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Background Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD). Objectives The authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD). Methods Patients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD. Results Of 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell’s C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell’s C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models. Conclusions Comprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

Data on the association of multimorbidity and functional impairment with cardiovascular (CV) and non-CV outcomes among older myocardial infarction (MI) patients are limited.Multimorbidity and functional impairment among older MI patients are associated with CV and non-CV mortality.Patients aged ≥65 years, 1-3 years post-MI, and enrolled between June 2013 and Novemeber 2014 from 349 sites in 25 countries in the global TIGRIS registry were categorized by age, number of comorbidities, and presence and degree of functional impairment. Functional impairment was calculated using five-dimension EuroQol based on three domains-mobility, self-care, and usual activities. The association between age, number of comorbid conditions, and degree of functional impairment with 2-year incidence of CV and non-CV death was evaluated using Poisson regression analysis.Older age was associated with higher number of comorbidities and functional impairment; after adjustment, increasing age was significantly associated with non-CV mortality (p = .03) but not CV mortality (p = .38). Greater functional impairment was associated with a higher rate and relatively equal magnitude risk of CV (rate ratios [RR] 1.52, 95% confidence intervals [CI]: 1.29-1.79, per one-step increase) and non-CV mortality (RR 1.42, 95% CI: 1.17-1.73). Multimorbidity was more strongly associated with CV mortality (RR 1.52, 95% CI: 1.38-1.67, per additional comorbidity) versus non-CV mortality (RR 1.29, 95% CI: 1.14-1.47, per additional comorbidity).Multimorbidity and functional impairment are prevalent among older post-MI patients and are associated with increased CV and non-CV mortality. These findings highlight the importance of considering comorbid conditions and functional impairment as predictors of risk for adverse outcomes and aspects of medical decision making. Clinical Trial Registration: NCT01866904.

Background: We aimed to assess whether the effect of intravenous alteplase treatment (IVT) before endovascular treatment (EVT) on outcome is modified by first-line technique during EVT in IVT eligible patients. Methods: This was a post hoc analysis from MR CLEAN-NO IV (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands - Intravenous Treatment Followed by Intra-Arterial Treatment Versus Direct Intra-Arterial Treatment for Acute Ischemic Stroke Caused by a Proximal Intracranial Occlusion), a randomized trial of IVT followed by EVT versus EVT alone in patients presenting directly to EVT-capable centers. We included data from all patients who underwent EVT with a thrombectomy attempt. We compared patients treated with stent retriever (with or without aspiration) to aspiration alone as first-line EVT technique and assessed the interaction of first-line EVT technique with IVT treatment. Primary outcome was the 90-day modified Rankin Scale score, analyzed with mixed model ordinal regression for a shift towards better outcome. Secondary outcomes included successful reperfusion (extended Thrombolysis in Cerebral Infarction score 2b–3). Results: Of 473 included patients, 102 (21.6%) were treated with aspiration alone as first-line technique. In the full population, functional outcome was similar for patients treated with stent retriever versus aspiration only (adjusted common odds ratio [acOR]‚ 1.07 [95% CI, 0.69–1.66]). We observed a significant interaction between IVT and first-line EVT technique ( P =0.03). In the aspiration-only group, patients treated with EVT alone had worse functional outcome compared to those treated with IVT and EVT (acOR, 0.44 [95% CI, 0.21–0.90]). In the stent retriever group, functional outcome did not differ between patients treated with or without IVT (acOR, 1.08 [95% CI, 0.74–1.57]). There was no statistically significant interaction for successful reperfusion. Conclusions: In MR CLEAN-NO IV, the treatment effect of IVT was modified by first-line EVT technique. Patients treated with aspiration only as first-line technique had worse clinical outcomes if they did not receive IVT. No such difference was observed in patients treated with stent retrievers. Confirmation by pooling with results from other trials is needed to confirm these findings.

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:79 issue:22 pages:2219-2232 ispartof: location:United States status: published

Objective Closure of the artery during carotid endarterectomy (CEA) can be done with or without a patch, or performed with the eversion technique, while the use of intra-operative shunts is optional. The influence of these techniques on subsequent restenosis is uncertain. Long term carotid restenosis rates and risk of future ipsilateral stroke with these techniques were compared. Methods Patients who underwent CEA in the International Carotid Stenting Study were divided into patch angioplasty, primary closure, or eversion endarterectomy. Intra-operative shunt use was reported. Carotid duplex ultrasound was performed at each follow up. Primary outcomes were restenosis of ≥ 50% and ≥ 70%, and ipsilateral stroke after the procedure to the end of follow up. Results In total, 790 CEA patients had restenosis data at one and five years. Altogether, 511 (64.7%) had patch angioplasty, 232 (29.4%) primary closure, and 47 (5.9%) eversion endarterectomy. The cumulative incidence of ≥ 50% restenosis at one year was 18.9%, 26.1%, and 17.7%, respectively, and at five years it was 25.9%, 37.2%, and 30.0%, respectively. There was no difference in risk between the eversion and patch angioplasty group (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.45 – 1.81; p = .77). Primary closure had a higher risk of restenosis than patch angioplasty (HR 1.45, 95% CI 1.06 – 1.98; p = .019). The cumulative incidence of ≥ 70% restenosis did not differ between primary closure and patch angioplasty (12.1% vs. 7.1%, HR 1.59, 95% CI 0.88 – 2.89; p = .12) or between patch angioplasty and eversion endarterectomy (4.7%, HR 0.45, 95% CI 0.06 – 3.35; p = .44). There was no effect of shunt use on the cumulative incidence of restenosis. Post-procedural ipsilateral stroke was not more common in either of the surgical techniques or shunt use. Conclusion Restenosis was more common after primary closure than conventionally with a patch closure. Shunt use had no effect on restenosis. Patch closure is the treatment of choice to avoid restenosis.

ObjectiveThe effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM.MethodsProspective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrolment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited.ResultsDCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared with patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group: n=92, 94% vs n=306, 61%, p=ConclusionDCM patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation, but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with DCM.

Summary: Background: Uncertainty remains concerning the association of blood cholesterol with the risk of subsequent dementia. Using data from people with lipid measurements in the UK Clinical Practice Research Datalink (CPRD), we examined the association between blood lipid levels and dementia (both vascular and non-vascular, including Alzheimer's disease) by age at first measurement of blood lipids and duration of follow-up. Methods: We studied a cohort from the UK CPRD of people aged 40 years or older with a first total cholesterol recording between Jan 1, 1992, and Dec 31, 2009. Follow-up was until the first record of dementia, the last data collection date, patient death or transfer out of the practice, or Jan 5, 2015, whichever was earliest. We excluded individuals with a record of dementia before the total cholesterol measurement. We used Poisson regression to examine the association between baseline total cholesterol, LDL cholesterol and HDL cholesterol, and triglycerides and incident dementia diagnosis. Analyses were stratified by age at first measurement (

Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with

Background: IDH-wildtype glioblastoma is the most common malignant primary brain tumour in adults. As there is limited information on prognostic factors outside of clinical trials; thus, we conducted a retrospective study to characterise the glioblastoma population at our centre. Methods: Demographic, tumour molecular profiles, treatment, and survival data were collated for patients diagnosed with glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazard model associations with survival. Results: 490 patients were included; 60% had debulking surgery and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% had non-standard chemo/radio-therapy, and 19% had no further treatment. Overall survival was 9.2 months. In the multivariate analysis, longer survival was associated with debulking surgery vs. biopsy alone (14.9 vs. 8 months) (HR 0.54 [95% CI 0.41–0.70]), subsequent treatment after diagnosis (HR 0.12 [0.08–0.16]) (standard chemoradiotherapy [16.9 months] vs. non-standard regimens [9.2 months] vs. none [2.0 months]), tumour MGMT promotor methylation (HR 0.71 [0.58–0.87]), and younger age (hazard ratio vs. age < 50: 1.70 [1.26–2.30] for ages 50–59; 3.53 [2.65–4.70] for ages 60–69; 4.82 [3.54–6.56] for ages 70+). Conclusions: The median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.

Background Socioeconomic deprivation is associated with higher cardiovascular morbidity and mortality. Whether deprivation status should be incorporated in more cardiovascular risk estimation scores remains unclear. Purpose This study evaluates how socioeconomic deprivation status affects the performance of three primary prevention cardiovascular risk scores. Methods The Generation Scotland Scottish Family Health Study was used to evaluate the performance of three cardiovascular risk scores with (ASSIGN) and without (SCORE2, PCE) socioeconomic deprivation as a covariate in the risk prediction model. Deprivation was defined by Scottish Index of Multiple Deprivation score. The predicted 10-year risk was evaluated against the observed event rate for the cardiovascular outcome of each risk score. The comparison was made across three groups defined by the deprivation index score consisting of group 1 defined as most deprived, group 3 defined as least deprived and group 2 which consisted of individuals in the middle deprivation categories. Results The study population consisted of 15,506 individuals (60.0% female, median age of 51). Across the population 1,808 (12%) individuals were assigned to group 1 (most deprived), 8,119 (55%) to group 2, and 4,708 (32%) to group 3 (least deprived). Risk scores based on models that did not include deprivation status significantly under predicted risk in the most deprived (6.4% observed versus 4.6% predicted for SCORE2 and 6.7% observed versus 4.7% predicted for PCE, p Conclusions Socioeconomic status is a largely unrecognized risk factor in primary prevention of cardiovascular disease. Risk scores that exclude socioeconomic deprivation as a covariate under- and overestimate the risk in the most and least deprived individuals, respectively. This study highlights the importance of incorporating socioeconomic deprivation status in risk estimation systems to ultimately reduce inequalities in health care provision for cardiovascular disease. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The British Heart Foundation.Health Data Research UK which receives its funding from HDR UK Ltd (HDR-5012) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and the Wellcome Trust.

International audience; Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may induce an early post-initiation decrease of estimated glomerular filtration rate (eGFR), which does not impact the SGLT2i benefits. The occurrence, characteristics, determinants, and clinical significance of an initial eGFR change among patients with heart failure with reduced ejection fraction require further study. In this study we aimed to describe eGFR change from randomization to week 4 (as percent of change relative to randomization) and assess its impact in EMPEROR-Reduced.Methods and results: Landmark analyses (week 4) were performed. eGFR change was available in 3547 patients out of 3730 (95%). The tertiles of post-initiation % eGFR change for empagliflozin were: tertile 1 (T1) ≤-11.4%; T2 ≥-11.4% to ≤-1.0% and T3 ≥0.0%. The placebo group tertiles were: T1 ≤-6.5%; T2 ≥-6.4% to ≤+3.6%; and T3 ≥+3.6%. On average, empagliflozin induced a leftward distributional shift of initial eGFR changes of -2.5 ml/min/1.73 m2 versus placebo. In the empagliflozin group, after covariate adjustment, the risk of cardiovascular and renal outcomes did not differ between patients in whom early post-treatment initiation eGFR decreased (T1) and patients in whom it increased (T3). However, in the placebo group, patients in whom early post-treatment initiation eGFR decreased (T1) had a higher risk of sustained worsening kidney function and all-cause mortality compared to patients in whom eGFR increased (T3) (hazard ratio [HR] 2.38, 95% confidence interval [CI] 1.25-4.55 and HR 1.37, 95% CI 1.01-1.85, respectively).Conclusion: A mild eGFR decrease may be expected after the initiation of empagliflozin, and it is not associated with untoward heart failure, mortality, or kidney safety events. Clinicians should not be concerned with early eGFR changes post-initiation of empagliflozin.

AIMS: The aim of this study was to assess the one-year safety and efficacy of the transcatheter ARTO system in the treatment of functional mitral regurgitation (FMR). METHODS AND RESULTS: MAVERIC is a multicentre, prospective, non-randomised pre-commercial study. Eligible patients were on guideline-recommended therapy for NYHA Class II-IV systolic heart failure and had an FMR grade ≥2+. The ARTO system was implanted in forty-five (100%) patients. The primary safety composite endpoint (death, stroke, myocardial infarction, device-related surgery, cardiac tamponade, renal failure) at 30 days and one year was 4.4% (95% CI: 1.5-16.6) and 17.8% (95% CI: 9.3-32.4), respectively. Periprocedural complications occurred in seven patients (15.5% [95% CI: 6.5-29.5]), and five patients (11.1% [95% CI: 4.9-24.0]) died during one-year follow-up. Paired results for 36 patients demonstrated that 24 (66.7%) had grade 3+/4+ mitral regurgitation at baseline; however, only five (13.9%) and three (8.3%) patients remained at grade 3+/4+ 30 days and one year post procedure (p

Atrial fibrillation (AF) in hypertrophic cardiomyopathy (HC) is associated with significant symptomatic deterioration, heart failure, and thromboembolic disease. There is a need for better mechanistic insight and improved identification of at risk patients. We used cardiovascular magnetic resonance (CMR) to assess predictors of AF in HC, in particular the role of myocardial fibrosis. Consecutive patients with HC referred for CMR 2003 to 2013 were prospectively enrolled. CMR parameters including left ventricular volumes, presence and percentage of late gadolinium enhancement in the left ventricle (%LGE) and left atrial volume index (LAVi) were measured. Overall, 377 patients were recruited (age 62 ± 14 years, 73% men). Sixty-two patients (16%) developed new-onset AF during a median follow up of 4.5 (interquartile range 2.9 to 6.0) years. Multivariable analysis revealed %LGE (hazard ratio [HR] 1.3 per 10% (confidence interval: 1.0 to 1.5; p = 0.02), LAVi (HR 1.4 per 10 mL/m 2[1.2 to 1.5; p < 0.001]), age at HC diagnosis, nonsustained ventricular tachycardia and diabetes to be independent predictors of AF. We constructed a simple risk prediction score for future AF based on the multivariable model with a Harrell's C-statistic of 0.73. In conclusion, the extent of ventricular fibrosis and LA volume independently predicted AF in patients with HC. This finding suggests a mechanistic relation between fibrosis and future AF in HC. CMR with quantification of fibrosis has incremental value over LV and LA measurements in risk stratification for AF. A risk prediction score may be used to identify patients at high risk of future AF who may benefit from more intensive rhythm monitoring and a lower threshold for oral anticoagulation.

Arterial transit artifacts at arterial spin-labeling MRI were the only factor associated with recent ischemic symptoms in participants with carotid stenosis.

The win ratio was introduced in 2012 as a new method for examining composite endpoints and has since been widely adopted in cardiovascular (CV) trials. Improving upon conventional methods for analysing composite endpoints, the win ratio accounts for relative priorities of the components and allows the components to be different types of outcomes. For example, the win ratio can combine the time to death with the number of occurrences of a non-fatal outcome such as CV-related hospitalizations (CVHs) in a single hierarchical composite endpoint. The win ratio can provide greater statistical power to detect and quantify a treatment difference by using all available information contained in the component outcomes. The win ratio can also incorporate quantitative outcomes such as exercise tests or quality-of-life scores. There is a need for more practical guidance on how best to design trials using the win ratio approach. This manuscript provides an overview of the principles behind the win ratio and provides insights into how to implement the win ratio in CV trial design and reporting, including how to determine trial size.

Neoliberalism, in various ways, is radically new. It is nevertheless constructed from the conditions of liberal modernity, the inadequacies of which are crucial to neoliberal success. Liberalism in practice restricts moral agency through an impoverished, structurally-reinforced conception of practical reasoning, as Alasdair MacIntyre argues, and this is important to understanding neoliberal durability. This article argues that a bureaucratic culture that fails to evaluate or critically question the ends it pursues is both symptomatic of liberal inadequacies and a key factor in neoliberal success. Beyond its purely explanatory power, there is a political relevance to MacIntyre’s Aristotelian-inspired politics of local community. It is from those practices and communal movements that embody alternative conceptions of the good, that those interested in resisting neoliberalism can learn how it becomes possible to successfully challenge aspects of the contemporary social order.

Aims:\ud There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling.\ud \ud Methods and results:\ud Prospective study of patients with recent‐onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = −0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease‐modifying heart failure medication (beta‐blocker, P = 0.28; angiotensin‐converting enzyme inhibitor, P = 0.92) did not predict follow‐up LVEF.\ud \ud Conclusions:\ud Substantial recovery of LV function occurs within 12 months in most patients with recent‐onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.

Aims To develop a risk model for sudden cardiac death (SCD) in high‐risk acute myocardial infarction (AMI) survivors. Methods and results Data from the Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left Ventricular Dysfunction trial (CAPRICORN) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT) were used to create a SCD risk model (with non‐SCD as a competing risk) in 13 202 patients. The risk model was validated in the Eplerenone Post‐AMI Heart Failure Efficacy and Survival Study (EPHESUS). The rate of SCD was 3.3 (95% confidence interval 3.0–3.5) per 100 person‐years over a median follow‐up of 2.0 years. Independent predictors of SCD included age > 70 years; heart rate ≥ 70 bpm; smoking; Killip class III/IV; left ventricular ejection fraction ≤30%; atrial fibrillation; history of prior myocardial infarction, heart failure or diabetes; estimated glomerular filtration rate

BACKGROUND: Empirical evidence suggests a strong link between exposure to air pollution and heart failure incidence, hospitalizations, and mortality, but the biological basis of this remains unclear. We sought to determine the relationship between differential air pollution levels and changes in cardiac structure and function in patients with dilated cardiomyopathy.METHODS AND RESULTS: We undertook a prospective longitudinal observational cohort study of patients in England with dilated cardiomyopathy (enrollment 2009-2015, n = 716, 66% male, 85% Caucasian) and conducted cross sectional analysis at the time of study enrollment. Annual average air pollution exposure estimates for nitrogen dioxide (NO 2) and particulate matter with diameter of 2.5 µm or less (PM 2.5) at enrolment were assigned to each residential postcode (on average 12 households). The relationship between air pollution and cardiac morphology was assessed using linear regression modelling. Greater ambient exposure to NO 2 was associated with higher indexed left ventricular (LV) mass (4.3 g/m 2 increase per interquartile range increase in NO 2, 95% confidence interval 1.9-7.0 g/m 2) and lower LV ejection fraction (-1.5% decrease per interquartile range increase in NO 2, 95% confidence interval -2.7% to -0.2%), independent of age, sex, socioeconomic status, and clinical covariates. The associations were robust to adjustment for smoking status and geographical clustering by postcode area. The effect of air pollution on LV mass was greatest in women. These effects were specific to NO 2 exposure. CONCLUSIONS: Exposure to air pollution is associated with raised LV mass and lower LV ejection fraction, with the strongest effect in women. Although epidemiological associations between air pollution and heart failure have been established and supported by preclinical studies, our findings provide novel empirical evidence of cardiac remodeling and exposure to air pollution with important clinical and public health implications.

International audience; Background: Risk prediction tools are lacking for patients with stable disease some years after myocardial infarction (MI).Hypothesis: A practical long‐term cardiovascular risk index can be developed.Methods: The long‐Term rIsk, Clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post‐myocardial infarction patients prospective global registry enrolled patients 1 to 3 years post‐MI (369 centers; 25 countries), all with ≥1 risk factor (age ≥65 years, diabetes mellitus requiring medication, second prior MI, multivessel coronary artery disease, or chronic non‐end‐stage kidney disease [CKD]). Self‐reported health was assessed with EuroQoL‐5 dimensions. Multivariable Poisson regression models were used to determine key predictors of the primary composite outcome (MI, unstable angina with urgent revascularization [UA], stroke, or all‐cause death) over 2 years.Results: The primary outcome occurred in 621 (6.9%) of 9027 eligible patients: death 295 (3.3%), MI 195 (2.2%), UA 103 (1.1%), and stroke 58 (0.6%). All events accrued linearly. In a multivariable model, 11 significant predictors of primary outcome (age ≥65 years, diabetes, second prior MI, CKD, history of major bleed, peripheral arterial disease, heart failure, cardiovascular hospitalization (prior 6 months), medical management (index MI), on diuretic, and poor self‐reported health) were identified and combined into a user‐friendly risk index. Compared with lowest‐risk patients, those in the top 16% had a rate ratio of 6.9 for the primary composite, and 18.7 for all‐cause death (overall c‐statistic; 0.686, and 0.768, respectively). External validation was performed using the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events registry (c‐statistic; 0.748, and 0.849, respectively).Conclusions: In patients >1‐year post‐MI, recurrent cardiovascular events and deaths accrue linearly. A simple risk index can stratify patients, potentially helping to guide management.

Background M184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance and increased tenofovir disoproxil fumarate (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against human immunodeficiency virus-1 with these mutations possibly as a result of reduced replication capacity. In this study, we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside reverse-transcriptase inhibitor (NNRTI)-containing regimen. Methods We compared VL in the absence and presence of M184V/I across studies using random effects meta-analysis. The effect of mutations on virus reverse-transcriptase activity and infectiousness was analyzed in vitro. Results M184I/V was present in 817 (56.5%) of 1445 individuals with virologic failure (VF). Virus load was similar in individuals with or without M184I/V (difference in log10 VL, 0.18; 95% confidence interval, .05–.31). CD4 count was lower both at initiation of antiretroviral therapy and at VF in participants who went on to develop M184V/I. L74I was present in 10.2% of persons with M184V/I but absent in persons without M184V/I (P < .0001). In vitro, L74I compensated for defective replication of M184V-mutated virus. Conclusions Virus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. Therefore, we did not find evidence for a benefit of XTC in the context of first-line failure on this combination., Lamivudine is a cornerstone antiretroviral whose efficacy has been ascribed to high fitness cost of the lamivudine resistance mutation M184V. However, here we demonstrate elevated viral loads in the context of M184V, likely attributable to compensatory mutations such as L74I.

Introduction: In TRED-HF, 40% of patients with recovered dilated cardiomyopathy (DCM) relapsed during withdrawal of therapy. Non-invasive markers of relapse may be used to monitor patients who wish a trial of therapy withdrawal. Purpose: To profile the changes in clinical and imaging variables amongst patients with recovered DCM undergoing therapy withdrawal in TRED-HF. Methods: Patients with recovered DCM were randomised to phased withdrawal of therapy or to continue therapy for 6 months. After 6 months of continued therapy, those in the control arm underwent withdrawal of therapy in a crossover phase. Clinical variables were measured at each study visit and imaging variables were measured at baseline, 16 weeks and 6 months. Mean values and 95% CIs were calculated at each time point. Clinical variables were modelled using fractional polynomials. Results: Of 51 patients, 26 were assigned to continue therapy and 25 to withdraw therapy over the first 6 months. Of the former, 24 of 26 patients, withdrew therapy in the cross-over phase between 6-12 months. An increase in mean heart rate was noted within 4 weeks of beginning therapy withdrawal and was the earliest change observed. Heart rate and change in heart rate from baseline were closely associated with the occurrence of relapse in multivariable analysis. A rise in systolic and diastolic blood pressure was apparent by 8 weeks. A rise in mean log NT-pro-BNP was the latest change to occur and not observed until 6 months after starting therapy withdrawal. ( Figure 1 & Table 1) . A rise in mean LV mass and LVEDV and a reduction in mean LVEF was seen by 16 weeks ( Figure 2 & Table 1) . Conclusion(s): A rise in heart rate may be the earliest sign of relapse during withdrawal of medication. This is accompanied or closely followed by changes in LV structure and function, with changes in natriuretic peptide concentrations occurring later. This informs monitoring strategies in cases where it may be necessary to reduce heart failure therapy.

Aims The aim of this study was to generate a biomarker-driven prognostic tool for patients with chronic HFrEF. Circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) each have a marked positive relationship with adverse outcomes in heart failure with reduced ejection fraction (HFrEF). A risk model incorporating biomarkers and clinical variables has not been validated in contemporary heart failure (HF) trials. Methods and results In EMPEROR-Reduced, 33 candidate variables were pre-selected. Multivariable Cox regression models were developed using stepwise selection for: (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, and (iii) cardiovascular mortality. A total of 3730 patients were followed up for a median of 16 months, 823 (22%) patients had a primary outcome and 515 (14%) patients died, of whom 389 (10%) died from a cardiovascular cause. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last HF hospitalization, longer time since HF diagnosis, lower systolic blood pressure, New York Heart Association (NYHA) Class III or IV, higher heart rate and peripheral oedema were key predictors (eight variables in total, all P 9 times higher than those in the bottom 10th. Empagliflozin benefitted patients across risk levels for the primary outcome. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality, followed by NYHA Class III or IV and ischaemic aetiology (four variables in total, all P Conclusions The combination of NT-proBNP and hs-cTnT with a small number of readily available clinical variables provides prognostic assessment for patients with HFrEF. This predictive tool kit can be easily implemented for routine clinical use.

In randomized controlled trials, patient characteristics are expected to be well balanced between treatment groups; however, adjustment for characteristics that are prognostic can still be beneficial with a modest gain in statistical power. Nevertheless, previous reviews show that many trials use unadjusted analyses. In this article, we review current practice regarding covariate adjustment in cardiovascular trials among all 84 randomized controlled trials relating to cardiovascular disease published in the New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association during 2019. We identify trials in which use of covariate adjustment led to a change in the trial conclusions. By using these trials as case studies, along with data from the CHARM trial and simulation studies, we demonstrate some of the potential benefits and pitfalls of covariate adjustment. We discuss some of the complexities of using covariate adjustment, including how many covariates to choose, how covariates should be modeled, how to handle missing data for baseline covariates, and how adjusted analyses are viewed by regulators. We conclude that contemporary cardiovascular trials do not make best use of covariate adjustment and that more frequent use could lead to improvements in the efficiency of future trials.

AIMS We report the 2-year outcomes of the MitrAl ValvE RepaIr Clinical (MAVERIC) trial. Functional mitral regurgitation (FMR) is associated with poor outcomes for which there remains an unmet clinical need. ARTO is a transcatheter annular reduction device for the treatment of FMR and an emerging alternative for patients at high surgical risk. The MAVERIC trial was designed to evaluate the safety and performance of the ARTO system in FMR and heart failure (HF). METHODS AND RESULTS MAVERIC is an international multicentre, prospective, single arm study enrolling patients with FMR grade ≥ 2, New York Heart Association (NYHA) class ≥II symptoms despite maximal medical therapy. Patients were excluded if they had significant structural mitral valve abnormality or life expectancy

Objectives The objective of this study was to determine the relationship between heart rate and relapse among patients in the TRED-HF (Therapy withdrawal in REcovered Dilated cardiomyopathy trial). Background Understanding markers and mechanisms of relapse among patients with recovered dilated cardiomyopathy (DCM) may enable personalized management. Methods The relationship between serial heart rate measurements and relapse was examined among patients in the TRED-HF trial, a randomized trial which examined the safety and feasibility of withdrawing heart failure therapy from 51 patients with recovered DCM over 6 months. In total, 25 patients were randomized to therapy withdrawal and 26 to continue therapy, of whom 25 subsequently began therapy withdrawal in a single arm crossover phase. Results The mean ± SD heart rate for those who had therapy withdrawn and did not relapse was 64.6 ± 10.7 beats/min at baseline and 74.7 ± 10.4 beats/min at follow-up, compared to 68.3 ± 11.3 beats/min at baseline and 86.1 ± 11.8 beats/min at follow-up for those who relapsed. After adjusting for differences in heart rate at baseline, patients who had therapy withdrawn and relapsed had a 10.4 beats/min (95% CI: 4.0–16.8) greater rise in heart rate than patients who had therapy withdrawn and did not relapse (P = 0.002). After data were adjusted for age, log N-terminal pro–B-type natriuretic peptide, and left ventricular ejection fraction (LVEF), heart rate (per 10 beats/min; hazard ratio [HR]: 1.65; 95% CI: 1.10-2.57; P = 0.01) and change in heart rate from baseline (per 10 beats/min; HR: 1.70; 95% CI: 1.12–2.57; p = 0.01) were associated with relapse. The results remained qualitatively the same after adjusting for beta-blocker dose. Conclusions For patients with DCM and improved LVEF, the rise in heart rate after treatment is withdrawn treatment identifies patients who are more likely to relapse. Whether the increase in heart rate is a marker or a mediator of relapse requires investigation. (Therapy withdrawal in REcovered Dilated cardiomyopathy trial [TRED]; NCT02859311), Central Illustration

Most major clinical trials in cardiology report time-to-event outcomes using the Cox proportional hazards model so that a treatment effect is estimated as the hazard ratio between groups, accompanied by its 95% confidence interval and a log-rank p value. But nonproportionality of hazards (non-PH) over time occurs quite often, making alternative analysis strategies appropriate. This review presents real examples of cardiology trials with different types of non-PH: an early treatment effect, a late treatment effect, and a diminishing treatment effect. In such scenarios, the relative merits of a Cox model, an accelerated failure time model, a milestone analysis, and restricted mean survival time are examined. Some post hoc analyses for exploring any specific pattern of non-PH are also presented. Recommendations are made, particularly regarding how to handle non-PH in pre-defined Statistical Analysis Plans, trial publications, and regulatory submissions.

BACKGROUND AND PURPOSE: Elevated blood pressure (BP) is prevalent and modifiable and has been hypothesized to lead to increased risk of dementia. DATA: Data on 2 593 629 people from the UK Clinical Practice Research Database aged ≥40 years with a BP measurement between 1992 and 2011 and no prior record of dementia were collected. METHODS: Poisson regression models were used to study the association between BP and physician-diagnosed dementia. BP is believed to fall during the prodromal phase of dementia development, so associations were investigated by categories of time since BP measurement ( 10 years) and by subtypes of dementia. RESULTS: During a median follow-up of 8.2 years, 65 618 cases of dementia were observed: 49 161 Alzheimer's, 13 816 vascular dementia and 2541 other subtypes. For each 10 mmHg higher systolic BP, the future dementia risk was 9.2% (95% confidence interval 8.4%-10.0%) lower, but this association varied markedly by time since BP measurement. Short-term associations with dementia were inverse with a 15.8% (15.5%-17.0%) lower risk 0-5 years after BP measurement and a 5.8% (7.7%-4.4%) lower risk 5-10 years after BP measurement. During the period >10 years after BP measurement, dementia risk was only 1.6% (0.1%-3.0%) lower, with a 4.3% (2.5%-6.0%) lower risk of Alzheimer's disease and a 7.0% (3.8%-10.2%) higher risk of vascular dementia. CONCLUSIONS: Elevated BP is associated with decreased risk of dementia in the short term, possibly due to reverse causation. Long-term associations of BP with dementia are less marked and differ by dementia subtype.

Background: In time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides re...

Background: In patients at elevated cardiovascular risk, statins reduce the occurrence of ischemic stroke. However, residual stroke risk persists. Methods: REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low-density lipoprotein cholesterol, elevated triglycerides, and risk for, or evidence of, atherosclerosis to icosapent ethyl (IPE), a purified, stable ethyl ester of eicosapentaenoic acid (4 grams/day), or placebo. IPE reduced the primary composite endpoint (CV death, myocardial infarction (MI), stroke, coronary revascularization, hospitalization for unstable angina) and the key secondary composite endpoint (CV death, MI, stroke) by 25% and 26%, respectively, (each ppost hoc stroke endpoints. Results: Event rates for time to first fatal or nonfatal stroke were 2.4% vs. 3.3% for IPE vs. placebo; hazard ratio (HR) (95% CI) = 0.72 (0.55-0.93); P=0.01; the relative risk reduction (RRR) was 28%, absolute risk reduction (ARR) 0.9%, and number needed to treat (NNT) 114. For every 1,000 patients treated for 5 years with IPE, approximately 14 strokes (fatal or nonfatal) were averted; rate ratio (RR) (95%CI) = 0.68 (0.52-0.91); P=0.008 (Figure). Ischemic stroke time to first event rates were 2.0% vs 3.0% for IPE vs placebo a 36% reduction [HR=0.64 (0.49-0.85); P=0.002]. Hemorrhagic stroke occurred at low rates with no significant difference for IPE vs. placebo (0.3% vs 0.2%; P=0.55). Conclusions: In REDUCE-IT, icosapent ethyl significantly reduced the risk of ischemic stroke, with no excess in hemorrhagic stroke, in statin-treated patients with elevated triglycerides and atherosclerosis or diabetes.

International audience; Background: Uncontrolled blood pressure (BP) increases the risk of major adverse cardiovascular events. In SPRINT an intensive versus standard BP lowering strategy resulted in a lower rate of cardiovascular events and death. Whether BP reduction only or also the choice of anti-hypertensive drugs is associated with outcomes remains to be elucidated.Aims: We aim to study the association of BP and different anti-hypertensive drugs with several cardiovascular outcomes.Methods: Time-updated Cox and mixed-effects models. The primary outcome was a composite of first myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death.Results: A total of 9361 patients were included. The anti-hypertensive agents most frequently used were ACEi/ARBs, with an almost 20% higher prescription rate in the intensive arm (80% vs. 61%), followed by thiazide-type diuretics (65% vs. 42%), calcium-channel blockers (57% vs. 39%), and beta-blockers (52% vs. 26%). Mineralocorticoid receptor antagonists were rarely used (≤7% of the observations). In multivariate analysis, the use of ACEi/ARBs, especially in combination with thiazides, were independently associated with a lower primary outcome event-rate (HR [95%CI] 0.75 [0.61-0.92], p = .006), whereas a DBP