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Guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF) reduces morbidity and mortality, but its implementation is often poor in daily clinical practice. Barriers to implementation include clinical and organizational factors that might contribute to clinical inertia, i.e. avoidance/delay of recommended treatment initiation/optimization. The spectrum of strategies that might be applied to foster GDMT implementation is wide, and involves the organizational set-up of heart failure care pathways, tailored drug initiation/optimization strategies increasing the chance of successful implementation, digital tools/telehealth interventions, educational activities and strategies targeting patient/physician awareness, and use of quality registries. This scientific statement by the Heart Failure Association of the ESC provides an overview of the current state of GDMT implementation in HFrEF, clinical and organizational barriers to implementation, and aims at suggesting a comprehensive framework on how to overcome clinical inertia and ultimately improve implementation of GDMT in HFrEF based on up-to-date evidence., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The aim of this analysis was to provide data on the overall comorbidity burden, both cardiovascular (CV) and non-CV, in a large real-world heart failure (HF) population across the ejection fraction (EF)., Methods and Results: Patients with HF from the Swedish HF Registry between 2000 and 2021 were included. Of 91 463 patients (median age 76 years [interquartile range 67-82]), 98% had at least one among the 17 explored comorbidities (94% at least one CV and 85% at least one non-CV comorbidity). All comorbidities, except for coronary artery disease (CAD), were more frequent in HF with preserved EF (HFpEF). Patients with multiple comorbidities were older, more likely female, inpatients, with HFpEF, worse New York Heart Association class and higher N-terminal pro-B-type natriuretic peptide levels. In a multivariable Cox model, 12 comorbidities were independently associated with a higher risk of death from any cause. The highest risk was associated with dementia (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.45-1.65), chronic kidney disease (HR 1.37, 95% CI 1.34-1.41), chronic obstructive pulmonary disease (HR 1.32, 95% CI 1.28-1.35). Obesity was associated with a lower risk of all-cause death (HR 0.81, 95% CI 0.79-0.84). CAD and valvular heart disease were associated with a higher risk of all-cause and CV mortality, but not non-CV mortality, whereas cancer and musculo-skeletal disease increased the risk of non-CV mortality. A significant interaction with EF was observed for several comorbidities. Occurrence of CV and non-CV outcomes was related to the number of CV and non-CV comorbidities, respectively., Conclusion: The burden of both CV and non-CV comorbidities was high in HF regardless of EF, but overall higher in HFpEF. Multimorbidity was associated with a high risk of death with a different burden on CV or non-CV outcomes., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: In patients with atrial fibrillation (AF), improved management of modifiable risk factors and concomitant diseases is recommended by guidelines, yet many AF patients have sub-optimal risk factor management. Digital health solutions may offer support in this matter. This study aims to identify how patients with AF perceive they could be supported by a digital tool aimed to optimize management of comorbidities and modifiable risk factors associated with an unhealthy lifestyle., Methods and Results: This was a qualitative, descriptive study based on four semi-structured focus-group interviews analysed by manifest content analysis. Sixteen AF patients with recent in- or outpatient encounters were included [age 68 (52-78) years; 43% female; BMI 29.5 (20.4-35.8) kg/m2; paroxysmal/persistent AF (50%/50%); AF duration 7 (0-22) years]. Relevant comorbidities were hypertension (88%), heart failure (25%), diabetes mellitus type 2 (19%), and ischaemic heart disease (13%). The patients' suggestions were summarized into three main categories. First, person-centred information is essential, meaning that information should be customized and conveyed in an appropriate manner and include practical tips. Second, patients desire help with managing lifestyle habits in a way that is applicable in everyday life, and patients desire help with creating habits. Third, regular communication is necessary including inspirational reminders and motivational feedback., Conclusion: Patients with AF request person-centred information, support in managing healthy lifestyle habits, and more regular communication with caregivers. This study provides a first foundation on how to better support AF patients, and using a digital tool in standard care may improve outcomes and reduce cost of care., Competing Interests: Conflict of interest: E.S. has received speaker/consultancy fees from Bayer, Bristol–Myers Squibb–Pfizer, Boehringer Ingelheim, Johnson & Johnson, and Merck Sharp & Dohme. F.B. has received speaker/consultancy fees from Biotronik, Medtronic, Abbott, Boston Scientific, Boehringer, Novartis, Pfizer, and Orion. M.L. has received speaker/consultancy fees from Pfizer, Eli Lilly, Novo Nordisk, AbbVie, Sanofi, Bayer MSD, and UCB Pharma. For the remaining authors, none was declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The COVID-19 pandemic has had a significant impact on global public health, with long-term consequences that are still largely unknown. This study aimed to assess the data regarding acute cardiovascular hospital admissions in five European centers before and during the pandemic. A multicenter, multinational observational registry was created, comparing admissions to the emergency departments during a 3-months period in 2020 (during the pandemic) with the corresponding period in 2019 (pre-pandemic). Data on patient demographics, COVID-19 test results, primary diagnosis, comorbidities, heart failure profile, medication use, and laboratory results were collected. A total of 8778 patients were included in the analysis, with 4447 patients in 2019 and 4331 patients in 2020. The results showed significant differences in the distribution of cardiovascular diseases between the two years. The frequency of pulmonary embolism (PE) increased in 2020 compared to 2019, while acute heart failure (AHF) and other cardiovascular diseases decreased. The odds of PE incidence among hospitalized patients in 2020 were 1.316-fold greater than in 2019. The incidence of AHF was 50.83% less likely to be observed in 2020, and the odds for other cardiovascular diseases increased by 17.42% between the 2 years. Regarding acute coronary syndrome (ACS), the distribution of its types differed between 2019 and 2020, with an increase in the odds of ST-segment elevation myocardial infarction (STEMI) in 2020. Stratification based on sex revealed further insights. Among men, the incidence of AHF decreased in 2020, while other cardiovascular diseases increased. In women, only the incidence of STEMI showed a significant increase. When analyzing the influence of SARS-CoV-2 infection, COVID-positive patients had a higher incidence of PE compared to COVID-negative patients. COVID-positive patients with ACS also exhibited symptoms of heart failure more frequently than COVID-negative patients. These findings provide valuable information on the impact of the COVID-19 pandemic on acute cardiovascular hospital admissions. The increased incidence of PE and changes in the distribution of other cardiovascular diseases highlight the importance of monitoring and managing cardiovascular health during and post pandemic period. The differences observed between sexes emphasize the need for further research to understand potential sex-specific effects of COVID-19 on cardiovascular outcomes., (© 2023. Springer Nature Limited.)

Competing Interests: Declaration of Competing Interest FB has served as a member of adverse event adjudication committees in trials sponsored by Medtronic and Biotronik. The employer of FB has been paid for industry related activities as chair or speaker. No payment has been directly transferred to FB as a result of these activities.

Aims: To investigate whether a heart failure (HF) hospitalization is associated with initiation/discontinuation of guideline-directed medical HF therapy (GDMT) and consequent outcomes., Methods and Results: Among patients in the Swedish HF registry with an ejection fraction <50% enrolled in 2009-2018, initiation/discontinuation of GDMT was investigated by assessing dispensations of GDMT in those with versus without a HF hospitalization. Of 14 737 patients, 6893 (47%) were enrolled when hospitalized for HF. Initiation of GDMT was more likely than discontinuation following a HF hospitalization compared to a control group of patients without a HF hospitalization (odds ratio range 2.1-4.0 vs. 1.4-1.6 for the individual medications), although the proportion of patients not on GDMT was still high (8.1-44.0%). Key patient characteristics triggering less use of GDMT (i.e. less initiation or more discontinuation) were older age and worse renal function. Following a HF hospitalization, initiation of renin-angiotensin system inhibitors/angiotensin receptor-neprilysin inhibitors or beta-blockers was associated with lower and their discontinuation with higher mortality risk, but no association with mortality was observed for initiation/discontinuation of mineralocorticoid receptor antagonists., Conclusions: Following a HF hospitalization, initiation of GDMT was more likely than discontinuation, although still limited. Perceived or actual low tolerance were barriers to GDMT implementation. Early re-/initiation of GDMT was associated with better survival. Our findings represent a call for further implementing the current guideline recommendation for an early re-/initiation of GDMT following a HF hospitalization., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline-recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice., (© 2023 European Society of Cardiology.)

Aims: To investigate the association between catheter ablation for atrial fibrillation (AF) and mortality as well as hospitalization for heart failure (HF) in patients with HF across the ejection fraction (EF) spectrum., Methods and Results: Patients with first-time catheter ablation for AF (ablation group) compared to only medical treated AF patients (no ablation group) were identified from the Swedish Heart Failure Registry between 2005 and 2019. The primary outcome (all-cause mortality/first HF hospitalization) was assessed by Cox regression models in a 1:2 propensity score (PS) matched cohort and pre-specified EF subgroups (preserved EF [≥50%], mildly reduced EF [40-49%], reduced EF [&lt;40%]) of this cohort. A total of 452 patients in the ablation group and 43 766 patients in the no ablation group were identified. After PS matching, 434 patients in the ablation group were compared to 868 patients in the no ablation group. Over a median follow-up of 2.6 years (0.0-14.1 years), catheter ablation was associated with a lower risk of the primary outcome (all-cause mortality/first HF hospitalization) (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.65-0.94). Results were consistent across all EF subgroups. In HF with preserved EF (HFpEF), catheter ablation was also associated with a lower risk of recurrent HF hospitalization (incidence rate ratio 0.17, 95% CI 0.07-0.42)., Conclusion: In HF patients across the EF spectrum, catheter ablation for AF was associated with lower risk of the primary outcome (all-cause mortality/first HF hospitalization). This study supports catheter ablation as a treatment option for AF in HF patients, including those with HFpEF., (© 2022 European Society of Cardiology.)

Aims: Use of implantable cardioverter-defibrillators (ICD) for primary prevention of sudden cardiac death (SCD) in heart failure with reduced ejection fraction (HFrEF) is limited. We aimed to investigate barriers to ICD use in HFrEF while considering the predicted risk of mortality and SCD., Method and Results: Patients from the SwedeHF registered in 2011-2018 and with an indication for primary prevention ICD were analysed. The Seattle Proportional Risk and Seattle Heart Failure Models were used to predict the proportional SCD and all-cause mortality risk, respectively. A multivariable logistic regression model was fitted to identify independent predictors of ICD use/non-use; Cox regression models to evaluate the interaction between predicted SCD/mortality risk and ICD use for mortality. Of 13 475 patients, only 15.5% had an ICD. Those with higher predicted proportional SCD risk (>45%) had an ∼80% higher likelihood to have an ICD. Other predictors of non-use were follow-up in primary versus specialty care, higher comorbidity burden and lower socioeconomic status. ICD use was associated with lower mortality only in patients with higher predicted SCD and lower mortality risk (34% and 37% relative risk reduction for 3-year all-cause and cardiovascular mortality, respectively). In this subgroup of patients, underuse of ICD was 81.8%., Conclusion: In a contemporary registry, only 15.5% of patients with an indication for primary prevention ICD received the device. While a high predicted proportional SCD risk was appropriately linked to ICD use, the lack of specialized follow-up, higher comorbidity burden, and lower socioeconomic status were major unjustified impediments to implementation. Our findings suggest areas for improving ICD use for primary prevention of SCD in clinical practice., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Randomized data on the efficacy/safety of cardiac resynchronization therapy with vs. without defibrillator (CRT-D,-P) in heart failure with reduced ejection fraction (HFrEF) are scarce. We aimed to evaluate survival associated with use of CRT-D vs. CRT-P in a contemporary cohort with HFrEF., Methods and Results: Patients from Swedish HF Registry treated with CRT-D/CRT-P and fulfilling criteria for primary prevention defibrillator use were included. Logistic regression was used to evaluate predictors of CRT-D non-use. All-cause mortality was compared in CRT-D vs. CRT-P by Cox regression in a 1 : 1 propensity-score-matched cohort. Of 1988 patients with CRT, 1108 (56%) had CRT-D and 880 (44%) CRT-P. Older age, higher ejection fraction (EF), female sex, and the lack of referral to HF nurse-led outpatient clinic were major determinants of CRT-D non-use. After matching, 645 CRT-D patients were compared with 645 with CRT-P. The CRT-D use was associated with lower 1- and 3-year all-cause mortality [hazard ratio (HR):0.76, 95% confidence interval (CI):0.58-0.98; HR: 0.82, 95% CI: 0.68-0.99, respectively]. Results were consistent in all pre-specified subgroups except for CRT-D use being associated with lower 3-year mortality in patients with an EF < 30% but not in those with an EF ≥ 30% (HR: 0.73, 95% CI: 0.59-0.89 and HR: 1.24, 95% CI: 0.83-1.85, respectively; P-interaction = 0.02)., Conclusion: In a contemporary HFrEF cohort, CRT-D was associated with lower mortality compared with CRT-P. The CRT-D use was less likely in older patients, females, and in patients not referred to HF nurse-led outpatient clinic. Our findings support the use of CRT-D vs. CRT-P in HFrEF, in particular with severely reduced EF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: It is not fully understood whether and how socioeconomic status (SES) has a prognostic impact in patients with heart failure (HF). We assessed SES and its association with patient characteristics and outcomes in a contemporary and well-characterised HF cohort., Methods: Socioeconomic risk factors (SERF) were defined in the Swedish HF Registry based on income (low vs high according to the annual median value), education level (no degree/compulsory school vs university/secondary school) and living arrangement (living alone vs cohabitating)., Results: Of 44 631 patients, 21% had no, 33% one, 30% two and 16% three SERF. Patient characteristics strongly and independently associated with lower SES were female sex and no specialist referral. Additional independent associations were older age, more severe HF, heavier comorbidity burden, use of diuretics and less use of HF devices. Lower SES was associated with higher risk of HF hospitalisation/mortality, and overall cardiovascular and non-cardiovascular events. These associations persisted after extensive adjustment for patient characteristics, treatments and care. The magnitude of the association increased linearly with the increasing number of coexistent SERF: HR (95% CI) 1.09 (1.05 to 1.13) for one, 1.16 (1.12 to 1.20) for two and 1.22 (1.18 to 1.28) for three SERF (p<0.01)., Conclusions: In a contemporary and well-characterised HF cohort and after comprehensive adjustment for confounders, lower SES was linked with multiple factors such as less use of HF devices and age, but most strongly with female sex and lack of specialist referral; and associated with greater risk of morbidity/mortality., Competing Interests: Competing interests: BS reports personal fees from AstraZeneca. GS reports grants and personal fees from Vifor, grants from Boehringer Ingelheim, personal fees from Societa' Prodotti Antibiotici, grants from MSD, grants and personal fees from AstraZeneca, grants from Pharmacosmos, grants from Boston Scientific, personal fees from Roche, personal fees from Servier, personal fees from Medtronic, personal fees from Cytokinetics, grants from Novartis, personal fees from Genesis. UD reports grants and honoraria/consultancies from AstraZeneca, Honoraria/consultancies from Novartis and Amgen and grants from Boehringer Ingelheim. AS reports honoraria from Novartis. DW reports honorary from AstraZeneca, Bayer, Berlin-Chemie and Novartis. LHL reports personal fees from Merck, personal fees from Sanofi, grants and personal fees from Vifor-Fresenius, grants and personal fees from AstraZeneca, grants and personal fees from Relypsa, personal fees from Bayer, grants from Boston Scientific, grants and personal fees from Novartis, personal fees from Pharmacosmos, personal fees from Abbott, grants and personal fees from Mundipharma, personal fees from Medscape, personal fees from Myokardia, grants and personal fees from Boehringer Ingelheim, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Most randomized trials on implantable cardioverter-defibrillator (ICD) use for primary prevention of sudden cardiac death in heart failure with reduced ejection fraction enrolled patients >20 years ago. We investigated the association between ICD use and all-cause mortality in a contemporary heart failure with reduced ejection fraction cohort and examined relevant subgroups., Methods: Patients from the Swedish Heart Failure Registry fulfilling the European Society of Cardiology criteria for primary-prevention ICD were included. The association between ICD use and 1-year and 5-year all-cause and cardiovascular (CV) mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort and in prespecified subgroups., Results: Of 16 702 eligible patients, only 1599 (10%) had an ICD. After matching, 1305 ICD recipients were compared with 1305 nonrecipients. ICD use was associated with a reduction in all-cause mortality risk within 1 year (hazard ratio, 0.73 [95% CI, 0.60-0.90]) and 5 years (hazard ratio, 0.88 [95% CI, 0.78-0.99]). Results were consistent in all subgroups including patients with versus without ischemic heart disease, men versus women, those aged <75 versus ≥75 years, those with earlier versus later enrollment in the Swedish heart failure registry, and patients with versus without cardiac resynchronization therapy., Conclusions: In a contemporary heart failure with reduced ejection fraction population, ICD for primary prevention was underused, although it was associated with reduced short- and long-term all-cause mortality. This association was consistent across all the investigated subgroups. These results call for better implementation of ICD therapy.

Aims: Cardiac resynchronization therapy (CRT) improves outcomes in heart failure (HF) but may be underutilized. The reasons are unknown., Methods and Results: We linked the Swedish Heart Failure Registry to national registries with ICD-10 (International Classification of Diseases-10th Revision) co-morbidity diagnoses and demographic and socio-economic data. In patients with EF ≤39% and NYHA II-IV, we assessed prevalence of CRT indication and CRT use. In those with CRT indication, we assessed the association between 37 potential baseline covariates and CRT non-use using multivariable generalized estimating equation (GEE) models. Of 12 807 patients (mean age 71 ± 12 years, 28% female), 841 (7%) had CRT, 3094 (24%) had an indication for but non-use of CRT, and 8872 (69%) had no indication. Important variables independently associated with CRT non-use were: HF duration <6 months [risk ratio (RR) 1.21, 95% confidence interval (CI) 1.17-1.24]; non-cardiology planned follow-up (RR 1.14, 95% CI 1.09-1.18); age >75 years (RR 1.13, 95% CI 1.09-1.18); non-cardiology care at baseline (RR 1.10, 95% CI 1.07-1.14); small-town non-university centre (RR 1.08, 95% CI 1.05-1.12); female sex (RR 1.07 95% CI 1.03-1.10) (all P < 0.05); as was absence of AF, living alone; psychiatric diagnosis; smoking; and non-use of HF drugs. Education, income, cancer, or HF characteristics were not independently associated with CRT non-use., Conclusion: In this population-wide HF registry, CRT was underutilized. Non-use was associated mostly with demographic and organizational, but not clinical or socio-economic factors. This calls for programmes to raise awareness of CRT indications and improve access and referrals to cardiology specialists., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Objectives: The objective of this pilot study was to describe the impact of paced heart rate on left ventricular (LV) mechanical dyssynchrony in synchronous compared to dyssynchronous pacing modes in patients with heart failure., Methods: Echocardiography was performed in 14 cardiac resynchronization therapy (CRT) patients at paced heart rates of 70 and 90 bpm in synchronous- (CRT), and dyssynchronous (atrial pacing + wide QRS activation) pacing modes. LV dyssynchrony was quantified using the 12-segment standard deviation model (Ts-SD) derived from Tissue Doppler Imaging. In addition, cardiac cycle intervals were assessed using cardiac state diagrams and stroke volume (SV) and filling pressure were estimated., Results: Ts-SD decreased significantly with CRT at 90 bpm (25 ± 12 ms) compared to 70 bpm (35 ± 15 ms, p = .01), but remained unchanged with atrial pacing at different paced heart rates (p = .96). The paced heart rate dependent reduction in Ts-SD was consistent when Ts-SD was indexed to average Ts and systolic time interval. Cardiac state diagram derived analysis of cardiac cycle intervals demonstrated a significant reduction of the pre-ejection interval and an increase in diastole with CRT compared to atrial pacing. SV was maintained at the higher paced heart rate with CRT pacing but decreased with atrial pacing., Discussion: Due to the small sample size in this pilot study general and firm conclusions are difficult to render. However, the data suggest that pacing at higher heart rates acutely reduces remaining LV dyssynchrony during CRT, but not during atrial pacing with dyssynchronous ventricular activation. These results need confirmation in a larger patient cohort.

Background: Spinal cord stimulation (SCS) reduces sympathetic activity in animal models of heart failure with reduced ejection fraction (HF) but limited data exist of SCS in patients with HF. The aim of the present study was to test the primary hypothesis that SCS reduces cardiac sympathetic nerve activity in HF patients. Secondary hypotheses were that SCS improves left ventricular function and dimension, exercise capacity, and clinical variables relevant to HF., Methods: HF patients with a SCS device previously participating in the DEFEAT-HF trial were included in this crossover study with 6-week intervention periods (SCS-ON and SCS-OFF). SCS (50 Hz, 210-μs pulse duration, aiming at T2-T4 segments) was delivered for 12 hours daily. Indices of myocardial sympathetic neuronal function (heart-to-mediastinum ratio, HMR) and activity (washout rate, WR) were assessed using 123 I-metaiodobenzylguanidine (MIBG) scintigraphy. Echocardiography, exercise testing, and clinical data collection were also performed., Results: We included 13 patients (65.3 ± 8.0 years, nine males) and MIBG scintigraphy data were available in 10. HMR was not different comparing SCS-ON (1.37 ± 0.16) and SCS-OFF (1.41 ± 0.21, P = 0.46). WR was also unchanged comparing SCS-ON (41.5 ± 5.3) and SCS-OFF (39.1 ± 5.8, P = 0.30). Similarly, average New York Heart Association class (2.4 ± 0.5 vs 2.3 ± 0.6, P = 0.34), quality of life score (24 ± 16 vs 24 ± 16, P = 0.94), and left ventricular dimension and function as well as exercise capacity were all unchanged comparing SCS-ON and SCS-OFF., Conclusion: In patients with HF, SCS (12 hours daily, targeting the T2-T4 segments of the spinal cord) does not appear to influence cardiac sympathetic neuronal activity or function as assessed by MIBG scintigraphy., (© 2017 Wiley Periodicals, Inc.)

Aims: Symptom severity assessed by NYHA functional class and QRS duration are essential criteria for selection of heart failure (HF) patients for CRT. This study assessed the relationship between NYHA class, QRS duration, and survival in a nationwide HF registry., Methods and Results: We studied 13 423 patients with HF in NYHA class II-IV and LVEF <40% in the Swedish Heart Failure Registry. Survival was followed via the Swedish Population Registry. Of 12 534 patients without CRT (age 71 ± 12 years, 29% women), 51% and 49% were in NYHA class II and III-IV, respectively. Patients in NYHA class II compared with class III-IV were younger (69 vs. 73 years), and had a better systolic function (49% vs. 58% with LVEF <30%), P <0.001 for all, and a favourable co-morbidity profile. QRS duration was 116 ± 29 ms in NYHA class II and 119 ± 29 ms in NYHA class III-IV with QRS ≥120 ms found in 37% vs. 44%, and an LBBB in 23% vs. 28% (P < 0.001 for all). Upon multivariable Cox regression adjusting for 40 clinically relevant variables, mortality risk was higher in NYHA class III-IV vs. class II, with a hazard ratio (HR) of 1.31, 95% confidence interval (CI) 1.23-1.40. Mortality was also higher with QRS prolongation ≥120 ms vs. narrow QRS. The HR in NYHA class II patients with non-LBBB was 1.19 (95% CI 1.05 - 1.36) and in those with LBBB it was 1.16 (95% CI 1.03-1.41). The corresponding HRs in NYHA class III-IV were 1.33 (95% CI 1.21-1.47) and 1.12 (95% CI 1.02-1.22). There was no significant interaction between the effects of NYHA class and QRS duration or morphology on mortality. Applying different scenarios to estimate guideline adherence, fewer patients with NYHA class II (range 14.4-42.6%) compared with NYHA class III-IV (18.0-45.4%) had received a CRT device when indicated., Conclusions: In HF with reduced LVEF, QRS prolongation is common and independently linked to worse survival. The increase in mortality risk associated with QRS prolongation of both LBBB and non-LBBB morphology is similar in NYHA class II and III-IV., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Cardiac resynchronization therapy (CRT) is increasingly used in heart failure treatment and management of these patients imposes significant challenges. Remote monitoring is becoming essential for CRT follow-up and allows close surveillance of device function and patient condition. It is helpful to reduce clinic visits, increase device longevity and provide early detection of device failure. Clinical effects include prevention of appropriate and inappropriate shocks and early detection of arrhythmias, such as atrial fibrillation. For modification of heart failure the addition of monitoring to CRT by means of device-based multiparameters may help to modify disease progression and improve survival., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Heart failure (HF) is considered as an epidemic and affects 2% of the population in the Western world. About 15-30% of patients with HF and reduced ejection fraction (HFrEF) also have prolonged QRS duration on the surface ECG, most commonly as a result of left-bundle branch block (LBBB). Increased QRS duration is a marker of a dyssynchronous activation, and subsequent contraction, pattern in the left ventricle (LV). When dyssynchrony is superimposed on the failing heart it further reduced systolic function and ultimately worsens outcome. During the past 15 years several randomized controlled clinical trials have documented that resynchronization of the dyssynchronous failing heart with a biventricular pacemaker - cardiac resynchronization therapy (CRT) - which can restore a more synchronous activation and contraction pattern. This translates in halted or reversed disease progression and improved clinical outcome, including reduced mortality. In this review, we will discuss several aspects of CRT including mechanisms of dyssynchrony and resynchronization in the failing heart, evidence of CRT efficacy derived from clinical trials and current challenges in CRT including patient selection and optimization of therapy delivery. Last, we will discuss future perspectives including the role of CRT to prevent adverse events in patients with an indication for antibradycardia pacing, the role of leadless pacing in the CRT setting as well as a new clinical arena where dyssynchrony and resynchronization may be important.

Background: Decompensation is frequent in heart failure (HF) patients and predicts poor prognosis., Hypothesis: Volume-overload events in HF patients are preceded by changes in intrathoracic impedance (Z) and body weight (BW); monitoring these parameters may be useful to predict decompensation., Methods: Forty-three HF patients (LVEF 25% ± 12%) with a recent HF event and an implantable cardioverter-defibrillator providing daily Z were equipped with telemonitoring scales submitting daily BW. Changes in BW and Z 30 days prior to major (HF hospitalization) and minor (ambulatory adjustment of diuretics) were analyzed., Results: During median of 427 days follow-up 25 major and 41 minor events occurred. Z decreased by -4.8 (95% confidence interval [CI]: CI -6.7 to -3.0) and -4.3 (95% CI: -5.5 to -3.2) within 30 days prior to major and minor events respectively (P < 0.001). BW increased before major events by 2.3 kg (95% CI: 1.0 to 3.5, P < 0.01) and minor events 1 kg (95% CI: 0.5 to 1.4, P < 0.001). Sensitivity of Z for major/minor HF events was 83.3% (95% CI: 71.7 to 91.0) and for BW 43.9% (95% CI: 31.9 to 56.7). The unexplained detection rate per patient-year was 1.6 (interquartile range [IQR], 0-3.1) for Z and 4.8 (IQR 1.6-11.1) for BW. Combined Z and BW sensitivity was 42.4% (95% CI: 30.6 to 55.2) and unexplained detection rate was 0.8 (IQR, 0-1.5) per patient-year., Conclusions: Decompensation is marked by a decrease in Z and increase in BW the preceding 30 days. Monitoring of Z predicts HF decompensations with better sensitivity and lower unexplained detection rate than BW., (© 2016 Wiley Periodicals, Inc.)

Aims: Implantable device telemonitoring (DTM) is a diagnostic adjunct to traditional face-to-face hospital visits. Remote device follow-up and earlier diagnoses facilitated by DTM should reduce healthcare utilization. We explored whether DTM reduces healthcare utilization over standard of care (SoC), without compromising patient outcomes., Methods and Results: This systematic review and meta-analysis of 11 randomized controlled trials on DTM in patients with heart failure consisted of 5702 patients, with a median of 117 [interquartile range (IQR) 76-331] patients per study [age 65 years (IQR 63-67)] and follow-up range of 12-36 months. DTM was associated with a reduction in total number of visits [planned, unplanned, and emergency room (ER)] [relative risk (RR) 0.56; 95% confidence interval (CI) 0.43-0.73, P < 0.001]. Rates of cardiac hospitalizations (RR 0.96; 95% CI 0.82-1.12, P = 0.60) and the composite endpoints of ER, unplanned hospital visits, or hospitalizations (RR 0.99; 95% CI 0.68-1.43, P = 0.96) was similar between the DTM and the SoC groups. An increase in the total number of ER or unscheduled visits (RR 1.37; 95% CI 1.11-1.70, P = 0.004) was observed. This effect was consistent and statistically significant for all studies. Total and cardiac mortality were similar between the groups (DTM RR 0.90; 95% CI 0.69-1.16, P = 0.41; and DTM RR 0.93; 95% CI 0.51-1.69, P = 0.80). Monetary costs favoured DTM (10-55% reduction in five studies)., Conclusions: Compared with SoC, DTM is associated with a marked reduction in planned hospital visits. In addition, DTM was associated with lower monetary costs, despite a modest increase in unplanned hospital and ER visits. DTM did not compromise survival., (© 2016 The Authors European Journal of Heart Failure © 2016 European Society of Cardiology.)

Cardiac resynchronization therapy (CRT) is increasingly used in heart failure treatment and management of these patients imposes significant challenges. Remote monitoring is becoming essential for CRT follow-up and allows close surveillance of device function and patient condition. It is helpful to reduce clinic visits, increase device longevity and provide early detection of device failure. Clinical effects include prevention of appropriate and inappropriate shocks and early detection of arrhythmias, such as atrial fibrillation. For modification of heart failure the addition of monitoring to CRT by means of device-based multiparameters may help to modify disease progression and improve survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: It has been suggested that cardiac resynchronization therapy (CRT) is less utilized, dyssynchrony occurs at narrower QRS, and CRT is more beneficial in women compared with men. We tested the hypotheses that (i) CRT is more underutilized and (ii) QRS prolongation and left bundle branch block (LBBB) are more harmful in women., Methods and Results: We studied 14 713 patients (28% women) with left ventricular ejection fraction (LVEF) <40% in the Swedish Heart Failure Registry. In women vs. men, CRT was present in 4 vs. 7% (P < 0.001) and was absent but with indication in 30 vs. 31% (P = 0.826). Next, among 13 782 patients (28% women) without CRT, 9% of women and 17% of men had non-specific intraventricular conduction delay (IVCD) and 27% of women and 24% of men had LBBB. One-year survival with narrow QRS was 85% in women and 88% in men, with IVCD 74 and 78%, and with LBBB 84 and 82%, respectively. Compared with narrow QRS, IVCD had a multivariable hazard ratio of 1.24 (95% CI 1.05-1.46, P = 0.011) in women and 1.30 (95% CI 1.19-1.42, P < 0.001) in men, and LBBB 1.03 (95% CI 0.91-1.16, P = 0.651) in women and 1.16 (95% CI 1.07-1.26, P < 0.001) in men, P for interaction between gender and QRS morphology, 0.241., Conclusions: While the proportion with CRT was lower in women, CRT was equally underutilized in both genders. QRS prolongation with or without LBBB was not more harmful in women than in men. Efforts to improve CRT implementation should be directed equally towards women and men., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: To test the hypothesis that acute increased biventricularly (BiV) paced heart rate (pHR) results in decreased muscle sympathetic nerve activity (MSNA), and that dyssynchronous pacing (AAI) attenuates this effect, in heart failure patients receiving cardiac resynchronization therapy (CRT)., Methods and Results: Fourteen CRT patients (NYHA II-III, 12 males, mean EF 28 ± 14%) were recruited. Three different pHRs (50-90 b.p.m.) were randomly programmed in BiV- and AAI-pacing modes. Muscle sympathetic nerve activity (total sympathetic nerve activity/min (units) and number of bursts/100 RR) were recorded from the peroneal nerve using a microelectrode. In addition, cardiac output (CO) and mean blood pressure (mBP) were measured. With BiV pacing, the total MSNA/min was lower at 70 b.p.m. (-7 ± 21%, P = 0.18) and 90 b.p.m. (-29 ± 18%, P = 0.01) compared with at 50 b.p.m. (280 ± 180 U). Similarly, bursts/100RR decreased with increased BiV pHR. Cardiac output (3.7 L/min at 50 b.p.m., +12 ± 12% at 70 b.p.m., and +18 ± 19% at 90 b.p.m.) and mBP (78 ± 11 mmHg at 50 b.p.m., +6 ± 6% at 70 b.p.m. and +11 ± 8% at 90 b.p.m.) increased significantly at elevated pHRs in BiV-pacing mode. The effect on MSNA, CO, and mBP was less pronounced in AAImode but we found no significant differences between the pacing modes., Conclusion: Increased pHR acutely reduces MSNA and improves haemodynamics in HF patients treated with CRT with no evident differences between BiV- and AAI-pacing modes. Further studies are warranted to guide the programming of basic pHR in CRT patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Age is not a contraindication to cardiac resynchronization therapy (CRT), but the prevalence and prognostic impact of QRS prolongation with intraventricular conduction delay (IVCD) and left bundle branch block (LBBB), as well as CRT utilization, may differ with age. We tested the hypotheses that in the elderly: (i) IVCD and LBBB are more prevalent, (ii) IVCD and LBBB are more harmful, and (iii) CRT is underutilized., Methods and Results: We studied 14 713 patients with ejection fraction ≤39% in the Swedish Heart Failure Registry and divided into age groups ≤65 years, 66-80 years and >80 years. Among 13 782 patients without CRT, IVCD was present in the three age groups in 11% vs. 15% vs. 19% and LBBB was present in 20% vs. 27% vs. 28%, respectively, (P < 0.001). The multivariable hazard ratio (HR) for all-cause mortality over a median (interquartile range) follow-up of 29 (12-53) months for IVCD vs. narrow QRS was 1.31 (1.06-1.63, P = 0.013) in the ≤65 year group, 1.32 (1.17-1.47, P < 0.001) in the 66-80 year group, and 1.26 (1.21-1.41, p < 0.001) in the >80 year group. For LBBB vs. narrow QRS it was 1.29 (1.07-1.56, P = 0.009), 1.17 (1.06-1.30, P = 0.002), and 1.10 (0.99-1.22, P = 0.091), respectively. The adjusted P for interaction between age and QRS morphology was 0.664. In the three age groups, CRT was present in 6% vs. 8% vs. 4% and absent but with indication in 23% vs. 32% vs. 37%, respectively (P < 0.001)., Conclusions: Both IVCD and LBBB were more common with increasing age and were similarly strong independent predictors of mortality and in all ages. The underutilization of CRT was worse with increasing age., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Background: Physical activity (PA) predicts cardiovascular mortality in the population at large. Less is known about its prognostic value in patients with chronic heart failure (HF)., Methods and Results: Data from 836 patients with implantable cardioverter defibrillator without or with cardiac resynchronization therapy enrolled in the Sensitivity of the InSync Sentry OptiVol feature for the prediction of Heart Failure (SENSE-HF)(1) study and the Diagnostic Outcome Trial in Heart Failure (DOT-HF) were pooled. The devices continuously measured and stored total daily active time (single-axis accelerometer). Early PA (average daily activity over the earliest 30-day study period) was studied as a predictor of time to death or HF-related hospital admission (primary end point). Data from 781 patients were analyzed (65±10 years; 85% men; left ventricular ejection fraction, 26±7%). Older age, shorter height, ischemic cause, peripheral artery disease, atrial fibrillation, diabetes mellitus, rales, peripheral edema, higher New York Heart Association class, lower diastolic blood pressure, and no angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor use were associated with reduced early PA. The primary end point occurred in 135 patients (15±7 months of follow-up). In multivariable analysis including baseline variables, early PA predicted death or HF hospitalization, with a 4% reduction in risk for each 10 minutes per day additional activity (hazard ratio [HR], 0.96; confidence interval [CI], 0.94-0.98; P=0.0002 compared with a model with the same baseline variables but without PA). PA also predicted death (HR, 0.93; CI, 0.90-0.96; P<0.0001) and HF hospitalization (HR, 0.97; CI, 0.95-0.99; P=0.011)., Conclusions: Early PA, averaged over a 30-day window early after defibrillator implantation or cardiac resynchronization therapy in patients with chronic HF, predicted death or HF hospitalization, as well as mortality and HF hospitalization separately, accounting for baseline HF severity. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00400985, NCT00480077.

Aims: To determine the long-term costs of extending device longevity in four patient populations requiring a single-chamber implantable cardioverter-defibrillator (ICD) or requiring cardiac resynchronization therapy with defibrillation (CRT-D) device over a 15-year time window., Methods and Results: We considered patient populations with an accepted indication for a single-chamber ICD for prevention of sudden cardiac death in the context of preserved (Population A) or impaired (Population B) left ventricular function; or with indication for a CRT-D device in the context of heart failure in New York Heart Association class II (Population C) or III (Population D). Expected patient survival and a cost analysis, including the cost of complications, was undertaken from a hospital perspective. Extended device longevity of 5 vs. 9 years for ICDs (Populations A and B); 4 vs. 7 years for CRT-Ds (Populations C and D) were considered. Over a 15-year time horizon, total, yearly, and per diem savings, per patient, from extending ICD longevity to 9 years were €10 926.91, €728.46, and €1.99 for Population A, and €7661.32, €510.75, and €1.40 for Population B. Total, yearly, and per diem savings from extending CRT-D longevity to 7 years were €13 630.38, €908.69, and €2.49 for Population C, and €10 968.29, €731.22, and €2.00 for Population D. Avoidance of a generator replacement amounted up to 46.6-62.5% of the saving., Conclusion: Extending device longevity has an important effect on the long-term cost of device therapy, both for ICD and CRT-D. This has important implications for device choice.

Aims: The impact of different basic paced heart rates (pHRs) in patients receiving cardiac resynchronization therapy (CRT) remains largely unknown. The aim of the present study was to investigate the haemodynamic effects of different pHRs (60 or 80 b.p.m.), using an implanted haemodynamic monitor (IHM), during a 2-week period in ambulatory CRT patients., Methods and Results: Ten CRT patients received an IHM (Chronicle(®), Medtronic Inc.) to continuously record right ventricular systolic (RVSP) and diastolic (RVDP) pressure, as well as estimated pulmonary artery diastolic pressure (ePAD) during a 2-week period at two basic pHR programming (60 and 80 b.p.m.). Cardiac output (CO) was calculated using a validated IHM algorithm. At the end of each period, 6 min walk test (6MWT), quality of life (QoL), and plasma levels of brain natriuretic peptide (BNP) were also assessed. Pacing at 80 b.p.m. significantly reduced the 2-week average of ePAD compared with 60 b.p.m. (23.4 ± 6.2 vs. 25.1 ± 6.5 mmHg, P = 0.03), whereas CO was increased (4.5 ± 1.3 vs. 4.2 ± 1.4 L/min; P = 0.01). Similarly ePAD, RVSP, and RVDP were significantly lower with a pHR of 80 b.p.m. (P < 0.05). The 6MWT, QoL score, and BNP were not affected by the pHR., Conclusion: In CRT patients, a basic pHR of 80 b.p.m. compared with 60 b.p.m. reduces filling pressures and increases CO during a 2-week period of ambulatory living. This suggests that increasing the basic pHR may be considered to achieve short-term haemodynamic improvement. The long-term effects of differential pHR programming remain to be established.

Aims: Non-responder rates for cardiac resynchronization therapy (CRT) vary from 11% to 46%. Retrospective data imply a better outcome with stimulation of the latest contracting left ventricular (LV) region. Our study analysed the feasibility, safety and clinical outcome of prospectively planned LV lead placement at the site of latest mechanical activation., Methods and Results: Thirty-eight heart failure patients with CRT indication were assessed by three-dimensional (3D) transoesophageal echocardiography and rotation angiography of the coronary sinus (CS). Both images were merged into a single 3D-model to identify CS target veins close to the site of latest mechanical activation. Subsequently, LV lead deployment was attempted at the desired target position. Patients were clinically and echocardiographically evaluated at baseline, after 3 and 6 months. The area of latest mechanical activation covered 6 ± 2 segments (38 ± 13% of LV surface) and was found lateral in 24 of 37 (65%), anterior in 11 of 37 (30%), inferior in 2 of 37 (5%), and septal in 1 of 37 (3%) patients. In 36 of 37 (97%) patients an appropriate target vein was identified and successful implantation could be performed in 34 of 37 (92%) patients. Among those patients clinical and echocardiographic response was observed in 91% and 81%, respectively., Conclusion: Individualized lead placement at the latest contracting LV site can be performed safely and successfully in the majority of patients. Initial clinical outcome data are encouraging. Identification of target sites requires multimodality integration between LV wall motion data and CS anatomy. Future developments need to improve those technologies and require randomized data on clinical outcome parameters.

Background: Acute kidney injury (AKI) after coronary artery bypass grafting (CABG) is common and increases the risk of postoperative complications and mortality. There is little information on the association between AKI after CABG and long-term risk of incident heart failure (HF)., Methods and Results: All patients (n=24 018) undergoing primary, isolated CABG in Sweden between 2000 and 2008 with complete information on pre- and postoperative serum creatinine values, and no prior hospitalization for HF were included. The postoperative increase in serum creatinine was used to define different stages of AKI: stage 1, 0.3 to 0.5 mg/dL; stage 2, 0.5 to 1 mg/dL; stage 3, >1 mg/dL. Hazard ratios with 95% confidence intervals were calculated for first hospitalization for HF for each stage of AKI using Cox proportional hazards regression. Twelve percent of the study population developed AKI. During a mean follow-up of 4.1 years, there were 1325 cases (5.5%) of incident HF. Hazard ratios with 95% confidence interval for HF in AKI stage 1, 2, and 3 were 1.60 (1.34-1.92), 1.87 (1.54-2.27), and 1.98 (1.53-2.57), respectively, after multivariable adjustment for age, sex, diabetes mellitus, estimated glomerular filtration rate, left ventricular ejection fraction, and myocardial infarction before surgery or during follow-up., Conclusions: AKI is associated with increased long-term risk of HF after CABG. Patients with AKI after CABG should be followed closely to detect early changes in cardiac function.

Heart failure is now considered an epidemic. In patients with heart failure, electrical and mechanical dyssynchrony, evident primarily as prolongation of the QRS-complex on the surface electrocardiogram, is associated with detrimental effects on the cardiovascular system at several levels. In the past 10 years, studies have demonstrated that by stimulating both cardiac ventricles simultaneously, or almost simultaneously [cardiac resynchronization therapy (CRT)], the adverse effects of dyssynchrony can be overcome. Here, we provide a comprehensive overview of different aspects of CRT including the rationale behind and evidence for efficacy of the therapy. Issues with regard to gender effects and patient follow-up as well as a number of unresolved concerns will also be discussed., (© 2012 The Association for the Publication of the Journal of Internal Medicine.)

Aims: Cardiac resynchronization therapy (CRT) improves prognosis in patients with moderate-to-severe heart failure, reduced left ventricular ejection fraction, and wide QRS complexes. However, CRT may be under-utilized in women and data on long-term follow-up are still scarce. The aim was to investigate long-term mortality and hospitalization and prognostic impact of gender after CRT., Methods and Results: Data on 619 consecutive patients (19% women) that received CRT at a single centre between 1998 and 2008 were collected from electronic medical records and national death and hospitalization registries up to 2010. The primary endpoint was death of any cause and the secondary endpoint was combined death of any cause or heart failure hospitalization. Over a mean follow-up of 1320 ± 786 days, 215 (35%) patients reached the primary endpoint and 437 (71%) the secondary endpoint. Overall, 1-, 5-, and 10-year survivals were 91, 63, and 39%, respectively. Female gender was the only independent predictor of all-cause mortality; hazard ratio (HR) 0.44 [95% confidence interval (CI), 0.21-0.90; P= 0.025]. Women also had a trend towards lower risk for the secondary endpoint, HR 0.68 (95% CI, 0.45-1.04; P= 0.072)., Conclusion: In this registry analysis, patients with CRT had similarly high short-term survival to those in controlled trials, and this favourable prognosis was sustained over the long term.Women had lower all-cause mortality than men.

Aims: Volume overload exacerbations in patients with chronic heart failure (HF) are associated with a dismal prognosis and are often triggered by dietary incompliance. We aimed to describe the effects of dietary changes on measures of fluid retention in HF patients., Methods and Results: Thirty-one HF patients with an implantable defibrillator (age 64 ± 11 years, ejection fraction 25 ± 12%, median NT-proBNP 2090 ng/L, resynchronization therapy: n= 25) were followed by daily body weight (BW) (telemonitoring) and intrathoracic impedance (by the implanted device) around Swedish Midsummer 2009, a holiday traditionally celebrated with meals including salty fish dishes and ample intake of fluids. Midsummer Eve celebrations caused a distinct and rapid increase in BW and a decrease in impedance indicating increased fluid retention. Compared with baseline values, peak BW increased by 1225 g [interquartile range (IQR) 475-2013 g)] which was accompanied by a decrease in impedance (3 Ω; IQR -5.2 to -1.2) and a clear deflection on the impedance-based fluid detection algorithm (OptiVol) that crossed the preset fluid-alert threshold six times following Midsummer. Body weight and impedance values were normalized after a period of 20 and 8 days, respectively. A clustering of minor clinical events following Midsummer suggests a possible adverse impact of dietary incompliance. However, none of the patients were hospitalized for HF., Conclusions: Dietary incompliance, e.g. on the occasion of a ceremonial meal, may lead to marked disturbances in the fluid balance of patients with HF reflected by increased BW and decreased intrathoracic impedance. These findings underline the importance of maintaining stable volume conditions in HF patients.

Background: Heart failure is associated with frequent hospitalizations, often resulting from volume overload. Measurement of intrathoracic impedance with an implanted device with an audible patient alert may detect increases in pulmonary fluid retention early. We hypothesized that early intervention could prevent hospitalizations and affect outcome., Methods and Results: We studied 335 patients with chronic heart failure who had undergone implantation of an implantable cardioverter-defibrillator alone (18%) or with cardiac resynchronization therapy (82%). All devices featured a monitoring tool to track changes in intrathoracic impedance (OptiVol) and other diagnostic parameters. Patients were randomized to have information available to physicians and patients as an audible alert in case of preset threshold crossings (access arm) or not (control arm). The primary end point was a composite of all-cause mortality and heart failure hospitalizations. During 14.9±5.4 months, this occurred in 48 patients (29%) in the access arm and in 33 patients (20%) in the control arm (P=0.063; hazard ratio, 1.52; 95% confidence interval, 0.97-2.37). This was due mainly to more heart failure hospitalizations (hazard ratio, 1.79; 95% confidence interval, 1.08-2.95; P=0.022), whereas the number of deaths was comparable (19 versus 15; P=0.54). The number of outpatient visits was higher in the access arm (250 versus 84; P<0.0001), with relatively more signs of heart failure among control patients during outpatient visits. Although the trial was terminated as a result of slow enrollment, a post hoc futility analysis indicated that a positive result would have been unlikely., Conclusion: Use of an implantable diagnostic tool to measure intrathoracic impedance with an audible patient alert did not improve outcome and increased heart failure hospitalizations and outpatient visits in heart failure patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00480077.

Background: Cardiac output (CO) is an important determinant of the hemodynamic state in patients with congestive heart failure (CHF). We tested the hypothesis that CO can be estimated from the right ventricular (RV) pressure waveform in CHF patients using a pulse contour cardiac output algorithm that considers constant but patient specific RV outflow tract characteristic impedance., Method: In 12 patients with CHF, breath-by-breath Fick CO and RV pressure waveforms were recorded utilizing an implantable hemodynamic monitor during a bicycle exercise protocol. These data were analyzed retrospectively to assess changes in characteristic impedance of the RV outflow tract during exercise. Four patients that were implanted with an implantable cardiac defibrillator (ICD) implementing the algorithm were studied prospectively. During a two staged sub-maximal bicycle exercise test conducted at 4 and 16 weeks of implant, COs measured by direct Fick technique and estimated by the ICD were recorded and compared., Results: At rest the total pulmonary arterial resistance and the characteristic impedance were 675 ± 345 and 48 ± 18 dyn.s.cm(-5), respectively. During sub-maximal exercise, the total pulmonary arterial resistance decreased (Δ 91 ± 159 dyn.s.cm(-5), p < 0.05) but the characteristic impedance was unaffected (Δ 3 ± 9 dyn.s.cm(-5), NS). The algorithm derived cardiac output estimates correlated with Fick CO (7.6 ± 2.5 L/min, R(2) = 0.92) with a limit of agreement of 1.7 L/min and tracked changes in Fick CO (R(2) = 0.73)., Conclusions: The analysis of right ventricular pressure waveforms continuously recorded by an implantable hemodynamic monitor provides an estimate of CO and may prove useful in guiding treatment in patients with CHF.

Heart failure , a syndrome associated with increasing prevalence, high mortality, and frequent hospital admissions, imposes a significant economic burden on western healthcare systems that is expected to further increase in the future due to the ageing population. Hospitalizations are responsible for the largest part of treatment costs and, thus, the main target for strategies aiming at cost reduction. Current literature suggests that evidence-based therapy with drugs, devices, and modern disease management programmes improves clinical outcomes of the large population of heart failure patients in a largely cost-effective manner. However, comprehensive knowledge about the cost of treatment is important to guide clinicians in the responsible allocation of today's limited health-care resources. This review provides information about the total cost of heart failure and the contribution of different treatment components to the overall costs.

Aims: The aim of this study was to investigate the acute effects of different biventricularly paced heart rates (pHRs) on right ventricular (RV) haemodynamics in heart failure (HF) patients with an implantable haemodynamic monitor (IHM)., Methods and Results: At rest, seven pHRs, range 60-120 bpm (steps of 10), were randomly programmed and maintained for 60 s in 10 patients (male, 65±12 years, New York Heart Association II-III). Right ventricular systolic (RVSP) and diastolic pressures, estimated pulmonary artery diastolic (ePAD) pressure, and RV+dP/dt were recorded beat-to-beat using the IHM. Cardiac output (CO) was estimated from the RV pressure waveforms and arterial blood pressure was measured (Portapres®). To compare the haemodynamic effects of increased pHR at rest to that of spontaneous, sinus-driven heart rate (HR) increase, patients also performed a symptom-limited bicycle exercise. At rest, RV+dP/dt increased significantly with elevated pHR (P, main effect, <0.001), whereas filling pressures (ePAD and RVSP) decreased significantly in the range 60-100 bpm (P<0.03 and P<0.003, respectively) but tended to increase or level out at pHRs>00 bpm. At a pHR of 100 bpm, ePAD was 1.4 mmHg lower compared with 60 bpm (P<0.01). Cardiac output increased gradually with elevated pHR at rest (P<0.001). Both total peripheral and estimated pulmonary arterial resistance significantly decreased with increased pHR. During exercise-induced maximum HR increase, RV+dP/dt, ePAD, and CO were all significantly higher compared with the corresponding pHR at rest., Conclusion: During cardiac resynchronization therapy in HF patients, the force frequency relationship is present in the RV, as increasing the pHR in the range 60-100 bpm results in decreased filling pressures and increased CO.

Objectives: The aim of this study was to evaluate an algorithm that estimates changes in cardiac output (CO) from right ventricular (RV) pressure waveforms derived from an implantable hemodynamic monitor (IHM) in heart failure patients., Design: Twelve heart failure patients (NYHA II-III, EF 32%) with an implantable hemodynamic monitor (Chronicle) were included in this study. Changes in cardiac output were provoked by body position change at rest (left lateral supine, horizontal supine, sitting, and standing) and a steady state bicycle exercise at 20 watts. Estimated CO derived from the IHM (CO(IHM)) was compared to CO measured with inert gas rebreathing (CO(RB)), echocardiography (CO(ECHO)) and impedance cardiography (CO(ICG)). CO(RB) was considered the reference method., Results: The median intra-patient correlation coefficient comparing CO(RB) and CO(IHM) was 0.83 (range: 0.63-0.98). Comparing CO(RB) with CO(ECHO) and CO(ICG) resulted in mean intra-patient correlation coefficients of 0.73 (-0.29-0.94) and 0.63 (-0.29-0.96). In a statistical model where slope and intercept was considered random between patients the coefficient of determination (R2) comparing CO(RB) and CO(IHM) was 0.91. Mean bias was -0.39 L/min (11%). Limits of agreement were +/-1.56 L/min and relative error was 21%., Conclusions: A simple algorithm based on RV pressure wave form characteristics derived from an IHM can be used to estimate changes in CO in heart failure patients. These findings encourage further research aiming to improve and validate the algorithm.

Background: Hemodynamic monitoring using implantable devices may provide early warning of volume overload in patients with heart failure (HF). This study was designed to prospectively compare information from intrathoracic impedance monitoring and continuous right ventricular pressure measurements in patients with HF., Methods and Results: Sixteen patients with HF (age, 63.5+/-13.8 years; left ventricular ejection fraction, 23.2+/-11.3%; New York Heart Association, II and III) and a previous HF decompensation received both a cardiac resynchronization therapy defibrillator providing a daily average of intrathoracic impedance and an implantable hemodynamic monitor providing an estimate of the pulmonary artery diastolic pressure. At the end of a 6-month investigator-blinded period, baseline reference hemodynamic values were determined over 4 weeks during which the patient was clinically stable. A major HF event was defined as HF decompensation requiring hospitalization, IV diuretic treatment, or leading to death. Sixteen major HF events occurred in 10 patients. Within 30 days and 14 days before a major HF event, impedance decreased by 0.12+/-0.21 Omega/d and 0.20+/-0.20 Omega/d, respectively, whereas estimated pulmonary arterial diastolic pressure increased by 0.10+/-0.20 mm Hg/d and 0.16+/-0.15 mm Hg/d, respectively. During these periods, impedance decreased by 3.8+/-5.4 Omega (P<0.02) and 4.9+/-6.1 Omega (P<0.007), respectively, whereas estimated pulmonary arterial diastolic pressure increased by 5.8+/-5.7 mm Hg (P<0.002) and 6.8+/-6.1 mm Hg (P<0.001), respectively, compared with baseline. In all patients, impedance and estimated pulmonary arterial diastolic pressure were inversely correlated (r = -0.48+/-0.25). Within 30 days preceding a major HF event, this correlation improved to r =-0.58+/-0.24., Conclusions: Decompensated HF develops based on hemodynamic derangements and is preceded by significant changes in intrathoracic impedance and right ventricular pressures during the month prior to a major clinical event. Impedance and pressure changes are moderately correlated. Future research may establish the complementary contribution of both parameters to guide diagnosis and management of patients with HF by implantable devices.

Aims: The aim of this study was to study the haemodynamic effect of atrioventricular delay (AVD) modifications within a narrow range in different body positions and during exercise in patients receiving cardiac resynchronization therapy (CRT)., Methods: The previously optimized AVD was shortened and prolonged by 40 ms in 27 CRT patients and 9 controls without heart failure. Cardiac output (CO) was measured by inert gas rebreathing (Innocor) as the average over different body positions (left-lateral, supine, sitting, standing, and exercise). In eight CRT patients with an implantable haemodynamic monitor, the estimated pulmonary artery diastolic pressure (ePAD) was analysed., Results: The magnitude of CO response to AVD changes was greater in CRT patients than in controls (0.25 vs. 0.20 L/min, P<0.05), varied substantially between individuals (range: 0.12-0.56 L/min), and correlated with left atrial size (r=0.61, P<0.001). On average, AVD shortening decreased CO slightly (0.07+/-0.17 L/min) and increased ePAD (1.1+/-0.8 mmHg, both P<0.05), whereas prolongation had no significant effect., Conclusion: The haemodynamic response to AVD modifications within a narrow range is larger in CRT patients than in normal controls and varies substantially between individuals. These findings suggest that optimal AVD tuning is clinically important in selected patients.

Aims: To compare haemodynamic responses during the 6-min walk test (6MWT) and daily living activities in heart failure (HF) patients., Methods and Results: Eighteen HF patients received an implantable haemodynamic monitor, which continuously measured heart rate (HR), estimated pulmonary artery diastolic pressure (ePAD), and several right ventricular (RV) pressure parameters. During the 6MWT, haemodynamics were assessed at rest and peak exercise. Ambulatory values were measured as the daily minimum, maximum, and median, averaged over the 14-day period surrounding each 6MWT. During the 6MWT, HR increased from 71 +/- 17 to 101 +/- 20 b.p.m. and ePAD from 20 +/- 5 to 34 +/- 8 mmHg. Daily minimum values were significantly lower and daily maximum values higher compared with rest and peak exercise. Patients with a walked distance above the median (402 m) had lower resting HR (64 +/- 10 vs. 77 +/- 20, P = 0.001) and ePAD (18 +/- 4 vs. 21 +/- 7, P = 0.022) compared to patients with walked distances below the median; values at peak exercise were similar. This pattern was also observed during the ambulatory periods., Conclusion: Ranges of HR and RV pressures are significantly larger during daily living activities compared with 6MWT in HF patients. Haemodynamic characteristics of patients with greater exercise capacity include lower resting HR and RV pressures and are similar during the 6MWT and daily life.

Background: Chronic heart failure is associated with frequent hospitalisations which are often due to volume-overload decompensation. Monitoring of intrathoracic impedance, measured from an implanted device, can detect increases in pulmonary fluid retention early and facilitate timely treatment interventions., Objective: The DOT-HF trial is designed to investigate if ambulatory monitoring of intrathoracic impedance together with other device-based diagnostic information can reduce morbidity and mortality in patients with chronic heart failure who are treated with cardiac resynchronization therapy (CRT) and/or an implantable defibrillator (ICD)., Methods: Approximately 2400 patients will be randomised in a 1:1 fashion to a management strategy with access to the diagnostic information from the implantable device ("access arm"), or a "control arm", where this information is not made available. Study subjects fulfil standard indications for CRT and/or ICD as outlined in current guidelines. In the access arm, a fluid alert algorithm is used to give early warning of decreasing intrathoracic impedance indicating a high risk of an impending volume-overload decompensation. The primary endpoint of DOT-HF is the composite of all-cause mortality or heart failure hospitalisation. Secondary and exploratory endpoints include all-cause mortality, the impact on total health care utilization, quality of life and cost effectiveness. The study is expected to close recruitment during 2010 and to report in 2012.

Electrical devices, Cardiac Resynchronization Therapy (CRT) pacemakers, the Implantable Cardiac Defibrillator (ICD) and a combination of both, constitute an important line of treatment in the therapy of moderate to severe chronic heart failure. The effectiveness of these devices in the treatment of acute decompensated heart failure has yet to be systematically evaluated. However, the beneficial clinical effects of CRT translate into a marked reduction of heart failure-related hospitalization. Devices also offer unique diagnostic applications by continuous measurement of clinically useful physiological parameters over time. Of particular interest, monitoring of intrathoracic impedance and right ventricular pressures allows to detect changes in volume load in an early stage prior to the development of clinical symptoms. This information could be helpful to stop further progression to acute cardiac decompensation and to avoid hospitalization and acute clinical events. Using modern telecommunication technology, patients can also be remotely monitored in their daily living environment. In consequence, the incorporation of device technology into heart failure management programs calls for a close cooperation between heart failure specialists and electrophysiologists. This review addresses therapeutic and diagnostic aspects of device therapies in the context of acute heart failure.

Background: Haemodynamic and functional effects of cardiac resynchronization therapy (CRT) have been studied mostly at rest. CRT effects on left ventricular (LV) dyssynchrony and function during stress have not been evaluated in detail., Aims: We studied the electromechanical effects of CRT at rest and during Dobutamine stress echocardiography (DSE), during active and withheld CRT., Methods: Twenty-one responders to CRT (62+/-12 yr) were assessed by walking test, quality of life, and BNP with active CRT ("on") and 2 weeks after pacing withdrawal ("off"). DSE (10 microg/kg/min) was performed both at "on" and "off" to evaluate dyssynchrony parameters, systolic and diastolic function., Results: At rest, CRT withdrawal was associated with an increased interventricular mechanical delay (IVMD, from 21+/-18 ms to 49+/-24 ms, p<0.001) and impaired intraventricular synchrony. There was a significant decrease in LV systolic function and LV filling time. Dobutamine infusion had no impact on inter- and intraventricular synchrony. During stress, there was an improvement in LV performance both at "on" and "off". However, LV dp/dt, aortic VTI, cardiac output, mean systolic peak velocities and LV filling time during dobutamine stress were significantly greater with CRT "on"., Conclusion: In long-term responders, CRT improves LV performance both at rest and during dobutamine stress. This is attributable to an improvement in LV synchrony, which is maintained during stress.