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Dilated cardiomyopathy is a heterogeneous entity that leads to heart failure and malignant arrhythmias. Nearly 50% of cases are inherited; therefore, genetic analysis is crucial to unravel the cause and for the early identification of carriers at risk. A large number of variants remain classified as ambiguous, impeding an actionable clinical translation. Our goal was to perform a comprehensive update of variants previously classified with an ambiguous role, applying a new algorithm of already available tools. In a cohort of 65 cases diagnosed with dilated cardiomyopathy, a total of 125 genetic variants were classified as ambiguous. Our reanalysis resulted in the reclassification of 12% of variants from an unknown to likely benign or likely pathogenic role, due to improved population frequencies. For all the remaining ambiguous variants, we used our algorithm; 60.9% showed a potential but not confirmed deleterious role, and 24.5% showed a potential benign role. Periodically updating the population frequencies is a cheap and fast action, making it possible to clarify the role of ambiguous variants. Here, we perform a comprehensive reanalysis to help to clarify the role of most of ambiguous variants. Our specific algorithms facilitate genetic interpretation in dilated cardiomyopathy.

Background: Conduction system pacing (CSP) has emerged as an alternative to biventricular pacing (BiVP). Randomized studies comparing both therapies are scarce and do not include left bundle branch pacing., Objectives: This study aims to compare ventricular resynchronization achieved by CSP vs BiVP in patients with cardiac resynchronization therapy indication., Methods: LEVEL-AT (Left Ventricular Activation Time Shortening with Conduction System Pacing vs Biventricular Resynchronization Therapy) was a randomized, parallel, controlled, noninferiority trial. Seventy patients with cardiac resynchronization therapy indication were randomized 1:1 to BiVP or CSP, and followed up for 6 months. Crossover was allowed when primary allocation procedure failed. Primary endpoint was the change in left ventricular activation time, measured using electrocardiographic imaging. Secondary endpoints were left ventricular reverse remodeling and the combined endpoint of heart failure hospitalization or death at 6-month follow-up., Results: Thirty-five patients were allocated to each group. Eight (23%) patients crossed over from CSP to BiVP; 2 patients (6%) crossed over from BiVP to CSP. Electrocardiographic imaging could not be performed in 2 patients in each group. A similar decrease in left ventricular activation time was achieved by CSP and BiVP (-28 ± 26 ms vs -21 ± 20 ms, respectively; mean difference -6.8 ms; 95% CI: -18.3 ms to 4.6 ms; P < 0.001 for noninferiority). Both groups showed a similar change in left ventricular end-systolic volume (-37 ± 59 mL CSP vs -30 ± 41 mL BiVP; mean difference: -8 mL; 95% CI: -33 mL to 17 mL; P = 0.04 for noninferiority) and similar rates of mortality or heart failure hospitalizations (2.9% vs 11.4%, respectively) (P = 0.002 for noninferiority)., Conclusions: Similar degrees of cardiac resynchronization, ventricular reverse remodeling, and clinical outcomes were attained by CSP as compared to BiVP. CSP could be a feasible alternative to BiVP. (LEVEL-AT [Left Ventricular Activation Time Shortening With Conduction System Pacing vs Biventricular Resynchronization Therapy]; NCT04054895)., Competing Interests: Funding Support and Author Disclosures Drs Pujol-Lopez, Tolosana, Castel, and Jiménez-Arjona have received funding for a Project in Conduction System Pacing: FIS PI21/00615 Instituto de Salud Carlos III (Madrid, Spain). Dr Pujol-Lopez has received the Catalan Society of Cardiology research grant in 2019 and 2020 (Catalonia, Spain), the Josep Font ResearchGrant in 2019 from Hospital Clínic Barcelona (Catalonia, Spain), and the Research Grant 2020 from Asociación del Ritmo Cardiaco (Spanish Society of Cardiology); and has received speaker honoraria from Medtronic. Dr Roca-Luque has received honoraria as a lecturer and consultant from Abbott and Biosense Webster. Dr Sitges has received consultant fees and speaker honoraria from Abbott, Medtronic, General Electric, and Edwards Lifesciences. Dr Tolosana has received honoraria as a lecturer and consultant from Abbott, Boston Scientific, and Medtronic. Dr Mont has received unrestricted research grants, fellowship program support, and honoraria as a lecturer and consultant from Abbott, Biotronik, Boston Scientific, Livanova, and Medtronic; and holds stock in Galgo Medical and Corify. Dr Castel has received speaker honoraria from Boston Scientific, Abbott, and Microport. Dr Arbelo has received speaker honoraria from Biosense Webster and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Longer QRS duration (QRSd) improves, but increased left ventricular (LV) end-diastolic volume (LVEDV) reduces, efficacy of cardiac resynchronization therapy (CRT). QRSd/LVEDV ratios differ between sexes. We hypothesized that in the EchoCRT (Echocardiography Guided Cardiac Resynchronization Therapy) trial enrolling patients with heart failure with QRSd <130 ms, those with larger LVEDV would deteriorate but those with the highest QRSd/LVEDV would improve with CRT., Methods and Results: Primary outcome in patients (n=787, 72% men, 93% New York Heart Association class III, QRSd <130 ms, LV ejection fraction ≤35%, LV dilation and dyssynchrony) randomized to CRT-ON or CRT-OFF and followed up for 19 months was compared according to LVEDV (height indexed) or QRSd/LVEDV ratio, in multivariable analysis. Structural remodeling was assessed echocardiographically 6 months after implantation. Patients with baseline LVEDV higher than or equal to median worsened with CRT (death/heart failure hospitalization: CRT-ON versus CRT-OFF, 35.2% versus 24.5% [hazard ratio, 1.64; 95% confidence interval, 1.11-2.42; P =0.012]), but those with LVEDV lower than median remained unaffected. Patients with the highest QRSd/LVEDV ratio improved with CRT (death/heart failure hospitalization in top quartile: 20.9% in CRT-ON [n=91] versus 28.3% in CRT-OFF [n=106] [hazard ratio, 0.64; 95% confidence interval, 0.34-1.24; P =0.188], versus the remaining quartiles: 31.7% in CRT-ON [n=300] versus 24.8% in CRT-OFF [n=290] [hazard ratio, 1.47; 95% confidence interval, 1.07-2.02; P =0.016], test for interaction P =0.046). QRSd and dyssynchrony were similar between groups. The 3-way test for interaction indicated no sex-specific effects. However, numerically, men with LVEDV higher than or equal to median accounted for worse outcomes of CRT-ON. Women, with the highest QRSd/LVEDV ratio exhibited significant reverse remodeling., Conclusion: CRT has opposite effects among patients with heart failure with QRSd <130 ms according to LV size: worsening outcomes in patients with larger LV, but inducing beneficial effects in those with smaller LV., Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00683696., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Cross correlation analysis (CCA) using tissue Doppler imaging has been shown to be associated with outcome after cardiac resynchronization therapy (CRT) in patients with heart failure (HF) with wide QRS. However, its significance in patients with narrow QRS treated with CRT is unknown., Objectives: The aim of the current study was to investigate the association of mechanical activation delay by CCA with study outcome in patients with HF enrolled in the EchoCRT trial., Methods: Baseline CCA could be performed from tissue Doppler imaging in the apical views in 807 of 809 (99.7%) enrolled patients, and 6-month follow-up could be performed in 610 of 635 (96%) patients with available echocardiograms. Patients with a pre-specified maximal activation delay ≥35 ms were considered to have significant delay. The study outcome was HF hospitalization or death., Results: Of 807 patients, 375 (46%) did not have delayed mechanical activation at baseline by CCA. Patients without delayed mechanical activation who were randomized to CRT-On compared with CRT-Off had an increased risk of poor outcome (hazard ratio: 1.70; 95% confidence interval: 1.13 to 2.55; p = 0.01) with a significant interaction term (p = 0.04) between delayed mechanical activation and device randomization for the endpoint. Among patients with paired baseline and follow-up data with no events before 6-month follow-up (n = 541), new-onset delayed mechanical activation in the CRT-On group showed a significant increase in unfavorable events (hazard ratio: 3.73; 95% confidence interval: 1.15 to 12.14; p = 0.03)., Conclusions: In the EchoCRT population, absence of delayed mechanical activation by CCA was significantly associated with poor outcomes, possibly due to the onset of new delayed mechanical activation with CRT pacing. (Echocardiography Guided Cardiac Resynchronization Therapy [EchoCRT] Trial; NCT00683696)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFPEF) is the most frequent form of heart failure in ambulatory patients with new-onset symptoms. We previously showed that lung function abnormalities are highly prevalent in HFPEF patients. In this observational, longitudinal study, we tested the hypothesis that the presence of airflow limitation and/or arterial hypoxemia predicts mortality and/or cardiovascular hospitalizations during follow-up in HFPEF outpatients., Materials and Methods: HFPEF was diagnosed following the international recommendations. Forced spirometry and arterial blood gases were measured at recruitment according to international recommendations. The primary endpoint of the study was all-cause mortality and the secondary one was any cardiovascular hospitalization., Results: We included in the analysis all consecutive outpatients newly diagnosed of HFPEF in our clinic between April 2009 and January 2013 (n = 71). Patients were prospectively followed up for a mean of 4 years (range 10 months to 5.8 years). All-cause mortality was 18.3%. It was higher in patients with airflow limitation (30%) than those with normal spirometry (10%) or other spirometric defects (19%) (p = 0.036). The presence of arterial hypoxemia did not predict mortality (p = 0.179) but was significantly related to cardiovascular hospitalizations during follow-up (p = 0.038)., Conclusions: The presence of airflow limitation or arterial hypoxemia identify a group of patients with HFPEF at higher risk of death or cardiovascular hospitalizations, respectively. Given that both airflow limitation and arterial hypoxemia are treatable, we propose that lung function should be routinely evaluated in the outpatient management of HFPEF patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The NECTAR-HF study evaluated safety and feasibility of vagal nerve stimulation (VNS) for the treatment of heart failure patients. The first six-month randomized phase of the study did not show improvement in left ventricular remodelling in response to VNS. This study reports the 18-month results and provides novel findings aiming to understand the lack of efficacy of VNS, including a new technique assessing the effects of VNS., Methods: Ninety-six patients were randomized 2:1 to active or inactive VNS for 6months, thereafter VNS was activated for all patients. The primary safety endpoint was 18-month all-cause mortality., Results: Ninety-one patients continued in the long-term evaluation with active VNS. The on-therapy survival estimate at 18months was 95% with a 95% one-sided lower confidence limit of 91%, (better than the predefined criterion). Left ventricular systolic volume decreased in the crossover group (VNS OFF→ON; 144±37 to 139±40, p<0.05) after VNS activation; LVESD (5.02±0.77 to 4.96±0.82, p>0.05) and LVEF (33.2±4.9 to 33.3±6.5, p>0.05) did not change. A new technique to detect subtle heart rate changes during Holter recordings, i.e. "heat maps", revealed that VNS evoked heart rate response in only 13/106 studies (12%) at 6 and 12months with active VNS., Conclusions: Although a favourable long-term safety profile was found, improvements in the efficacy endpoints were not seen with VNS. A new technique for detecting acute heart rate responses to VNS suggests that the recruitment of nerve fibres responsible for heart rate changes were substantially lower in NECTAR-HF than in pre-clinical models., (Copyright © 2017 Elsevier B.V. All rights reserved.)

: Chronic heart failure is a common clinical condition characterized by persistent excessive sympathetic nervous system activation. The derangement of the sympathetic activity has relevant implications for disease progression and patient survival. Aiming to positively impact patient outcome, autonomic nervous system modulatory therapies have been developed and tested in animal and clinical studies. As a general gross assumption, direct vagal stimulation and baroreflex activation are considered equivalent. This assumption does not take into account the fact that direct cervical vagal nerve stimulation involves activation of both afferent and efferent fibers innervating not only the heart, but the entire visceral system, leading to undesired responses to and from this compartment. The different action of baroreflex activation is based on generating a centrally mediated reduction of sympathetic outflow and increasing parasympathetic activity to the heart via a physiological reflex pathway. Thus, baroreflex activation rebalances the unbalanced autonomic nervous system via a specific path. Independent and complementary investigations have shown that sympathetic nerve activity can be rebalanced via control of the arterial baroreflex in heart failure patients.Results from recent pioneering research studies support the hypothesis that baroreflex activation can add significant therapeutic benefit on top of guideline-directed medical therapy in patients with advanced heart failure. In the present review, baroreflex activation therapy results are discussed, focusing on critical aspects like patient selection rationale to support clinician orientation in opting for baroreflex activation therapy when, on top of current guideline-directed medical treatment, other therapies are to be considered.

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.)

Aims: As patients with heart failure (HF) and concomitant diabetes carry a poor prognosis, this post-hoc subgroup analysis aimed to compare the outcomes of patients with and without diabetes randomized in the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study., Methods and Results: EchoCRT randomized patients with a QRS duration <130 ms and echocardiographic evidence of left ventricular dyssynchrony to CRT turned on (CRT=ON) vs. off (CRT=OFF) following device implantation. At study entry, 328 patients (40.5%) had diabetes. The primary outcome (all-cause death or first hospitalization for worsening HF) occurred more frequently in patients with than without diabetes (32.6% vs. 23%, P = 0.003). A significant treatment interaction was observed for the primary outcome indicating a higher risk for CRT=ON vs. CRT-OFF in patients without [26.5% vs. 19.8%, hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.08-2.31] vs. with diabetes (31.4% vs. 34%; HR 0.86, 95% CI 0.58-1.27; P for interaction 0.041). This effect was mainly driven by a lower rate in HF hospitalizations, but was only of borderline significance after multivariate adjustment (P = 0.063). The most pronounced effect was observed in patients with non-ischaemic cardiomyopathy, where a significantly reduced risk of reaching the primary endpoint for CRT=ON vs. CRT-OFF was observed in patients with (HR 0.27, P = 0.003) vs. patients without diabetes (HR 1.79, P = 0.038; P for interaction 0.005). No treatment interaction by diabetes diagnosis was found for mortality endpoints., Conclusion: In EchoCRT, HF patients with a narrow QRS complex and coexisting diabetes demonstrated a signal for less harm caused by CRT compared with patients without diabetes, which was driven by differences in hospitalizations owing to HF., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: In EchoCRT, a randomized controlled trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS duration of <130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome (death from any cause or first hospitalization for worsening heart failure) occurred more frequently in the CRT-ON when compared with the control group. In this prespecified subgroup analysis, we evaluated the effect of sex on clinical outcome in EchoCRT., Methods and Results: In EchoCRT, 585 (72%) of included patients were men. At baseline, male patients had a higher incidence of ischemic cardiomyopathy and longer QRS duration. On uni- and multivariable analysis, no significant interaction was observed regarding sex for the primary or any of the secondary end points. Numerically, a higher all-cause mortality was observed in male patients randomized to CRT-ON versus CRT-OFF on univariable analysis (hazard ratio, 1.83; 95% confidence interval, 1.08-3.12); however, no statistically significant interaction compared with females randomized to CRT-ON versus CRT-OFF was noted (hazard ratio, 0.99; P interaction, 0.56). There was no difference in the primary safety end point of system-related complications, including CRT system- and implantation-related events., Conclusions: The largest hazard for all-cause mortality in EchoCRT was observed in men randomized to CRT-ON; the comparison with women did not reach statistical significance, which may be because of the premature termination of the trial and the limited data. These results suggest that male sex may be a risk factor for harm by CRT in patients with narrow QRS width, an observation which deserves further investigation., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00683696., (© 2016 American Heart Association, Inc.)

Aims: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in cardiac remodelling. Available information regarding their prognostic utility in heart failure (HF) and cardiac resynchronization therapy (CRT) is controversial. The aim of this study was to analyse MMP-2 and TIMP-1 levels as predictors of long-term mortality in HF patients treated with CRT., Methods and Results: We prospectively included 42 consecutive patients with successfully implanted CRT. Matrix metalloproteinase-2 and TIMP-1 assays were performed prior to implant. Patients were evaluated at baseline and at the outpatient clinic at 6-month intervals. Clinical response, left ventricular (LV) remodelling, and mortality were analysed. During a mean follow-up of 60 ± 34 months, long-term mortality from any cause was 36% (15 patients). The cause of death was end stage of HF in 12 patients, sudden death in 2 patients, and 1 unknown. After adjustment using a Cox regression model, the independent predictors of long-term mortality were baseline TIMP-1, hazard ratio (HR) 1.18 (95% confidence interval (95% CI) [1.05-1.33], P = 0.007), baseline glomerular filtration rate (GFR), HR 0.97 (95% CI [0.94-1.00], P = 0.05), and permanent atrial fibrillation (AF), HR 3.14 (95% CI [1.02-9.67], P = 0.04). Area under receiver operating characteristic curve for TIMP-1 was 0.79 (95% CI [0.63-0.94]). Tissue inhibitor of matrix metalloproteinase-1 ≥ 248 ng/mL predicts mortality with 80% sensitivity and 71% specificity., Conclusion: Tissue inhibitor of matrix metalloproteinase-1 is a powerful predictor of long-term mortality in HF patients treated with CRT., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: EchoCRT was a randomized trial of cardiac resynchronization therapy (CRT) in severely symptomatic heart failure (HF) patients with narrow QRS width <130 ms, ejection fraction ≤35%, and echocardiographic dyssynchrony. All received CRT implants which were then randomized to CRT-On or CRT-Off. While the trial showed no benefit of CRT to these patients, the aim of this subgroup analysis was to test the hypothesis that persistent or worsening dyssynchrony is associated with unfavourable clinical outcomes., Methods and Results: We studied 614 EchoCRT patients with baseline and 6-month echocardiograms. Baseline dyssynchrony required for study inclusion was either tissue Doppler imaging longitudinal velocity delay ≥80 ms or speckle-tracking radial strain delay ≥130 ms. Persistent dyssynchrony at 6 months was observed similarly in both groups (77% in CRT-On; 76% in CRT-Off). Persistent dyssynchrony was associated with a significantly higher primary end point of death or HF hospitalization (HR = 1.54, 95% CI 1.03-2.30, P = 0.03), and in particular secondary endpoint of HF hospitalization (HR = 1.66, 95% CI 1.07-2.57, P = 0.02). HF hospitalizations were also associated with worsening longitudinal dyssynchrony (HR = 1.45, 95% CI 1.02-2.05, P = 0.037), and worsening radial dyssynchrony (HR = 1.81, 95% CI 1.16-2.81, P = 0.008). Associations of persistent or worsening dyssynchrony with outcomes were similar in CRT-Off and CRT-On groups., Conclusions: Persistent or worsening echocardiographic dyssynchrony in HF patients with narrow QRS width was a marker for unfavourable clinical outcomes unaffected by CRT. In particular, echocardiographic dyssynchrony on follow-up was strongly associated with HF hospitalizations and appears to be a prognostic marker of disease severity., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: In EchoCRT, a randomized trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS duration of <130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome occurred more frequently in the CRT when compared with the control group. According to current heart failure guidelines, CRT is recommended in patients with a QRS duration of ≥120 ms. However, there is some ambiguity from clinical trial data regarding the benefit of patients with a QRS duration of 120-130 ms., Methods and Results: The main EchoCRT trial was prematurely terminated due to futility. For the current subgroup analysis we compared data for CRT-ON vs. -OFF in patients with QRS < 120 (n = 661) and QRS 120-130 ms (n = 139). On uni- and multivariable analyses, no significant interaction was observed between the two groups and randomized treatment for the primary or any of the secondary endpoints. On multivariable analysis, a higher risk for the primary endpoint was observed in patients with a QRS duration of 120-130 ms randomized to CRT-ON vs. CRT-OFF (hazard ratio 2.18, 95% CI 1.02-4.65; P = 0.044). However, no statistically significant interaction, compared with patients with QRS < 120 ms randomized to CRT-ON vs. CRT-OFF, was noted (P-interaction = 0.160)., Conclusions: In this pre-specified subgroup analysis of EchoCRT, no benefit of CRT was evident in patients with a QRS duration of 120-130 ms. These data further question the usefulness of CRT in this patient population., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Prognosis of heart failure patients has been defined in hospital-based or retrospective studies. This study aimed to characterize prognosis of outpatients with new-onset preserved or reduced ejection fraction heart failure; to explore the role of collagen turnover biomarkers (MMP2, MMP9, TIMP1) in predicting prognosis; and to analyse their relationship with echocardiographic parameters and final diagnosis., Methods: This is an observational, prospective, longitudinal study. Outpatients with new-onset heart failure symptoms referred to a one-stop clinic were included. Echocardiography and biomarkers plasma levels determination were performed at the inclusion. A prospective follow-up was conducted to report cardiovascular events. The discriminant analysis was applied to identify the parameters related to cardiovascular outcomes., Results: A total of 172 patients (75 ± 9 years) were included, 67% with heart failure (64% preserved and 36% with reduced ejection fraction). During follow-up (median 34.5 months), 32.6% had at least one cardiovascular event and 9.9% died. Heart failure groups showed no differences in cardiovascular outcomes with a higher rate of events than nonheart failure patients. MMP2 and TIMP1 were correlated with diastolic dysfunction (Rho 0.349 and 0.294, P < 0.001). In the discriminant analysis, the combination of biomarkers with clinical, biochemical and echocardiographic parameters was useful to predict cardiovascular outcomes (AUC ROC 0.806, Wilks lambda 0.7688, P < 0.001)., Conclusions: Prognosis of outpatients with new-onset heart failure symptoms is comparable between heart failure with preserved or reduced subgroups. The addition of biomarkers specially MMP2 and high sensitive troponin I to other clinical, biochemical and echocardiographic variables can predict cardiovascular prognosis at the time of diagnosis., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Aim: The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy., Methods: Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers., Results: Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was -0.04 ± 0.25 cm in the therapy group compared with -0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group., Conclusion: Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Biventricular pacing (CRT) shows clear benefits in heart failure with wide QRS, but results in narrow QRS have appeared conflicting. We tested the hypothesis that study design might have influenced findings., Method and Results: We identified all reports of CRT-P/D therapy in subjects with narrow QRS reporting effects on continuous physiological variables. Twelve studies (2074 patients) met these criteria. Studies were stratified by presence of bias-resistance steps: the presence of a randomized control arm over a single arm, and blinded outcome measurement. Change in each endpoint was quantified using a standardized effect size (Cohen's d). We conducted separate meta-analyses for each variable in turn, stratified by trial quality. In non-randomized, non-blinded studies, the majority of variables (10 of 12, 83%) showed significant improvement, ranging from a standardized mean effect size of +1.57 (95%CI +0.43 to +2.7) for ejection fraction to +2.87 (+1.78 to +3.95) for NYHA class. In the randomized, non-blinded study, only 3 out of 6 variables (50%) showed improvement. For the randomized blinded studies, 0 out of 9 variables (0%) showed benefit, ranging from -0.04 (-0.31 to +0.22) for ejection fraction to -0.1 (-0.73 to +0.53) for 6-minute walk test., Conclusions: Differences in degrees of resistance to bias, rather than choice of endpoint, explain the variation between studies of CRT in narrow-QRS heart failure addressing physiological variables. When bias-resistance features are implemented, it becomes clear that these patients do not improve in any tested physiological variable. Guidance from studies without careful planning to resist bias may be far less useful than commonly perceived., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objectives: Our aim was to identify "correctable abnormalities" using conventional grayscale and blood-pool Doppler echocardiography and evaluate their ability to predict both response and midterm survival., Background: Identification of mechanical abnormalities that may be corrected with cardiac resynchronization therapy (CRT) is useful for predicting echocardiographic response at 1-year follow-up., Methods: A total of 200 CRT patients were included. Clinical evaluation and echocardiography were performed before and after CRT to assess the presence of the mechanical abnormalities of interest (septal flash, abnormal ventricular filling, or exaggerated interventricular dependence). Response to CRT was defined as a reduction in left ventricular (LV) end-systolic volume (ESV) ≥15%. Four subgroups of extent of response were defined: LVESV reduction >26.68% (extensive remodeling); LVESV reduction 6.8% to 26.68% (slight remodeling); LVESV reduction <6.8% (no remodeling) and clinical response; and LVESV reduction <6.8% without clinical response or the occurrence of death or heart transplantation. Midterm cardiovascular survival was evaluated (mean follow-up 38 ± 19 months)., Results: The presence of a correctable abnormality was independently associated with a better rate (odds ratio: 0.03 [95% confidence interval (CI): 0.01 to 0.10], p < 0.001) and extent of response to CRT (n = 59 [96.7%] for the extensive remodeling subgroup vs. n = 53 [85.5%] for the slight remodeling subgroup vs. n = 19 [47.5%] for the no remodeling with clinical response subgroup vs. n = 17 [45.9%] for the no remodeling without clinical response subgroup, p = 0.0001), as well as with increased midterm survival (hazard ratio: 0.11 [95% CI: 0.2 to 0.6]). Other independent predictors included creatinine level and LV end-systolic diameter for response; New York Heart Association functional class IV, creatinine, LV end-systolic diameter, and transmurality index for extent of response; and New York Heart Association functional class IV for cardiovascular mortality., Conclusions: The presence of a correctable abnormality evaluated by conventional echocardiography is associated with LV reverse remodeling and better survival at midterm follow-up. Clinical characteristics and myocardial viability also have an influence., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The beneficial effects of CRT in patients with advanced heart failure, wide QRS, and low LVEF have been clearly established. Nevertheless, mortality remains high in some patients. The aims of our study were to identify the predictors of mortality in patients treated with CRT and to design a risk score for mortality., Methods and Results: A cohort of 608 consecutive patients treated with CRT from 2000 to 2011 in our centre was prospectively analysed. Baseline clinical and echocardiography variables were analysed and mortality data were collected. During a mean follow-up of 36.2 ± 29.2 months, 174 patients died: 123/174 (71%) due to cardiovascular causes, 25/174 (14%) non-cardiac causes, and 26/174 (15%) unknown aetiology. In a multivariate analysis the predictors of mortality were NYHA class IV [hazard ratio (HR) 2.54, 95% confidence interval (CI) 1.7-3.7, P < 0.001], glomerular filtration rate (GFR) <60 mL/min/1.73 m2 (HR 1.61, 95% CI 1.14-2.30, P = 0.008), AF (HR 1.67, 95% CI 1.19-2.3, P = 0.01), age ≥70 years (HR 1.44, (95% CI 1.04-2.00, P = 0.02), and LVEF <22% (HR 1.83, 95% CI 1.33-2.52, P ≤ 0.001). The EAARN score (EF, Age, AF, Renal dysfunction, NYHA class IV) summarizes the predictors. Each additional predictor increased the mortality: one predictor, HR 3.28 (95% CI 1.37-7.8, P = 0.008); two, HR 5.23 (95% CI 2.24-12.10, P < 0.001); three, HR 9.63 (95% CI 4.1-22.60, P < 0.001); and four or more, HR 14.38 (95% CI 5.8-35.65, P < 0.001)., Conclusion: The predictors of mortality have a significant add-on predictive effect on mortality. The EAARN score could be useful to stratify the prognosis of CRT patients., (© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Increased sympathetic activation and reduced parasympathetic tone are important pathophysiological contributors to the progression of heart failure, and are associated with poor outcome in patients. The aim of this study is to determine if vagal nerve stimulation (VNS) is a promising approach to modulate autonomic function and slow cardiac remodelling and the progression of heart failure., Methods: The NECTAR-HF (NEural Cardiac TherApy foR Heart Failure) trial is designed to evaluate whether the Boston Scientific VNS device is safe and may attenuate cardiac remodelling, improve cardiac function and increase exercise capacity, in symptomatic heart failure patients (New York Heart Association Class II-III) with left ventricular systolic dysfunction (ejection fraction ≤35%) and receiving optimal medical therapy. Patients will be randomized in a 2:1 ratio to receive standard optimal medical treatment plus VNS system in an active mode vs. optimal medical treatment plus VNS system in an inactive mode, for a 6 month period. After the 6 month control period, inactive VNS systems will be activated and all patients will receive VNS. The study is powered to detect differences in the primary efficacy endpoint of change in left ventricular end systolic diameter. Secondary endpoints include ejection fraction, left ventricular volumes, quality of life scores, functional capacity, and changes in biomarkers., Conclusion: This Phase II, randomized clinical trial conducted with vagal stimulation for heart failure will provide important new information on the potential of this novel and promising technique., (© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Monitoring early signs of clinical deterioration could allow physicians to adjust medical treatment for patients at risk of acute heart failure decompensation. To date, several strategies using different surrogate measures of clinical status emerged, but none has yet been proven to predict clinical events. We hypothesized that the Physiological Diagnostic feature, which combines data from minute ventilation and physical activity sensors, predicts heart failure events in patients implanted with cardiac resynchronization therapy with defibrillation (CRT-D) devices., Methods and Results: The Clinical Evaluation of the Physiological Diagnostic feature in the PARADYM CRT device (CLEPSYDRA) trial is a multicentre, prospective, non-randomized, double-blind study comprising 521 CRT-D patients with heart failure [67.4 ± 10.1 years (mean ± SD), 82% male, New York Heart Association class III/IV 85.0%/6.7%, QRS 155.3 ± 26.6 ms, left ventricular ejection fraction 25.7 ± 7.7%]. The objective of the study was the sensitivity and false positive rate of the Physiological Diagnostic algorithm to predict heart failure events within the following month. After a mean follow-up of 17.0 ± 8.7 months, 130 (25.6%) patients experienced a heart failure event. The sensitivity of the algorithm to predict an event was 34% and the false positive rate was 2.4 per patient-year., Conclusion: Thirty-four per cent of heart failure events occurring within a month were predicted by the Physiological Diagnostic algorithm, and 2.4 alerts per patient per year were not followed by an heart failure event within the subsequent month., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Although cardiac resynchronization therapy (CRT) is effective in most patients with heart failure (HF) and ventricular dyssynchrony, a significant minority of patients (approximately 30%) are non-responders. Optimal atrioventricular and interventricular delays often change over time and reprogramming these intervals might increase CRT effectiveness. The SonR algorithm automatically optimizes atrioventricular and interventricular intervals each week using an accelerometer to measure change in the SonR signal, which was shown previously to correlate with hemodynamic improvement (left ventricular [LV] dP/dtmax). The RESPOND CRT trial will evaluate the effectiveness and safety of the SonR optimization system in patients with HF New York Heart Association class III or ambulatory IV eligible for a CRT-D device. Enrolled patients will be randomized in a 2:1 ratio to either SonR CRT optimization or to a control arm employing echocardiographic optimization. All patients will be followed for at least 24 months in a double-blinded fashion. The primary effectiveness end point will be evaluated for non-inferiority, with a nested test of superiority, based on the proportion of responders (defined as alive, free from HF-related events, with improvements in New York Heart Association class or improvement in Kansas City Cardiomyopathy Questionnaire quality of life score) at 12 months. The required sample size is 876 patients. The two primary safety end points are acute and chronic SonR lead-related complication rates, respectively. Secondary end points include proportion of patients free from death or HF hospitalization, proportion of patients worsened, and lead electrical performance, assessed at 12 months. The RESPOND CRT trial will also examine associated reverse remodeling at 1 year., (Copyright © 2014 The Authors. Published by Mosby, Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFPEF) is the most prevalent form of heart failure in outpatients. Yet, the pathophysiology of this syndrome is unclear and pharmacological treatment does not improve prognosis. Because breathlessness during activities of daily living is the most frequent complaint of patients with HFPEF, we hypothesised that lung function may be often abnormal in these patients due to either a direct effect of HFPEF and/or shared risk factors. In this study we explore the frequency, type and severity of lung function abnormalities in HFPEF., Methods: We measured forced spirometry, static lung volumes, pulmonary diffusing capacity (DL(CO)) and arterial blood gases in 69 outpatients with newly diagnosed symptomatic HFPEF., Results: We found that 94% of the patients showed abnormalities in at least one of the lung function measurements obtained: spirometry was abnormal in 59%, DL(CO) in 83% and arterial hypoxaemia was present in 62%. Their severity varied between patients, they were more prevalent in patients with NYHA functional class III/IV, and most often they were undiagnosed and untreated., Conclusions: Lung function abnormalities are very frequent in HFPEF patients. A greater awareness among clinicians may contribute to improve their management and health status., (Copyright © 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Aims: Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs., Methods and Results: Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups., Conclusion: LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted.

Objectives: a) To assess the usefulness of a one-stop clinic for the diagnosis of outpatients with new onset heart failure; b) to characterize these patients comparing preserved (HF-PEF) versus reduced ejection fraction (HF-REF), and c) to determine brain natriuretic peptide (BNP) cut-off limit to identify HF in outpatients., Design: Observational descriptive study., Setting: Primary care., Participants and Measurements: A total of 143 outpatients with new onset HF were assessed in a one-stop clinic. A cardiologist evaluation, electrocardiogram, chest X-ray, BNP, and echocardiography (diastolic and systolic study) were performed., Results: Almost two-thirds (65.7%) were diagnosed with HF: 67% with HF-PEF and 33% HF-REF. Women (71.4% versus 38.7%, P=.002), presence of swelling ankles (61.9% versus 35.5%, P=.016) and higher body mass index (29.8±5.1 versus 27.2±5.0 P=.021) were more frequent in the first group of patients. Echocardiographic signs of diastolic dysfunction and pulmonary hypertension were found in both groups, with higher values of BNP (153.3±123.1 versus 400.8±579.8 P=.025) and troponin I (0.024±0.019 versus 0.071±0.12, P=.037) in HF-REF patients. Female gender and swelling ankles were predictors of HF-PEF in the multivariate analysis, while Q waves and higher values of BNP and heart rate were predictors of HF-REF. A cut-off value of 60.12 pg/ml for BNP provided 83% sensitivity, 84% specificity (AUC=0.898; 95% CI; 0.848-0.948; P <.001)., Conclusions: The one-stop HF clinic has diagnosed and characterized outpatients with new onset HF and high prevalence of HF-PEF. The cut-off value of 60.12 pg/ml for BNP provides high sensitivity and specificity to identify HF in this population., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Background: The mechanism of sudden cardiac death in patients with heart failure (HF) is uncertain. Both electrical instability and structural remodelling could be factors that lead to fatal arrhythmias. We sought to analyse the expression of the sodium (SCN5A) and potassium (KCND3) channels as well as the fibrosis content in the ventricles of human HF and of non-diseased hearts under different post-mortem intervals., Methods and Results: We analysed normal human hearts as controls [n=20 for the right ventricle (RV) and n=13 for the left ventricle (LV)] and human hearts from HF patients, which were obtained at the time of cardiac transplantation, as cases (n=48 for RV and n=34 for LV). Transcription of the SCN5A (probes SCN5A E4-5, E11-12, and E28) and KCND3 channels and of COLLAGEN I and III were assayed by real-time polymerase chain reaction. In addition, paraffin sections were used to analyse the percentage of collagen deposition in both cases and controls. KCND3 mRNA expression in the LV was lower in the cases than in controls (P<.001). Higher levels of SCN5A mRNA were found in the HF samples when analysed with probe SCN5A E4-5 (P<.05). SCN5A expression was lower in the controls with longer post-mortem interval (n=4) than in the controls with a shorter post- mortem interval (n=16, P<.01). KCND3 mRNA levels were also different between the two control groups (P<.05). Collagen deposition was higher in the LV tissues of the cases when compared to controls (P<.001), and it was higher in the LV from HF patients than in the RV (P<.05). Furthermore, collagen deposition was higher in the LV samples from patients with implanted cardiac defibrillator (ICD) therapy than in the LV of patients with no ICD therapy (P<.05)., Conclusions: These data indicate that ionic and structural remodelling could be pathophysiological mechanisms of cardiac arrhythmias in HF patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) involves alterations in metabolism, but little is known about cardiomyopathy-(CM)-specific or diabetes-independent alterations in gene expression of proteins involved in fatty-acid (FA) uptake and oxidation or in calcium-(Ca(2+))-handling in the human heart., Methods: RT-qPCR was used to quantify mRNA expression and immunoblotting to confirm protein expression in left-ventricular myocardium from patients with HF (n = 36) without diabetes mellitus of ischaemic (ICM, n = 16) or dilated (DCM, n = 20) cardiomyopathy aetiology, and non-diseased donors (CTL, n = 6)., Results: Significant increases in mRNA of genes regulating FA uptake (CD36) and intracellular transport (Heart-FA-Binding Protein (HFABP)) were observed in HF patients vs CTL. Significance was maintained in DCM and confirmed at protein level, but not in ICM. mRNA was higher in DCM than ICM for peroxisome-proliferator-activated-receptor-alpha (PPARA), PPAR-gamma coactivator-1-alpha (PGC1A) and CD36, and confirmed at the protein level for PPARA and CD36. Transcript and protein expression of Ca(2+)-handling genes (Two-Pore-Channel 1 (TPCN1), Two-Pore-Channel 2 (TPCN2), and Inositol 1,4,5-triphosphate Receptor type-1 (IP3R1)) increased in HF patients relative to CTL. Increases remained significant for TPCN2 in all groups but for TPCN1 only in DCM. There were correlations between FA metabolism and Ca(2+)-handling genes expression. In ICM there were six correlations, all distinct from those found in CTL. In DCM there were also six (all also different from those found in CTL): three were common to and three distinct from ICM., Conclusion: DCM-specific increases were found in expression of several genes that regulate FA metabolism, which might help in the design of aetiology-specific metabolic therapies in HF. Ca(2+)-handling genes TPCN1 and TPCN2 also showed increased expression in HF, while HF- and CM-specific positive correlations were found among several FA and Ca(2+)-handling genes.

Aims: The European CRT Survey is a joint initiative of the Heart Failure Association (HFA) and the European Heart Rhythm Association (EHRA) of the European Society of Cardiology evaluating the contemporary implantation practice of cardiac resynchronization therapy (CRT) in Europe., Methods and Results: Patients who had a successful CRT implantation were enrolled from 141 centres in 13 countries between November 2008 and June 2009. Baseline demographics, clinical and implantation data were collected, with a follow-up of ∼1 year (9-15 months). The current report describes clinical outcomes including symptom severity, cardiovascular (CV) hospitalization, and survival. A total of 2438 patients were enrolled, and follow-up data were acquired from 2111 patients (87%). The population included important groups of patients poorly represented in randomized controlled trials, including very elderly patients and those with prior device implantation, atrial fibrillation, and/or QRS duration <120 ms. Investigators reported substantial improvement in New York Heart Association (NYHA) functional class at follow-up. Patient self-assessment indicated that 81% of the patients felt improved, 16% reported no change, and 4% reported deterioration. During follow-up, 207 (10%) patients died, 346 (16%) had a CV hospitalization, and 501 (24%) died or had CV hospitalization. Worse NYHA functional class, atrial fibrillation, ischaemic aetiology, and device type (CRT-P, i.e. CRT alone) were associated with poorer survival. Women had a better outcome, as did patients who had a CRT-D (with an implantable cardioverter defibrillator function) device., Conclusions: Outcomes including death and hospitalization in this European CRT survey were consistent with results from clinical trials of CRT. At 1 year follow-up, most patients who received a CRT device considered their symptoms improved compared with their pre-implant assessment. Although prospective, this is an observational study of successful CRT implantations, and outcomes in subgroup analyses must be interpreted with appropriate conservatism.

Introduction: Echocardiographic optimization of the VV interval may improve CRT response, but it is time-consuming and not routinely performed. The aim of this study was to compare the response to cardiac resynchronization therapy (CRT) when the interventricular pacing (VV) interval was optimized by tissue Doppler imaging (TDI) to CRT response when it was optimized following QRS width criteria., Methods and Results: The study included 156 consecutive CRT patients with severe heart failure and left bundle-branch block configuration. Atrioventricular interval was selected according to a pulsed Doppler assessment, and VV optimization was randomly assigned to echocardiography (ECHO group, n = 78) or electrocardiography (ECG group, n = 78). Optimal VV was defined for the ECHO group as producing the best LV intraventricular synchrony according to TDI displacement curves and for the ECG group as resulting in the narrowest QRS measured from the earliest deflection. At 6-month follow-up, percentage of echocardiographic responders (defined as neither death nor heart transplantation and a LV end-systolic volume reduction >10%) was higher in the ECG optimized group (50.0% vs 67.9%; P = 0.023), whereas clinical response (defined as neither death nor heart transplantation and >10% improvement in the 6-minute walking test) was similar in both groups (71.8% vs 73.1%; P = 0.858)., Conclusions: VV optimization based on QRS width obtained a higher percentage of responders in terms of LV reverse remodeling compared to the TDI method., (© 2011 Wiley Periodicals, Inc.)

The present case illustrates that in patients with right ventricular (RV) failure and right bundle branch block it is possible to resynchronize the RV without further worsening RV or left ventricular (LV) pump function, even in cases with various degrees of atrioventricular block. The acute response to different pacing configurations was analyzed in terms of dP/dt variations. Bifocal RV pacing (His bundle plus RV outflow tract pacing) achieved the best acute results and was chosen for permanent pacing. This pacing configuration was associated to clinical and echocardiographic improvement., (©2010, The Authors. Journal compilation ©2010 Wiley Periodicals, Inc.)

Aims: Monitoring systems integrated into electronic implantable devices for heart failure (HF) have significantly expanded the possibility of obtaining diagnostic information and can be used to enhance patient follow-up. The ability to obtain advance warning of worsening HF is currently being explored using a variety of diagnostic parameters. A novel device-based algorithm, physiological diagnostic (PhD), combines data from minute ventilation and accelerometer sensors to provide an indicator of the overall status of HF patients and detect clinically relevant acute HF events. The objective of this study was to evaluate the effectiveness of the PhD algorithm for detecting HF events in patients with HF., Methods: CLEPSYDRA is a multicentre, prospective, non-randomized, single-arm double-blinded study in 62 centres in Europe, the USA, and Canada. Patients with moderate-to-severe HF, on stable optimal pharmacological therapy, QRS≥120 ms, and ejection fraction≤0.35% will be included. Patients will be followed at 3-month intervals until study end, or for a minimum of 13 months. The primary endpoint is the sensitivity of the PhD (proportion of HF-related clinical events occurring within a 4-week period after a PhD HF indication). Secondary endpoints include the sensitivity of PhD with regard to HF events related to oral treatment modification, and adverse events. The first patient was included in October 2009. At the time of manuscript submission (Week 26, 2010), 214 patients had been enrolled. Study results are expected in 2012., Perspective: CLEPSYDRA will provide essential data on the utility of the PhD algorithm in a HF population with blinded investigators and patients. A successful outcome will demonstrate the potential for the algorithm to be implemented in clinical practice. This would improve clinical management and further the ability to generate dynamic and reliable risk profiles for patients with HF.

Background: Analysis of myocardial strain using two-dimensional (2D) echocardiography to assess left ventricular (LV) mechanical dyssynchrony by measuring time differences in peak systolic strains from opposing LV walls has been proposed. However, peak systolic strain may be difficult to identify., Objective: The purpose of this study was to evaluate (1) LV dyssynchrony by assessing the overlap among strain traces of the LV walls throughout the cardiac cycle and (2) its usefulness in identifying responders to cardiac resynchronization therapy (CRT)., Methods: Fifty patients with heart failure and LV systolic dysfunction undergoing CRT were studied with 2D echocardiography at baseline and 6-month follow-up. Myocardial radial strain and circumferential strain were analyzed using commercially available software. The resulting strain traces were postprocessed with a mathematical script., Results: Quantification of LV dyssynchrony was expressed as an index of temporal overlap from the analyzed traces. Responders to CRT were defined by ≥15% reduction of LV end-systolic volume at 6-month follow-up. Responders to CRT had higher LV dyssynchrony in both radial strain and circumferential strain analysis. A cutoff time overlap ≥7% for radial strain (area under the curve 0.79) and ≥8.5% for circumferential strain (area under the curve 0.66) identified responders to CRT., Conclusion: Quantifying the temporal superposition of LV wall deformations with a computed algorithm allows measurement of LV intraventricular dyssynchrony throughout the cardiac cycle. The derived index is useful in stratifying the probability of response to CRT., (Copyright © 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Although the benefit of cardiac resynchronization therapy (CRT) in selected patients with heart failure is well established, its effect on mortality in New York Heart Association (NYHA) class IV patients remains unclear. Our study evaluated the effect of CRT on urgent transplant-free survival in NYHA class IV patients treated with CRT, compared with medication-only treatment., Methods and Results: Forty NYHA class IV patients treated with CRT (80% men, 62.5% ischaemic, mean age of 65) were matched 1:1 by age, gender and aetiology of cardiomyopathy with patients treated with optimal medical therapy (OPT group). No significant differences were found between the groups in left ventricular diastolic diameter (71 +/- 6 vs. 73 +/- 9 mm), left ventricular systolic diameter (58 +/- 7 vs. 61 +/- 11 mm), and left ventricular ejection fraction (23 +/- 5 vs. 22 +/- 6%). Mean follow-up was 13.2 +/- 9.5 months for the CRT group and 17.3 +/- 11.6 months for the OPT group. Time to all-cause death or urgent transplantation [hazard ratios (HR), 1.29; 95% CI: 0.59-2.83; P = 0.52] or to cardiovascular death or urgent transplantation (HR, 1.53; 95% CI: 0.64-3.67; P = 0.34) was not reduced significantly in patients treated with CRT., Conclusion: In this study, CRT did not significantly improve survival of NYHA class IV heart failure patients compared with pharmacological therapy.

Aims: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular structural remodelling. The aim of our study was to analyse MMP-2 and TIMP-1 levels as predictors of poor response to cardiac resynchronization therapy (CRT)., Methods and Results: A cohort of 42 CRT patients from our centre was prospectively evaluated at baseline and after 12-month follow-up. MMP-2 and TIMP-1 assays were performed prior to CRT implant. Cardiac resynchronization therapy responders were defined as patients who survived, were not transplanted, and increased their basal 6 min walking distance test (6MWDT) by >or=10% or improved their NYHA functional class. Overall, 25 patients (60%) were classed as responders. At 12-month follow-up, six patients (14.2%) had died and one (2.4%) patient had been transplanted. Compared with responders, non-responders had higher levels of TIMP-1 (277 +/- 59 vs. 216 +/- 46 ng/mL, P = 0.001), MMP-2 (325 +/- 115 vs. 258 +/- 56 ng/mL, P = 0.02), and creatinine (1.76 +/- 0.8 vs. 1.25 +/- 0.3 mg/dL, P = 0.01). In a multivariate analysis, TIMP-1 was the only independent predictor of non-response to CRT [OR 0.97, 95% (CI 0.96-0.99) P = 0.005]. TIMP-1>or=248 ng/mL predicted non-response with 71% sensitivity and 72% specificity., Conclusion: TIMP-1 is an independent predictor of non-response in patients treated with CRT.

Cardiac resynchronization therapy (CRT) is a highly efficient treatment modality for patients with severe congestive heart failure and intraventricular dyssynchrony. However, the high individual cost and technical complexity of the implantation may limit its widespread utilization. The European Heart Rhythm Association (EHRA) launched a project to assess treatment of arrhythmias in all European Society of Cardiology member countries in order to have a platform for a progressive harmonization of arrhythmia treatment. As a result, two EHRA White Books have been published in 2008 and 2009 based on governmental, insurance, and professional society data. Our aim was to analyse the local differences in the utilization of CRT, based on these surveys. A total of 41 countries provided enough data to analyse years 2006-2008. Significant differences were found in the overall number of implantations and the growth rate between 2006 and 2008. Other contributing factors include local reimbursement of CRT, the existence of national guidelines, and a high number of conventional implantable cardioverter-defibrillator implantations, while GDP or healthcare spending has less effect. Focusing on improving these factors may increase the availability of CRT in countries where it is currently underutilized.

Aims: We hypothesized that a very advanced stage of dilated cardiomyopathy is associated with lower response to cardiac resynchronization therapy (CRT)., Methods and Results: A consecutive cohort of 147 patients was studied before device implantation and at 12 months follow-up. All patients were in NYHA functional class III-IV and had left-ventricular (LV) systolic dysfunction (LV ejection fraction 24 +/- 7%) and a wide QRS (171 +/- 29 ms). A patient who was alive without heart transplantation and had improved by at least 10% in the 6 min walking test at 12 months follow-up was considered a clinical responder. Fifty-four patients (36%) did not respond to CRT (15 cardiac deaths, 4 heart transplantations). Quality of life indicators (>41 points), LV end-diastolic volumes (>200 mL) and mitral regurgitant orifice area (>16 mm(2)) at baseline were independent predictors of response to CRT. Patients were assigned 1 point for each predictive parameter. Patients with higher scores showed a significantly higher likelihood of non-response to CRT (chi(2) = 12 891, P = 0.005)., Conclusion: The results show that non-responder patients have a more advanced stage of the disease, which suggests that CRT should be indicated earlier in the disease process.

Aims: Some authors recommend avoiding fusion with left ventricular (LV) intrinsic depolarization during cardiac resynchronization therapy (CRT). If fusion is still present during optimized biventricular (Biv) pacing and its long-term effects on the response to CRT are currently unknown. The aim of the study was to analyse the endocardial LV activation pattern induced by echocardiographically optimized Biv pacing and its influence on LV reverse remodelling., Methods and Results: Contact electro-anatomical mapping was performed in 15 heart failure (HF) patients with left bundle branch block and echocardiographically optimized CRT (seven ischaemic aetiology, 64 +/- 8 years, three women, New York Heart Association class 3 +/- 0.4, LV ejection fraction 25 +/- 5%). Left ventricular activation maps were performed in sinus rhythm (SR), during DDD right ventricular apical (RVA) and optimized Biv pacing. Fusion with intrinsic rhythm during pacing was considered when LV septal activation was produced at least partially by intrinsic depolarization, when compared with LV activation map during SR. Patients were considered responders to CRT if they had > or =10% reduction in LV end-systolic volume (LVESV) after 6 months of CRT. During SR, the LV breakthrough was mid-septal (n = 12), basal septum (n = 2), and apical (n = 1). During RVA pacing, LV breakthrough shifted apical in all patients. Right ventricular apical/Biv pacing proved fusion with intrinsic depolarization in 8 of 15 patients. The PR interval was shorter in patients with fusion RVA/Biv pacing (164 +/- 24 vs. 234 +/- 55 ms, P = 0.006). There was a trend for shorter LV activation time (LV(at)) in patients with fusion during RVA pacing (87 +/- 33 vs. 113 +/- 21 ms, P = 0.08) as well as during optimized Biv pacing (83 +/- 18 vs. 104 +/- 24 ms, P = 0.07), although LV(at) was similar in SR (100 +/- 22 vs. 106 +/- 20, P = NS). In patients with fusion, 6 months responder rate was significantly higher (100 vs. 28.5%, P < 0.007) as was the degree of LVESV reduction (39 +/- 17 vs. 1.0 +/- 14%, P < 0.001)., Conclusion: Biventricular pacing with fusion may substantially increase the structural responder rate probably by shortening LV(at).

Optimization of the interventricular pacing delay (VV) in cardiac resynchronization therapy is time-consuming and not routinely performed. The aim of the present study was to compare the acute hemodynamic response obtained by different VV programming methods. Several methods for optimizing the VV using electrocardiographic or echocardiographic measurements were performed. The effect of programming an empirical prefixed VV of 0 ms was also evaluated. Invasive first derivative of left ventricular (LV) pressure over time (dP/dt max) was measured at several VV values, and the hemodynamic response that could be obtained by each noninvasive VV selection method was extrapolated from the curve of LV dP/dt max versus VV. The study included 25 patients (80% men, age 66 +/- 9 years, 44% ischemic). The maximum achievable LV dP/dt during biventricular pacing was obtained by a median left ventricular preactivation of 30 ms and increased the baseline unpaced LV dP/dt from 774 +/- 181 to 934 +/- 179 mm Hg/s (p <0.001). The noninvasive optimization method selected the VV leading to the narrowest QRS measured from the earliest deflection and obtained the smallest difference with regard to the maximum achievable LV dP/dt. Furthermore, of all the VV optimization methods tested, this was the only 1 that significantly improved on the hemodynamic response obtained by programming a predefined VV of 0 ms in all patients (925 +/- 178 vs 906 +/- 183 mm Hg/s; p = 0.003). In conclusion, achieving the narrowest QRS measured from the earliest deflection obtained a better acute hemodynamic response than the other VV optimization methods. It also improved the response obtained by default simultaneous biventricular pacing, although this improvement was limited in magnitude.

Background: Cardiac resynchronization therapy (CRT) has been shown to reduce functional mitral regurgitation (MR). It has been proposed that the mechanism of MR reduction relates to geometric change or, alternatively, changes in left ventricular (LV) contractile function. Normal mitral valve (MV) function relies on a balance between tethering and closing forces on the MV leaflets. Functional MR results from a derangement of this force-balance relationship, and CRT may be an important modulator of MV function by its ability to enhance the force-balance relationship on the MV. We hypothesized that CRT improves the comprehensive force balance acting on the valve, including favorable changes in both geometry and LV contractile function., Methods and Results: We examined the effect of CRT on 34 patients with functional MR before and after CRT (209+/-81 days). MR regurgitant volume, closing forces on MV (derived from Doppler transmitral pressure gradients), including dP/dt and a factor (closing pressure ratio) expressing how long the peak closing gradient is maintained over systole (closing pressure ratio=velocity time integral/MR peak velocityxmitral regurgitation time), and dyssynchrony by tissue Doppler were measured. End-diastolic volume, end-systolic volume, mitral valve annular area (MAA) and contraction (percent change in MAA from end-diastole to midsystole), leaflet closing area (leaflet area during valve closure), and tenting volume (volume under leaflets to annular plane) were measured by 3D echocardiography. After CRT, end-diastolic volume (253+/-111 versus 221+/-110 mL, P<0.001) and end-systolic volume (206+/-97 versus 167+/-91 mL, P<0.001) decreased and ejection fraction (19+/-6 versus 27+/-9%, P<0.001) increased. MR regurgitant volume decreased from 35+/-17 to 23+/-14 mL (P<0.001), MAA from 11.6+/-3.5 to 10.5+/-3.1 cm(2) (P<0.001), leaflet closing area from 15.4+/-5 to 13.7+/-3.8 cm(2) (P<0.001), and tenting volume from 5.7+/-2.6 to 4.6+/-2.2 mL (P<0.001). Peak velocity (and therefore transmitral closing pressure) was more sustained throughout systole, as reflected by the increase in the closing pressure ratio (0.77+/-0.1 versus 0.84+/-0.1 before CRT versus after CRT, P=0.01); dP/dt also improved after CRT. There was no change in dyssynchrony or MAA contraction., Conclusions: Reduction in MR after CRT is associated with favorable changes in MV geometry and closing forces on the MV. It does so by favorably affecting the force balance acting on the MV in 2 ways: reducing tethering through reversal of LV remodeling and increasing the systolic duration of peak transmitral closing pressures.

Aims: The European cardiac resynchronization therapy (CRT) survey is a joint initiative taken by the Heart Failure Association and the European Heart Rhythm Association of the European Society of Cardiology. The primary aim of this survey is to describe current European practice associated with CRT implantations., Methods and Results: A total of 140 centres from 13 European countries contributed data from consecutive patients successfully implanted with a CRT device with or without an ICD between November 2008 and June 2009. The total number of patients enrolled was 2438. The median age of the patients was 70 years (IQR 62-76) and 31% were > or =75 years. It was found that 78% were in NYHA functional class III or IV and 22% in I or II. The mean ejection fraction was 27% +/- 8 and the mean QRS duration 157 ms +/- 32. The QRS duration was <120 ms in 9%. Atrial fibrillation was reported in 23%. It was found that 26% of patients had a previously implanted permanent pacemaker or ICD; 76% of procedures were performed by an electrophysiologist; 82% had an elective admission for implantation and the median duration of hospitalization was 3 days (IQR 2-7); and 73% received a CRT-D device which was more often implanted in men, younger patients, and with ischaemic aetiology. The mean QRS duration was reduced to 133 ms +/- 27 (P < 0.0001) at discharge. Peri-procedural complication rates were comparable to the rates reported in randomized trials., Conclusion: This CRT survey provides important information describing current European practice with regard to patient demographics, selection criteria, procedural routines, and status at discharge. These data should be useful for benchmarking individual patient management and national practice against wider experience.

Objectives: The purpose of the present study was to assess the anatomy and geometry of the mitral valve by using 64-slice multislice computed tomography (MSCT)., Background: Because it yields detailed anatomic information, MSCT may provide more insight into the underlying mechanisms of functional mitral regurgitation (FMR)., Methods: In 151 patients, including 67 patients with heart failure (HF) and 29 patients with moderate to severe FMR, 64-slice MSCT coronary angiography was performed. The anatomy of the subvalvular apparatus of the mitral valve was assessed; mitral valve geometry, comprising the mitral valve tenting height and leaflet tethering, was evaluated at the anterolateral, central, and posteromedial levels., Results: In the majority of patients, the anatomy of the subvalvular apparatus was highly variable because of multiple anatomic variations in the posterior papillary muscle (PM): the anterior PM had a single insertion, whereas the posterior PM showed multiple heads and insertions (n = 114; 83%). The assessment of mitral valve geometry demonstrated that patients with HF with moderate to severe FMR had significantly increased posterior leaflet angles and mitral valve tenting heights at the central (44.4 degrees +/- 11.9 degrees vs. 37.1 degrees +/- 9.0 degrees, p = 0.008; 6.6 +/- 1.4 mm/m(2) vs. 5.3 +/- 1.3 mm/m(2), p < 0.0001, respectively) and posteromedial levels (35.9 degrees +/- 10.6 degrees vs. 26.8 degrees +/- 10.1 degrees, p = 0.04; 5.4 +/- 1.6 mm/m(2) vs. 4.1 +/- 1.2 mm/m(2), p < 0.0001, respectively), as compared with patients with HF without FMR. In addition, a more outward displacement of the PMs, reflected by a higher mitral valve sphericity index, was observed in patients with HF with FMR (1.4 +/- 0.3 vs. 1.2 +/- 0.3, p = 0.004). Mitral valve tenting height at the central level and mitral valve sphericity index were the strongest determinants of FMR severity., Conclusions: MSCT provides anatomic and geometric information on the mitral valve apparatus. In patients with HF with moderate to severe FMR, a more pronounced tethering of the mitral leaflets at the central and posteromedial levels was demonstrated using MSCT.

Aims: Cardiac resynchronization therapy (CRT) has been proven to be effective in patients suffering from chronic heart failure (CHF) associated with electrical dyssynchrony. However, long-term predictors of mortality in that subset have not been extensively investigated. The aim of this study was to establish baseline long-term predictors of cardiovascular mortality in CHF patients treated with CRT., Methods and Results: A total of 188 consecutive patients with moderate to severe CHF who had undergone a successful CRT implant were evaluated. Baseline measurements included clinical history, a 6-min walking test (6MWT), and echocardiographic parameters. Patients with cardiac or non-cardiac diseases limiting their ability to perform a 6MWT were excluded, with the final count totalling 155 patients [82% men, mean age 69 +/- 8 years, New York Heart Association (NYHA) functional class: II 22%, III 73.5%, IV 4.5%]. A total of 24 patients (15.5%) died of cardiovascular causes and one patient underwent heart transplantation during a mean follow-up of 24.4 +/- 18.1 months. Univariate analysis showed that NYHA class, distance walked in the 6MWT, left atrial diameter, digoxine and left ventricle (LV) ejection fraction were all significantly related to rates of mortality. Multivariate Cox regression after adjustment for the presence of a defibrillator showed that the LV ejection fraction [HR 0.91 (95% CI: 0.84-0.98) P = 0.008] and 6MWT distance <225 m [HR 5.6 (95% CI: 1.2-25.3) P = 0.026] were independent predictors of cardiovascular mortality., Conclusion: Baseline functional capacity, measured by the 6MWT distance, and LV ejection fraction are independent predictors of mortality in moderate to severe CHF patients, despite CRT. A 6MWT distance walked of <225 m identifies patients at high risk of cardiovascular death at mid-long term.

Heart failure is a prevalent condition that is associated with high morbidity and mortality and that places a substantial demand on healthcare resources. As the condition often affects older individuals with comorbidities, its treatment requires the implementation of an integrated model of care that can be applied in primary care, in hospitals, and in the patient's home. The use of heart failure units has improved quality of life in these patients and has reduced hospital admissions. However, in Spain integrated care has not yet been widely implemented. Clinical and preclinical research on heart failure is complex and, consequently, it is essential for investigators to work together in research networks. As a result, 16 Spanish centers have organized themselves into a heart failure research network (REDINSCOR). This network is considering the establishment of a national heart failure registry and is involved in seven research projects, whose subjects range from molecular biology and cell physiology to diagnosis, treatment, and the development of integrated healthcare models.

This study was conducted to investigate the clinical impact of cardiac resynchronization device optimization. A series of 100 consecutive patients received cardiac resynchronization therapy. In the first 49 patients, an empirical atrioventricular delay of 120 ms was set, with simultaneous biventricular stimulation (interventricular [VV] interval=0 ms). In the next 51 patients, systematic atrioventricular optimization was performed. VV optimization was also performed, selecting 1 VV delay: right or left ventricular preactivation (+30 or -30 ms) or simultaneous (VV interval=0 ms), according to the best synchrony obtained by tissue Doppler-derived wall displacement. At follow-up, patients who were alive without cardiac transplantation and showed improvement of >or=10% in the distance walked in the 6-minute walking test were considered responders. There were no differences between the 2 groups at baseline. Left ventricular ejection fraction improved in the 2 groups, but left ventricular cardiac output improved only in the optimized group. At 6 months, patients with optimized devices walked slightly further in the 6-minute walking test (497+/-167 vs 393+/-123 m, p<0.01), with no differences in New York Heart Association functional class or quality of life compared with nonoptimized patients. Overall, the number of nonresponders were similar in the 2 groups (27% vs 23%, p=NS). In conclusion, the echocardiographic optimization of cardiac resynchronization devices provided a slight incremental clinical benefit at midterm follow-up. Simple and rapid methods to routinely optimize the devices are warranted.

There are discordant data about the utility of septal-to-posterior wall motion delay (SPWMD) assessed using M-mode echocardiography to predict an improvement with cardiac resynchronization therapy (CRT). Baseline SPWMD was measured using M-mode in a parasternal short-axis view in a series of 67 patients undergoing CRT and followed up after 6 months. Heart failure was caused by coronary artery disease in 27 patients. Clinical responders were patients who were alive, had not undergone heart transplantation, and also increased the distance walked in 6 minutes by >10%. Baseline SPWMDs were mean 155 +/- 113 ms and median 135. Thirty-four patients (51%) had an SPWMD >130 ms. At 6-month follow-up, there were 17 nonresponders. At baseline, there were no significant differences between patients with SPWMD >130 or <130 ms in age, drug therapy, permanent atrial fibrillation, New York Heart Association functional class, underlying cause of cardiomyopathy, QRS duration, left ventricular (LV) ejection fraction, LV dimensions, or neurohormonal activation (norepinephrine and atrial and brain natriuretic peptide). At 6-month follow-up, baseline SPWMD was not associated with clinical response, New York Heart Association functional class, distance walked in 6 minutes, LV reverse remodeling, or neurohormonal activation. SPWMD >130 ms was also not a predictor. In conclusion, SPWMD is not a good predictor of response to CRT.

Cardiac resynchronization therapy (CRT) reverses left ventricular (LV) remodeling in patients with congestive heart failure. However, the mechanisms leading to the clinical response to CRT remain unclear. The aim of this study was to analyze whether patients who improve clinically have greater LV reverse remodeling than nonresponders after a 12-month follow-up period. The sample comprised 64 consecutive patients with heart failure, complete left bundle branch block, and LV ejection fractions (EFs) < or =35% who were treated with CRT. Doppler echocardiographic scans were taken just before and immediately after the implantation of the pacemakers and at 6- and 12-month follow-up examinations. LV diameters, volumes, and EFs were compared. Responders were defined as those patients who were alive without cardiac transplantation and with > or =10% improvement in the 6-minute walking test after 1 year of follow-up. There were no clinical differences at baseline between responders and nonresponders. At 6- and 12-month follow-up, LV dimensions decreased significantly in responders but did not change in nonresponders. Furthermore, LVEFs improved only in responders. In conclusion, patients who clinically respond to CRT have greater LV reverse remodeling than nonresponders after 6 and 12 months of follow-up. The effect of CRT on LV remodeling may explain, at least in part, the clinical benefit of this therapy.

About 30% of patients treated with cardiac resynchronization therapy (CRT) do not respond to treatment. The aim of this study was to identify clinical predictors of lack of improvement in patients receiving CRT. From 197 consecutive patients scheduled to receive CRT, 143 fulfilled the inclusion criteria. Mean age was 68 +/- 7 years and 79% were men. Heart failure was due to ischemic heart disease in 49 patients (34%). Mean QRS duration was 165 +/- 26 ms, and left ventricular ejection fraction was 27 +/- 7%. Nonresponder patients were defined as those who died of heart failure, underwent heart transplantation, or did not increase the distance walked in 6 minutes >10%. At 6-month follow-up, there were 28 nonresponders (20%). Among nonresponders, 2 patients received a heart transplantation and 9 patients died of heart failure. In logistic regression analysis, independent predictors of lack of response to CRT were ischemic heart disease (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.2 to 7; p = 0.023), severe mitral regurgitation (OR 3.5, 95% CI 1.3 to 9; p = 0.014), and left ventricular end-diastolic diameter > or =75 mm (OR 3.1, 95% CI 1.1 to 8; p = 0.026). Patients with these 3 predictors had a probability response of 27%.