd to identify severe AS in BAV patients were 2315 arbitrary units (AU) (sensitivity [Se]/specificity [Spe] = 82/78%) in men, 1103 AU (Se/Spe = 80/82%) in women, and 561 AU/cm2 (Se/Spe = 86/91%) in men, and 301 AU/cm2 (Se/Spe = 83/ 82%) in women, respectively. According to ethnicity, thresholds for severe AS in Caucasian patients were, respectively, in men and women: 2208 AU (Se/Spe = 83/83%) and 1230 AU (Se/Spe = 87/82%) for AVC and 474 AU/cm2 (Se/Spe = 88/83%) and 358 AU/cm2 (Se/Spe = 80/82%) for AVCd. In Asian patients, they were 2582 AU (Se/Spe = 76/78%) and 924 AU (Se/Spe = 84/80%) for AVC and 640 AU/cm2 (Se/Spe = 82/89%) and 255 AU/cm2 (Se/Spe = 86/80%) for AVCd. Conclusions: The optimal thresholds to identify hemodynamically severe AS in BAV patients are similar in Caucasians but appear to be higher in Asian men, compared with thresholds previously reported in tricuspid aortic valve patients. Nonetheless, the thresholds currently proposed in the guidelines have good accuracy and can be applied in BAV patients to confirm AS severity. Show less
This dissertation contains four works during my PhD. Different biomaterials have been designed based on coiled-coil peptides. These biomaterials have a range of applications, inclusing drug... Show moreThis dissertation contains four works during my PhD. Different biomaterials have been designed based on coiled-coil peptides. These biomaterials have a range of applications, inclusing drug delivery, cell sorting to cell-cell fusion. By knowledge-guideddesign and modification, coiled-coil induced membrane fusion systems are expected to achieve drug delivery in vivo. Finally, L-forms obtained by coiled-coil induced fusion of different strains are expected to be an ideal model for studying questions related to the origin of life and novel antibiotics. Show less
Aims In patients with bicuspid aortic valve (BAV) and preserved left ventricular (LV) ejection fraction (EF), the frequency of impaired LV global longitudinal strain (GLS) and its prognostic... Show moreAims In patients with bicuspid aortic valve (BAV) and preserved left ventricular (LV) ejection fraction (EF), the frequency of impaired LV global longitudinal strain (GLS) and its prognostic implications are unknown. The present study evaluated the proportion and prognostic value of impaired LV GLS in patients with BAV and preserved LVEF.Methods and results Five hundred and thirteen patients (68% men; mean age 44 +/- 18 years) with BAV and preserved LVEF (>50%) were divided into five groups according to the type of BAV dysfunction: (i) normal function BAV, (ii) mild aortic stenosis (AS) or aortic regurgitation (AR), (iii) >= moderate isolated AS, (iv) >= moderate isolated AR, and (v) >= moderate mixed AS and AR. LV systolic dysfunction based on 2D speckle-tracking echocardiography was defined as a cut-off value of LVGLS (-13.6%). The primary outcome was aortic valve intervention or all-cause mortality. The proportion of patients with LVGLS <=-13.6% was the highest in the normal BAV group (97%) and the lowest in the group with moderate and severe mixed AS and AR (79%). During a median follow-up of 10 years, 210 (41%) patients underwent aortic valve replacement and 17 (3%) died. Patients with preserved LV systolic function (LVGLS <= -13.6%) had significantly better event-free survival compared to those with impaired LV systolic function (LVGLS > -13.6%). LVGLS was independently associated with increased risk of events (mainly aortic valve replacement): hazard ratio 1.09; P < 0.001.Conclusion Impaired LVGLS in BAV with preserved LVEF is not infrequent and was independently associated with increased risk of events (mainly aortic valve replacement events). Show less
BACKGROUND The optimal timing of intervention in patients with asymptomatic severe aortic stenosis (AS) remains controversial.OBJECTIVES This multicenter study sought to test and validate the... Show moreBACKGROUND The optimal timing of intervention in patients with asymptomatic severe aortic stenosis (AS) remains controversial.OBJECTIVES This multicenter study sought to test and validate the prognostic value of the staging of cardiac damage in patients with asymptomatic moderate to severe AS.METHODS This study retrospectively analyzed the clinical, Doppler echocardiographic, and outcome data that were prospectively collected in 735 asymptomatic patients (71 +/- 14 years of age; 60% men) with at least moderate AS (aortic valve area < 1.5 cm(2)) and preserved left ventricular ejection fraction (>= 50%) followed in the heart valve clinics of 4 high-volume centers. Patients were classified according to the following staging classification: no cardiac damage associated with the valve stenosis (Stage 0), left ventricular damage (Stage 1), left atrial or mitral valve damage (Stage 2), pulmonary vasculature or tricuspid valve damage (Stage 3), or right ventricular damage or subclinical heart failure (Stage 4). The primary endpoint was all-cause mortality.RESULTS At baseline, 89 (12%) patients were classified in Stage 0, 200 (27%) in Stage 1, 341 (46%) in Stage 2, and 105 (14%) in Stage 3 or 4. Median follow-up was 2.6 years (interquartile range: 1.1 to 5.2 years). There was a stepwise increase in mortality rates according to staging: 13% in Stage 0, 25% in Stage 1, 44% in Stage 2, and 58% in Stages 3 to 4 (p < 0.0001). The staging was significantly associated with excess mortality in multivariable analysis adjusted for aortic valve replacement as a time-dependent variable (hazard ratio: 1.31 per each increase in stage; 95% CI: 1.06 to 1.61; p = 0.01), and showed incremental value to several clinical variables (net reclassification index = 0.34; p = 0.003).CONCLUSIONS The new staging system characterizing the extra-aortic valve cardiac damage provides incremental prognostic value in patients with asymptomatic moderate to severe AS. This staging classification may be helpful to identify asymptomatic AS patients who may benefit from elective aortic valve replacement. (C) 2019 by the American College of Cardiology Foundation. Show less
The zwitterionic Streptococcus pneumoniae serotype 1 polysaccharide (Sp1) is an important anchor point for our immune system to act against streptococcal infections. Antibodies can recognize Sp1... Show moreThe zwitterionic Streptococcus pneumoniae serotype 1 polysaccharide (Sp1) is an important anchor point for our immune system to act against streptococcal infections. Antibodies can recognize Sp1 saccharides, and it has been postulated that Sp1 can elicit a T-cell-dependent immune reaction as it can be presented by MHC-II molecules. To unravel the molecular mode of action of this unique polysaccharide we here describe the chemical synthesis of a set of Sp1 fragments, ranging from 3 to 12 monosaccharides in length. We outline a unique synthetic approach to overcome the major synthetic challenges associated with the complex Sp1 structure and provide a stereoselective route of synthesis for the oligosaccharide backbone as well as a strategy to introduce the carboxylic acid functions. Molecular dynamics (MD) simulations together with NMR spectroscopy studies reveal that the oligosaccharides take up helical structures with the nona- and dodecasaccharide completing a full helical turn. The 3D structure of the oligosaccharides coincides with the topology required for good interaction with anti-Sp1 antibodies, which has been mapped in detail using STD-NMR. Our study has revealed the Sp1 nona- and dodecasaccharides as promising synthetic antigens, displaying all (3D) structural elements required to mimic the natural polysaccharide and required to unravel the molecular mode of action of these unique zwitterionic polysaccharides. Show less
