Asymptomatic Severe and Moderate Aortic Stenosis:Time for Appraisal of Treatment Indications

Over the last decades, we have witnessed considerable improvements in diagnostics and risk stratification of patients with significant aortic stenosis (AS), paralleled by advances in operative and anesthetic techniques. In addition, accumulating evidence points to the potential benefit of early valve replacement in such patients prior to the onset of symptoms. In parallel, interventional randomized trials have proven the benefit of transcatheter aortic valve replacement in comparison to a surgical approach to valve replacement over a broad risk spectrum in symptomatic patients with AS. This article reviews contemporary management approaches and scrutinizes open questions regarding timing and mode of intervention in asymptomatic patients with severe AS. We also discuss the challenges surrounding the management of symptomatic patients with moderate AS as well as emerging dilemmas related to the concept of a life-long treatment strategy for patients with AS.</p

In-stent neoatherosclerosis: Are first generation drug eluting stents different than bare metal stents? An optical coherence tomography study

Purpose : In-stent neoatherosclerosis has been recognised in pathologic specimens of bare metal stents (BMS), and recently in first generation drug eluting stents (1st-DES), as well. However, in vivo data are scarce. By optical coherence tomography, we investigated the incidence and morphological characteristics of neoatherosclerosis (NA) very late after BMS or 1st-DES implantation. Methods : From 1/1/2007 to 31/1/2012, 52 patients from two institutions underwent >24 months follow-up OCT assessment of a BMS or a 1st-DES. NA was characterized using criteria for native atherosclerosis. Results : BMS had longer follow-up interval but no differences in clinical presentation at follow-up. No significant differences were evident in the incidence of NA, neointimal rupture, lipid content, neovascularization or macrophage infiltration between BMS and 1st-DES. There was however a trend for lower fibrous cap thickness (FCT) and for higher calcification in BMS. 1st-DES with neoatherosclerosis had longer interval from implantation compared to 1st-DES with homogeneous coverage, but there was no difference for BMS with or without neoatherosclerosis. Conclusions : The incidence and morphological characteristics of NA are similar between 1st-DES and BMS of more prolonged follow-up. Our findings suggest a time-dependent pattern in the incidence of NA in 1st-DES with 2-11 years follow-up

Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial.

peer reviewedAIMS: The SEISMIC study was an open-label, prospective, randomised study to assess the safety and feasibility of percutaneous myoblast implantation in heart failure patients with implanted cardioverter-defibrillators (ICD). METHODS AND RESULTS: Patients were randomised 2:1 to autologous skeletal myoblast therapy vs. optimal medical treatment. The primary safety end-point was defined as the incidence of procedural and device related serious adverse events, whereas the efficacy endpoints were defined as the change in global LVEF by MUGA scan, change in NYHA classification of heart failure and in the distance achieved during a six-minute walk test (6MW) at 6-month follow-up. Forty subjects were randomised to the treatment arm (n=26), or to the control arm (n=14). There were 12 sustained arrhythmic events and one death after episodes of ventricular tachycardia (VT) in the treatment group and 14 events in the control group (P=ns). At 6-month follow-up, 6MW distance improved by 60.3+/-54.1?meters in the treated group as compared to no improvement in the control group (0.4+/-185.7?meters; P=ns). In the control group, 28.6% experienced worsening of heart failure status (4/14), while 14.3% experienced an improvement in NYHA classification (2/14). In the myoblast-treatment arm, one patient experienced a deterioration in NYHA classification (8.0%), whereas five patients improved one or two classes (20.0%; P=0.06). However, therapy did not improve global LVEF measured by MUGA at 6-month follow-up. CONCLUSIONS: These data indicate that implantation of myoblasts in patients with HF is feasible, appears to be safe and may provide symptomatic relief, though no significant effect was detected on global LVEF

Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency

Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models

Computed tomography predictors of mortality, stroke and conduction disturbances in women undergoing TAVR: A sub-analysis of the WIN-TAVI registry

Background: Aortic valve calcification patterns were associated with short- and long-term outcomes in previous small observational datasets of patients undergoing transcatheter aortic valve implantation (TAVI). The specific impact of multi detector-row computed tomography (MDCT) findings on outcomes in women has not been reported. We sought to describe the associations between MDCT characteristics and clinical outcomes in a registry of 547 women undergoing TAVI. Methods: WIN-TAVI is the first all-female registry to study the safety and effectiveness of TAVI in women (n = 1019). Thirteen sites participated in the MDCT sub-study and contributed pre-TAVI MDCT studies in 547 consecutive subjects. All MDCT data were analyzed in an independent core lab blinded to clinical outcomes. Key measurements included number of valve leaflets, aortic annulus area and perimeter, left and right coronary artery height, aortic cusp calcium volume, commissural calcification and left ventricular outflow tract (LVOT) calcification. Calcium volume of the aortic valvular complex was quantified using a threshold relative to patient-specific contrast attenuation in the arterial blood pool. We examined univariate and multivariate associations between ECG-gated contrast MDCT characteristics and 1-year mortality or stroke, new pacemaker implantation and new onset atrial fibrillation (AF). Results: The CT sub-study sample had a mean age of 82.8 ± 6.3 years, mean logistic EuroSCORE of 17.8 ± 11.3%, and mean STS score of 8.2 ± 7.4%. Transfemoral access was used in 89.6% of patients. After multivariate adjustment, moderate or severe LVOT calcification was an independent predictor of 1-year mortality or stroke (HR = 1.91; 95% CI: 1.11–3.30; p = 0.02). Calcium volume in the right coronary cusp was an independent predictor of new pacemaker (HR = 1.18 per 100 m3 increment; p = 0.04), whereas calcium volume of the non-coronary cusp had a protective effect (HR = 0.78 per 100 mm3 increment; p = 0.004). Severe calcification of the non-coronary/right-coronary commissure was an independent predictor of new AF (HR = 5.1; p = 0.008). Conclusion: Computed tomography provides important prognostic information in women undergoing TAVI. Moderate or severe LVOT calcification is associated to an almost two-fold increased risk of mortality or stroke at one year. Different calcification patterns of the aortic valve may predict diverse rhythm abnormalities

Acute and 30-Day Outcomes in Women After TAVR: Results From the WIN-TAVI (Women's INternational Transcatheter Aortic Valve Implantation) Real-World Registry

The study sought to examine the safety and performance of transcatheter aortic valve replacement (TAVR) using an all-female registry and to further explore the potential impact of female sex-specific characteristics on clinical outcomes after TAVR

1-Year Clinical Outcomes in Women After Transcatheter Aortic Valve Replacement: Results From the First WIN-TAVI Registry

Objectives This study sought to examine the safety and performance of contemporary transcatheter aortic valve replacement (TAVR) in an exclusive all-women TAVR population, and to further investigate the potential impact of female sexâ\u80\u93specific characteristics on composite 1-year clinical outcomes. Background Women comprise â\u89¥50% patients undergoing TAVR. Several data have shown the noninferiority of TAVR compared with surgical aortic valve replacement for symptomatic significant aortic stenosis, but no study so far has been specifically powered to detect differences by sex. Methods The WIN-TAVI (Women's INternational Transcatheter Aortic Valve Implantation) registry is a multinational, prospective, observational registry of women undergoing TAVR for significant aortic stenosis, across 18 sites in Europe and 1 site in the United States, between January 2013 and December 2015. The primary Valve Academic Research Consortium (VARC)-2 efficacy endpoint was a composite of mortality, stroke, myocardial infarction, hospitalization for valve-related symptoms or heart failure or valve-related dysfunction beyond 30 days. Secondary endpoints included composite 1-year death or stroke. Predictors of 1-year outcomes were determined using Cox regression methods. Results A total of 1,019 intermediate to high-risk women, with mean age 82.5 ± 6.3 years, mean European System for Cardiac Operative Risk Evaluation (EuroSCORE) I 17.8 ± 11.7% and mean Society of Thoracic Surgeons score 8.3 ± 7.4% were enrolled. TAVR was performed via transfemoral access in 90.6% and new-generation devices were used in 42.1%. The primary VARC-2 efficacy composite endpoint occurred in 111 (10.9%) patients beyond 30 days and in 167 (16.5%) patients at 1 year. The incidence of 1-year death or stroke was 13.9% (n = 141). Death occurred in 127 (12.5%) patients and stroke in 22 (2.2%) patients. Prior coronary revascularization (hazard ratio [HR]: 1.72; 95% confidence interval [CI]: 1.17 to 2.52; p = 0.006) and EuroSCORE I (HR: 1.02; 95% CI: 1.00 to 1.04; p = 0.027) were independent predictors of the VARC-2 efficacy endpoint. Similarly, EuroSCORE I (HR: 1.02; 95% CI: 1.00 to 1.04; p = 0.013), baseline atrial fibrillation (HR: 1.58; 95% CI: 1.07 to 2.33; p = 0.022), and prior percutaneous coronary intervention (HR: 1.50; 95% CI: 1.03 to 2.19; p = 0.035) were independent predictors of 1-year death or stroke. After adjustment, no significant association was observed between history of pregnancy or any sex-specific factors and 1-year TAVR outcomes. Conclusions Intermediate to high-risk women enrolled in this first ever all-women contemporary TAVR registry experienced a 1-year VARC-2 composite efficacy endpoint of 16.5%, with a low incidence of 1-year mortality and stroke. Prior revascularization and EuroSCORE I were independent predictors of the VARC-2 efficacy endpoint, whereas EuroSCORE I, baseline atrial fibrillation, and prior percutaneous coronary intervention were independent predictors of the 1-year death or stroke