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

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

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

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

Prognostic Impact of Nutritional Status After Transcatheter Edge-to-Edge Mitral Valve Repair: The MIVNUT Registry

Background Malnutrition is associated with poor prognosis in several cardiovascular diseases. However, its prognostic impact in patients undergoing transcatheter edge-to-edge mitral valve repair (TEER) is not well known. This study sought to assess the prevalence, clinical associations, and prognostic consequences of malnutrition in patients undergoing TEER. Methods and Results A total of 892 patients undergoing TEER from the international MIVNUT (Mitral Valve Repair and Nutritional Status) registry were studied. Malnutrition status was assessed with the Controlling Nutritional Status score. The association of nutritional status with mortality was analyzed with multivariable Cox regression models, whereas the association with heart failure admission was assessed by Fine-Gray models, with death as a competing risk. According to the Controlling Nutritional Status score, 74.4% of patients with TEER had any degree of malnutrition at the time of TEER (75.1% in patients with body mass index <25?kg/m2, 72.1% in those with body mass index ?25?kg/m2). However, only 20% had moderate-severe malnutrition. TEER was successful in most of patients (94.2%). During a median follow-up of 1.6?years (interquartile range, 0.6-3.0), 267 (29.9%) patients died and 256 patients (28.7%) were admitted for heart failure after TEER. Compared with normal nutritional status moderate-severe malnutrition resulted a strong predictor of mortality (adjusted hazard ratio [HR], 2.1 [95% CI, 1.1-2.4]; P<0.001) and heart failure admission (adjusted subdistribution HR, 1.6 [95% CI, 1.1-2.4]; P=0.015). Conclusions Malnutrition is common among patients submitted to TEER, and moderate-severe malnutrition is strongly associated with increased mortality and heart failure readmission. Assessment of nutritional status in these patients may help to improve risk stratification

Standardized Definitions for Bioprosthetic Valve Dysfunction Following Aortic or Mitral Valve Replacement: JACC State-of-the-Art Review.

peer reviewedBioprosthetic valve dysfunction (BVD) and bioprosthetic valve failure (BVF) may be caused by structural or nonstructural valve dysfunction. Both surgical and transcatheter bioprosthetic valves have limited durability because of structural valve deterioration. The main objective of this summary of experts participating in a virtual workshop was to propose standardized definitions for nonstructural and structural BVD and BVF following aortic or mitral biological valve replacement with the goal of facilitating research reporting and implementation of these terms in clinical practice. Definitions of structural BVF, based on valve reintervention or death, underestimate the true incidence of BVF. However, definitions solely based on the presence of high transprosthetic gradient at a given echocardiogram during follow-up overestimate the incidence of structural BVD and BVF. Definitions of aortic or mitral structural BVD must therefore include the confirmation by imaging of permanent structural changes to the leaflets alongside evidence of deterioration in valve hemodynamic function at echocardiography follow-up