Effect of Transcatheter Aortic Valve Implantation vs Surgical Aortic Valve Replacement on All-Cause Mortality in Patients With Aortic Stenosis: A Randomized Clinical Trial.

Importance: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear. Objective: To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk. Design, Setting, and Participants: In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019. Interventions: TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455). Main Outcomes and Measures: The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation. Results: Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of -2.0% (1-sided 97.5% CI, -∞ to 1.2%; P < .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75]). Conclusions and Relevance: Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year. Trial Registration: isrctn.com Identifier: ISRCTN57819173.

Prognostic impact of impaired left ventricular midwall function during progression of aortic stenosis.

OBJECTIVE: In hypertension, indexes of midwall left ventricular (LV) function may identify patients at higher cardiovascular (CV) risk independent of normal LV ejection fraction (EF). We analyzed the association of baseline and new-onset LV midwall dysfunction with CV outcome in a large population of patients with asymptomatic aortic stenosis (AS). METHODS: One thousand four hundred seventy-eight patients with asymptomatic AS and normal EF (≥50%) at baseline in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study were followed for a median of 4.3 years. LV systolic function was assessed by biplane EF and midwall shortening (MWS, low if <14% in men/16% in women) at baseline and annual echocardiographic examinations. RESULTS: One hundred twenty-three CV deaths and heart failure hospitalizations occurred during follow-up. In Cox analyses, adjusting for age, gender, body mass index, hypertension, EF, AS severity, LV hypertrophy and systemic arterial compliance, low baseline MWS predicted 61% higher risk of a major CV event and a twofold higher risk of death and heart failure hospitalization (P < .05). New-onset low MWS developed in 574 patients, particularly in elderly women with higher blood pressure and more severe AS (P < .05). In time-varying Cox analysis, new-onset low MWS was associated with a twofold higher risk of CV death and heart failure hospitalization, independent of changes over time in EF, AS severity, LV hypertrophy and systemic arterial compliance (P < .05). CONCLUSIONS: Low MWS develops in a large proportion of patients with AS and normal EF during valve disease progression and is a marker of increased CV risk.

Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial.

AIMS: Migraine with aura and patent foramen ovale (PFO) are associated. The Percutaneous Closure of PFO in Migraine with Aura (PRIMA) trial is a multicentre, randomized trial to investigate the effect of percutaneous PFO closure in patients refractory to medical treatment. METHODS: Migraine with aura patients and PFO who were unresponsive to preventive medications were randomized to PFO closure or medical treatment. Both groups were given acetylsalicylic acid 75-100 mg/day for 6 months and clopidogrel 75 mg/day for 3 months. The primary endpoint was reduction in monthly migraine days during months 9-12 after randomization compared with a 3-month baseline phase before randomization. The committee reviewing the headache diaries were blinded to treatment assignment. RESULTS: One hundred and seven patients were randomly allocated to treatment with an Amplatzer PFO Occluder (N = 53) or control with medical management (N = 54). The trial was terminated prematurely because of slow enrolment. Eighty-three patients (40 occluder, 43 control) completed 12-month follow-up. Mean migraine days at baseline were 8 (±4.7 SD) in the closure group and 8.3 (±2.4) in controls. The primary endpoint was negative with -2.9 days after PFO closure vs. -1.7 days in control group (P = 0.17). Patent foramen ovale closure caused five adverse events without permanent sequelae. CONCLUSION: In patients with refractory migraine with aura and PFO, PFO closure did not reduce overall monthly migraine days.

Secondary syphilis presenting with aortitis and coronary ostial occlusion.

Aortitis is an established manifestation of tertiary syphilis. We report a rare case of aortitis with ostial occlusion and left ventricular failure in secondary syphilis. Her management required a true multidisciplinary approach from multiple specialities due to complications of concomitant psychosis and a history of anaphylaxis to penicillin. This case illustrates the complexities of diagnosing and managing a rare presentation of this increasingly prevalent infection.

The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy.

The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We investigate here the role of mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. Mst2(-/-) mice showed no alteration in cardiomyocyte proliferation. However, Mst2(-/-) mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of MST2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the prohypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (Yes-associated protein) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human MST2 gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart.

Prognostic value of energy loss index in asymptomatic aortic stenosis.

BACKGROUND: Aortic valve area index adjusted for pressure recovery (energy loss index [ELI]) has been suggested as a more accurate measure of aortic stenosis (AS) severity, but its prognostic value has not been determined in a prospective study. METHODS AND RESULTS: The relation between baseline ELI and rate of aortic valve events and combined total mortality and hospitalization for heart failure resulting from the progression of AS was assessed by multivariate Cox regression and reclassification analysis in 1563 patients with initial asymptomatic AS in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. During 4.3 years follow-up, a total of 498 aortic valve events and 181 combined total mortalities and hospitalizations for heart failure caused by the progression of AS occurred. In Cox regression analyses, 1-cm(2)/m(2) lower baseline ELI predicted a 2-fold higher risk both for aortic valve events and for combined total mortality and hospitalization for heart failure independently of baseline peak aortic jet velocity or mean aortic gradient and independently of aortic root size (all P<0.05). In reclassification analysis, ELI improved the prediction of aortic valve events by 13% (95% confidence interval, 5-19), whereas the prediction of combined total mortality and hospitalization for heart failure resulting from the progression of AS did not improve significantly. CONCLUSIONS: In asymptomatic AS patients without known atherosclerotic disease or diabetes mellitus, ELI provides independent and additional prognostic information to that derived from conventional measures of AS severity, suggesting that ELI should be measured in such patients. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Stroke in patients with aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study.

BACKGROUND AND PURPOSE: There are limited data on risk stratification of stroke in aortic stenosis. This study examined predictors of stroke in aortic stenosis, the prognostic implications of stroke, and how aortic valve replacement (AVR) with or without concomitant coronary artery bypass grafting influenced the predicted outcomes. METHODS: Patients with mild-to-moderate aortic stenosis enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Diabetes mellitus, known atherosclerotic disease, and oral anticoagulation were exclusion criteria. Ischemic stroke was the primary end point, and poststroke survival a secondary outcome. Cox models treating AVR as a time-varying covariate were adjusted for atrial fibrillation and congestive heart failure, hypertension, age≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years and female sex (CHA2DS2-VASc) scores. RESULTS: One thousand five hundred nine patients were followed for 4.3±0.8 years (6529 patient-years). Rates of stroke were 5.6 versus 21.8 per 1000 patient-years pre- and post-AVR; 429 (28%) underwent AVR and 139 (9%) died. Atrial fibrillation (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.1-6.6), CHA2DS2-VASc score (HR 1.4 per unit; 95% CI, 1.1-1.8), diastolic blood pressure (HR, 1.4 per 10 mm Hg; 95% CI, 1.1-1.8), and AVR with concomitant coronary artery bypass grafting (HR, 3.2; 95% CI, 1.4-7.2, all P≤0.026) were independently associated with stroke. Incident stroke predicted death (HR, 8.1; 95% CI, 4.7-14.0; P<0.001). CONCLUSIONS: In patients with aortic stenosis not prescribed oral anticoagulation, atrial fibrillation, AVR with concomitant coronary artery bypass grafting, and CHA2DS2-VASc score were the major predictors of stroke. Incident stroke was strongly associated with mortality. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Multiparametric cardiovascular magnetic resonance surveillance of acute cardiac allograft rejection and characterisation of transplantation-associated myocardial injury: a pilot study.

BACKGROUND: Serial surveillance endomyocardial biopsies are performed in patients who have recently undergone heart transplantation in order to detect acute cardiac allograft rejection (ACAR) before symptoms occur, however the biopsy process is associated with a number of limitations. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterize graft recovery following transplantation. METHODS: All patients receiving a heart transplant at a single UK centre over a period of 25 months were approached within one month of transplantation. Multiparametric CMR was prospectively performed on the same day as biopsy on four separate occasions (6 weeks, 10 weeks, 15 weeks and 20 weeks post-transplant). CMR included assessment of global and regional ventricular function, myocardial tissue characterization (T1 mapping, T2 mapping, extracellular volume, LGE) and pixel-wise absolute myocardial blood flow quantification. CMR parameters were compared with biopsy findings. As is standard, grade 2R or higher ACAR was considered significant. RESULTS: 88 CMR-matched biopsies were performed in 22 patients. Eight (9%) biopsies in 5 patients demonstrated significant ACAR. Significant ACAR was associated with a reduction in circumferential strain (-12.7±2.5% vs. -13.7±3.6%, p=0.047) but there was considerable overlap between groups. Whilst trends were observed between ACAR and proposed CMR markers of oedema, particularly after adjusting for primary graft dysfunction, differences were not significant. Significant improvements were seen in markers of graft structure and contractility, oedema and microvascular function over the period studied, although few parameters normalised. CONCLUSIONS: This study provides novel insight into the myocardial injury associated with transplantation, and its recovery, however multiparametric CMR was not able to accurately detect ACAR during the early phase post-transplantation.

Voxel-wise quantification of myocardial blood flow with cardiovascular magnetic resonance: effect of variations in methodology and validation with positron emission tomography.

BACKGROUND: Quantitative assessment of myocardial blood flow (MBF) from cardiovascular magnetic resonance (CMR) perfusion images appears to offer advantages over qualitative assessment. Currently however, clinical translation is lacking, at least in part due to considerable disparity in quantification methodology. The aim of this study was to evaluate the effect of common methodological differences in CMR voxel-wise measurement of MBF, using position emission tomography (PET) as external validation. METHODS: Eighteen subjects, including 9 with significant coronary artery disease (CAD) and 9 healthy volunteers prospectively underwent perfusion CMR. Comparison was made between MBF quantified using: 1. Calculated contrast agent concentration curves (to correct for signal saturation) versus raw signal intensity curves; 2. Mid-ventricular versus basal-ventricular short-axis arterial input function (AIF) extraction; 3. Three different deconvolution approaches; Fermi function parameterization, truncated singular value decomposition (TSVD) and first-order Tikhonov regularization with b-splines. CAD patients also prospectively underwent rubidium-82 PET (median interval 7 days). RESULTS: MBF was significantly higher when calculated using signal intensity compared to contrast agent concentration curves, and when the AIF was extracted from mid- compared to basal-ventricular images. MBF did not differ significantly between Fermi and Tikhonov, or between Fermi and TVSD deconvolution methods although there was a small difference between TSVD and Tikhonov (0.06 mL/min/g). Agreement between all deconvolution methods was high. MBF derived using each CMR deconvolution method showed a significant linear relationship (p<0.001) with PET-derived MBF however each method underestimated MBF compared to PET (by 0.19 to 0.35 mL/min/g). CONCLUSIONS: Variations in more complex methodological factors such as deconvolution method have no greater effect on estimated MBF than simple factors such as AIF location and observer variability. Standardization of the quantification process will aid comparison between studies and may help CMR MBF quantification enter clinical use.

The Year in Cardiology 2012: echocardiography.

This brief review focuses on recent developments in the role of echocardiography for illuminating the pathophysiology of cardiac valve disease.

Development and validation of the ASGARD risk score for safe monitoring in asymptomatic nonsevere aortic stenosis.

AIMS: Current guidelines recommend serial echocardiography at minimum 1-2 year intervals for monitoring patients with nonsevere aortic valve stenosis (AS), which is costly and often clinically inconsequential.We aimed to develop and test whether the biomarker-based ASGARD risk score (Aortic Valve Stenosis Guarded by Amplified Risk Determination) can guide the timing of echocardiograms in asymptomatic patients with nonsevere AS. METHODS: The development cohort comprised 1,093 of 1,589 (69%) asymptomatic patients with mild-to-moderate AS who remained event-free one year after inclusion into the SEAS trial. Cox regression landmark analyses with a 2-year follow-up identified the model (ASGARD) with the lowest Akaike information criterion for association to AS-related composite outcome (heart failure hospitalization, aortic valve replacement, or cardiovascular death). Fine-Gray analyses provided cumulative event rates by ASGARD score quartiles. The ASGARD score was internally validated in the remaining 496 patients (31%) from the SEAS-cohort and externally in 71 asymptomatic outpatients with nonsevere AS from six Copenhagen hospitals. RESULTS: The ASGARD score comprises updated measurements of heart rate and age- and sex-adjusted N-terminal pro-brain natriuretic peptide upon transaortic maximal velocity (Vmax) from the previous year. The ASGARD score had high predictive accuracy across all cohorts (external validation: area under the curve: 0.74 [95% CI, 0.62-0.86]), and similar to an updated Vmax measurement. An ASGARD score ≤50% was associated with AS-related event rates ≤5% for a minimum of 15 months. CONCLUSION: The ASGARD score could provide a personalized and safe surveillance alternative to routinely planned echocardiograms, so physicians can prioritize echocardiograms for high-risk patients.

In this study, we developed and examined the potential of the novel ASGARD risk score to tailor personalized follow-up intervals for diagnostic heart scans, incorporating updated heart rate and blood marker measurements along with the heart scan data from the previous year. Patients with the ASGARD risk score within the lowest 50% had a low annual risk of aortic valve-related events (less than 5%) for a minimum of 15 months.In clinical settings, the ASGARD score could provide a personalized and safe monitoring alternative to routine heart scans, prioritizing the diagnostic heart scans for high-risk patients.

Clinical implications of electrocardiographic left ventricular strain and hypertrophy in asymptomatic patients with aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study.

BACKGROUND: The prognostic impact of ECG left ventricular strain and left ventricular hypertrophy (LVH) in asymptomatic aortic stenosis is not well described. METHODS AND RESULTS: Data were obtained in asymptomatic patients randomized to simvastatin/ezetimibe combination versus placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Primary end point was the first of myocardial infarction, nonhemorrhagic stroke, heart failure, aortic valve replacement, or cardiovascular death. The predictive value of ECG left ventricular strain (defined as T-wave inversion in leads V(4) through V(6)) and LVH, assessed by Sokolow-Lyon voltage criteria (R(V5-6)+S(V1) ≥35 mV) and Cornell voltage-duration criteria {[RaVL+S(V3)+(6 mV in women)]×QRS duration ≥2440 mV · ms}, was evaluated by adjustment for other prognostic covariates. A total of 1533 patients were followed for 4.3±0.8 years (6592 patient-years of follow-up), and 627 cardiovascular events occurred. ECG strain was present in 340 patients (23.6%), with LVH by Sokolow-Lyon voltage in 260 (17.1%) and by Cornell voltage-duration product in 220 (14.6%). In multivariable analyses, ECG left ventricular strain was associated with 3.1-fold higher risk of in-study myocardial infarction (95% confidence interval, 1.4-6.8; P=0.004). Similarly, ECG LVH by both criteria predicted, compared with no ECG LVH, 5.8-fold higher risk of heart failure (95% confidence interval, 2.0-16.8), 2.0-fold higher risk of aortic valve replacement (95% confidence interval, 1.3-3.1; both P=0.001), and 2.5-fold higher risk of a combined end point of myocardial infarction, heart failure, or cardiovascular death (95% confidence interval, 1.3-4.9; P=0.008). CONCLUSIONS: ECG left ventricular strain and LVH were independently predictive of poor prognosis in patients with asymptomatic aortic stenosis. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Adult congenital heart disease interventions: recommendations from a joint working group of the British Congenital Cardiac Association, British Cardiovascular Intervention Society, and the British Cardiovascular Society.

In order to optimise care of the adult patients with complex congenital heart disease, there is a need to develop recommendations for interventions. This document is the work of representatives of the three relevant societies and provides recommendations for institutions and operators performing cardiac interventions in these patients.

Getting It Right First Time (GIRFT): transforming cardiology care.

The Getting It Right First Time (GIRFT) process is designed to improve the care of patients in the National Health Service (NHS) in England through in-depth review of services, benchmarking and presenting a data-driven evidence base to support change. Although it started as a pilot project targeting unwarranted variation in elective orthopaedic surgery, it rapidly became apparent that the approach of clinically led deep dives to review the activity in individual orthopaedic units was effective in improving standards of care and resulted in substantial cost savings that could be reinvested in the clinical service. GIRFT has now expanded to encompass 40 clinical specialties and is funded nationally by the NHS in England. The purpose of this article is to describe its application and benefit to cardiology.

Association of high-sensitivity troponin T with outcomes in asymptomatic non-severe aortic stenosis: a post-hoc substudy of the SEAS trial.

Background: High-sensitivity Troponin T (hsTnT), a biomarker of cardiomyocyte overload and injury, relates to aortic valve replacement (AVR) and mortality in severe aortic stenosis (AS). However, its prognostic value remains unknown in asymptomatic patients with AS. We aimed to investigate if an hsTnT level >14 pg/mL (above upper limit of normal 99th percentile) is associated with echocardiographic AS-severity, subsequent AVR, ischaemic coronary events (ICE), and mortality in asymptomatic patients with non-severe AS. Methods: In this post-hoc sub-analysis of the multicentre, randomised, double-blind, placebo-controlled SEAS trial (ClinicalTrials.gov, NCT00092677), we included asymptomatic patients with mild to moderate-severe AS. We ascertained baseline and 1-year hsTnT concentrations and examined the association between baseline levels and the risk of the primary composite endpoint, defined as the first event of all-cause mortality, isolated AVR (without coronary artery bypass grafting (CABG)), or ICE. Multivariable regressions and competing risk analyses examined associations of hsTnT level >14 pg/mL with clinical correlates and 5-year risk of the primary endpoint. Findings: Between January 6, 2003, and March 4, 2004, a total of 1873 patients were enrolled in the SEAS trial, and 1739 patients were included in this post-hoc sub-analysis. Patients had a mean (SD) age of 67.5 (9.7) years, 61.0% (1061) were men, 17.4% (302) had moderate-severe AS, and 26.0% (453) had hsTnT level >14 pg/mL. The median hsTnT difference from baseline to 1-year was 0.8 pg/mL (IQR, -0.4 to 2.3). In adjusted linear regression, log(hsTnT) did not correlate with echocardiographic AS severity (p = 0.36). In multivariable Cox regression, a hsTnT level >14 pg/mL vs. hsTnT ≤14 pg/mL was associated with an increased risk of the primary composite endpoint (HR, 1.41; 95% CI, 1.18-1.70; p = 0.0002). In a competing risk model of first of the individual components of the primary endpoint, a hsTnT level >14 pg/mL was associated with ICE risk (HR 1.71; 95% CI, 1.23-2.38; p = 0.0013), but not with isolated AVR (p = 0.064) or all-cause mortality (p = 0.49) as the first event. Interpretation: hsTnT level is within the reference range (≤14 pg/mL) in 3 out of 4 non-ischaemic patients with asymptomatic mild-to-moderate AS and remains stable during a 1-year follow-up regardless of AS-severity. An hsTnT level >14 pg/mL was mainly associated with subsequent ICE, which suggest that hsTnT concentration is primarily a risk marker of subclinical coronary atherosclerotic disease. Funding: Merck & Co., Inc., the Schering-Plough Corporation, the Interreg IVA program, Roche Diagnostics Ltd., and Gangstedfonden. Open access publication fee funding provided by prof. Olav W. Nielsen and Department of Cardiology, Bispebjerg University Hospital, Denmark.

Outcome of patients with low-gradient "severe" aortic stenosis and preserved ejection fraction.

BACKGROUND: Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area < 1.0 cm² and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient "severe" stenosis (defined as aortic valve area < 1.0 cm² and mean gradient ≤ 40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. METHODS AND RESULTS: Outcome in patients with low-gradient "severe" aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm²; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67 ± 10 years; ejection fraction, ≥ 55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182 ± 64 versus 212 ± 68 g; P < 0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P = 0.37; major cardiovascular events, 50.9% versus 48.5%, P = 0.58; cardiovascular death, 7.8% versus 4.9%, P = 0.19). Low-gradient severe stenosis patients with reduced stroke volume index (≤ 35 mL/m²; n = 223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P = 0.53). CONCLUSIONS: Patients with low-gradient "severe" aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Effect of lipid lowering on new-onset atrial fibrillation in patients with asymptomatic aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study.

BACKGROUND: Lipid-lowering drugs, particularly statins, have anti-inflammatory and antioxidant properties that may prevent atrial fibrillation (AF). This effect has not been investigated on new-onset AF in asymptomatic patients with aortic stenosis (AS). METHODS: Asymptomatic patients with mild-to-moderate AS (n = 1,421) were randomized (1:1) to double-blind simvastatin 40 mg and ezetimibe 10 mg combination or placebo and followed up for a mean of 4.3 years. The primary end point was the time to new-onset AF adjudicated by 12-lead electrocardiogram at a core laboratory reading center. Secondary outcomes were the correlates of new-onset AF with nonfatal nonhemorrhagic stroke and a combined end point of AS-related events. RESULTS: During the course of the study, new-onset AF was detected in 85 (6%) patients (14.2/1,000 person-years of follow-up). At baseline, patients who developed AF were, compared with those remaining in sinus rhythm, older and had a higher left ventricular mass index a smaller aortic valve area index. Treatment with simvastatin and ezetimibe was not associated with less new-onset AF (odds ratio 0.89 [95% CI 0.57-1.97], P = .717). In contrast, age (hazard ratio [HR] 1.07 [95% CI 1.05-1.10], P < .001) and left ventricular mass index (HR 1.01 [95% CI 1.01-1.02], P < .001) were independent predictors of new-onset AF. The occurrence of new-onset AF was independently associated with 2-fold higher risk of AS-related outcomes (HR 1.65 [95% CI 1.02-2.66], P = .04) and 4-fold higher risk of nonfatal nonhemorrhagic stroke (HR 4.04 [95% CI 1.18-13.82], P = .03). CONCLUSIONS: Simvastatin and ezetimibe were not associated with less new-onset AF. Older age and greater left ventricular mass index were independent predictors of AF development. New-onset AF was associated with a worsening of prognosis.

Global left ventricular load in asymptomatic aortic stenosis: covariates and prognostic implication (the SEAS trial).

INTRODUCTION: Valvuloarterial impedance (Zva) is a measure of global (combined valvular and arterial) load opposing left ventricular (LV) ejection in aortic stenosis (AS). The present study identified covariates and tested the prognostic significance of global LV load in patients with asymptomatic AS. METHODS: 1418 patients with mild-moderate, asymptomatic AS in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study were followed for a mean of 43±14 months during randomized, placebo-controlled treatment with combined simvastatin 40 mg and ezetimibe 10 mg daily. High global LV load was defined as Zva >5 mm Hg/ml/m2. The impact of baseline global LV load on rate of major cardiovascular (CV) events, aortic valve events and total mortality was assessed in Cox regression models reporting hazard ratio (HR) and 95% Confidence Intervals (CI). RESULTS: High global LV load was found in 18% (n=252) of patients and associated with female gender, higher age, hypertension, more severe AS and lower ejection fraction (all p<0.05). A total of 476 major CV events, 444 aortic valve events and 132 deaths occurred during follow-up. In multivariate Cox regression analyses, high global LV load predicted higher rate of major CV events (HR 1.35 [95% CI 1.08-1.71], P=0.010) and aortic valve events (HR 1.41 [95% CI 1.12-1.79], P=0.004) independent of hypertension, LV ejection fraction, female gender, age, abnormal LV geometry and AS severity, but failed to predict mortality. CONCLUSION: In asymptomatic AS, assessment of global LV load adds complementary information on prognosis to that provided by hypertension or established prognosticators like AS severity and LV ejection fraction.