Expression profiling of chromatin-modifying enzymes and global DNA methylation in CD4+ T cells from patients with chronic HIV infection at different HIV control and progression states

Abstract Background Integration of human immunodeficiency virus type 1 (HIV-1) into the host genome causes global disruption of the chromatin environment. The abundance level of various chromatin-modifying enzymes produces these alterations and affects both the provirus and cellular gene expression. Here, we investigated potential changes in enzyme expression and global DNA methylation in chronically infected individuals with HIV-1 and compared these changes with non-HIV infected individuals. We also evaluated the effect of viral replication and degree of disease progression over these changes. Results Individuals with HIV-1 had a significant surge in the expression of DNA and histone methyltransferases (DNMT3A and DNMT3B, SETDB1, SUV39H1) compared with non-infected individuals, with the exception of PRMT6, which was downregulated. Some histone deacetylases (HDAC2 and HDAC3) were also upregulated in patients with HIV. Among individuals with HIV-1 with various degrees of progression and HIV control, the group of treated patients with undetectable viremia showed greater differences with the other two groups (untreated HIV-1 controllers and non-controllers). These latter two groups exhibited a similar behavior between them. Of interest, the overexpression of genes that associate with viral protein Tat (such as SETDB1 along with DNMT3A and HDAC1, and SIRT-1) was more prevalent in treated patients. We also observed elevated levels of global DNA methylation in individuals with HIV-1 in an inverse correlation with the CD4/CD8 ratio. Conclusions The current study shows an increase in chromatin-modifying enzymes and remodelers and in global DNA methylation in patients with chronic HIV-1 infection, modulated by various levels of viral control and progression

Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: Analysis of the HIV-2 Belgium and Luxembourg database

BACKGROUND: Guidelines established for the treatment of HIV-1 infection and genotype interpretation do not apply for HIV-2. Data about antiretroviral (ARV) drug efficacy and resistance mutations is scarce. METHODS: Clinical data about HIV-2 infected patients in Belgium and Luxembourg were collected and the effect of ARV therapy on plasma viral load and CD4 counts were analysed. Viral RNA encoding for protease (PR) and reverse transcriptase (RT) from ARV-naive and treated patients were sequenced. RESULTS: Sixty-five HIV-2 infected patients were included in this cohort. Twenty patients were treated with 25 different ARV combinations in a total of 34 regimens and six months after the start of ARV therapy, only one third achieved viral load suppression. All of these successful regimens bar one contained protease inhibitors (PIs). Mean CD4 gains in the group of viral load suppressors and the group of patients treated with PI-containing regimens were respectively significantly higher than in the group of non-suppressors and the group of PI-sparing regimens. The most frequent mutations selected under therapy (compared to HIV-2 ROD) were V71I, L90M and I89V within PR. Within RT, they were M184V, Q151M, V111I and K65R. All of these mutations, except K65R and M184V, were also found in variable proportions in ARV-naive patients. CONCLUSION: Despite a high rate of ARV treatment failure, better virological and immunological results were achieved with PI-containing regimens. The analysis of polymorphic positions and HIV-2 specific mutations selected during therapy showed for the first time that transmission of drug resistant viruses has occurred in Belgium and Luxembourg. The high heterogeneity in ARV combinations reflects a lack of guidelines for the treatment of HIV-2 infection

Impact of Low Flow on the Outcome of High-Risk Patients Undergoing Transcatheter Aortic Valve Replacement

ObjectivesThis study sought to assess the impact of baseline left ventricular (LV) outflow, LV ejection fraction (LVEF), and transvalvular gradient on outcomes following transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis (AS).BackgroundLow flow (i.e., reduced stroke volume index [SVi]) can occur with both reduced and preserved LVEF. Low flow is often associated with low gradient despite severe stenosis and with worse outcomes following surgical aortic valve replacement. However, there are few data about the impact of low flow on outcomes following TAVR.MethodsWe retrospectively analyzed the clinical, Doppler-echocardiographic, and outcome data prospectively collected in 639 patients who underwent TAVR for symptomatic severe AS in 2 Canadian centers.ResultsIn this cohort, 334 (52.3%) patients had a low flow (SVi <35 ml/m2) and these patients had increased 30-day mortality (11.4 vs. 5.9%, p = 0.01), 2-year all-cause mortality (35.3 vs. 30.9%, p = 0.005), and 2-year cardiovascular mortality (25.7 vs. 16.8%, p = 0.01) compared with patients with normal flow. Reduced flow was an independent predictor of 30-day mortality (odds ratio: 1.94, p = 0.026), cumulative all-cause mortality (hazard ratio: 1.27 per 10 ml/m² SVi decrease, p = 0.016), and cumulative cardiovascular mortality (hazard ratio: 1.29 per 10 ml/m² decrease, p = 0.04). Despite significant association in univariable analyses, low LVEF and low mean gradient were not found to be independent predictors of outcomes in multivariable analyses.ConclusionsLow flow but not low LVEF or low gradient is an independent predictor of early and late mortality following TAVR in high-risk patients with severe AS. SVi should be integrated in the risk stratification process of these patients

Sex Differences in Mortality After Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis

ObjectivesThe aim of this study was to examine sex differences in outcome after transcatheter aortic valve replacement (TAVR) with real-world data from 2 large centers in Canada.BackgroundTranscatheter aortic valve replacement is an effective alternative to surgical valve replacement in symptomatic patients with severe aortic stenosis, but the impact of sex on outcomes remains unclear. The PARTNER (Placement of Aortic Transcatheter Valves) 1A trial demonstrated greater benefit of TAVR over surgery in women, but whether this was due to the poorer surgical outcome of women or better TAVR outcome, compared with men, is unknown.MethodsConsecutive patients (n = 641) undergoing TAVR in Vancouver and Quebec City, Canada, were evaluated. Differences in all-cause mortality were examined with Kaplan-Meier estimates, adjusted logistic regression, and proportional hazards models.ResultsWomen comprised 51.3% of the cohort. Balloon-expandable valves were used in 97% of cases, with transapical approach in 51.7 % women and 38.1% men. Women had more major vascular complications (12.4% vs. 5.4%, p = 0.003) and borderline significantly more major/life-threatening bleeds (21.6% vs. 15.8%, p = 0.08). At baseline, women had higher aortic gradients and worse renal function but better ejection fractions. Men had more comorbidities: prior myocardial infarction, prior revascularization, and chronic obstructive pulmonary disease. The adjusted odds ratio for 30-day all-cause mortality favored women, 0.39 (95% confidence interval: 0.19 to 0.80; p = 0.01), and this benefit persisted for 2 years, hazard ratio 0.60 (95% confidence interval: 0.41 to 0.88; p = 0.008).ConclusionsFemale sex is associated with better short- and long-term survival after TAVR. Added to the PARTNER 1A findings, these results suggest TAVR might be the preferred treatment option for elderly women with symptomatic severe aortic stenosis

Revisiting Sex Equality With Transcatheter Aortic Valve Replacement Outcomes A Collaborative, Patient-Level Meta-Analysis of 11,310 Patients

AbstractBackgroundThere has been conflicting clinical evidence as to the influence of female sex on outcomes after transcatheter aortic valve replacement.ObjectivesThe aim of this study was to evaluate the impact of sex on early and late mortality and safety end points after transcatheter aortic valve replacement using a collaborative meta-analysis of patient-level data.MethodsFrom the MEDLINE, Embase, and the Cochrane Library databases, data were obtained from 5 studies, and a database containing individual patient-level time-to-event data was generated from the registry of each selected study. The primary outcome of interest was all-cause mortality. The safety end point was the combined 30-day safety end points of major vascular complications, bleeding events, and stroke, as defined by the Valve Academic Research Consortium when available.ResultsFive studies and their ongoing registry data, comprising 11,310 patients, were included. Women constituted 48.6% of the cohort and had fewer comorbidities than men. Women had a higher rate of major vascular complications (6.3% vs. 3.4%; p < 0.001), major bleeding events (10.5% vs. 8.5%; p = 0.003), and stroke (4.4% vs. 3.6%; p = 0.029) but a lower rate of significant aortic incompetence (grade ≥2; 19.4% vs. 24.5%; p < 0.001). There were no differences in procedural and 30-day mortality between women and men (2.6 % vs. 2.2% [p = 0.24] and 6.5% vs. 6.5% [p = 0.93], respectively), but female sex was independently associated with improved survival at median follow-up of 387 days (interquartile range: 192 to 730 days) from the index procedure (adjusted hazard ratio: 0.79; 95% confidence interval: 0.73 to 0.86; p = 0.001).ConclusionsAlthough women experience more bleeding events, as well as vascular and stroke complications, female sex is an independent predictor of late survival after transcatheter aortic valve replacement. This should be taken into account during patient selection for this procedure

Incidence and Sequelae of Prosthesis-Patient Mismatch in Transcatheter Versus Surgical Valve Replacement in High-Risk Patients With Severe Aortic Stenosis A PARTNER Trial Cohort-A Analysis

AbstractBackgroundLittle is known about the incidence of prosthesis-patient mismatch (PPM) and its impact on outcomes after transcatheter aortic valve replacement (TAVR).ObjectivesThe objectives of this study were: 1) to compare the incidence of PPM in the TAVR and surgical aortic valve replacement (SAVR) randomized control trial (RCT) arms of the PARTNER (Placement of AoRTic TraNscathetER Valves) I Trial cohort A; and 2) to assess the impact of PPM on regression of left ventricular (LV) hypertrophy and mortality in these 2 arms and in the TAVR nonrandomized continued access (NRCA) registry cohort.MethodsThe PARTNER Trial cohort A randomized patients 1:1 to TAVR or bioprosthetic SAVR. Postoperative PPM was defined as absent if the indexed effective orifice area (EOA) was >0.85 cm2/m2, moderate if the indexed EOA was ≥0.65 but ≤0.85 cm2/m2, or severe if the indexed EOA was <0.65 cm2/m2. LV mass regression and mortality were analyzed using the SAVR-RCT (n = 270), TAVR-RCT (n = 304), and TAVR-NRCA (n = 1,637) cohorts.ResultsThe incidence of PPM was 60.0% (severe: 28.1%) in the SAVR-RCT cohort versus 46.4% (severe: 19.7%) in the TAVR-RCT cohort (p < 0.001) and 43.8% (severe: 13.6%) in the TAVR-NRCA cohort. In patients with an aortic annulus diameter <20 mm, severe PPM developed in 33.7% undergoing SAVR compared with 19.0% undergoing TAVR (p = 0.002). PPM was an independent predictor of less LV mass regression at 1 year in the SAVR-RCT (p = 0.017) and TAVR-NRCA (p = 0.012) cohorts but not in the TAVR-RCT cohort (p = 0.35). Severe PPM was an independent predictor of 2-year mortality in the SAVR-RCT cohort (hazard ratio [HR]: 1.78; p = 0.041) but not in the TAVR-RCT cohort (HR: 0.58; p = 0.11). In the TAVR-NRCA cohort, severe PPM was not a predictor of 1-year mortality in all patients (HR: 1.05; p = 0.60) but did independently predict mortality in the subset of patients with no post-procedural aortic regurgitation (HR: 1.88; p = 0.02).ConclusionsIn patients with severe aortic stenosis and high surgical risk, PPM is more frequent and more often severe after SAVR than TAVR. Patients with PPM after SAVR have worse survival and less LV mass regression than those without PPM. Severe PPM also has a significant impact on survival after TAVR in the subset of patients with no post-procedural aortic regurgitation. TAVR may be preferable to SAVR in patients with a small aortic annulus who are susceptible to PPM to avoid its adverse impact on LV mass regression and survival. (The PARTNER Trial: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894

Elevation changes of the Fennoscandian Ice Sheet interior during the last deglaciation

The dynamics of ice sheet interiors during the last deglaciation are poorly constrained, hindering evaluation of ice sheet models. We provide direct evidence of Fennoscandian Ice Sheet (FIS) interior behaviour during deglaciation through surface exposure dating. Our results demonstrate early thinning of the FIS, prior to the Younger Dryas (YD, 12.8‐11.7 ka). Interior thinning in central Norway was concurrent with retreat along the coastline, exposing ice‐free mountainous tracts, potentially as early as 20‐15 ka. The FIS then formed moraines in these ice‐free tracts during the YD. This is contrary to current hypotheses advocating a landscape fully covered by cold, inactive ice during this period. Present empirical and model reconstructions fail to capture rapid interior down‐wastage, increasing uncertainties in ice sheet volume estimates and sea level contributions

Incidence and severity of paravalvular aortic regurgitation with multidetector computed tomography nominal area oversizing or undersizing after transcatheter heart valve replacement with the Sapien 3 : a comparison with the Sapien XT.

Objectives : This study sought to compare the influence of the extent of multidetector computed tomography (MDCT) area oversizing on the incidence of paravalvular aortic regurgitation (PAR) between the Sapien 3 and the Sapien XT transcatheter heart valve (THV) to define a new MDCT sizing guideline suitable for the Sapien 3 platform. Background : The inverse relationship of PAR occurrence and oversizing has been demonstrated for the Sapien XT but the incidence of PAR with comparable oversizing with the Sapien 3 is not known. Methods : Sixty-one prospectively enrolled patients who underwent transcatheter aortic valve replacement with the Sapien 3 THV were compared with 92 patients who underwent transcatheter aortic valve replacement with the Sapien XT THV. Patients were categorized depending on the degree of MDCT area oversizing percentage: undersizing (below 0%), 0% to 5%, 5% to 10%, and above 10%. The primary endpoint was mild or greater PAR on transthoracic echocardiography. Results : Mild or greater PAR was present in 19.7% of patients (12 of 61) in the Sapien 3 group and in 54.3% of patients (50 of 92) in the Sapien XT group (p 10% (p for interaction = 0.54). Moderate or severe PAR rates were also lower in the Sapien 3 group than in the Sapien XT group (3.3% vs. 13.0%, p = 0.04). In the Sapien 3 group, a MDCT area oversizing percentage value of =4.17% was identified as the optimal cutoff value to discriminate patients with or without mild or greater PAR. Conclusions : Our retrospective analysis suggests that the Sapien 3 THV displays significantly lower rates of PAR than does the Sapien XT THV. A lesser degree of MDCT area oversizing may be employed for this new balloon-expandable THV

Tricuspid Valve Academic Research Consortium Definitions for Tricuspid Regurgitation and Trial Endpoints.

Interest in the pathophysiology, etiology, management, and outcomes of patients with tricuspid regurgitation (TR) has grown in the wake of multiple natural history studies showing progressively worse outcomes associated with increasing TR severity, even after adjusting for multiple comorbidities. Historically, isolated tricuspid valve surgery has been associated with high in-hospital mortality rates, leading to the development of transcatheter treatment options. The aim of this first Tricuspid Valve Academic Research Consortium document is to standardize definitions of disease etiology and severity, as well as endpoints for trials that aim to address the gaps in our knowledge related to identification and management of patients with TR. Standardizing endpoints for trials should provide consistency and enable meaningful comparisons between clinical trials. A second Tricuspid Valve Academic Research Consortium document will focus on further defining trial endpoints and will discuss trial design options

Tricuspid Valve Academic Research Consortium Definitions for Tricuspid Regurgitation and Trial Endpoints.

Interest in the pathophysiology, etiology, management, and outcomes of patients with tricuspid regurgitation (TR) has grown in the wake of multiple natural history studies showing progressively worse outcomes associated with increasing TR severity, even after adjusting for multiple comorbidities. Historically, isolated tricuspid valve surgery has been associated with high in-hospital mortality rates, leading to the development of transcatheter treatment options. The aim of this first Tricuspid Valve Academic Research Consortium document is to standardize definitions of disease etiology and severity, as well as endpoints for trials that aim to address the gaps in our knowledge related to identification and management of patients with TR. Standardizing endpoints for trials should provide consistency and enable meaningful comparisons between clinical trials. A second Tricuspid Valve Academic Research Consortium document will focus on further defining trial endpoints and will discuss trial design options