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Measuring the treatment effect on recurrent events like hospitalization in the presence of death has long challenged statisticians and clinicians alike. Traditional inference on the cumulative frequency unjustly penalizes survivorship as longer survivors also tend to experience more adverse events. Expanding a recently suggested idea of the "while‐alive" event rate, we consider a general class of such estimands that adjust for the length of survival without losing causal interpretation. Given a user‐specified loss function that allows for arbitrary weighting, we define as estimand the average loss experienced per unit time alive within a target period and use the ratio of this loss rate to measure the effect size. Scaling the loss rate by the width of the corresponding time window gives us an alternative, and sometimes more photogenic, way of showing the data. To make inferences, we construct a nonparametric estimator for the loss rate through the cumulative loss and the restricted mean survival time and derive its influence function in closed form for variance estimation and testing. As simulations and analysis of real data from a heart failure trial both show, the while‐alive approach corrects for the false attenuation of treatment effect due to patients living longer under treatment, with increased statistical power as a result. The proposed methods are implemented in the R‐package WA, which is publicly available from the Comprehensive R Archive Network (CRAN). [ABSTRACT FROM AUTHOR]

Aims We investigated the prevalence and clinical value of assessing multi-organ congestion by ultrasound in heart failure (HF) outpatients. Methods and results Ultrasound congestion was defined as inferior vena cava of ≥21 mm, highest tertile of lung B-lines, or discontinuous renal venous flow. Associations with clinical characteristics and prognosis were explored. We enrolled 310 HF patients [median age: 77 years, median NT-proBNP: 1037 ng/L, 51% with a left ventricular ejection fraction (LVEF) <50%], and 101 patients without HF. There were no clinical signs of congestion in 224 (72%) patients with HF, of whom 95 (42%) had at least one sign of congestion by ultrasound (P < 0.0001). HF patients with ≥2 ultrasound signs were older, and had greater neurohormonal activation, lower urinary sodium concentration, and larger left atria despite similar LVEF. During a median follow-up of 13 (interquartile range: 6–15) months, 77 patients (19%) died or were hospitalized for HF. HF patients without ultrasound evidence of congestion had a similar outcome to patients without HF [reference; hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.86–1.35], while those with ≥2 ultrasound signs had the worst outcome (HR 26.7, 95% CI 12.4–63.6), even after adjusting for multiple clinical variables and NT-proBNP. Adding multi-organ assessment of congestion by ultrasound to a clinical model, including NT-proBNP, provided a net reclassification improvement of 28% (P = 0.03). Conclusion Simultaneous assessment of pulmonary, venous, and kidney congestion by ultrasound is feasible, fast, and identifies a high prevalence of sub-clinical congestion associated with poor outcomes. [ABSTRACT FROM AUTHOR]

Background Timely diagnosis of heart failure (HF) is essential to optimize treatment opportunities that improve symptoms, quality of life, and survival. While most patients consult their general practitioner (GP) prior to HF, the early stages of HF may be difficult to identify. An integrated clinical support tool may aid in identifying patients at high risk of HF. We therefore constructed a prediction model using routine health care data. Methods Our study involved a dynamic cohort of patients (≥35 years) who consulted their GP with either dyspnoea and/or peripheral oedema within the Amsterdam metropolitan area from 2011 to 2020. The outcome of interest was incident HF, verified by an expert panel. We developed a regularized, cause-specific multivariable proportional hazards model (TARGET-HF). The model was evaluated with bootstrapping on an isolated validation set and compared to an existing model developed with hospital insurance data as well as patient age as a sole predictor. Results Data from 31,905 patients were included (40% male, median age 60 years) of whom 1,301 (4.1%) were diagnosed with HF over 124,676 person-years of follow-up. Data were allocated to a development (n  = 25,524) and validation (n  = 6,381) set. TARGET-HF attained a C-statistic of 0.853 (95% CI, 0.834 to 0.872) on the validation set, which proved to provide a better discrimination than C = 0.822 for age alone (95% CI, 0.801 to 0.842, P  < 0.001) and C = 0.824 for the hospital-based model (95% CI, 0.802 to 0.843, P  < 0.001). Conclusion The TARGET-HF model illustrates that routine consultation codes can be used to build a performant model to identify patients at risk for HF at the time of GP consultation. [ABSTRACT FROM AUTHOR]

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: The aim of this study is to evaluate whether the MADIT-ICD benefit score can predict who benefits most from the addition of implantable cardioverter-defibrillator (ICD) to cardiac resynchronization therapy (CRT) in real-world patients with heart failure with reduced ejection fraction (HFrEF) and to compare this with selection according to a multidisciplinary expert centre approach.Methods and Results: Consecutive HFrEF patients who received a CRT for a guideline indication at a tertiary care hospital (Ziekenhuis Oost-Limburg, Genk, Belgium) between October 2008 and September 2016, were retrospectively evaluated. The MADIT-ICD benefit groups (low, intermediate, and high) were compared with the current multidisciplinary expert centre approach. Endpoints were (i) sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and (ii) non-arrhythmic mortality. Of the 475 included patients, 165 (34.7%) were in the lowest, 220 (46.3%) in the intermediate, and 90 (19.0%) in the highest benefit group. After a median follow-up of 34 months, VT/VF occurred in 3 (1.8%) patients in the lowest, 9 (4.1%) in the intermediate, and 13 (14.4%) in the highest benefit group (P < 0.001). Vice versa, non-arrhythmic death occurred in 32 (19.4%) in the lowest, 32 (14.6%) in the intermediate, and 3 (3.3%) in the highest benefit group (P = 0.002). The predictive power for ICD benefit was comparable between expert multidisciplinary judgement and the MADIT-ICD benefit score: Uno's C-statistic 0.69 vs. 0.69 (P = 0.936) for VT/VF and 0.62 vs. 0.60 (P = 0.790) for non-arrhythmic mortality.Conclusion: The MADIT-ICD benefit score can identify who benefits most from CRT-D and is comparable with multidisciplinary judgement in a CRT expert centre. [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]

Aims Elevated left ventricular filling pressure (LVFP) is a powerful indicator of worsening clinical outcomes in heart failure with preserved ejection fraction (HFpEF); however, detection of elevated LVFP is often challenging. This study aimed to determine the association between the newly proposed echocardiographic LVFP parameter, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score, and clinical outcomes of HFpEF. Methods and results We retrospectively investigated 310 well-differentiated HFpEF patients in stable conditions. VMT was scored from 0 to 3 using two-dimensional echocardiographic images, and VMT ≥2 was regarded as a sign of elevated LVFP. The primary endpoint was a composite of cardiac death or heart failure hospitalization during the 2 years after the echocardiographic examination. In all patients, Kaplan–Meier curves showed that VMT ≥2 (n  = 54) was associated with worse outcomes than the VMT ≤1 group (n  = 256) (P  < 0.001). Furthermore, VMT ≥2 was associated with worse outcomes when tested in 100 HFpEF patients with atrial fibrillation (AF) (P  = 0.026). In the adjusted model, VMT ≥2 was independently associated with the primary outcome (hazard ratio 2.60, 95% confidence interval 1.46–4.61; P  = 0.001). Additionally, VMT scoring provided an incremental prognostic value over clinically relevant variables and diastolic function grading (χ 2 10.8–16.3, P  = 0.035). Conclusions In patients with HFpEF, the VMT score was independently and incrementally associated with adverse clinical outcomes. Moreover, it could also predict clinical outcomes in HFpEF patients with AF. [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.

Background B-lines have been associated with adverse clinical outcomes in patients with heart failure (HF) when found at hospital discharge or during outpatient visits. Whether lung ultrasound (LUS) assessed B-lines may predict in-hospital mortality in patients with acute HF is still undetermined. Aim To evaluate the association between B-lines on admission and in-hospital mortality among patients admitted with acute HF. Methods Hand-held LUS was used to examine patients with acute HF. LUS was performed in eight chest zones with a pocket ultrasound device and analyzed offline. The association between B-lines and in-hospital mortality was assessed using Cox regression models. Results We included 62 patients with median age 56 years, 69.4% men, and median left ventricle ejection fraction 25%. The sum of B-lines ranged from 0 to 53 (median 6.5). An optimal receiver operating characteristic-determined cut-off of ≥19 B-lines demonstrated a sensitivity of 57% and a specificity of 86% (area under the curve 0.788) for in-hospital mortality. The incremental prognostic value of LUS when compared with lung crackles or peripheral edema by integrated discrimination improvement was 12.96% (95% CI: 7.0–18.8, P  = 0.02). Patients with ≥19 B-lines had a 4-fold higher risk of in-hospital mortality (HR 4.38; 95% CI: 1.37–13.95, P   <  0.01). Conclusion In patients admitted with acute HF, point-of-care LUS measurements of pulmonary congestion (B-lines) are associated with in-hospital mortality. [ABSTRACT FROM AUTHOR]

Aims Functional mitral regurgitation (FMR) is a well-known pathophysiological factor in heart failure (HF) patients, and left atrial function (LAF) is a novel determinant of clinical status and outcome in this setting. However, little is known about the pathophysiological role of FMR on LAF in HFrEF patients. Aim of this study is to explore the possible interplay between the severity of FMR and LAF in heart failure with reduce ejection fraction (HFrEF) patients and their possible consequences. Methods and results We studied 97 consecutive patients with FMR classified in two groups: mild-to-moderate MR ore less (FMR group, n = 38) and moderate-to-severe or more (SFMR group, n = 59). Using the phasic method, left atrial contractile, conduit, reservoir, and total emptying function (TLAEF) were calculated to assess LAF. SFMR group showed significantly lower values of LAF compared to FMR group. LA dysfunction (LA-dys) was defined for TLAEF values below the median and groups divided in four subgroups based on its presence. Patient with LA-Dys in SFMR group showed a worse clinical status, higher incidence of right ventricular dysfunction (RV-Dys), and pulmonary hypertension (PH), and a significant worse clinical survival compared to all other groups. Conclusion In our study, the survival was significantly lower in SFMR/LA-Dys+ group. Furthermore, LA-Dys was strongly related with worse clinical status and higher incidence of PH and RV-Dys. These results suggest that in patients with SFMR and HFrEF, LA-Dys may represent both a marker of more advanced disease and a novel prognostic factor. [ABSTRACT FROM AUTHOR]

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Background We aimed to determine if immune-unreactive albumin excretion (IURAE) is associated with cardiovascular (CV) events in a representative sample of a general population from Spain. Methods We included 1297 subjects (mean age ± standard error 48.0 ± 0.2 years, 48% females), who participated in the Hortega Follow-Up Study. The primary endpoint was incidence of fatal and non-fatal CV events. Urinary albumin excretion (UAE) was measured in spot voided urine, frozen at –80°C, by immunonephelometry [immune-reactive albumin excretion (IRAE)] and by high-performance liquid chromatography (HPLC) [total albumin excretion (AE)]. IURAE was calculated as the difference between HPLC measurements and IRAE. We estimated fully adjusted hazard ratios (HRs) of CV incidence by Cox regression for IRAE, IURAE and total AE. Results After an average at-risk follow-up of 13 years, we observed 172 CV events. urinary albumin to creatinine ratio (UACR) of ≥30 mg/g assessed by IRAE, IURAE or total AE concentrations was observed in 74, 273 and 417 participants, respectively. Among discordant pairs, there were 49 events in those classified as micro- and macroalbuminuric by IURAE, but normoalbuminuric by IRAE. Only the IRAE was a significant independent factor for the incidence of CV events [HR (95% confidence interval) 1.15 (1.04–1.27)]. The association of UAE with CV events was mainly driven by heart failure (HF) [HR 1.33 (1.15–1.55) for IRAE; HR 1.38 (1.06–1.79) for IURAE; HR 1.62 (1.22–2.13) for total AE]. Those subjects who were micro- and macroalbuminuric by both IRAE and IURAE had a significant increase in risk for any CV event, and especially for HF. Conclusions IRAE, IURAE and AE were associated with an increased risk for CV events, but IRAE offered better prognostic assessment. [ABSTRACT FROM AUTHOR]

Aims Heart failure (HF) has become an epidemic and constitutes a major medical, social, and economic problem worldwide. Despite advances in medical treatment, HF prognosis remains poor. The development of efficient therapies is hampered by the lack of appropriate animal models in which HF can be reliably determined, particularly in mice. The development of HF in mice is often assumed based on the presence of cardiac dysfunction, but HF itself is seldom proved. Lung ultrasound (LUS) has become a helpful tool for lung congestion assessment in patients at all stages of HF. We aimed to apply this non-invasive imaging tool to evaluate HF in mouse models of both systolic and diastolic dysfunction. Methods and results We used LUS to study HF in a mouse model of systolic dysfunction, dilated cardiomyopathy, and in a mouse model of diastolic dysfunction, diabetic cardiomyopathy. LUS proved to be a reliable and reproducible tool to detect pulmonary congestion in mice. The combination of LUS and echocardiography allowed discriminating those mice that develop HF from those that do not, even in the presence of evident cardiac dysfunction. The study showed that LUS can be used to identify the onset of HF decompensation and to evaluate the efficacy of therapies for this syndrome. Conclusions This novel approach in mouse models of cardiac disease enables for the first time to adequately diagnose HF non-invasively in mice with preserved or reduced ejection fraction, and will pave the way to a better understanding of HF and to the development of new therapeutic approaches. [ABSTRACT FROM AUTHOR]

The article presents an update on recommendations for left ventricular (LV) diastolic function by echocardiography from the American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI). Topics discussed include general principles for echocardiographic LV diastolic function assessment, diastolic dysfunction diagnosis in presence of normal LV ejection fraction (LVEF), and echocardiographic LV filling pressures and diastolic dysfunction grade assessment.

Background: Hip fracture (HF) is increasingly frequent with advancing age. Studies describing the HF incidence rate and survival after surgery in centenarians are scanty. To fill this gap, we performed a large population-based investigation on Lombardy centenarians (Italy).Methods: Retrospective observational cohort study based on information from the Healthcare Utilization Database. Among the cohort of 7,830 residents that reached 100 years of age between 2004 and 2011, incidence rate of HF was calculated. Two hundred fifty-nine patients were discharged alive from a hospital after HF and surgical repair (HF cohort). For each HF cohort member, a control was randomly selected from the initial cohort to be matched for gender and date of birth, and who did not experience HF from the date of their hundredth birthday until the date of hospital discharge of the corresponding HF cohort member. The survival curves and the hazard functions of HF and control cohort were calculated within 2 years.Results: Over a mean follow-up of 1.85 years, HF incidence rate was 23.1 per 1,000 centenarians per year. Survival probability was significantly lower in HF cohort than in control cohort (31.5 vs 48.1%, p < .001). Hazard functions showed an increased risk of death in HF cohort than in control cohort, especially in the 3 months after surgery.Conclusion: Survival analysis exhibited an excess mortality in the first 3 months among HF cohort members, but not beyond this period. Every effort to counteract HF is warranted, including prevention of falls and high quality of care, especially in the early postsurgical time. [ABSTRACT FROM AUTHOR]

Aims: It is not known whether heart failure (HF) patients with prolonged QRS who undergo cardiac resynchronization therapy combined with a defibrillator (CRT-D) have a prognostic advantage over HF patients with narrow QRS (therefore without indication for CRT) treated with an implantable cardioverter defibrillator (ICD) only. The aim of this study was to compare the long-term mortality of a group of HF patients with prolonged QRS receiving CRT-D with that of a similar group of patients with narrow QRS receiving ICD only.Methods and Results: A total of 312 patients (mean age 66 ± 13 years; 84% male, mean left ventricular ejection fraction 25 ± 4%, mean New York Heart Association class 2.6 ± 0.5) were included in the analysis. Of these, 138 with a QRS complex duration ≥120 ms received a CRT-D. During follow-up, the time and cause of death were assessed. During a median follow-up of 46 months, CRT-D patients showed significantly lower overall mortality (P = 0.038). Compared with patients receiving ICD only, CRT-D patients showed lower HF mortality (P = 0.003). Coronary mortality, non-cardiac mortality, and sudden mortality were similar in both groups (all P > 0.05). A positive response to CRT was an independent predictor of reduced mortality on multivariate analysis (hazard ratio: 0.27; P = 0.047).Conclusion: In HF patients treated with ICD, the subgroup of patients with prolonged QRS who receive CRT-D displays better long-term survival than narrow QRS ICD recipients, owing to their reduced HF mortality. [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: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure. However, prediction of the outcome remains difficult. We aimed to investigate for echocardiographic predictors of ventricular arrhythmias and fatal outcome and to explore how myocardial function is changed by biventricular pacing in heart failure. METHODS AND RESULTS: We prospectively included 170 heart failure patients (66 ± 10 years, New York Heart Association class 2.8 ± 0.5, 48% ischaemic cardiomyopathy) and recorded ventricular arrhythmias and fatal end point defined as death, heart transplantation, or left ventricular assist device implantation during 2 years. Two-dimensional echocardiography was performed before and 6 months after CRT implantation. CRT response was defined as ≥15% reduction in end-systolic volume at 6 months. Speckle-tracking technique was performed to assess longitudinal and circumferential left ventricular function, defined as global longitudinal (GLS) and circumferential strain (GCS), and to assess mechanical dyssynchrony, defined as mechanical dispersion. GLS before CRT was a predictor of fatal end point independently of CRT response [hazard ratio, HR 1.14 (1.02-1.27), P = 0.02]. Patients with GLS better than -8.3% showed event-free survival benefit (log rank, P < 0.001). Mechanical dispersion at 6 months was an independent predictor of ventricular arrhythmias [HR 1.20 (1.06-1.35), P = 0.005]. CRT responders (59%) had improvement of both GLS and GCS. CONCLUSION: In heart failure patients with CRT, worse longitudinal function before CRT was an important predictor of fatal outcome during 2 years, independently of CRT response. Mechanical dispersion at 6 months was a strong predictor of ventricular arrhythmias. CRT response by reverse remodelling was dependent on improvement of both longitudinal and circumferential function. [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]

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]

Aims To investigate the relative importance of individual tissue Doppler imaging variables to predict adverse events in a high-risk population with diabetes, ischaemic heart disease, and/or systolic dysfunction. Methods and results Transthoracic echocardiograms were analysed in 388 diabetic patients without significant valve disease, bundle branch block, and atrial fibrillation who underwent coronary angiography. Multivariable Cox's regression analyses were used to establish the association between peak systolic (s′), early diastolic (e′), and late diastolic (a′) tissue velocities and outcomes (hospitalization for heart failure or death). The mean age and left ventricular ejection fraction (LVEF) was 66 ± 10 years and 45 ± 12%, respectively. During 2.3 (±1.0) years of follow-up, 91 patients (24%) met the combined endpoint. After adjustment for LVEF, coronary artery pathology, heart failure at baseline, age, and gender, each 1 cm/s decrease in s′, e′, and a′ was associated with a hazard ratio (HR) of 1.18 (0.89–1.57), 1.03 (0.86–1.22), and 1.20 (1.05–1.37), respectively. A significant interaction was found between s′ and a′, P < 0.01. In patients with lower than mean s′, 1 cm/s decrease in a′ was associated with HR 1.31 (1.10–1.55, P < 0.01), whereas a′ was without prognostic importance in patients with higher than mean s′ [HR 0.99 (0.78–1.25, P = 0.6)]. Patients having lower than mean values of both s′ and a′ had a poorer prognosis than patients having at least one of s′ and a′ high. Conclusion Peak systolic and late diastolic tissue velocities add prognostic information beyond LVEF in high-risk patients. Variables should be considered together as they interact on prognosis. [ABSTRACT FROM PUBLISHER]

Aims The purpose of this study was to test the hypothesis that left ventricular (LV) mechanical dyssynchrony deteriorates the longitudinal systolic and diastolic function of the left ventricle (LV) in patients with heart failure with a normal LV ejection fraction (HFNEF). Methods and results In patients with HFNEF and in a control group consisting of asymptomatic patients with LV diastolic dysfunction [LVDD], matched by age, gender, and LV ejection fraction, we assessed the global longitudinal systolic (global strain), diastolic [global early-diastolic strain rate (SRe)], and synchronous (standard deviation of time-to-peak systolic strain) function of the LV by two-dimensional speckle-tracking echocardiography using a 18-segment LV model. A total of 325 patients were included (85 with HFNEF and 240 with asymptomatic LVDD). Patients with HFNEF had a significant impairment of the longitudinal systolic and diastolic function of the LV as compared with the control group. Concerning the pathophysiological mechanisms linked to these findings, we found that HFNEF patients with asynchronous LV contractions had significantly more impaired longitudinal systolic and diastolic LV function (global strain −14.76 ± 3.44%, global SRe 0.79 ± 0.24 s−1) than patients without asynchronous LV contractions (global strain −18.57 ± 3.10%, global SRe 1.06 ± 0.32 s−1; all P < 0.0001). Accordingly, in HFNEF patients with LV mechanical dyssynchrony the rates of LV longitudinal systolic and diastolic dysfunction were 64 and 70%, respectively, whereas these rates were significantly lower (19.5 and 41.3%), respectively, in patients without asynchronous LV contractions. In addition, HFNEF patients with LV mechanical dyssynchrony presented higher LV filling pressures and worse NYHA functional class than those with normal LV contractions. Conclusion In patients with HFNEF, LV mechanical dyssynchrony is associated with an important impairment of the longitudinal systolic and diastolic function of the LV. Therefore, the restoration of asynchronous LV contractions could help to improve and/or correct both the systolic and the diastolic longitudinal dysfunction of the LV in HFNEF and thereby improve the symptomatology of these patients. [ABSTRACT FROM AUTHOR]

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]