Myocardial Perfusion Reserve but not fibrosis predicts outcomes in initially asymptomatic patients with moderate to severe aortic stenosis : the PRognostic Importance of MIcrovascular Dysfunction in AS study- PRIMID AS

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Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions

INTRODUCTION: Bicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated. AIM: The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations. METHODS: The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease. RESULTS: NOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees. CONCLUSIONS: Pathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Short-term adverse remodeling progression in asymptomatic aortic stenosis.

ObjectivesAortic stenosis (AS) is characterised by a long and variable asymptomatic course. Our objective was to use cardiovascular magnetic resonance imaging (MRI) to assess progression of adverse remodeling in asymptomatic AS.MethodsParticipants from the PRIMID-AS study, a prospective, multi-centre observational study of asymptomatic patients with moderate to severe AS, who remained asymptomatic at 12 months, were invited to undergo a repeat cardiac MRI.ResultsForty-three participants with moderate-severe AS (mean age 64.4 ± 14.8 years, 83.4% male, aortic valve area index 0.54 ± 0.15 cm2/m2) were included. There was small but significant increase in indexed left ventricular (LV) (90.7 ± 22.0 to 94.5 ± 23.1 ml/m2, p = 0.007) and left atrial volumes (52.9 ± 11.3 to 58.6 ± 13.6 ml/m2, p ConclusionsThere is progression in cardiac remodeling with increasing scar burden even in asymptomatic AS. Given the lack of reversibility of LGE post-AVR and its association with long-term mortality post-AVR, this suggests the potential need for earlier intervention, before the accumulation of LGE, to improve the long-term outcomes in AS.</div

Symptom Onset in Aortic Stenosis: Relation to Sex Differences in Left Ventricular Remodeling.

The aim of this study was to establish sex differences in remodeling and outcome in aortic stenosis (AS) and their associations with biomarkers of myocardial fibrosis.The remodeling response and timing of symptoms is highly variable in AS, and sex plays an important role.A total of 174 patients (133 men, mean age 66.2 ± 13.3 years) with asymptomatic moderate to severe AS underwent comprehensive stress cardiac magnetic resonance imaging, transthoracic echocardiography, and biomarker analysis (matrix metalloproteinase [MMP]-2, -3, -7, -8, and -9; tissue inhibitor matrix metalloproteinases-1 and -4; syndecan-1 and -4; and N-terminal pro-B-type natriuretic peptide), and were followed up at 6-month intervals. A primary endpoint was a composite of typical AS symptoms necessitating referral for aortic valve replacement, cardiovascular death, or major adverse cardiovascular events.For a similar severity of AS, male patients demonstrated higher indexed left ventricular (LV) volumes and mass, more concentric remodeling (higher LV mass/volume), a trend to more late gadolinium enhancement (present in 51.1% men vs. 34.1% women; p = 0.057), and higher extracellular volume index than female patients (13.27 [interquartile range (IQR): 11.5 to 17.0] vs. 11.53 [IQR: 10.5 to 13.5] ml/m2, p = 0.017), with worse systolic and diastolic function and higher MMP-3 and syndecan-4 levels, whereas female patients had higher septal E/e'. Male sex was independently associated with indexed LV mass (β = 13.32 [IQR: 9.59 to 17.05]; p < 0.001). During median follow-up of 374 (IQR: 351 to 498) days, a primary outcome, driven by spontaneous symptom onset, occurred in 21.8% of male and 43.9% of female patients (relative risk: 0.50 [95% confidence interval: 0.31 to 0.80]; p = 0.004). Measures of AS severity were associated with the primary outcome in both sexes, whereas N-terminal pro-B-type natriuretic peptide, MMP-3, and mass/volume were only associated in men.In AS, women tolerate pressure overload with less concentric remodeling and myocardial fibrosis but are more likely to develop symptoms. This may be related to higher wall stress and filling pressures in women

The neighbourhood effects of new immigration

Since the early 1990s global migration flows have become larger in scale and more varied in form. In the UK, controversy has surrounded this new phase of migration and it has often been assumed to be having a detrimental affect on the well-being of settled residents. Yet, there is dearth of information about the impacts of new immigration and what evidence does exist is curiously placeless, making it difficult to say anything about local effects. This paper is an attempt to fill this gap in understanding by outlining a framework to support the exploration of neighbourhood effects of new immigration. At its heart lies a commitment to three types of explanation for geographical variations in local experiences of new immigration: the individuals living in a place; the opportunity structures apparent in the local environment; and the sociocultural features of local communities