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Cardiometabolic diseases contribute more to global morbidity and mortality than any other group of disorders. Polygenic risk scores (PRSs), the weighted summation of individually small-effect genetic variants, represent an advance in our ability to predict the development and complications of cardiometabolic diseases. This article reviews the evidence supporting the use of PRS in seven common cardiometabolic diseases: coronary artery disease (CAD), stroke, hypertension, heart failure and cardiomyopathies, obesity, atrial fibrillation (AF), and type 2 diabetes mellitus (T2DM). Data suggest that PRS for CAD, AF, and T2DM consistently improves prediction when incorporated into existing clinical risk tools. In other areas such as ischaemic stroke and hypertension, clinical application appears premature but emerging evidence suggests that the study of larger and more diverse populations coupled with more granular phenotyping will propel the translation of PRS into practical clinical prediction tools. [ABSTRACT FROM AUTHOR]

Aims Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. Methods and results In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N -terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60–3.45]; fifth quintile HR 3.73 (95% CI 2.58–5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75–0.91). Conclusion It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively. [ABSTRACT FROM AUTHOR]

Aims To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods and results The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9–3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n  = 118, 21%); desmoplakin (DSP) (n  = 79, 14%); other desmosomal (n  = 59, 11%); and gene elusive (n  = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. Conclusion The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC. [ABSTRACT FROM AUTHOR]

Aims Previously, guidelines recommended initiating therapy in patients with heart failure and reduced ejection fraction (HFrEF) in a sequence that follows the chronological order in which trials were conducted, with cautious up-titration of each treatment. It remains unclear whether this historical approach is optimal and alternative approaches may improve patient outcomes. Methods and results The potential reductions in events that might result from (i) more rapid up-titration of therapies used in the conventional order (based on the chronology of the trials), and (ii) accelerated up-titration and using treatments in different orders than is conventional were modelled using data from six pivotal trials in HFrEF. Over the first 12 months from starting therapy, using a rapid up-titration schedule led to 23 fewer patients per 1000 patients experiencing the composite of heart failure hospitalization or cardiovascular death and seven fewer deaths from any cause. In addition to accelerating up-titration of treatments, optimized alternative ordering of the drugs used resulted in a further reduction of 24 patients experiencing the composite outcome and six fewer deaths at 12 months. The optimal alternative sequences included sodium–glucose cotransporter 2 inhibition and a mineralocorticoid receptor antagonist as the first two therapies. Conclusion Modelling of accelerated up-titration schedule and optimized ordering of treatment suggested that at least 14 deaths and 47 patients experiencing the composite outcome per 1000 treated might be prevented over the first 12 months after starting therapy. Standard treatment guidance may not lead to the best patient outcomes in HFrEF, though these findings should be tested in clinical trials. [ABSTRACT FROM AUTHOR]

Debate articles that appraise the value of a universal definition of heart failure (HF) based on the determination of circulating natriuretic peptide (NP) levels are presented. Topics covered include difficulties in diagnosing and treating HF with preserved ejection fraction (HFpEF), caveats precluding the introduction of NP elevation for HF diagnosis, and congestion due to cardiac dysfunction.

Aims Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction. Methods and results In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan–Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67–14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63–45.90; P  = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients. Conclusion In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events. [ABSTRACT FROM AUTHOR]

Aims To investigate the risk of stroke/thromboembolism (TE) and major bleeding associated with anaemia among patients with atrial fibrillation (AF). Also, to assess the effects of oral anticoagulation (OAC) and time in therapeutic range (TTR) with vitamin K antagonists according to level of haemoglobin (Hb). Methods and results Through administrative registry databases, we identified all Danish patients diagnosed with AF from 1997 to 2012. We included 18 734 AF patients with recent available data on Hb. Multiple Cox regression analyses were used to estimate hazard ratios and to compute standardized absolute 1-year risks of stroke/TE and major bleeding. Among included patients, 3796 (20%) had mild anaemia (Hb 6.83–7.45 mmol/L for women and Hb 6.83–8.03 mmol/L for men) and 2562 (14%) had moderate/severe anaemia (Hb <6.83 mmol/L). Moderate/severe anaemia was associated with increased risk of major bleeding and 9.1% lower median TTR compared with no anaemia. Use of OAC was associated with reduced risk of stroke/TE among patients without anaemia [standardized absolute 1-year difference −2.5%, 95% confidence interval (CI) −3.8 to −1.7%] or with mild anaemia (−2.3%, 95% CI −2.8 to −1.8%), but not with moderate/severe anaemia, (0.03%, −1.8 to +2.8%, interaction P = 0.01). Oral anticoagulation was associated with a 5.3% (95% CI 2.1–8.7%) increased standardized absolute risk of major bleeding among AF patients with moderate/severe anaemia. Conclusion Anaemia was common in patients with AF and associated with major bleeding and lower TTR. Oral anticoagulation was associated with more major bleeding, but no reduction in risk of stroke/TE among AF patients with moderate/severe anaemia. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

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Aims Although presenting features and early sequelae of non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are well described, less is known about longer-term risks and modes of death. The purpose of this study was to characterize modes of death following NSTE-ACS in clinical trial populations. Methods and results We evaluated 66 252 patients with NSTE-ACS enrolled in 14 Thrombolysis in Myocardial Infarction (TIMI) trials, examining baseline characteristics and modes and timing of death. Of the 66 252 patients followed for a median of 372 (interquartile range 218–521) days, 3147 (4.8%) died by the time of last follow-up. Of the 2606 patients (82.8%) with known modes of death, 75.1% were related to a cardiovascular (CV) event, 3.0% were related to a bleeding event (including intracranial haemorrhage), and 21.8% were related to a non-CV/non-bleeding event. The most common modes of CV death were sudden death (SD) and recurrent myocardial infarction (MI) (36.4% and 23.4%, respectively, of CV deaths). The proportion of CV deaths related to recurrent MI was higher in the first 30 days than it was after 30 days following NSTE-ACS (30.6% vs. 18.7%), whereas the proportion of SD was lower in the first 30 days than after 30 days (21.6% vs. 46.2%). Conclusion Sudden death represents the largest proportion of CV deaths after 30 days among patients enrolled in CV clinical trials with NSTE-ACS. Further investigations aimed at defining the epidemiology of SD and developing specific therapies and management approaches to reduce SD following NSTE-ACS may be critical to reducing late mortality. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

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Aim Left ventricular (LV) global longitudinal strain (GLS) reflects LV systolic function and correlates inversely with the extent of LV myocardial scar and fibrosis. The present subanalysis of the Echocardiography Guided CRT trial investigated the prognostic value of LV GLS in patients with narrow QRS complex. Methods and results Left ventricular (LV) global longitudinal strain (GLS) was measured on the apical 2-, 4- and 3-chamber views using speckle tracking analysis. Measurement of baseline LV GLS was feasible in 755 patients (374 with cardiac resynchronization therapy (CRT)-ON and 381 with CRT-OFF). The median value of LV GLS in the overall population was 7.9%, interquartile range 6.2-10.1%. After a mean follow-up period of 19.4 months, 95 patients in the CRT-OFF group and 111 in the CRT-ON group reached the combined primary endpoint of all-cause mortality and heart failure hospitalization. Each 1% absolute unit decrease in LV GLS was independently associated with 11% increase in the risk to reach the primary endpoint (Hazard ratio 1.11; 95% confidence interval 95% 1.04-1.17, P<0.001), after adjusting for ischaemic cardiomyopathy and randomization treatment among other clinically relevant variables. When categorizing patients according to quartiles of LV GLS, the primary endpoint occurred more frequently in patients in the lowest quartile (<6.2%) treated with CRT-ON vs. CRT-OFF (45.6% vs. 28.7%, P=0.009) whereas, no differences were observed in patients with LV GLS_6.2% treated with CRT-OFF vs. CRT-ON (23.7% vs. 24.5%, respectively; P ≥0.62). Conclusion Low LV GLS is associated with poor outcome in heart failure patients with QRS width <130 ms, independent of randomization to CRT or not. Importantly, in the group of patients with the lowest LV GLS quartile, CRT may have a detrimental effect on clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction Stratification for subsequent coronary events among patients with coronary artery disease (CAD) is of considerable interest because of the potential to guide secondary preventive therapies. Recently, we identified eight microRNAs (miRNAs), which facilitated acute coronary syndrome (ACS) diagnosis. In this study, we aimed to evaluate their potential role as prognostic biomarkers for cardiovascular disease. Methods The serum concentrations of eight candidate miRNAs -miR-19a, miR-19b, miR-132, miR-140-3p, miR-142-5p, miR-150, miR-186, and miR-210 were measured in a cohort of 1112 patients with documented CAD—including 430 patients with ACS and 682 patients with stable angina pectoris. Cardiovascular death was the main outcome measure. Results During a median follow-up of 4.0 years, most miRNAs reliably predicted cardiovascular death in ACS patients. Cox regression analyses indicated that in particular miR-132 (HR 2.85 per 1 SD increase, P = 0.022), miR-140-3p (HR 2.88 per 1 SD increase, P = 0.022), and miR-210 (HR 3.10 per 1 SD increase, P = 0.039) were able to precisely predict cardiovascular death. Circulating miR-132, miR-140-3p, and miR-210 clearly improved various model performance measures, including C-statistics (AUC [area under the receiver-operating characteristic curve] for miR-132: 0.737; AUC for miR-140-3p: 0.756; AUC for miR-210: 0.754). Conclusions This is the largest study so far evaluating the prognostic value of circulating miRNAs in cardiovascular disease. Our study shows that single miRNAs derived from peripheral blood predict mortality in secondary prevention settings, and thereby represent valuable biomarkers for risk estimation in CAD. [ABSTRACT FROM AUTHOR]

The implantable cardiac defibrillator (ICD) has been an effective tool for prevention of sudden cardiac death (SCD) in populations at high risk for life-threatening sustained ventricular tachycardia (VT) and ventricular fibrillation (VF). However, ICD implantation is dependent on defining ventricular substrate, evaluating the future risk of SCD and estimation of the patient’s overall survival. The ability to predict risk of SCD is often difficult. If ventricular dysfunction (a surrogate marker for the risk of SCD) improves, ICD therapy may not be indicated. The wearable cardiac defibrillator (WCD) provides an option for protection during this vulnerable period when the risk of SCD is unclear. It combines an electrocardiogram-monitoring system with an external automatic defibrillator. The WCD can be a safe and effective tool for prevention of VT/VF related SCD events and is used in a variety of clinical situations where the risk of SCD is changing. Such situations include the early phase after acute myocardial infarction with poor left ventricular function (≤35%), after acute coronary revascularization procedures and reduced left ventricular ejection fraction (≤35%), acute heart failure and non-ischemic cardiomyopathy of uncertain duration and prior to medical therapy initiation. The WCD also has a role in patients waiting for heart transplantation or who need a ventricular-assist device and those who have an acute contra-indication to implantation such as active infection. This review discusses the technical aspects of the WCD, its potential clinical application and summarizes the currently available data on the WCD in different populations and future directions. [ABSTRACT FROM AUTHOR]

Aims The SCORE risk estimation system is used for cardiovascular risk stratification in apparently healthy adults and is based on known cardiovascular risk factors. The purpose of the current study was to evaluate whether exercise capacity can improve the accuracy of the SCORE overall survival risk estimation. Methods and results We investigated 22 878 asymptomatic men and women who were annually screened in a tertiary medical centre. All subjects were free of known ischaemic heart disease, and had completed maximal exercise stress test according to the Bruce protocol. The SCORE risk estimation system was used to evaluate individual cardiovascular risk for all subjects. The primary endpoint was mortality, after exclusion of patients with metastatic cancer during follow-up. The incremental contribution of exercise capacity in predicting the risk of death was evaluated by net reclassification improvement (NRI) and area under the receiver operating curve (AUROC). Mean age of the study population was 47.4±10.3, and 71.6% were men. There were 505 (2.21%) deaths during a mean follow-up of 9.2±4.1 years. Kaplan-Meier survival analysis showed that both SCORE and low exercise capacity were associated with reduced survival. When added to the SCORE risk prediction, exercise capacity allowed more accurate risk stratification: NRI analysis showed an overall improvement of 56.8% in the accuracy of classification and the AUROC increased (0.782 vs. 0.766). Conclusion Both SCORE and exercise capacity are strong independent predictors of all-cause mortality. The addition of exercise capacity to the SCORE risk model can improve the accuracy of the model. [ABSTRACT FROM AUTHOR]

Extravascular lung water (EVLW) is a key variable in heart failure management and prognosis, but its objective assessment remains elusive. Lung imaging has been traditionally considered off-limits for ultrasound techniques due to the acoustic barrier of high-impedance air wall. In pulmonary congestion however, the presence of both air and water creates a peculiar echo fingerprint. Lung ultrasound shows B-lines, comet-like signals arising from a hyper-echoic pleural line with a to-and-fro movement synchronized with respiration. Increasing EVLW accumulation changes the normal, no-echo signal (black lung, no EVLW) into a black-and-white pattern (interstitial sub-pleural oedema with multiple B-lines) or a white lung pattern (alveolar pulmonary oedema) with coalescing B-lines. The number and spatial extent of B-lines on the antero-lateral chest allows a semi-quantitative estimation of EVLW(from absent, =5, to severe pulmonary oedema, .30 B-lines).Wet B-lines are made by water and decreased by diuretics, which cannot modify dry B-lines made by connective tissue. B-lines can be evaluated anywhere (including extreme environmental conditions with pocket size instruments to detect high-altitude pulmonary oedema), anytime (during dialysis to titrate intervention), by anyone (even a novice sonographer after 1 h training), and on anybody (since the chest acoustic window usually remains patent when echocardiography is not feasible). Cardiologists can achieve much diagnostic gain with little investment of technology, training, and time. B-lines represent 'the shape of lung water'. They allow non-invasive detection, in real time, of even sub-clinical forms of pulmonary oedema with a low cost, radiation-free approach. [ABSTRACT FROM AUTHOR]

Left ventricular ejection fraction (LVEF) has been the central parameter used for diagnosis and management in patients with heart failure. A good predictor of adverse outcomes in heart failure when below ~45%, LVEF is less useful as a marker of risk as it approaches normal. As a measure of cardiac function, ejection fraction has several important limitations. Calculated as the stroke volume divided by end-diastolic volume, the estimation of ejection fraction is generally based on geometric assumptions that allow for assessment of volumes based on linear or two-dimensional measurements. Left ventricular ejection fraction is both preload- and afterload-dependent, can change substantially based on loading conditions, is only moderately reproducible, and represents only a single measure of risk in patients with heart failure. Moreover, the relationship between ejection fraction and risk in patients with heart failure is modified by factors such as hypertension, diabetes, and renal function. A more complete evaluation and understanding of left ventricular function in patients with heart failure requires a more comprehensive assessment: we conceptualize an integrative approach that incorporates measures of left and right ventricular function, left ventricular geometry, left atrial size, and valvular function, as well as non-imaging factors (such as clinical parameters and biomarkers), providing a comprehensive and accurate prediction of risk in heart failure. [ABSTRACT FROM AUTHOR]

Aims Pulmonary congestion is a common and important finding in heart failure (HF). While clinical examination and chest radiography are insensitive, lung ultrasound (LUS) is a novel technique that may detect and quantify subclinical pulmonary congestion. We sought to independently relate LUS and clinical findings to 6-month HF hospitalizations and all-cause mortality (composite primary outcome). Methods We used LUS to examine 195 NYHA class II-IV HF patients (median age 66, 61% men, 74% white, ejection fraction 34%) during routine cardiology outpatient visits. Lung ultrasound was performed in eight chest zones with a pocket ultrasound device (median exam duration 2 min) and analysed offline. Results In 185 patients with adequate LUS images in all zones, the sum of B-lines (vertical lines on LUS) ranged from 0 to 13. Blines, analysed by tertiles, were associated with clinical and laboratory markers of congestion. Thirty-two per cent of patients demonstrated ≥3 B-lines on LUS, yet 81% of these patients had no findings on auscultation. During the followup period, 50 patients (27%) were hospitalized for HF or died. Patients in the third tertile (≥3 B-lines) had a four-fold higher risk of the primary outcome (adjusted HR 4.08, 95% confidence interval, CI 1.95, 8.54; P < 0.001) compared with those in the first tertile and spent a significantly lower number of days alive and out of the hospital (125 days vs. 165 days; adjusted P < 0.001). Conclusions Pulmonary congestion assessed by ultrasound is prevalent in ambulatory patients with chronic HF, is associated with other features of clinical congestion, and identifies those who have worse prognosis. [ABSTRACT FROM AUTHOR]

Aims Global measures of left ventricular (LV) function, in particular LV ejection fraction (LVEF) and global myocardial strain measures, are powerful predictors of outcomes in patients with LV dysfunction, heart failure, or both. However, less is known about the relationship between regional myocardial function, especially that assessed by strain echocardiography and clinical prognosis. Methods and results We studied 248 patients with LV dysfunction, heart failure, or both 5 days after first myocardial infarction (MI) from the VALIANT study.We assessed peak longitudinal strain (LS) via B-mode speckle tracking in 12 segments from the apical 4- and 2-chamber views and visually assessed LV wall motion score (WMS). We related these measures of regional myocardial function to each other and to clinical outcomes over 20-month follow-up. Normal reference values for segmental LS were derived from 50 healthy controls. Regional LS (27.7%, Q1: -11.2%, Q3: -4.9%) was worse in segments with abnormal WMS, although was significantly impaired even in segments scored as normokinetic compared with normal controls (-10.4±5.2% vs. -20.0±7.6%, P < 0.001). In multivariable Cox proportional hazards models, each additional abnormal LS segment was associated with an increased risk of all-cause mortality (hazard ratio: 1.42, 95% confidence interval: 1.06-1.90, P = 0.02) even after adjustment for clinical covariates, including LVEF, LV endsystolic volume, and number of abnormal segments by WMS. Conclusion In patients with LV dysfunction, heart failure, or both after MI, regional LS is significantly depressed even in segments with normal WMS, and this measure was related to adverse outcome. [ABSTRACT FROM AUTHOR]

Aims Patients with type 2 diabetes mellitus (T2DM) are at high risk of developing cardiovascular (CV) and renal disease.We examined the burden of, and risk of death following, CV and renal events in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), a randomized trial of alikiren vs. placebo. Methods and results We followed 8561 patients with T2DM and evidence of chronic kidney disease, CV disease, or both in ALTITUDE until the first non-fatal CV or renal event of myocardial infarction (MI), stroke, heart failure (HF), and end-stage renal disease (ESRD; initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL) and then to death or censoring. Time-updated multivariable Cox models were used to estimate the relative risk of death following each event. In total 1008 patients (12%) experienced at least one first non-fatal CV or renal event (4.1% HF, 2.8% MI, 2.8% stroke, and 2.2% ESRD). Death occurred subsequently in 26.4% of those experiencing a first HF event, 29.7% of those experiencing an MI event, 23.7% of those experiencing a stroke, and 14.7% of those experiencing ESRD, and in 6.5% (488) of the 7553 patients (88%) who did not experience a non-fatal CV or renal event. Compared with patients who did not experience a non-fatal event, the adjusted hazard ratiofor death was 5.9 (95% confidence interval 4.6-7.6) after HF, 9.7 (7.5-12.6) after MI, 7.1 (5.3-9.5) after stroke, and 5.8 (3.7-9.0) after ESRD. Conclusion The majority of deaths occurred in patients who did not experience a non-fatal CV or renal event, although the risk of death was higher following an event. Our findings illustrate continuing opportunities to reduce morbidity and mortality in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the prospective comparison of ARNI with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of LCZ696 on mode of death. Methods and results PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure, New York Heart Association Class II-IV symptoms, and left ventricular ejection fraction ≤40% receiving guidelinerecommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72-0.89, P < 0.001). Among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68-0.94, P = 0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64-0.98, P = 0.034) were reduced by treatment with LCZ696 compared with enalapril. Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and distributed evenly between treatment groups, as were non-cardiovascular deaths. Conclusions LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths. [ABSTRACT FROM AUTHOR]

Background Patients who have both atrial fibrillation (AF) and renal failure have an increased risk of thrombo-embolism. Renal failure is also a risk factor for bleeding, which makes decisions regarding thromboprophylaxis complicated. Our aim was to determine risks for ischaemic stroke and bleeding in patients with AF and renal failure in relation to anticoagulant strategies. Methods and results This is retrospective non-randomized study of Swedish health registers comprising 307 351 patients with AF, of whom 13 435 had a previous diagnosis of renal failure. Ischaemic stroke occurred more often in AF patients with renal failure (annual rate, 3.9% vs. no renal failure, 2.9%), but this was related to concomitant comorbidities [adjusted hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.95–1.10]. Conclusions Patients with both AF and renal failure will probably benefit most from having the same treatment as is recommended for other patients with AF, without setting a higher or lower threshold for treatment. Adding additional points for renal failure to the CHADS2 and CHA2DS2-VASc scores did not improve their predictive value. [ABSTRACT FROM PUBLISHER]

Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds. [ABSTRACT FROM PUBLISHER]

Aims Diastolic dysfunction in acute myocardial infarction (MI) is associated with adverse outcome. Recently, the ratio of early mitral inflow velocity (E) to global diastolic strain rate (e′sr) has been proposed as a marker of elevated LV filling pressure. However, the prognostic value of this measure has not been demonstrated in a large-scale setting when existing parameters of diastolic function are known. We hypothesized that the E/e′sr ratio would be independently associated with an adverse outcome in patients with MI. Methods and results We prospectively included patients with MI and performed echocardiography with comprehensive diastolic evaluation including E/e′sr. The relationship between E/e′sr and the primary composite endpoint (all-cause mortality, hospitalization for heart failure (HF), stroke, and new onset atrial fibrillation) was analysed with Cox models. A total of 1048 patients (mean age 63 ± 12, 73% male) were included and 142 patients (13.5%) reached the primary endpoint (median follow-up 29 months). A significant prognostic value was found for E/e′sr [hazard ratio (HR) per 1 unit change: 2.36, 95% confidence interval (CI): 2.02–2.75, P < 0.0001]. After multivariable adjustment E/e′sr remained independently related to the combined endpoint (HR per 1 unit change, 1.50; CI: 1.05–2.13, P = 0.02). The prognostic value of E/e′sr was driven by mortality (HR per 1 unit change, 2.52; CI: 2.09–3.04, P < 0.0001) and HF admissions (HR per 1 unit change, 2.79; CI: 2.23–3.48, P < 0.0001). Conclusion Deformation-based E/e′sr contributes important information about global myocardial relaxation superior to velocity-based analysis and is independently associated with the outcome in acute MI. [ABSTRACT FROM PUBLISHER]

Aims Limited data are available on long-term prognosis or causes-of-death analysis among survivors of acute myocardial infarction (MI) according to whether or not they developed ventricular fibrillation (VF) during the acute stage of MI. Methods and results Among 3670 MI patients hospitalized in France in 2005 and enrolled in this prospective follow-up cohort study, we assessed in-hospital mortality and 5-year cause of death among those who survived to hospital discharge, according to whether they developed VF (116 cases) or not, during the acute stage. 94.5% of patients had complete follow-up at 5 years. In-hospital mortality was significantly higher among VF patients (adjusted OR 7.38, 95% CI 4.27–12.75, P < 0.001). Among 3463 survivors at hospital discharge, 1024 died during a mean follow-up of 52 ± 2 months. The overall survival rate at 5 years was 74.4% (95% CI 72.8–76.0). In Cox multivariate analysis, occurrence of VF during the acute phase of MI was not associated with an increased mortality at 5 years (HR 0.78, 95% CI 0.38–1.58, P = 0.21). The distribution of causes of death at 5 years did not statistically differ according to the presence or absence of VF, especially for sudden cardiac death (13.1% in VF group vs.12.9% in non-VF group), despite a very low rate of implantation of cardioverter defibrillator in both groups (Overall rate 1.2%). Conclusion Patients developing VF in the setting of acute MI are at higher risk of in-hospital mortality. However, VF is not associated with a higher long-term all-cause or sudden cardiac death mortality. [ABSTRACT FROM PUBLISHER]

Aims Mechanical dyssynchrony has been postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF). Methods and results We quantified left ventricular (LV) systolic dyssynchrony in 130 HFpEF patients with NYHA class II-IV symptoms, ejection fraction (EF) ≥45%, and NT-proBNP levels >400 pg/mL enrolled in the PARAMOUNT trial, and compared them to 40 healthy controls of similar age and gender. Dyssynchrony was assessed by 2D speckle tracking as standard deviation (SD) of time to peak longitudinal systolic strain in 12 ventricular segments and related to measures of systolic and diastolic function. Heart failure with preserved ejection fraction patients (62% women, mean age of 71 ± 9 years, body mass index of 30.2 ± 5.9 kg/m2, systolic blood pressure 139 ± 15 mmHg) demonstrated significantly greater dyssynchrony than controls (SD of time to peak longitudinal strain; 90.6 ± 50.9 vs. 56.4 ± 33.5 ms, P < 0.001), even in the subset of patients (n = 63) with LVEF ≥55% and narrow QRS (≤100 ms). Among HFpEF patients, dyssynchrony was related to wider QRS interval, higher LV mass, and lower early diastolic tissue Doppler myocardial velocity (E′). Greater dyssynchrony remained significantly associated with worse diastolic function even after restricting the analysis to patients with EF≥55% and adjusting for age, gender, systolic blood pressure, LV mass index, and LVEF. Conclusion Heart failure with preserved EF is associated with greater mechanical dyssynchrony compared with healthy controls of similar age and gender. Within an HFpEF population, the severity of dyssynchrony is related to the width of QRS complex, LV hypertrophy, and diastolic dysfunction. [ABSTRACT FROM PUBLISHER]

In part II of this review, we describe the epidemiology and clinical consequences of vascular disease in patients with diabetes, and discuss the efficacy of risk factor modification and antiplatelet treatment. Specifically, evidence-based cardiovascular therapies are discussed through novel clinical insights on management of hyperglycaemia, hypertension, dyslipidaemia as well as platelet dysfunction. Recent trends in the incidence and outcomes of vascular disease in diabetes suggest that timely and effective implementation of therapies is making a favourable impact. [ABSTRACT FROM PUBLISHER]

Aims Left ventricular (LV) circumferential strain (Ecc) is a sensitive index of regional myocardial function. Currently, no studies have assessed its prognostic value in general population. We sought to investigate whether Ecc has a prognostic value for predicting incident heart failure (HF) and other major cardiovascular events in asymptomatic individuals without a history of previous cardiovascular diseases. Methods and results We, prospectively, assessed incident HF and atherosclerotic events during a 5.5 ± 1.3-year period in 1768 asymptomatic individuals aged 45–84 (mean age 65 years; 47% female) who underwent tagged magnetic resonance imaging for strain determination. During the follow-up period, 39 (2.2%) participants experienced incident HF and 108 (6.1%) participants had atherosclerotic cardiovascular events. Average of peak Ecc of 12-LV segments (Ecc-global) and mid-slice (Ecc-mid) was −17.0 ± 2.4 and −17.5 ± 2.7%, respectively. Participants with average absolute Ecc-mid lower than −16.9% had a higher cumulative hazard of incident HF (log-rank test, P = 0.001). In cox regression analysis, Ecc-mid predicted incident HF independent of age, diabetes status, hypertension, interim myocardial infarction, LV mass index, and LV ejection fraction (hazard ratio 1.15 per 1%, 95% CI: 1.01–1.31, P = 0.03). This relationship remained significant after adjustment for LV-end-systolic wall stress into covariates. In addition, by adding Ecc-mid to risk factors, LV ejection fraction, and the LV mass index, both the global χ2 value (76.6 vs. 82.4, P = 0.04) and category-less net-reclassification index (P = 0.01, SE = 0.18, z = 2.53) were augmented for predicting HF. Circumferential strain was also significantly related to the composite atherosclerotic cardiovascular events, but its relationship was attenuated after introducing the LV mass index. Conclusion Circumferential shortening provides robust, independent, and incremental predictive value for incident HF in asymptomatic subjects without any history of previous clinical cardiovascular disease. Clinical Trial Registration http://www.clinicaltrials.gov. Unique identifier: NCT00005487. [ABSTRACT FROM PUBLISHER]

The benefit of implantable cardioverter-defibrillator (ICD) therapy depends upon appropriate evaluation of a persisting risk of sudden death and estimation of the patient's overall survival. Assessment of a stable and unchangeable arrhythmogenic substrate is often difficult. Structural abnormality and ventricular dysfunction, the two major risk parameters, may recover, and heart failure symptoms can improve so that ICD therapy may not be indicated. Risk stratification can take time while the patient continues to be at high risk of arrhythmic death, and patients may need temporary bridging by a defibrillator in cases of interrupted ICD therapy. The wearable cardioverter-defibrillator (WCD) combines a long-term electrocardiogram (ECG)-monitoring system with an external automatic defibrillator. The LIfeVest® (ZOLL, Pittsburgh, PA, USA) is composed of a garment, containing two defibrillation patch electrodes on the back, and an elastic belt with a front-defibrillation patch electrode and four non-adhesive ECG electrodes, connected to a monitoring and defibrillation unit. The WCD is a safe and effective tool to terminate ventricular tachycardia/ventricular fibrillation events, unless a conscious patient withholds shock delivery. It may be used in patients in the early phase after acute myocardial infarction with poor left ventricular function, after acute coronary revascularization procedures (percutaneous coronary intervention or coronary artery bypass grafting) and reduced left ventricular ejection fraction (≤35%), in patients with acute heart failure in non-ischaemic cardiomyopathy of uncertain aetiology and prognosis. The WCD may be helpful in subjects with syncope of assumed tachyarrhythmia origin or in patients with inherited arrhythmia syndromes. The WCD may replace ICD implantation in patients waiting for heart transplantation or who need a ventricular-assist device. This review describes the technical details and characteristics of the WCD, discusses its various potential applications, and reports the currently available experience with the wearable defibrillator. [ABSTRACT FROM PUBLISHER]

Aims Digoxin is frequently used for rate control of atrial fibrillation (AF). It has, however, been associated with increased mortality. It remains unclear whether digoxin itself is responsible for the increased mortality (toxic drug effect) or whether it is prescribed to sicker patients with inherently higher mortality due to comorbidities. The goal of our study was to determine the relationship between digoxin and mortality in patients with AF. Methods and results The association between digoxin and mortality was assessed in patients enrolled in the AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial using multivariate Cox proportional hazards models. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF), as defined by a history of HF and/or an ejection fraction <40%. Digoxin was associated with an increase in all-cause mortality [estimated hazard ratio (EHR) 1.41, 95% confidence interval (CI) 1.19–1.67, P < 0.001], cardiovascular mortality (EHR 1.35, 95% CI 1.06–1.71, P = 0.016), and arrhythmic mortality (EHR 1.61, 95% CI 1.12–2.30, P = 0.009). The all-cause mortality was increased with digoxin in patients without or with HF (EHR 1.37, 95% CI 1.05–1.79, P = 0.019 and EHR 1.41, 95% CI 1.09–1.84, P = 0.010, respectively). There was no significant digoxin–gender interaction for all-cause (P = 0.70) or cardiovascular (P = 0.95) mortality. Conclusion Digoxin was associated with a significant increase in all-cause mortality in patients with AF after correcting for clinical characteristics and comorbidities, regardless of gender or of the presence or absence of HF. These findings call into question the widespread use of digoxin in patients with AF. [ABSTRACT FROM PUBLISHER]

Aims To evaluate the effects of cardiac resynchronization therapy (CRT) on long-term survival of patients without baseline left ventricular (LV) mechanical dyssynchrony. Methods and results A total of 290 heart failure patients (age 67 ± 10 years, 77% males) without significant baseline LV dyssynchrony (<60 ms as assessed with tissue Doppler imaging) were treated with CRT. Patients were divided according to the median LV dyssynchrony measured after 48 h of CRT into two groups. All-cause mortality was compared between the subgroups. In addition, the all-cause mortality rates of these subgroups were compared with the all-cause mortality of 290 heart failure patients treated with CRT who showed significant LV dyssynchrony (≥60 ms) at baseline. In the group of patients without significant LV dyssynchrony, median LV dyssynchrony increased from 22 ms (inter-quartile range 16–34 ms) at baseline to 40 ms (24–56 ms) 48 h after CRT. The cumulative mortality rates at 1-, 2-, and 3-year follow-up of patients with LV dyssynchrony ≥40 ms 48 h after CRT implantation were significantly higher when compared with patients with LV dyssynchrony <40 ms (10, 17, and 23 vs. 3, 8, and 10%, respectively; log-rank P< 0.001). Finally, the cumulative mortality rates at 1-, 2-, and 3-year follow-up of patients with baseline LV dyssynchrony were 3, 8, and 11%, respectively (log-rank P= 0.375 vs. patients with LV dyssynchrony <40 ms). Induction of LV dyssynchrony after CRT was an independent predictor of mortality (hazard ratio: 1.247; P= 0.009). Conclusion In patients without significant LV dyssynchrony, the induction of LV dyssynchrony after CRT may be related to a less favourable long-term outcome. [ABSTRACT FROM PUBLISHER]

Aims To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT. Methods and results We studied 761 patients in New York Heart Association I/II, ejection fraction ≤30%, and QRS ≥130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, −29 ± 83 ms and −1 ± 2.9%. However, both LV dyssynchrony (CRT-D: −47 ± 83 ms vs. ICD: −6 ± 76 ms, P < 0.001) and contractile function (CRT-D: −1.4 ± 3.1% vs. ICD: −0.4 ± 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001). Conclusion Cardiac resynchronization therapy resulted in a significant improvement in both LV dyssynchrony and contractile function measured by GLS compared with ICD only and these improvements were associated with better subsequent outcomes. [ABSTRACT FROM PUBLISHER]