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Aims The left atrium (LA) has a pivotal role in cardiac performance and LA deformation is a well-known prognostic predictor in several clinical conditions including heart failure with reduced ejection fraction. The aim of this study is to investigate the effect of cardiac resynchronization therapy (CRT) on both LA morphology and function and to assess the impact of LA reservoir strain (LARS) on left ventricular (LV) systolic and diastolic remodelling after CRT. Methods and results Two hundred and twenty-one CRT-candidates were prospectively included in the study in four tertiary centres and underwent echocardiography before CRT-implantation and at 6-month follow-up (FU). CRT-response was defined by a 15% reduction in LV end-systolic volume. LV systolic and diastolic remodelling were defined as the percent reduction in LV end-systolic and end-diastolic volume at FU. Indexed LA volume (LAVI) and LV-global longitudinal (GLS) strain were the main parameters correlated with LARS, with LV-GLS being the strongest determinant of LARS (r = −0.59, P < 0.0001). CRT induced a significant improvement in LAVI and LARS in responders (both P < 0.0001). LARS was an independent predictor of both LV systolic and diastolic remodelling at follow-up (r = −0.14, P = 0.049 and r = −0.17, P = 0.002, respectively). Conclusion CRT induces a significant improvement in LAVI and LARS in responders. In CRT candidates, the evaluation of LARS before CRT delivery is an independent predictor of LV systolic and diastolic remodelling at FU.

International audience; Aims In the heart failure (HF) with preserved ejection fraction (HFpEF) PARAGON-HF trial, sacubitril/valsartan vs. valsartan improved mortality/morbidity in patients with left ventricular ejection fraction (LVEF) below median (57%). We assessed eligibility for sacubitril/valsartan based on four scenarios. Methods and results Eligibility was assessed in the Karolinska-Rennes study (acute HFpEF, LVEF >= 45%, and N-terminal pro-B-type natriuretic peptide >= 300 pg/mL subsequently assessed as outpatients including echocardiography) in (i) a trial scenario (all trial criteria); (ii) a pragmatic scenario (selected trial criteria); (iii) LVEF below lower limit of normal range (= 45%) with N-terminal pro-B-type natriuretic peptide and cardiac structure/function assessed, eligibility for sacubitril/valsartan was according to PARAGON-HF complete criteria 34%, pragmatic criteria 63%, LVEF below lower limit of normal range 5.4%, and LVEF below mean of normal range 41%. Cardiac structural impairment was almost ubiquitous. Ineligibility was more due to exclusion criteria than failing to meet inclusion criteria.

International audience; Aims Echocardiographic predictors of outcomes in heart failure with preserved ejection fraction (HFpEF) have not been systematically or independently validated. We aimed at identifying echocardiographic predictors of cardiovascular events in a large cohort of patients with HFpEF and to validate these in an independent large cohort. Methods and results We assessed the association between echocardiographic parameters and cardiovascular outcomes in 515 patients with heart failure with preserved left ventricular (LV) ejection fraction (>50%) in the MEtabolic Road to DIAstolic Heart Failure (MEDIA) multicentre study. We validated out findings in 286 patients from the Karolinska-Rennes Prospective Study of HFpEF (KaRen). After multiple adjustments including N-terminal pro-brain natriuretic peptide (NT-proBNP), the significant predictors of death or cardiovascular hospitalization were pulmonary arterial systolic pressure > 40 mmHg, respiratory variation in inferior vena cava diameter > 0.5, E/e' > 9, and lateral mitral annular s' < 7 cm/s. The combination of these four variables differentiated patients with 35% 1 year risk. Adding these four echocardiographic variables on top of clinical variables and NT-proBNP yielded significant net reclassification improvement (33.8%, P < 0.0001) and increase in C-index (5.3%, a change from 72.2% to 77.5%, P = 0.015) of similar magnitude as the addition of NT-proBNP on top of clinical variables alone. In the KaRen cohort, these four variables yielded a similar improvement in net reclassification improvement (22.3%, P = 0.014) and C-index (4.0%, P = 0.029). Conclusions Use of four simple echocardiographic parameters (within the MEDIA echo score), indicative of pulmonary hypertension, elevated central venous pressure, LV diastolic dysfunction, and LV long-axis systolic dysfunction, independently predicted prognosis and improved risk stratification additionally to clinical variables and NT-proBNP in HFpEF. This finding was validated in an independent cohort.

Funding Acknowledgements Type of funding sources: None. Background Despite having all a systolic heart failure and broad QRS, patients proposed for cardiac resynchronization therapy (CRT) are highly heterogeneous and it remains extremely complicated to predict the impact of the device on left ventricular (LV) function and outcomes. Objectives We sought to evaluate the relative impact of clinical, electrocardiographic, and echocardiographic data on the left ventricular (LV) remodeling and prognosis of CRT-candidates by the application of machine learning (ML) approaches. Methods 193 patients with systolic heart failure undergoing CRT according to current recommendations were prospectively included in this multicentre study. We used a combination of the Boruta algorithm and random forest methods to identify features predicting both CRT volumetric response and prognosis (Figure 1). The model performance was tested by the area under the receiver operating curve (AUC). We also applied the K-medoid method to identify clusters of phenotypically-similar patients. Results From 28 clinical, electrocardiographic, and echocardiographic-derived variables, 16 features were predictive of CRT-response; 11 features were predictive of prognosis. Among the predictors of CRT-response, 7 variables (44%) pertained to right ventricular (RV) size or function. Tricuspid annular plane systolic excursion was the main feature associated with prognosis. The selected features were associated with a very good prediction of both CRT response (AUC 0.81, 95% CI: 0.74-0.87) and outcomes (AUC 0.84, 95% CI: 0.75-0.93) (Figure 1, Supervised Machine Learning Panel). An unsupervised ML approach allowed the identifications of two phenogroups of patients who differed significantly in clinical and parameters, biventricular size and RV function. The two phenogroups had significant different prognosis (HR 4.70, 95% CI: 2.1-10.0, p Conclusions Machine learning can reliably identify clinical and echocardiographic features associated with CRT-response and prognosis. The evaluation of both RV-size and function parameters has pivotal importance for the risk stratification of CRT-candidates and should be systematically assessed in patients undergoing CRT. Abstract Figure 1

Aims: Neuregulin1-β (NRG1-β) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1-β is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF). Methods and results: Circulating NRG1-β was quantified in 86 stable patients with HFpEF (EF ≥45% and N-terminal pro-brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1-β and the composite outcome of all-cause mortality/HF hospitalization in HFpEF and all-cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th–75th percentile) NRG1-β was 6.5 (2.1–11.3) ng/mL; in HFrEF, 3.6 (2.1–7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9–3.6) ng/mL; after HTx 2.1 (1.4–3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1–34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1-β was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04–2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1-β with outcomes was modified by ischaemia (log-rank P = 0.020; Pinteraction = 0.553) such that only in ischaemic patients, higher NRG1-β was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1-β trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48–1.05, P = 0.085). Conclusions: Neuregulin1-β was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1-β with outcomes in non-ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1-β from microvascular endothelial dysfunction in the former (non-ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).

International audience; Aims In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF. Methods and results MPO, MPO-related biomarkers, and echocardiography were assessed in 86 patients, 4-8 weeks after presentation with acute HF (EF >= 45%), and in 46 healthy controls. Patients were followed up for median 579 days (Q1;Q3 276;1178) regarding the composite endpoint all-cause mortality or HF hospitalization. Patients were 73 years old, 51% were female, EF was 64% (Q1;Q3 58;68), E/e ' was ratio 10.8 (8.3;14.0), and left atrial volume index (LAVI) was 43 mL/m(2) (38;52). Controls were 60 (57;62) years old (vs. patients; P < 0.001), 24% were female (P = 0.005), and left ventricular EF was 63% (59;66; P = 0.790). MPO was increased in HFpEF compared with controls, 101 (81;132) vs. 86 (74;101 ng/mL, P = 0.015), as was uric acid 369 (314;439) vs. 289 (252;328 mu mol/L, P < 0.001), calprotectin, asymmetric dimethyl arginine (ADMA), and symmetric dimethyl arginine (SDMA), while arginine was decreased. MPO correlated with uric acid (r = 0.26; P = 0.016). In patients with E/e ' > 14, uric acid and SDMA were elevated (421 vs. 344 mu M, P = 0.012; 0.54 vs. 0.47 mu M, P = 0.039, respectively), and MPO was 121 vs. 98 ng/mL (P = 0.090). The ratios of arginine/ADMA (112 vs. 162; P < 0.001) and ADMA/SDMA (1.36 vs. 1.17; P = 0.002) were decreased in HFpEF patients, suggesting reduced NO availability and increased enzymatic clearance of ADMA, respectively. Uric acid independently predicted the endpoint [hazard ratio (HR) 3.76 (95% CI 1.19-11.85; P = 0.024)] but not MPO [HR 1.48 (95% CI 0.70-3.14; P = 0.304)] or the other biomarkers. Conclusions In HFpEF, MPO-dependent oxidative stress reflected by uric acid and calprotectin is increased, and SDMA is associated with diastolic dysfunction and uric acid with outcome. This suggests microvascular neutrophil involvement mirroring endothelial dysfunction, a central component of the HFpEF syndrome and a potential treatment target.

Aims Left ventricular (LV) failure in left bundle branch block is caused by loss of septal function and compensatory hyperfunction of the LV lateral wall (LW) which stimulates adverse remodelling. This study investigates if septal and LW function measured as myocardial work, alone and combined with assessment of septal viability, identifies responders to cardiac resynchronization therapy (CRT). Methods and results In a prospective multicentre study of 200 CRT recipients, myocardial work was measured by pressure-strain analysis and viability by cardiac magnetic resonance (CMR) imaging (n = 125). CRT response was defined as ≥15% reduction in LV end-systolic volume after 6 months. Before CRT, septal work was markedly lower than LW work (P Conclusion Assessment of myocardial work and septal viability identified CRT responders with high accuracy.

International audience; Background - The first European Cardiac Resynchronization Therapy (CRT) Survey, conducted in 2008-2009, showed considerable variations in guideline adherence and implantation practice. A second prospective survey (CRT Survey II) was then performed to describe contemporary clinical practice regarding CRT among 42 European countries. Aim - To compare the characteristics of French CRT recipients with the overall European population of CRT Survey II. Methods - Demographic and procedural data from French centres recruiting all consecutive patients undergoing either de novo CRT implantation or an upgrade to a CRT system were collected and compared with data from the European population. Results - A total of 11,088 patients were enrolled in CRT Survey II, 754 of whom were recruited in France. French patients were older (44.7% aged≥75 years vs 31.1% in the European group), had less severe heart failure symptoms, a higher baseline left ventricular ejection fraction and fewer co-morbidities. Additionally, French patients had a shorter intrinsic QRS duration (19.1% had a QRS

Aims This study aims to assess prognostic impact of Framingham criteria for heart failure (FC‐HF) in patients with stable heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results In the prospective Karolinska‐Rennes (KaRen) study, we assessed stable HFpEF patients after an acute HF episode. We evaluated associations between the four descriptive models of HFpEF and the composite endpoint of all‐cause mortality and HF hospitalization. The descriptive models were FC‐HF alone, FC‐HF + natriuretic peptides (NPs) according to the PARAGON trial, FC‐HF + NPs + echocardiographic HFpEF criteria according to European Society of Cardiology HF guidelines, and FC‐HF + NPs + echocardiographic criteria according to the PARAGON trial. Out of the 539 patients enrolled in KaRen, 438 returned for the stable state revisit after 4–8 weeks, 13 (2.4%) patients died before the planned follow‐up, and 88 patients (16%) declined or were unable to return. Three hundred ninety‐nine patients have FC registered at follow‐up, and among these, the four descriptive models were met in 107 (27%), 82 (22%), 61 (21%), and 69 (22%) patients, and not met in 292 (73%). The 107 patients that had FC‐HF at stable state (descriptive model 1) could also be part of the other models because all patients in models 1–4 had to fulfil the FC‐HF. The patients in model 0 did not fulfil the criteria for FC‐HF but could have single FC. Of single FC, only pleural effusion predicted the endpoint [hazard ratio (HR) 3.38, 95% confidence interval (CI) 1.47–7.76, P = 0.004]. Patients without FC‐HF had better prognosis than patients meeting FC‐HF. The unadjusted associations between the four HFpEF descriptive models and the endpoint were HR 1.54, 95% CI 1.14–2.09, P = 0.005; HR 1.71, 95% CI 1.24–2.36, P = 0.002; HR 1.95, 95% CI 1.36–2.81, P = 0.001; and HR 2.05, 95% CI 1.45–2.91, P

International audience; Objectives - Soluble suppression of tumorigenecity 2 (sST2) is prognostic in acute and chronic heart failure with reduced ejection fraction (HFrEF) but less studied in HF with preserved EF (HFpEF). We evaluated sST2 concentrations, correlations with biomarkers and echocardiographic measures of diastolic and systolic function, and associations with outcomes in HFpEF and HFrEF. Design and results - A total of 193 subjects from three different cohorts were included. Eighty-six HFpEF patients were obtained from the Karolinska Rennes (KaRen) study, 86 patients with HFrEF were recruited from referrals to Karolinska University Hospital for advanced assessment of HF, and 21 controls were included (ClinicalTrials.gov Identifier for KaRen: NCT01091467). HFrEF and controls cohorts did not have ClinicalTrials.gov registrations. sST2 was lower in HFpEF, median (interquartile range); 23 (17-31) compared to HFrEF; 35 (23-52) µg/L, p

International audience; We aimed to characterize of the role of insulin-like growth factor-binding protein 7 (IGFBP-7) in heart failure (HT) pathophysiology. IGFBP-7 has been associated with cardiac hypertrophy and diastolic dysfunction in HF. In 86 patients with HF with a preserved ejection fraction (HFpEF) (ejection fraction [EF] >= 45%) and 79 with HF with a reduced ejection fraction (HFrEF), we assessed concentrations of serum IGFBP-7, correlations between serum IGFBP-7 and clinical data, diastolic function, and associations with outcome. IGFBP-7 was lower in HFpEF than HFrEF (102 vs 152 mu g/L, p

International audience; Aims - Left ventricular (LV) mechanics have been extensively investigated in heart failure with preserved ejection fraction (HFpEF) overshadowing for a long time the potential role of left atrium (LA) in that setting. Soluble suppression of tumorigenicity-2 receptor (ST2) is a novel biomarker of pro-fibrotic burden in HF. We hypothesized that due to the thinner LA wall, the fibrotic myocardial changes in HFpEF as indicated by elevated ST2 levels might more readily be reflected by impairments in the LA rather than the LV performance.Methods and results - In 86 patients with HFpEF, enrolled in the Karolinska Rennes (KaRen) biomarker prospective substudy, global LA strain (GL-LS) along with other echocardiographic as well as haemodynamic parameters and ST2 levels were measured. ST2 levels were inversely associated with LA-GS (r = -0.30, P = 0.009), but not with LA size, LV geometry, systolic or diastolic LV function (P > 0.05 for all). Furthermore, symptom severity correlated with ST2 and LA-GS, but not with LV structural or functional indices. Finally, during a median 18-month follow-up, LA-GS independently predicted the composite endpoint of HF hospitalization and all-cause mortality, even after adjustment for potential clinical and cardiac mechanical confounders, including LV global longitudinal strain and filling pressures (odds ratio: 4.15; confidence interval: 1.2-14, P = 0.023).Conclusions - Reduced LA-GS but not LV functional systolic and diastolic parameters were associated with the pro-fibrotic ST2 marker, HF symptoms and outcome in HFpEF.

International audience; BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) exhibits a "reverse metabolic profile". Whether this profile exists in HF with preserved ejection fraction (HFpEF) is unknown. We tested the hypothesis that HFpEF and HFrEF are similar regarding concentrations of and prognostic impact of leptin and adiponectin. METHODS: In patients with HFpEF(n=79), HFrEF(n=84), and controls(n=71), we analyzed serum leptin and adiponectin concentrations, their correlations, and associations with outcome. RESULTS: Leptin levels in HFpEF and HFrEF were increased (p

Background— Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. Methods and Results— In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3–like protein 1 (1.35), C–C motif chemokine 20 (1.35), fatty acid–binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF-related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e′) and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome. Conclusions— In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov ; Unique identifier: NCT00774709.

International audience; Introduction The prognostic value of atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFPEF) remains controversial. The objective of the KaRen (Karolinska-Rennes) sub-study was to explore this question. Methods KaRen was a prospective, multicenter, international, observational study intended to characterize HFPEF; 538 patients presenting acute decompensated cardiac failure with a left ventricular ejection fraction >45% were included. A physical exam as well as an EKG and an echocardiogram were scheduled 4-8 week following the index hospitalization, and the patients were evaluated at 6-month intervals. We compared clinical and echocardiographic characteristics of patients in sinus rhythm vs. patients with documented AF upon their 4-8-week visit. The primary study endpoint was death from any cause or first hospitalization for decompensated heart failure (HF). Results A total of 413 patients (244 patients in sinus rhythm and 134 in AF; 32% of overall population) were analyzed, with a mean follow-up period of 28 months. The patients were primarily elderly individuals (76.2 years), with a slight female predominance and a high prevalence of comorbidities. The baseline echo-cardiographic characteristics and the natriuretic peptide levels were indicative of a more severe heart condition among the patients with AF. However, the patients with AF exhibited a similar survival-free interval compared with the patients in sinus rhythm (p=0.89). Similar survival was observed according to patients’ heart rhythm on enrolment (decompensated HF) or according to patients’ cardiac history. Heart rate (stratified in tertiles), neurohormonal blockade or anticoagulant treatments at the 4-8-week visit were not independent predictors of outcome. Conclusion In this HFPEF population with a high prevalence of non-cardiovascular comorbidities, the presence of AF was not associated with a poorer prognosis despite impaired clinical and echocardiographic features

International audience; Background KaRen is a multicentre study designed to characterize and follow patients with heart failure and preserved ejection fraction (HFpEF). In a subgroup of patients with clinical signs of congestion but left ventricular ejection fraction (LVEF) \textgreater45%, we sought to describe and analyse the potential prognostic value of echocardiographic parameters recorded not only at rest but also during a submaximal exercise stress echocardiography. Exercise-induced changes in echo parameters might improve our ability to characterize HFpEF patients.Method and results Patients were prospectively recruited in a single tertiary centre following an acute HF episode with NT-pro-BNP \textgreater300 pg/mL (BNP \textgreater 100 pg/mL) and LVEF \textgreater 45% and reassessed by exercise echo-Doppler after 4–8 weeks of dedicated treatment. Image acquisitions were standardized, and analysis made at end of follow-up blinded to patients' clinical status and outcome. In total, 60 patients having standardized echocardiographic acquisitions were included in the analysis. Twenty-six patients (43%) died or were hospitalized for HF (primary outcome). The mean ± SD workload was 45 ± 14 watts (W). Mean ± SD resting LVEF and LV global longitudinal strain was 57.6 ± 9.5% and −14.5 ± 4.2%, respectively. Mean ± SD resting E/e′ was 11.3 ± 4.7 and 13.1 ± 5.3 in those patients who did not and those who did experience the primary outcome, respectively (P = 0.03). Tricuspid regurgitation (TR) peak velocity during exercise were 3.3 ± 0.5 and 3.7 ± 0.5 m/s (P = 0.01). Exercise TR was independently associated with HF-hospitalization or death after adjustment on baseline clinical and biological characteristics.Conclusion Exercise echocardiography may contribute to identify HFpEF patients and especially high-risk ones. Our study suggested a prognostic value of TR recorded during an exercise. That was demonstrated independently of the value of resting E/e′

Background Cardiac resynchronization therapy results in improved ejection fraction in patients with heart failure. We sought to determine whether these effects were mediated by changes in contractility, afterload, or volumes. Methods and Results In 610 patients with New York Heart Association class I/ II heart failure from the Re synchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction ( REVERSE ) study, we performed detailed quantitative echocardiography assessment prior to and following cardiac resynchronization therapy. We derived measures of contractility (the slope [end‐systolic elastance] and the volume intercept of the end‐systolic pressure–volume relationship, stroke work, and preload recruitable stroke work), measures of arterial load and ventricular–arterial coupling, and measures of chamber size (volume intercept, end‐systolic and end‐diastolic volumes). At 6 and 12 months, cardiac resynchronization therapy was associated with a reduction in the volume intercept and end‐systolic and end‐diastolic volumes ( P CI 1.04 to 1.63, P =0.02). The volume intercept was associated with mortality (hazard ratio 1.90, 95% CI 1.01 to 3.59, P =0.047) and more modestly with the combined end point of mortality or heart failure hospitalization (hazard ratio 1.48, 95% CI 0.8 to 2.25, P =0.06). In contrast, end‐systolic elastance, stroke work, preload recruitable stroke work, and ventricular–arterial coupling were not associated with any outcomes. Conclusion In patients with NYHA Class I/ II heart failure, cardiac resynchronization therapy exerts favorable changes in left ventricular end‐systolic and end‐diastolic volumes and the volume intercept. The volume intercept may be useful to gain insight into prognosis in heart failure. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00271154.

International audience; Background Cardiac resynchronization therapy (CRT) reduces mortality, improves functional status, and induces reverse left ventricular remodeling in selected populations with heart failure (HF). The magnitude of reverse remodeling predicts survival with many HF medical therapies. However, there are few studies assessing the effect of remodeling on long-term survival with CRT. Objective The purpose of this study was to assess the effect of CRT-induced reverse remodeling on long-term survival in patients with mildly symptomatic heart failure. Methods The REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction trial was a multicenter, double-blind, randomized trial of CRT in patients with mild HF. Long-term follow-up of 5 years was preplanned. The present analysis was restricted to the 353 patients who were randomized to the CRT ON group with paired echocardiographic studies at baseline and 6 months postimplantation. The left ventricular end-systolic volume index (LVESVi) was measured in the core laboratory and was an independently powered end point of the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction trial. Results A 68% reduction in mortality was observed in patients with ≥15% decrease in LVESVi compared to the rest of the patients (P = .0004). Multivariable analysis showed that the change in LVESVi was a strong independent predictor (P = .0002), with a 14% reduction in mortality for every 10% decrease in LVESVi. Other remodeling parameters such as left ventricular end-diastolic volume index and ejection fraction had a similar association with mortality. Conclusion The change in left ventricular end-systolic volume after 6 months of CRT is a strong independent predictor of long-term survival in mild HF

International audience; AIMS: For patients undergoing cardiac resynchronization therapy (CRT) with implantable cardioverter-defibrillator (ICD; CRT-D), the effect of an improvement in left ventricular ejection fraction (LVEF) on appropriate ICD therapy may have significant implications regarding management at the time of ICD generator replacement. METHODS AND RESULTS: We conducted a meta-analysis to determine the effect of LVEF recovery following CRT on the incidence of appropriate ICD therapy. A search of multiple electronic databases identified 709 reports, of which 6 retrospective cohort studies were included (n = 1740). In patients with post-CRT LVEF ≥35% (study n = 4), the pooled estimated rate of ICD therapy (5.5/100 person-years) was significantly lower than patients with post-CRT LVEF \textless35% [incidence rate difference (IRD): -6.5/100 person-years, 95% confidence interval (95% CI): -8.8 to -4.2, P \textless 0.001]. Similarly, patients with post-CRT LVEF ≥45% (study n = 4) demonstrated lower estimated rates of ICD therapy (2.3/100 person-years) compared with patients without such recovery (IRD: -5.8/100 person-years, 95% CI: -7.6 to -4.0, P \textless 0.001). Restricting analysis to studies discounting ICD therapies during LVEF recovery (study n = 3), patients with LVEF recovery (≥35 or ≥45%) had significantly lower rates of ICD therapy compared with patients without such recovery (P for both \textless0.001). Patients with primary prevention indication for ICD, regardless of LVEF recovery definition, had very low rates of ICD therapy (0.4 to 0.8/100-person years). CONCLUSION: Recovery of LVEF post-CRT is associated with significantly reduced appropriate ICD therapy. Patients with improvement of LVEF ≥45% and those with primary prevention indication for ICD appear to be at lowest risk

International audience; BACKGROUND: Karolinska Rennes (KaRen) is a prospective observational study to characterize heart failure patients with preserved ejection fraction (HFpEF) and to identify prognostic factors for long-term mortality and morbidity. AIMS: To report characteristics and echocardiography at entry and after 4-8 weeks of follow-up. METHODS: Patients were included following an acute heart failure presentation with B-type natriuretic peptide (BNP)\textgreater100 ng/L or N-terminal pro-BNP (NT-proBNP)\textgreater300 ng/L and left ventricular ejection fraction (LVEF)\textgreater45%. RESULTS: The mean ± SD age of 539 included patients was 77 ± 9 years and 56% were women. Patient history included hypertension (78%), atrial tachyarrhythmia (44%), prior heart failure (40%) and anemia (37%), but left bundle branch block was rare (3.8%). Median NT-proBNP was 2448 ng/L (n=438), and median BNP 429 ng/L (n=101). Overall, 101 patients did not return for the follow-up visit, including 13 patients who died (2.4%). Apart from older age (80 ± 9 vs. 76 ± 9 years; P=0.006), there were no significant differences in baseline characteristics between patients who did and did not return for follow-up. Mean LVEF was lower at entry than follow-up (56% vs. 62%; P\textless0.001). At follow-up, mean E/e' was 12.9 ± 6.1, left atrial volume index 49.4±17.8mL/m(2). Mean global left ventricular longitudinal strain was -14.6 ± 3.9%; LV mass index was 126.6 ± 36.2g/m(2). CONCLUSIONS: Patients in KaRen were old with slight female dominance and hypertension as the most prevalent etiological factor. LVEF was preserved, but with increased LV mass and depressed LV diastolic and longitudinal systolic functions. Few patients had signs of electrical dyssynchrony (ClinicalTrials.gov.- NCT00774709).

Background— Cardiac resynchronization therapy (CRT) decreases mortality, improves functional status, and induces reverse left ventricular remodeling in selected populations with heart failure. These benefits have been noted with both CRT-pacemakers as well as those devices with defibrillator backup (CRT-D). However, there are little data comparing mortality between these 2 device types. Methods and Results— REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) was a multicenter, randomized trial of CRT among patients with mild heart failure. Long-term annual follow-up for 5 years was preplanned. The present analysis was confined to the 419 patients who were randomized to active CRT group. CRT-pacemakers or CRT-D devices were implanted based on national guidelines at the time of enrollment, with 74 patients receiving CRT pacemaker devices and the remaining 345 patients receiving CRT-D devices. After 12 months of CRT, changes in the clinical composite score, left ventricular end systolic volume index, 6-minute walk time, and quality of life indices were similar between CRT pacemaker and CRT-D patients. However, long-term follow-up showed lower morality in the CRT-D group. Specifically, multivariable analysis showed that CRT-D (hazard ratio, 0.35; P =0.003) was a strong independent predictor of survival. Female sex, longer unpaced QRS duration, and smaller baseline left ventricular end systolic volume index also were also associated with better survival. Conclusions— REVERSE demonstrated that the addition of implantable cardioverter-defibrillator therapy to CRT is associated with improved long-term survival compared with CRT pacing alone in mild heart failure. Clinical Trial Registration— URL: http://clinicaltrials.gov . Unique Identifier: NCT00271154.

International audience; Background: KaRen is a prospective study designed to characterize and follow a multicentric cohort of HFpEF patients. We sought to describe the echocardiographic characteristics of our population according presence or not of right ventricular dysfunction as indicated by a tricuspid annular excursion 300 pg/mL and LVEF > 45%, patients were reassessed by echo-Doppler after 4 to 8 weeks after dedicated treatment.Image acquisition was standardized and the analysis was centralized. 349 patients had complete data set. The mean EF was 62±13%, mean LV global longitudinal strain was -15±3%, E/e' 12.9±6.2 was and LA volume was 49±18 ml/m2. Tricuspid regurgitation was 2.9±0.9m/s. TAPSE

Background— Current guidelines recommend cardiac resynchronization therapy (CRT) in mild heart failure (HF) patients with QRS prolongation and ejection fraction (EF) ≤30%. To assess the effect of CRT in less severe systolic dysfunction, outcomes in the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study were evaluated in which patients with left ventricular (LV) ejection fraction (LVEF) >30% were included. Methods and Results— The results of patients with baseline EF >30% (n=177) and those with EF ≤30% (n=431), as determined by a blinded core laboratory, were compared. In the LVEF >30% subgroup, there was a trend for improvement in the clinical composite response with CRT ON versus CRT OFF ( P =0.06) and significant reductions in LV end systolic volume index (−6.7±21.1 versus 2.1±17.6 mL/m 2 ; P =0.01) and LV mass (−20.6±50.5 versus 5.0±42.4 g; P =0.04) after 12 months. The time to death or first HF hospitalization was significantly prolonged with CRT (hazard ratio, 0.26; P =0.012). In the LVEF P =0.02), reverse remodeling parameters, and time to death or first HF hospitalization (hazard ratio, 0.58; P =0.047) were observed. After adjusting for important covariates, the CRT ON assignment remained independently associated with improved time to death or first HF hospitalization (hazard ratio, 0.54; P =0.035), whereas there was no significant interaction with LVEF. Conclusions— Among subjects with mild HF, QRS prolongation, and LVEF >30%, CRT produced reverse remodeling and similar clinical benefit compared with subjects with more severe LV systolic dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00271154.

Objectives The objective of this study is to ascertain the effects of the left (LV) and right (RV) ventricular lead tip position in response to cardiac resynchronization therapy (CRT). Background The REVERSE randomized trial examined the effects of CRT in patients with asymptomatic or mildly symptomatic heart failure (HF). Methods We analysed data collected from the active group (CRT-ON) of REVERSE in whom the precise locations of the LV and RV ventricular lead tips were determined from postoperative chest roentgenograms as part of a prespecified sub-study. LV position was classified as lateral or non-lateral, and apical or non-apical. RV position was classified as apical or non-apical. Echocardiographic LV end-systolic volume index (LVESVi), QRS duration, and clinical outcomes at 12–24 months of follow-up were evaluated with respect to the lead tip position. The primary trial endpoint was the proportion of patients with a worsened HF clinical composite response, scored as improved, unchanged, or worsened. Results Totally 346 patients included in this analysis were followed for a median of 12.6 months (interquartile range: 11.9–23.9 months). The proportion of worsened HF clinical composite response did not correlate with lead position, whereas a significantly greater decrease in the powered secondary endpoint of LVESVi was observed with the non-apical vs. the apical LV lead positions. CRT-paced QRS duration was significantly shorter than at baseline in patients with lateral vs. non-lateral LV position, as well non-apical vs. apical LV position. The incidence of composite endpoint of death and first hospitalization for HF was lower in the LV lateral than in the non-lateral (HR 0.44; 95% CI 0.19–0.99; P = 0.04), and in the LV non-apical than in the apical group (HR 0.27; 95% CI 0.11–0.63; P = 0.001). No significant differences were observed between RV apical and non-apical positions of the lead tip. Conclusions A more favourable outcome of CRT with regard to LV reverse remodelling and the composite of time to death or first HF hospitalization was observed when the LV lead tip was implanted in the lateral wall, away from the apex, while the position of the RV lead tip was indifferent. The long-term change in QRS duration was significantly associated with the position of the LV lead tip. ClinicalTrials.gov Identifier: [NCT00271154][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00271154&atom=%2Fehj%2F33%2F21%2F2662.atom

Background Heart failure (HF) with a preserved (P) left ventricular (LV) ejection fraction (EF) is common, though its diagnosis and physiopathology remains unclear. We sought to analyse the myocardial characteristics at rest and during a sub-maximal exercise test in patients with HFPEF. Methods and results Standardized sub-maximal exercise stress echocardiography was performed in (i) 21 patients from the Karolinska Rennes Prospective Study of Heart Failure with Preserved Left Ventricular Ejection Fraction HFPEF registry, whose LVEF was ≥45% and (ii) 15 control patients free of any manifestations of HF. During a sub-maximal exercise test, LV systolic function measured as a global four-chamber longitudinal strain was −17 ± 5% in patients with HFPEF vs. −22 ± 4% in controls ( P < 0.001), LV longitudinal diastolic relaxation, expressed as e ′ (septal and lateral walls averaged) was 9 ± 2 cm/s in patients vs. 15 ± 4 cm/s in controls ( P < 0.001), and RV longitudinal systolic function, expressed as RV s ′, was 14 ± 3 cm/s in patients vs. 18±1 cm/s in controls ( P = 0.03). LV afterload (arterial elastance) was 2.7 ± 1 mmHg/mL and was correlated with a decrease in LV longitudinal strain ( R = 0.51, P < 0.01) during exercise. Conclusion The assessment of longitudinal systolic and diastolic LV and RV functions is valuable during a sub-maximal exercise stress echocardiography to confirm the heart dysfunction related to the HFPEF symptoms. It might be used as a diagnostic test for difficult clinical situations. ClinicalTrials.gov identifier: NCT 01091467 .

It has been firmly established that cardiac resynchronization therapy (CRT) reduces symptoms and decreases morbidity and mortality1–6 in a subgroup of patients who remain in moderate to severe chronic heart failure (HF) (New York Heart Association [NYHA] class III/IV) despite optimal medication. These patients are characterized by wide QRS on the surface ECG as a sign of ventricular dyssynchrony and poor left ventricular (LV) systolic function with ejection fraction (LVEF) of ≤35%. This is now a Class I recommendation, Level of Evidence A indication for CRT in US and European guidelines for practice.7–10 The recent focus in CRT studies has been to investigate whether CRT can prevent or reverse disease progression in patients with mild HF symptoms. This review aims at assessing the current evidence of a beneficial effect of CRT in earlier stages of HF. The classification of severity of HF has varied in recent years. Mild, moderate, and severe are levels of symptomatic HF. “Mild” describes minimal functional limitations, dyspnea, or fatigue; “severe” is reserved for patients who are markedly symptomatic and need frequent medical attention; and “moderate” includes all patients in between mild and severe. Because of the poor correlation between symptoms and severity of cardiac dysfunction, the 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines introduced a new 4-stage classification to better discriminate the degrees of HF, its substrate, and its prognosis.11 Stage A includes patients at risk of developing HF who have no structural or functional abnormality (Figure 1). Stage B indicates the presence of structural heart disease strongly associated with the development of HF, particularly LV systolic dysfunction, although without present or past manifestations of HF. Stage C corresponds to past or present symptomatic HF associated with structural heart disease. The clinical outcomes of patients in NYHA functional class I/stage …

Background— Cardiac resynchronization therapy (CRT) improves LV structure, function, and clinical outcomes in New York Heart Association class III/IV heart failure with prolonged QRS. It is not known whether patients with New York Heart Association class I/II systolic heart failure exhibit left ventricular (LV) reverse remodeling with CRT or whether reverse remodeling is modified by the cause of heart failure. Methods and Results— Six hundred ten patients with New York Heart Association class I/II heart failure, QRS duration ≥120 ms, LV end-diastolic dimension ≥55 mm, and LV ejection fraction ≤40% were randomized to active therapy (CRT on; n=419) or control (CRT off; n=191) for 12 months. Doppler echocardiograms were recorded at baseline, before hospital discharge, and at 6 and 12 months. When CRT was turned on initially, immediate changes occurred in LV volumes and ejection fraction; however, these changes did not correlate with the long-term changes (12 months) in LV end-systolic ( r =0.11, P =0.31) or end-diastolic ( r =0.10, P =0.38) volume indexes or LV ejection fraction ( r =0.07, P =0.72). LV end-diastolic and end-systolic volume indexes decreased in patients with CRT turned on (both P P Conclusions— CRT in patients with New York Heart Association I/II resulted in major structural and functional reverse remodeling at 1 year, with the greatest changes occurring in patients with a nonischemic cause of heart failure. CRT may interrupt the natural disease progression in these patients. Clinical Trial Registration— Clinicaltrials.gov Identifier: NCT00271154.

International audience; AIMS: Heart failure with preserved ejection fraction (HFPEF) is common but not well understood. Electrical dyssynchrony in systolic heart failure is harmful. Little is known about the prevalence and the prognostic impact of dyssynchrony in HFPEF. METHODS AND RESULTS: We have designed a prospective, multicenter, international, observational study to characterize HFPEF and to determine whether electrical or mechanical dyssynchrony affects prognosis. Patients presenting with acute heart failure (HF) will be screened so as to identify 400 patients with HFPEF. Inclusion criteria will be: acute presentation with Framingham criteria for HF, left ventricular ejection fraction>or=45%, brain natriuretic peptide (BNP)>100 pg/mL or NT-proBNP>300 pg/mL. Once stabilized, 4-8 weeks after the index presentation, patients will return and undergo questionnaires, serology, ECG, and Doppler echocardiography. Thereafter, patients will be followed for mortality and HF hospitalization every 6 months for at least 18 months. Sub-studies will focus on echocardiographic changes from the acute presentation to the stable condition and on exercise echocardiography, cardiopulmonary exercise testing, and serological markers. CONCLUSION: KaRen aims to characterize electrical and mechanical dyssynchrony and to assess its prognostic impact in HFPEF. The results might improve our understanding of HFPEF and generate answers to the question whether dyssynchrony could be a target for therapy in HFPEF.