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Aims: We explored whether a missed cohort of patients in the community with heart failure (HF) and left ventricular systolic dysfunction (LVSD) could be identified and receive treatment optimization through a primary care heart failure (PCHF) service., Methods and Results: PCHF is a partnership between Inspira Health, National Health Service Cardiologists and Medtronic. The PCHF service uses retrospective clinical audit to identify patients requiring a prospective face-to-face consultation with a consultant cardiologist for clinical review of their HF management within primary care. The service is delivered via five phases: (i) system interrogation of general practitioner (GP) systems; (ii) clinical audit of medical records; (iii) patient invitation; (iv) consultant reviews; and (v) follow-up. A total of 78 GP practices (864 194 population) have participated. In total, 19 393 patients' records were audited. HF register was 9668 (prevalence 1.1%) with 6162 patients coded with LVSD (prevalence 0.7%). HF case finder identified 9725 additional patients to be audited of whom 2916 patients required LVSD codes adding to the patient medical record (47% increase in LVSD). Prevalence of HF with LVSD increased from 0.7% to 1.05%. A total of 662 patients were invited for consultant cardiologist review at their local GP practice. The service found that within primary care, 27% of HF patients identified for a cardiologist consultation were eligible for complex device therapy, 45% required medicines optimization, and 47% of patients audited required diagnosis codes adding to their GP record., Conclusion: A PCHF service can identify a missed cohort of patients with HF and LVSD, enabling the optimization of prognostic medication and an increase in device prescription., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To test the value of Periodic Repolarization Dynamics (PRD), a recently validated electrocardiographic marker of sympathetic activity, as a novel approach to predict sudden cardiac death (SCD) and non-sudden cardiac death (N-SCD) and to improve identification of patients that profit from ICD-implantation., Methods and Results: We included 856 post-infarction patients with left-ventricular ejection fraction (LVEF) ≤30% of the MADIT-II trial in sinus rhythm. Of these, 507 and 348 patients were randomized to ICD or conventional treatment. PRD was assessed from multipolar 10-min baseline ECGs. Primary and secondary endpoints were total mortality, SCD and N-SCD. Multivariable analyses included treatment group, QRS-duration, New York Heart Association classification, blood-urea nitrogen, diabetes mellitus, beta-blocker therapy and LVEF. During follow-up of 20.4 months, 119 patients died (53 SCD and 36 N-SCD). On multivariable analyses, increased PRD was a significant predictor of mortality (standardized coefficient 1.37[1.19-1.59]; P < 0.001) and SCD (1.40 [1.13-1.75]; P = 0.003) but also predicted N-SCD (1.41[1.10-1.81]; P = 0.006). While increased PRD predicted SCD in conventionally treated patients (1.61[1.23-2.11]; P < 0.001), it was predictive of N-SCD (1.63[1.28-2.09]; P < 0.001) and adequate ICD-therapies (1.20[1.03-1.39]; P = 0.017) in ICD-treated patients. ICD-treatment substantially reduced mortality in the lowest three PRD-quartiles by 53% (P = 0.001). However, there was no effect in the highest PRD-quartile (mortality increase by 29%; P = 0.412; P < 0.001 for difference) as the reduction of SCD was compensated by an increase of N-SCD., Conclusion: In post-infarction patients with impaired LVEF, PRD is a significant predictor of SCD and N-SCD. Assessment of PRD is a promising tool to identify post-MI patients with reduced LVEF who might benefit from intensified treatment., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Over two decades after the introduction of cardiac resynchronization therapy (CRT) into clinical practice, ∼30% of candidates continue to fail to respond to this highly effective treatment of drug-refractory heart failure (HF). Since the causes of this non-response (NR) are multifactorial, it will require multidisciplinary efforts to overcome. Progress has, thus far, been slowed by several factors, ranging from a lack of consensus regarding the definition of NR and technological limitations to the delivery of therapy. We critically review the various endpoints that have been used in landmark clinical trials of CRT, and the variability in response rates that has been observed as a result of these different investigational designs, different sample populations enrolled and different means of therapy delivered, including new means of multisite and left ventricular endocardial simulation. Precise recommendations are offered regarding the optimal device programming, use of telemonitoring and optimization of management of HF. Potentially reversible causes of NR to CRT are reviewed, with emphasis on loss of biventricular stimulation due to competing arrhythmias. The prevention of NR to CRT is essential to improve the overall performance of this treatment and lower its risk-benefit ratio. These objectives require collaborative efforts by the HF team, the electrophysiologists and the cardiac imaging experts., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

In patients with left ventricular heart failure (HF), the development of pulmonary hypertension (PH) and right ventricular (RV) dysfunction are frequent and have important impact on disease progression, morbidity, and mortality, and therefore warrant clinical attention. Pulmonary hypertension related to left heart disease (LHD) by far represents the most common form of PH, accounting for 65-80% of cases. The proper distinction between pulmonary arterial hypertension and PH-LHD may be challenging, yet it has direct therapeutic consequences. Despite recent advances in the pathophysiological understanding and clinical assessment, and adjustments in the haemodynamic definitions and classification of PH-LHD, the haemodynamic interrelations in combined post- and pre-capillary PH are complex, definitions and prognostic significance of haemodynamic variables characterizing the degree of pre-capillary PH in LHD remain suboptimal, and there are currently no evidence-based recommendations for the management of PH-LHD. Here, we highlight the prevalence and significance of PH and RV dysfunction in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), and provide insights into the complex pathophysiology of cardiopulmonary interaction in LHD, which may lead to the evolution from a 'left ventricular phenotype' to a 'right ventricular phenotype' across the natural history of HF. Furthermore, we propose to better define the individual phenotype of PH by integrating the clinical context, non-invasive assessment, and invasive haemodynamic variables in a structured diagnostic work-up. Finally, we challenge current definitions and diagnostic short falls, and discuss gaps in evidence, therapeutic options and the necessity for future developments in this context., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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.)

Background: Through contemporary literature, the optimal strategy to manage coronary chronic total occlusions (CTOs) remains under debate., Objectives: The aim of the Italian Registry of Chronic Total Occlusions (IRCTO) was to provide data on prevalence, characteristics, and outcome of CTO patients according to the management strategy., Methods: The IRCTO is a prospective real world multicentre registry enrolling patients showing at least one CTO. Clinical and angiographic data were collected independently from the therapeutic strategy [optimal medical therapy (MT), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG)]; a comparative 1-year clinical follow-up was performed., Results: A total of 1777 patients were enrolled for an overall CTO prevalence of 13.3%. The adopted therapeutic strategies were as follows: MT in 826 patients (46.5%), PCI in 776 patients (43.7%), and CABG in the remaining 175 patients (9.8%). At 1-year follow-up, patients undergoing PCI showed lower rate of major adverse cardiac and cerebrovascular events (MACCE) (2.6% vs. 8.2% and vs. 6.9%; P < 0.001 and P < 0.01) and cardiac death (1.4% vs. 4.7% and vs. 6.3%; P < 0.001 and P < 0.001) in comparison with those treated with MT and CABG, respectively. After propensity score-matching analysis, patients treated with PCI showed lower incidence of cardiac death (1.5 vs. 4.4%; P < 0.001), acute myocardial infarction (1.1 vs. 2.9%; P = 0.03), and re-hospitalization (2.3 vs. 4.4% P = 0.04) in comparison with those managed by MT., Conclusions: Our data showed how CTO PCI might significantly improve the survival and decrease MACCE occurrence at 1 year follow-up in comparison with MT and/or CABG., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Pre-clinical and few clinical studies suggest that transplantation of autologous bone marrow mononuclear cells (BMNC) improves heart function in dilated cardiomyopathies. Our objective was to determine if intracoronary injection of autologous BMNC improves the left ventricular ejection fraction (LVEF) of patients with non-ischaemic dilated cardiomyopathy (NIDCM)., Methods and Results: This study was a multicentre, randomized, double-blind, placebo controlled trial with a follow-up of 12 months. Patients with NIDCM and LVEF <35% were recruited at heart failure ambulatories in specialized hospitals around Brazil. One hundred and sixty subjects were randomized to intracoronary injection of BMNC or placebo (1:1). The primary endpoint was the difference in change of LVEF between BMNC and placebo groups as determined by echocardiography. One hundred and fifteen patients completed the study. Left ventricular ejection fraction decreased from 24.0% (21.6-26.3) to 19.9% (15.4-24.4) in the BMNC group and from 24.3% (22.1-26.5) to 22.1% (17.4-26.8) in the placebo group. There were no significant differences in changes between cell and placebo groups for left ventricular systolic and diastolic volumes and ejection fraction. Mortality rate was 20.37% in placebo and 21.31% in BMNC., Conclusion: Intracoronary injection of autologous BMNC does not improve left ventricular function in patients with NIDCM., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00333827., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

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 <35% [incidence rate difference (IRD): -6.5/100 person-years, 95% confidence interval (95% CI): -8.8 to -4.2, P < 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 < 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 <0.001). 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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: The management and outcomes of patients with functional moderate/severe mitral regurgitation and severe left ventricular (LV) systolic dysfunction are not well defined. We sought to determine the characteristics, management strategies, and outcomes of patients with moderate or severe mitral regurgitation (MR) and LV systolic dysfunction., Methods and Results: For the period 1995-2010, the Duke Echocardiography Laboratory and Duke Databank for Cardiovascular Diseases databases were merged to identify patients with moderate or severe functional MR and severe LV dysfunction (defined as LV ejection fraction ≤ 30% or LV end-systolic diameter > 55 mm). We examined treatment effects in two ways. (i) A multivariable Cox proportional hazards model was used to assess the independent relationship of different treatment strategies and long-term event (death, LV assist device, or transplant)-free survival among those with and without coronary artery disease (CAD). (ii) To examine the association of mitral valve (MV) surgery with outcomes, we divided the entire cohort into two groups, those who underwent MV surgery and those who did not; we used inverse probability weighted (IPW) propensity adjustment to account for non-random treatment assignment. Among 1441 patients with moderate (70%) or severe (30%) MR, a significant history of hypertension (59%), diabetes (28%), symptomatic heart failure (83%), and CAD (52%) was observed. Past revascularization in 26% was noted. At 1 year, 1094 (75%) patients were treated medically. Percutaneous coronary intervention was performed in 114 patients, coronary artery bypass graft (CABG) surgery in 82, CABG and MV surgery in 96, and MV surgery alone in 55 patients. Among patients with CAD, compared with medical therapy alone, the treatment strategies of CABG surgery [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.42-0.76] and CABG with MV surgery (HR 0.58, 95% CI 0.44-0.78) were associated with long-term, event-free survival benefit. Percutaneous intervention treatment produced a borderline result (HR 0.78, 95% CI 0.61-1.00). However, the relationship with isolated MV surgery did not achieve statistical significance (HR 0.64, 95% CI 0.33-1.27, P = 0.202). Among those with CAD, following IPW adjustment, MV surgery was associated with a significant event-free survival benefit compared with patients without MV surgery (HR 0.71, 95% CI 0.52-0.95). In the entire cohort, following IPW adjustment, the use of MV surgery was associated with higher event-free survival (HR 0.69, 95% CI 0.53-0.88)., Conclusion: In patients with moderate or severe MR and severe LV dysfunction, mortality was substantial, and among those selected for surgery, MV surgery, though performed in a small number of patients, was independently associated with higher event-free survival., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Comparative studies suggest that stem cells committed to a cardiac lineage are more effective for improving heart function than those featuring an extra-cardiac phenotype. We have therefore developed a population of human embryonic stem cell (ESC)-derived cardiac progenitor cells., Methods and Results: Undifferentiated human ESCs (I6 line) were amplified and cardiac-committed by exposure to bone morphogenetic protein-2 and a fibroblast growth factor receptor inhibitor. Cells responding to these cardio-instructive cues express the cardiac transcription factor Isl-1 and the stage-specific embryonic antigen SSEA-1 which was then used to purify them by immunomagnetic sorting. The Isl-1(+) SSEA-1(+) cells were then embedded into a fibrin scaffold which was surgically delivered onto the infarct area in a 68-year-old patient suffering from severe heart failure [New York Heart Association [NYHA] functional Class III; left ventricular ejection fraction (LVEF): 26%]. A coronary artery bypass was performed concomitantly in a non-infarcted area. The implanted cells featured a high degree of purity (99% were SSEA-1(+)), had lost the expression of Sox-2 and Nanog, taken as markers for pluripotency, and strongly expressed Isl-1. The intraoperative delivery of the patch was expeditious. The post-operative course was uncomplicated either. After 3 months, the patient is symptomatically improved (NYHA functional Class I; LVEF: 36%) and a new-onset contractility is echocardiographically evident in the previously akinetic cell/patch-treated, non-revascularized area. There have been no complications such as arrhythmias, tumour formation, or immunosuppression-related adverse events., Conclusion: This observation demonstrates the feasibility of generating a clinical-grade population of human ESC-derived cardiac progenitors and combining it within a tissue-engineered construct. While any conclusion pertaining to efficacy would be meaningless, the patient's functional outcome yet provides an encouraging hint. Beyond this case, the platform that has been set could be useful for generating different ESC-derived lineage-specific progenies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: In at-risk patients with left ventricular dysfunction, implantable cardioverter defibrillators (ICDs) prolong life. Implantable cardioverter defibrillators are increasingly implanted for primary prevention and therefore into lower risk patients. Trial data have demonstrated the benefit of these devices but does not provide an estimate of potential lifespan-gain over longer time periods, e.g. a patient's lifespan., Methods: Using data from landmark ICD trials, lifespan-gain was plotted against baseline annual mortality in the individual trials. Lifespan-gain was then extrapolated to a time-horizon of >20 years while adjusting for increasing 'competing' risk from ageing and non-sudden cardiac death (pump failure)., Results: At 3 years, directly observed lifespan-gain was strongly dependent on baseline event rate (r = 0.94, P < 0.001). However, projecting beyond the duration of the trial, lifespan-gain increases rapidly and non-linearly with time. At 3 years, it averages 1.7 months, but by 10 years up to 9-fold more. Lifespan-gain over time horizons >20 years were greatest in lower risk patients (∼5 life-years for 5% baseline mortality, ∼2 life-years for 15% baseline mortality). Increased competing risks significantly reduce lifespan-gain from ICD implantation., Conclusion: While high-risk patients may show the greatest short-term gain, the dramatic growth of lifespan-gain over time means that it is the lower risk patients, e.g. primary prevention ICD implantation, who gain the most life-years over their lifetime. Benefit is underestimated when only trial data are assessed as trials can only maintain randomization over limited periods. Lifespan-gain may be further increased through advances in ICD device programming., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aim: Chronic right ventricle (RV) apical (RVA) pacing is standard treatment for an atrioventricular (AV) block but may be deleterious to left ventricle (LV) systolic function. Previous clinical studies of non-apical pacing have produced conflicting results. The aim of this randomized, prospective, international, multicentre trial was to compare change in LV ejection fraction (LVEF) between right ventricular apical and high septal (RVHS) pacing over a 2-year study period., Methods and Results: We randomized 240 patients (age 74 ± 11 years, 67% male) with a high-grade AV block requiring >90% ventricular pacing and preserved baseline LVEF >50%, to receive pacing at the RVA (n = 120) or RVHS (n = 120). At 2 years, LVEF decreased in both the RVA (57 ± 9 to 55 ± 9%, P = 0.047) and the RVHS groups (56 ± 10 to 54 ± 10%, P = 0.0003). However, there was no significant difference in intra-patient change in LVEF between confirmed RVA (n = 85) and RVHS (n = 83) lead position (P = 0.43). There were no significant differences in heart failure hospitalization, mortality, the burden of atrial fibrillation, or plasma brain natriutetic peptide levels between the two groups. A significantly greater time was required to place the lead in the RVHS position (70 ± 25 vs. 56 ± 24 min, P < 0.0001) with longer fluoroscopy times (11 ± 7 vs. 5 ± 4 min, P < 0.0001)., Conclusion: In patients with a high-grade AV block and preserved LV function requiring a high percentage of ventricular pacing, RVHS pacing does not provide a protective effect on left ventricular function over RVA pacing in the first 2 years., Protect-Pace: ClinicalTrials.gov number NCT00461734., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

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.)

Aims: Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality., Methods and Results: Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (<75 or ≥75 years), and left ventricular ejection fraction (LVEF, ≤45 or >45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45-0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45-0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75-1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67-0.94); P = 0.009] or cardiovascular disease [0.82 (0.67-0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF., Conclusion: Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalization., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In the REPAIR-AMI trial, intracoronary infusion of bone marrow-derived cells (BMCs) was associated with a significantly greater recovery of contractile function in patients with acute myocardial infarction (AMI) at 4-month follow-up than placebo infusion. The current analysis investigates clinical outcome and predictors of event-free survival at 5 years., Methods and Results: In the multicentre, placebo-controlled, double-blind REPAIR-AMI trial, 204 patients received intracoronary infusion of BMCs (n = 101) or placebo (n = 103) into the infarct vessel 3-7 days following successful percutaneous coronary intervention. Fifteen patients died in the placebo group compared with seven patients in the BMC group (P = 0.08). Nine placebo-treated patients and five BMC-treated patients required rehospitalization for chronic heart failure (P = 0.23). The combined endpoint cardiac/cardiovascular/unknown death or rehospitalisation for heart failure was more frequent in the placebo compared with the BMC group (18 vs. 10 events; P = 0.10). Univariate predictors of adverse outcomes were age, the CADILLAC risk score, aldosterone antagonist and diuretic treatment, changes in left ventricular ejection fraction, left ventricular end-systolic volume, and N-terminal pro-Brain Natriuretic Peptide (all P < 0.01) at 4 months in the entire cohort and in the placebo group. In contrast, in the BMC group, only the basal (P = 0.02) and the stromal cell-derived factor-1-induced (P = 0.05) migratory capacity of the administered BMC were associated with improved clinical outcome., Conclusion: In patients of the REPAIR-AMI trial, established clinical parameters are associated with adverse outcome at 5 years exclusively in the placebo group, whereas the migratory capacity of the administered BMC determines event-free survival in the BMC-treated patients. These data disclose a potency-effect relationship between cell therapy and long-term outcome in patients with AMI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Intra-myocardial transplantation of CD133(+) bone marrow stem cells (BMC) yielded promising results in clinical pilot trials. We now performed the double-blinded, randomized, placebo-controlled CARDIO133 trial to determine its impact on left ventricular (LV) function and clinical symptoms., Methods and Results: Sixty patients with chronic ischaemic heart disease and impaired LV function (left ventricular ejection fraction, LVEF <35%) were randomized to undergo either coronary artery bypass grafting (CABG) and injection of CD133(+) BMC in the non-transmural, hypokinetic infarct border zone (CD133), or CABG and placebo injection (placebo). Pre-operative LVEF was 27 ± 6% in CD133 patients and 26 ± 6% in placebo patients. Outcome was assessed after 6 months, and the primary endpoint was LVEF measured by cardiac magnetic resonance imaging (MRI) at rest. The incidence of adverse events was similar in both groups. There was no difference in 6-min walking distance, Minnesota Living with Heart Failure score, or Canadian Cardiovascular Society (CCS) class between groups at follow-up, and New York Heart Association class improved more in the placebo group (P = 0.004). By cardiac MRI, LVEF at 6 months was 33 ± 8% in the placebo group and 31 ± 7% in verum patients (P = 0.3), with an average inter-group difference of -2.1% (95% CI -6.3 to 2.1). Systolic or diastolic LV dimensions at 6 months were not different, either. In the CD133 group, myocardial perfusion at rest recovered in more LV segments than in the placebo group (9 vs. 2%, P < 0.001). Scar mass decreased by 2.2 ± 5 g in CD133(+) patients (P = 0.05), but was unchanged in the placebo group (0.3 ± 4 g, P = 0.7; inter-group difference in change = 2 g (95% CI -1.1 to 5)). By speckle-tracking echocardiography, cell-treated patients showed a better recovery of regional wall motion when the target area was posterior., Conclusion: Although there may be some improvements in scar size and regional perfusion, intra-myocardial injection of CD133(+) BMC has no effect on global LV function and clinical symptoms. Improvements in regional myocardial function are only detectable in patients with posterior infarction, probably because the interventricular septum after anterior infarction is not accessible by trans-epicardial injection., Clinical Trial Registration: This trial was registered at http://www.clinicaltrials.gov under NCT00462774., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials., Methods and Results: We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction. We contacted the principal investigator for each participating trial to provide summary data with regard to different pre-specified subgroups [age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct-related artery, LV end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number] and three different endpoints [change in LVEF, LVEDVI, and LV end-systolic volume index (ESVI)]. Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC-treated patients compared with controls: [2.55% increase, 95% confidence interval (CI) 1.83-3.26, P < 0.001]. Cell therapy significantly reduced LVEDVI and LVESVI (-3.17 mL/m², 95% CI: -4.86 to -1.47, P < 0.001; -2.60 mL/m², 95% CI -3.84 to -1.35, P < 0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age <55, 3.38%, 95% CI: 2.36-4.39) compared with older patients (age ≥ 55 years, 1.77%, 95% CI: 0.80-2.74, P = 0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF <40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI: 4.27-6.33 in patients with LVEF <40% compared with 1.45%, 95% CI: 0.60 to 2.31 in LVEF ≥ 40%, P < 0.001. No clear interaction was observed between other subgroups and outcomes., Conclusion: Intracoronary BMC infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. Younger patients and patients with a more severely depressed LVEF at baseline derived most benefit from this adjunctive therapy.

Aims: Contradicting reports have been published regarding the relation between a dobutamine-induced increase in either cardiac dyssynchrony or left-ventricular ejection fraction (LVEF) and the response to cardiac resynchronization therapy (CRT). Using apical rocking (ApRock) as surrogate dyssynchrony parameter, we investigated the dobutamine stress echocardiography (DSE)-induced changes in left-ventricular (LV) dyssynchrony and LVEF and their potential pathophysiological interdependence., Methods and Results: Fifty-eight guideline-selected CRT candidates were prospectively enrolled for low-dose DSE. Dyssynchrony was quantified by the amplitude of ApRock. An LVEF increase during stress of >5% was regarded significant. Scar burden was assessed by magnetic resonance imaging. Mean follow-up after CRT implantation was 41 ± 13 months for the occurrence of cardiac death. ApRock during DSE predicted CRT response (AUC 0.88, 95% CI 0.77-0.99, P < 0.001) and correlated inversely with changes in EF (r = -0.6, P < 0.001). Left-ventricular ejection fraction changes during DSE were not associated with CRT response (P = 0.082). Linear regression analysis revealed an inverse association of LVEF changes during DSE with both, total scar burden (B = -2.67, 95CI -3.77 to -1.56, P < 0.001) and the DSE-induced change in ApRock amplitude (B = -1.23, 95% CI -1.53 to -0.94, P < 0.001). Kaplan-Meier analysis revealed that DSE-induced increase in ApRock, but not LVEF, was associated with improved long-term survival., Conclusion: During low-dose DSE in CRT candidates with baseline dyssynchrony, myocardial contractile reserve predominantly results in more dyssynchrony, but less in an increase in LVEF. Dyssynchrony at baseline and its dobutamine-induced changes are predictive of both response and long-term survival following CRT.

Aims: Cardiac resynchronization therapy (CRT) with or without a defibrillator reduces morbidity and mortality in selected patients with heart failure (HF) but response can be variable. We sought to identify pre-implantation variables that predict the response to CRT in a meta-analysis using individual patient-data., Methods and Results: An individual patient meta-analysis of five randomized trials, funded by Medtronic, comparing CRT either with no active device or with a defibrillator was conducted, including the following baseline variables: age, sex, New York Heart Association class, aetiology, QRS morphology, QRS duration, left ventricular ejection fraction (LVEF), and systolic blood pressure. Outcomes were all-cause mortality and first hospitalization for HF or death. Of 3782 patients in sinus rhythm, median (inter-quartile range) age was 66 (58-73) years, QRS duration was 160 (146-176) ms, LVEF was 24 (20-28)%, and 78% had left bundle branch block. A multivariable model suggested that only QRS duration predicted the magnitude of the effect of CRT on outcomes. Further analysis produced estimated hazard ratios for the effect of CRT on all-cause mortality and on the composite of first hospitalization for HF or death that suggested increasing benefit with increasing QRS duration, the 95% confidence bounds excluding 1.0 at ∼140 ms for each endpoint, suggesting a high probability of substantial benefit from CRT when QRS duration exceeds this value., Conclusion: QRS duration is a powerful predictor of the effects of CRT on morbidity and mortality in patients with symptomatic HF and left ventricular systolic dysfunction who are in sinus rhythm. QRS morphology did not provide additional information about clinical response., Clinicaltrialsgov Numbers: NCT00170300, NCT00271154, NCT00251251.

Background: The benefit of cardiac resynchronization therapy (CRT) among patients with mild heart failure (HF), reduced left ventricular (LV) function and wide QRS is well established. We studied the long-term stability of CRT., Methods: REVERSE was a randomized, double-blind study on CRT in NYHA Class I and II HF patients with QRS ≥120 ms and left ventricular ejection fraction (LVEF) ≤40%. After the randomized phase, all were programmed to CRT ON and prospectively followed through 5 years for functional capacity, echocardiography, HF hospitalizations, mortality, and adverse events. We report the results of the 419 patients initially assigned to CRT ON., Findings: The mean follow-up time was 54.8 ± 13.0 months. After 2 years, the functional and LV remodelling improvements were maximal. The 6-min hall walk increased by 18.8 ± 102.3 m and the Minnesota and Kansas City scores improved by 8.2 ± 17.8 and 8.2 ± 17.2 units, respectively. The mean decrease in left ventricular end-systolic volume index and left ventricular end-diastolic volume index was 23.5 ± 34.1 mL/m(2) (P < 0.0001) and 25.4 ± 37.0 mL/m2 (P < 0.0001) and the mean increase in LVEF 6.0 ± 10.8% (P < 0.0001) with sustained improvement thereafter. The annualized and 5-year mortality was 2.9 and 13.5% and the annualized and 5-year rate of death or first HF hospitalization 6.4, and 28.1%. The 5-year LV lead-related complication rate was 12.5%., Conclusion: In patients with mild HF, CRT produced reverse LV remodelling accompanied by very low mortality and need for heart failure hospitalization. These effects were sustained over 5 years. Cardiac resynchronization therapy in addition to optimal medical therapy produces long-standing clinical benefits in mild heart failure., Clinical Trial Registration: Clinicaltrials.gov identifier NCT00271154.

Aims: Several studies have reported a poor outcome with cardiac resynchronization therapy (CRT) in non-left bundle branch block (LBBB) patients. Although the left ventricular (LV) lead location is an important determinant of the clinical outcome, there is scant information regarding its role in non-LBBB patients. This study sought to examine the impact of electrical and anatomical location of the LV lead in relation to baseline QRS morphology on the CRT outcome., Methods and Results: A left ventricular lead electrical delay (LVLED) was measured intra-procedurally as an interval between QRS onset on the surface electrocardiogram (ECG) to the peak of sensed electrogram on LV lead and corrected for QRS width. The impact of the LVLED on time to first heart failure hospitalization (HFH), and composite outcome of all-cause mortality, HFH, LVAD implantation, and cardiac transplantation at 3 years was assessed. Among 144 patients (age 67 ± 12 years, QRS duration 156 ± 28 ms, non-LBBB 43%), HFH was higher in non-LBBB compared with LBBB (43.5 vs. 24%, P = 0.015). Within LBBB, patients with the long LVLED (≥50%) had 17% HFH vs. 53% in the short LVLED (<50%), P = 0.002. Likewise in non-LBBB, patients with the long LVLED compared with the short LVLED had a lower HFH (36 vs. 61%, P = 0.026). In adjusted Cox proportional hazards model, the long LVLED in LBBB and non-LBBB was associated with an improved outcome. Specifically, in non-LBBB, LVLED ≥50% was associated with improved event-free survival with respect to time to first HFH (HR: 0.34; P = 0.011) and composite outcome (HR: 0.41; P = 0.019)., Conclusion: Cardiac resynchronization therapy delivered from an LV pacing site characterized by the long LVLED was associated with the favourable outcome in LBBB and non-LBBB patients.

Aims: Immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) represents a novel therapeutic approach in the treatment of dilated cardiomyopathy (DCM) which leads to the improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical, and molecular parameters for the prediction of the response of patients with DCM to IA/IgG., Methods and Results: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In eight patients with normal LVEF (controls), EMBs were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes, and gene expression profiles of EMBs were analysed. Dilated cardiomyopathy patients displaying improvement of LVEF (≥20 relative and ≥5% absolute) 6 months after IA/IgG were considered responders. Compared with non-responders (n = 16), responders (n = 24) displayed shorter disease duration (P = 0.006), smaller LV internal diameter in diastole (P = 0.019), and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin-proteasome pathway. The integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (BL) [sensitivity of 100% (95% CI 85.8-100%); specificity up to 100% (95% CI 79.4-100%); cut-off value: -0.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only., Conclusion: Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at BL predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.

Aims: We have previously reported the cardioprotective effects of endothelial progenitor cell (EPC)-conditioned media (CM) therapy post-myocardial infarction (MI). In the present study, we have determined the insulin-like growth factor-1 (IGF-1) contribution to EPC CM effects on cardiomyocyte survival, contractility, and angiogenesis in vivo., Methods and Results: Conditioned media from porcine EPC were administered intracoronary in the presence and absence of specific neutralizing antibodies to IGF-1 or control IgG in a porcine model of MI. X-vivo (non-conditioned) medium was used as a control. Functional, histological, and biochemical parameters were evaluated at 24 h and 8-week post-therapy. Conditioned media therapy significantly abrogated infarct zone (IZ) apoptosis, hypocontractility, and impaired left ventricular (LV) relaxation observed in control infarcts acutely (24 h post-MI). At 8 weeks following treatment, CM therapy augmented LV contractility and relaxation, IZ angiogenesis and inhibited infarct size expansion, wall expansion, and wall thinning. All of these acute and chronic beneficial effects of CM therapy were vitiated by neutralizing antibodies to IGF-1 but not by control IgG. Moreover, the addition of neutralizing IGF-1 antibody to control medium had no effect on these structural or functional changes in the heart post-treatment., Conclusion: Insulin-like growth factor-1 within the EPC CM mediates potent acute myocardial repair and chronic remodelling effects post-MI. These findings may provide a rationale for comparative trials of specific growth factors vs. current progenitor cell strategies.

Aims: It remains unclear whether primary prophylactic implantable cardioverter-defibrillator (ICD) therapy is cost-effective compared with a 'no ICD strategy' in the European health care setting. We performed a cost-effectiveness analysis for a cohort of patients with a left ventricular ejection fraction <40% and ischaemic or non-ischaemic heart disease., Methods and Results: A Markov decision analytic model was used to evaluate long-term survival, quality-adjusted life years (QALYs), and lifetime costs for a cohort of patients with a reduced left ventricular function without previous arrhythmias, managed with a prophylactic ICD. Input data on effectiveness were derived from a meta-analysis of primary prophylactic ICD-only therapy randomized trials, from a prospective cohort study of ICD patients, from a health care utilization survey, and from the literature. Input data on costs were derived from a micro-cost analysis. Data on quality-of-life were derived from the literature. Deterministic and probabilistic sensitivity analysis was performed to assess the uncertainty. Probabilistic sensitivity analysis demonstrated a mean lifetime cost of €50 685 ± €4604 and 6.26 ± 0.64 QALYs for patients in the 'no ICD strategy'. Patients in the 'ICD strategy' accumulated €86 759 ± €3343 and an effectiveness of 7.08 ± 0.71 QALYs yielding an incremental cost-effectiveness ratio of €43 993/QALY gained compared with the 'no ICD strategy'. The probability that ICD therapy is cost-effective was 65% at a willingness-to-pay threshold of €80 000/QALY., Conclusion: Our results suggest that primary prophylactic ICD therapy in patients with a left ventricular ejection fraction <40% and ischaemic or non-ischaemic heart disease is cost-effective in the European setting.

Aims: Pre-implant assessment of longitudinal mechanical dyssynchrony using cross-correlation analysis (XCA) was tested for association with long-term survival and compared with other tissue Doppler imaging (TDI)-derived indices., Methods and Results: In 131 patients referred for cardiac resynchronization therapy (CRT) from two international centres, mechanical dyssynchrony was assessed from TDI velocity curves using time-to-peak opposing wall delay (OWD) ≥80 ms, Yu index ≥32 ms, and the maximal activation delay (AD-max) >35 ms. AD-max was calculated by XCA of the TDI-derived myocardial acceleration curves. Outcome was a composite of all-cause mortality, cardiac transplantation, or implantation of a ventricular assist device (left ventricular assist device) and modelled using the Cox proportional hazards regression. Follow-up was truncated at 1460 days. Dyssynchrony by AD-max was independently associated with improved survival when adjusted for QRS > 150 ms and aetiology {hazard ratio (HR) 0.35 [95% confidence interval (CI) 0.16-0.77], P = 0.01}. Maximal activation delay performed significantly better than Yu index, OWD, and the presence of left bundle branch block (P < 0.05, all, for difference between parameters). In subgroup analysis, patients without dyssynchrony and QRS between 120 and 150 ms showed a particularly poor survival [HR 4.3 (95% CI 1.46-12.59), P < 0.01, compared with the group with dyssynchrony and QRS between 120 and 150 ms]., Conclusion: Mechanical dyssynchrony assessed by AD-max was associated with long-term survival after CRT and was significantly better associated compared with other TDI-derived indices. Patients without dyssynchrony and QRS between 120 and 150 ms had a particularly poor prognosis. These results indicate a valuable role for XCA in selection of CRT candidates.

Aim: To evaluate the long-term effects of peripheral blood stem cell therapy in myocardial infarction (MI) patients., Methods and Results: A total of 163 patients with MI who were successfully revascularized with drug-eluting stents were enrolled and randomly assigned to four groups: acute MI (AMI) cell infusion, AMI control, old MI (OMI) cell infusion, and OMI control. We compared 5 years' clinical outcomes between the cell infusion group (57 and 22 patients with AMI and OMI, respectively) and the control (60 and 24 patients with AMI and OMI, respectively). In the time-sequence comparison from baseline to 6 and 24 months follow-up after AMI, left ventricular ejection fraction (LVEF) by cardiac magnetic resonance imaging was significantly improved in the cell infusion group (n = 57), but not in the control group (n = 60). In the between-group comparison, the difference in improvement of LVEF for 2 years after AMI did not reach statistical significance between cell infusion and control groups. Intriguingly, the major adverse cardiac events for 5 years were significantly reduced in the cell infusion group (n = 79) compared with the control (n = 84; composite of cardiac death, non-fatal MI, hospitalization for heart failure and angina, and target vessel revascularization; 22.8 vs. 39.3%, P = 0.015)., Conclusions: Peripheral blood stem cell therapy has potential to improve long-term cardiovascular outcomes in MI patients.

Aims: We sought to perform a systematic review and meta-analysis to evaluate the potential factors affecting ischaemic postconditioning (IPoC) for patients with ST-segment elevation acute myocardial infarction (STEMI) in primary percutaneous coronary intervention (PCI)., Methods and Results: Ten randomized controlled trials (RCTs) on IPoC reporting myocardial enzyme levels or left ventricular ejection fraction (LVEF) in a total of 560 STEMI patients were identified in PubMed, EMBase, and Cochrane Library (up to February 2012). Compared with controls, IPoC significantly reduced elevated cardiac enzyme levels [standardized mean difference = -0.84; 95% confidential interval (CI): -1.26 to -0.43; P < 0.00001; heterogeneity test, I(2) = 81.0%] and improved LVEF [weighted mean difference (WMD) = 3.98%; 95% CI: 1.27-6.70%; P = 0.004; heterogeneity test, I(2) = 87.1%]. The effect on LVEF remained significant after 1 year (WMD = 5.04%; 95% CI: 4.20-5.88%; P < 0.00001; heterogeneity test, I(2) = 0.0%). Univariate meta-regression analysis suggested that the major sources of significant heterogeneity (P < 0.1) were the use of direct-stenting technique (%) (coefficient = -0.886; P = 0.069; adjusted R(2) = 0.34) and male proportion (%) (coefficient = -0.022; P = 0.098; adjusted R(2) = 0.28) for myocardial enzyme levels, and age (coefficient = -1.34; P = 0.025; adjusted R(2)= 0.55) for LVEF (%). Subsequent multivariate regression and subgroup analysis confirmed these results., Conclusion: Available evidence from this systematic review and meta-analysis of 10 RCTs suggests that IPoC may confer cardioprotection in terms of myocardial enzyme levels and LVEF for STEMI during primary PCI. These effects are more pronounced among young and male patients, and those in whom direct-stenting techniques were used. Future studies should focus on the mortality in high-quality, large-scale clinical trials with long-term follow-up.

Aims: Because benefits of cardiac resynchronization therapy (CRT) appear to be less favourable in non-left bundle branch block (LBBB) patients, this prospective longitudinal study tested the hypothesis that QRS morphology and echocardiographic mechanical dyssynchrony were associated with long-term outcome after CRT., Methods and Results: Two-hundred and seventy-eight consecutive New York Heart Association class III and IV CRT patients with QRS ≥120 ms and ejection fraction ≤35% were studied. The pre-specified primary endpoint was death, heart transplant, or left ventricular assist device over 4 years. Dyssynchrony assessed before CRT included interventricular mechanical delay (IVMD) and speckle-tracking radial strain using pre-specified cut-offs for each. Of 254 with baseline quantitative echocardiographic data available, 128 had LBBB, 81 had intraventricular conduction delay (IVCD), and 45 had right bundle branch block (RBBB). Radial dyssynchrony was observed in 85% of the patients with LBBB, 59% with IVCD*, and 40% with RBBB* (*P < 0.01 vs. LBBB). Of 248 (98%) with follow-up, LBBB patients had a significantly more favourable long-term survival than non-LBBB patients. However, non-LBBB patients with dyssynchrony had a more favourable event-free survival than those without dyssynchrony: radial dyssynchrony hazard ratio 2.6, 95% confidence interval (CI) 1.47-4.53 (P = 0.0008) and IVMD hazard ratio 4.9, 95% CI 2.60-9.16 (P = 0.0007). Right bundle branch block patients who lacked dyssynchrony had the least favourable outcome., Conclusion: Non-LBBB patients with dyssynchrony had a more favourable long-term survival than non-LBBB patients who lacked dyssynchrony. Mechanical dyssynchrony and QRS morphology are associated with outcome following CRT.

Aims: Diastolic dysfunction (DD) was identified as a predictor of adverse prognosis in heart failure with reduced ejection fraction (HFREF). It is, however, unknown if DD is improved by exercise training, which is known to induce reverse remodelling, and if the training effect is attenuated in elderly HFREF patients. We therefore assessed DD in a cohort of referent controls (RCs) and HFREF patients and studied the response of DD to endurance exercise in two age groups (≤55 years and ≥65 years)., Methods and Results: Sixty RC (30 ≤ 55 years, mean age 50 ± 5 years; 30 ≥ 65 years, 72 ± 4 years) and 60 HFREF patients (30 ≤ 55 years, 46 ± 5 years; 30 ≥ 65 years, 72 ± 5 years, EF 28 ± 5%) were randomized to 4 weeks of supervised endurance training or to a control group. Exercise training was effective in reducing LV isovolumetric relaxation time by 29% in young and by 26% in old HFREF patients (P< 0.05 for both). As assessed by tissue Doppler, septal E' increased by 37% in young and by 39% among old HFREF patients (P< 0.005 for both) resulting in a significant decrease in the E/E' ratio from 13 ± 1 to 10 ± 1 in young and 14 ± 1 to 11 ± 1 in old HFREF patients (P< 0.05 for both). Serum levels of N-terminal pro brain natriuretic peptide were significantly reduced after endurance training in HFREF patients of all ages., Conclusion: In HFREF, diastolic function is significantly impaired in all age groups. Endurance training is highly effective in improving left ventricular diastolic function in HFREF patients regardless of age. This study is registered at ClinicalTrials.gov (number: NCT00176319).

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

Aims: The aim of the present study was to evaluate the relationship between left ventricular (LV) electrical delay, as measured by the QLV interval, and outcomes in a prospectively designed substudy of the SMART-AV Trial., Methods and Results: This was a multicentre study of patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) defibrillator implantation. In 426 subjects, QLV was measured as the interval from the onset of the QRS from the surface ECG to the first large peak of the LV electrogram. Left ventricular volumes were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. When separated by quartiles based on QLV duration, reverse remodelling response rates (>15% reduction in LV end systolic volume) increased progressively from 38.7 to 68.4% and QOL response rate (>10 points reduction) increased from 50 to 72%. Patients in the highest quartile of QLV had a 3.21-fold increase (1.58-6.50, P = 0.001) in their odds of a reverse remodelling response after correcting for QRS duration, bundle branch block type, and clinical characteristics by multivariate logistic regression analysis., Conclusion: Electrical dyssynchrony, as measured by QLV, was strongly and independently associated with reverse remodelling and QOL with CRT. Acute measurements of QLV may be useful to guide LV lead placement.

The number of patients with congenital heart disease (CHD) has significantly increased over the last decades. The CHD population has a high prevalence of heart failure during late follow-up and this is a major cause of mortality. Cardiac resynchronization therapy (CRT) may be a promising therapy to improve the clinical outcome of CHD and paediatric patients with heart failure. However, the CHD and paediatric population is a highly heterogeneous group with different anatomical substrates that may influence the effects of CRT. Echocardiography is the mainstay imaging modality to evaluate CHD and paediatric patients with heart failure and novel echocardiographic tools permit a comprehensive assessment of cardiac dyssynchrony that may help selecting candidates for CRT. This article reviews the role of CRT in the CHD and paediatric population with heart failure. The current inclusion criteria for CRT as well as the outcomes of different anatomical subgroups are evaluated. Finally, echocardiographic assessment of mechanical dyssynchrony in the CHD and paediatric population and its role in predicting response to CRT is comprehensively discussed.

Aims: Previous trials that investigated cell therapy as an adjunctive therapy after acute myocardial infarction (AMI) have shown conflicting results. We designed a randomized controlled trial to determine the effect of intracoronary infusion of mononuclear cells from bone marrow (BM) or peripheral blood in patients with AMI., Methods and Results: In a multicentre trial, 200 patients with large first AMI treated with primary percutaneous coronary intervention were randomly assigned to either intracoronary infusion of mononuclear BM cells (n = 69), mononuclear peripheral blood cells (n = 66), or standard therapy (without placebo infusion) (n = 65). Mononuclear cells were delivered intracoronary between 3 and 8 days after AMI. Regional and global left ventricular myocardial function and volumes were assessed by magnetic resonance imaging before randomization and at 4 months, and clinical events were reported. The primary endpoint of the percentage of dysfunctional left ventricular segments that improved during follow-up did not differ significantly between either of the treatment groups and control: 38.6 ± 24.7% in the BM group, 36.8 ± 20.9% in the peripheral blood group, and 42.4 ± 18.7% in the control group (P = 0.33 and P = 0.14). Improvement of left ventricular ejection fraction was 3.8 ± 7.4% in the BM group, 4.2 ± 6.2% in the peripheral blood group when compared with 4.0 ± 5.8% in the control group (P = 0.94 and P = 0.90). Furthermore, the three groups did not differ significantly in changes in left ventricular volumes, mass, and infarct size and had similar rates of clinical events., Conclusion: Intracoronary infusion of mononuclear cells from BM or peripheral blood following AMI does not improve regional or global systolic myocardial function in the HEBE trial., Registration: The Netherlands Trial Register #NTR166 (www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).

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

Aims: To assess the cost-effectiveness of cardiac resynchronization therapy (CRT) compared with optimal medical therapy in patients with New York Heart Association (NYHA) II heart failure (HF) or NYHA I with previous HF symptoms., Methods and Results: A proportion in state model with Monte Carlo simulation was developed to assess the costs, life years and quality-adjusted life year (QALYs) associated with CRT-ON and -OFF over a 10 year time period. Data from 262 patients in the European cohort of the REVERSE clinical trial (QRS ≥ 120 ms, left ventricular ejection fraction ≤ 40%, CRT-ON, n = 180, CRT-OFF, n = 82) were used to model all-cause mortality, change in NYHA class and resource use. EQ-5D preference weights were taken from a previous cost-effectiveness model of CRT and unit costs from national UK databases. Costs and benefits were discounted at 3.5% p.a. Extensive deterministic and probabilistic sensitivity analyses were performed. Compared with CRT-OFF, 0.94 life years or 0.80 QALYs were gained in the CRT ON group at an additional cost of €11 455, yielding an incremental cost-effectiveness ratio of €14.278 per quality-adjusted life year (QALY) gained. At a threshold of €33 000 (£30 000) per QALY gained, the probability that CRT is cost-effective is 79.6%. Cardiac resynchronization therapy becomes cost effective after ∼4.5 years. Cardiac resynchronization therapy needs only to demonstrate a modest impact on all cause mortality (hazard ratio = 0.82) in order to demonstrate cost-effectiveness. The results are robust to changes in all other parameters., Conclusion: Cardiac resynchronization therapy is a cost-effective intervention for patients with mildly symptomatic HF and for asymptomatic patients with left ventricular dysfunction and previous HF symptoms.

Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future.

Aims: Ischaemic heart disease negatively impacts response to cardiac resynchronization therapy (CRT), yet the impact of infarct scar burden on clinical outcomes and its interaction with mechanical dyssynchrony have not been well described., Methods and Results: We studied 620 NYHA classes III-IV heart failure patients with ejection fraction (EF) ≤ 35% and QRS duration ≥120 ms referred for CRT. Included were 190 ischaemic cardiomyopathy (ICM) CRT recipients with scar burden quantified by rest-redistribution Tl(201) myocardial perfusion imaging using a 17-segment (0 = normal to 4 = absence of uptake) summed rest score (SRS). Non-ICM (NICM) CRT recipients (n = 380) and 50 patients referred for CRT with unsuccessful LV lead implant comprised the comparison groups. Echocardiographic dyssynchrony analysis was performed in a subgroup of 150 patients. Follow-up left ventricular EF (LVEF) and volumes were examined at 7 ± 3 months in 143 patients. The outcome of death, cardiac transplant, or mechanical circulatory support was assessed in all. Over 2.1 ± 1.6 years, ICM patients had significantly worse survival and less LVEF improvement than NICM patients (P < 0.01). Ischaemic cardiomyopathy patients with low scar burden (SRS < 27) had favourable survival and LVEF improvement, similar to NICM patients. A high scar burden (SRS ≥ 27) was associated with reduced survival and lack of LV functional improvement (P ≤ 0.01), similar to those with unsuccessful LV lead implant, whereas baseline dyssynchrony was not predictive of outcome in these patients., Conclusion: Extensive scar burden in ICM patients unfavourably affected clinical and LV functional outcomes after CRT, regardless of baseline dyssynchrony measures. Patients with ICM and lower scar burden had significantly better outcomes, similar to NICM patients.

Aims: current criteria for cardiac resynchronization therapy (CRT) are restricted to patients with a wide QRS complex (>120 ms). Overall, only 30% of heart failure patients demonstrate a wide QRS complex, leaving the majority of heart failure patients without this treatment option. However, patients with a narrow QRS complex exhibit left ventricular (LV) mechanical dyssynchrony, as assessed with echocardiography. To further elucidate the possible beneficial effect of CRT in heart failure patients with a narrow QRS complex, this two-centre, non-randomized observational study focused on different echocardiographic parameters of LV mechanical dyssynchrony reflecting atrioventricular, interventricular and intraventricular dyssynchrony, and the response to CRT in these patients., Methods and Results: a total of 123 consecutive heart failure patients with a narrow QRS complex (<120 ms) undergoing CRT was included at two centres. Several widely accepted measures of mechanical dyssynchrony were evaluated: LV filling ratio (LVFT/RR), LV pre-ejection time (LPEI), interventricular mechanical dyssynchrony (IVMD), opposing wall delay (OWD), and anteroseptal posterior wall delay with speckle tracking (ASPWD). Response to CRT was defined as a reduction ≥15% in left ventricular end-systolic volume at 6 months follow-up. Measures of dyssynchrony can frequently be observed in patients with a narrow QRS complex. Nonetheless, for LVFT/RR, LPEI, and IVMD, presence of predefined significant dyssynchrony is <20%. Significant intraventricular dyssynchrony is more widely observed in these patients. With receiver operator characteristic curve analyses, both OWD and ASPWD demonstrated usefulness in predicting response to CRT in narrow QRS patients with a cut-off value of 75 and 107 ms, respectively., Conclusion: mechanical dyssynchrony can be widely observed in heart failure patients with a narrow QRS complex. In particular, intraventricular measures of mechanical dyssynchrony may be useful in predicting LV reverse remodelling at 6 months follow-up in heart failure patients with a narrow QRS complex, but with more stringent cut-off values than currently used in 'wide' QRS patients.

Aims: Cardioprotective effects of erythropoietin (EPO) have been shown in experimental and smaller clinical studies. We performed a prospective, multicentre, randomized trial to assess the effects of a single high dose of EPO after primary coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods and results Patients with a successful PCI for a first STEMI were randomized to receive either standard medical care alone, or in combination with a single bolus with 60,000 IU i.v. of epoetin alfa within 3 h after PCI. Primary endpoint was left ventricular ejection fraction (LVEF) after 6 weeks, assessed by planar radionuclide ventriculography. Pre-specified secondary endpoints included enzymatic infarct size and major adverse cardiovascular events. A total of 529 patients were enrolled (EPO n = 263, control n = 266). At baseline (before EPO administration), groups were well-matched for all relevant characteristics. After a mean of 6.5 (± 2.0) weeks, LVEF was 0.53 (± 0.10) in the EPO group and 0.52 (± 0.11) in the control group (P = 0.41). Median area under the curve (inter-quartile range) after 72 h for creatinine kinase was 50 136 (28 212-76 664)U/L per 72 h in the EPO group and 53 510 (33 973-90 486)U/L per 72 h in the control group (P = 0.058). More major adverse cardiac events occurred in the control than in the EPO group (19 vs. 8; P = 0.032). Conclusion A single high dose of EPO after a successful PCI for a STEMI did not improve LVEF after 6 weeks. However, the use of EPO was related to less major adverse cardiovascular events and a favourable clinical safety profile., Clinical Trial Registration Information: NCT00449488; http://www.clinicaltrials.gov/ct2/show/NCT00449488?term=voors&rank=2.

Coronary revascularization has been a cornerstone of the management of patients with coronary artery disease (CAD) for many years. Both coronary artery bypass grafting and percutaneous coronary intervention have evolved and improved over time such that increasingly complex and challenging cases can now be tackled with a high degree of procedural success. In parallel with this, there have been major advances in medical therapy for CAD. Consequently, one of the main decisions in the contemporary management of stable CAD concerns which patients and lesions should be revascularized. This is particularly true for patients with complex disease such as multivessel disease or those with left ventricular impairment. Such patients will potentially benefit the most but are also at highest risk of complications and it is therefore important that they are carefully selected. Recent major trials have challenged the conventional view that consideration of coronary anatomy alone is sufficient in this decision-making. An accumulating body of evidence underscores the importance of functional investigations when assessing the potential benefits of revascularization in these complex patients. In parallel with these developments, cardiac magnetic resonance (CMR) has matured into a robust technology that is able to measure many of the parameters required to accurately characterize these patients. This article will review the importance of myocardial viability and ischaemia when selecting patients with stable CAD for revascularization, the use of CMR imaging for assessing this pathophysiology, and planning complex revascularization, and finally give an outlook on how CMR may help address some important outstanding clinical questions.