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Aims Iron deficiency (ID) is common in heart failure (HF) patients and negatively impacts symptoms and prognosis. The aetiology of ID in HF is largely unknown. We studied determinants and the biomarker profile of ID in a large international HF cohort. Methods and results We studied 2357 worsening HF patients from the BIOSTAT-CHF cohort. ID was defined as transferrin saturation Conclusion Our data suggest that the aetiology of ID in worsening HF is complex, multifactorial and seems to consist of a combination of reduced iron uptake (malnutrition, fluid overload), impaired iron storage (inflammation, chronic kidney disease), and iron loss (antiplatelets).

Aims Lamin A/C (LMNA) mutations cause familial dilated cardiomyopathy (DCM) with frequent conduction blocks and arrhythmias. We explored the prevalence, cardiac penetrance, and expressivity of LMNA mutations among familial DCM in Norway. Furthermore, we explored the risk factors and the outcomes in LMNA patients. Methods and results During 2003–15, genetic testing was performed in patients referred for familial DCM. LMNA genotype-positive subjects were examined by electrocardiography, Holter monitoring, cardiac magnetic resonance imaging, and echocardiography. A positive cardiac phenotype was defined as the presence of atrioventricular (AV) block, atrial fibrillation/flutter (AF), ventricular tachycardia (VT), and/or echocardiographic DCM. Heart transplantation was recorded and compared with non-ischaemic DCM of other origin. Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation. Family screening diagnosed an additional 93 LMNA genotype-positive family members. We clinically followed up 79 LMNA genotype-positive [age 42 ± 16 years, ejection fraction (EF) 45 ± 13%], including 44 (56%) with VT. Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up. Ten (32%) had AV block, 7 (23%) AF, and 12 (39%) non-sustained VT. Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 ± 6.3 years of follow-up. Conclusion LMNA mutation prevalence was 6.2% of familial DCM in Norway. Cardiac penetrance was high in young asymptomatic LMNA genotype-positive family members with frequent AV block and VT, highlighting the importance of early family screening and cardiological follow-up. Nearly 20% of the LMNA patients required heart transplantation.

Aims The REGENERATE-DCM trial is the first phase II randomized, placebo-controlled trial aiming to assess if granulocyte colony-stimulating factor (G-CSF) administration with or without adjunctive intracoronary (IC) delivery of autologous bone marrow-derived cells (BMCs) improves global left ventricular (LV) function in patients with dilated cardiomyopathy (DCM) and significant cardiac dysfunction. Methods and results Sixty patients with DCM and left ventricular ejection fraction (LVEF) at referral of ≤45%, New York Heart Association (NYHA) classification ≥2 and no secondary cause for the cardiomyopathy were randomized equally into four groups: peripheral placebo (saline), peripheral G-CSF, peripheral G-CSF and IC serum, and peripheral G-CSF and IC BMC. All patients, except the peripheral placebo group, received 5 days of G-CSF. In the IC groups, this was followed by bone marrow harvest and IC infusion of cells or serum on Day 6. The primary endpoint was LVEF change from baseline to 3 months, determined by advanced cardiac imaging. At 3 months, peripheral G-CSF combined with IC BMC therapy was associated with a 5.37% point increase in LVEF (38.30% ± 12.97 from 32.93% ± 16.46 P = 0.0138), which was maintained to 1 year. This was associated with a decrease in NYHA classification, reduced NT-pro BNP, and improved exercise capacity and quality of life. No significant change in LVEF was seen in the remaining treatment groups. Conclusion This is the first randomized, placebo-controlled trial with a novel combination of G-CSF and IC cell therapy that demonstrates an improvement in cardiac function, symptoms, and biochemical parameters in patients with DCM.

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19–2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11–1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01–2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24–2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

Purpose The prognostic implications of blood glucose on a wide range of outcomes including early mortality, hospitalizations, and incident diabetes diagnoses have not been fully elucidated in acute heart failure syndromes (AHFS). Methods In a population-based cohort of 16 524 AHFS patients presenting to the emergency department (ED) in Ontario, Canada between 2004 and 2007, we performed a competing risk analysis for 30-day mortality, new diabetes diagnoses, and hospitalization outcomes. Presentation blood glucose concentrations were categorized as follows: 3.9–6.1 [referent], >6.1–7.8, >7.8–9.4, >9.4–11.1, and >11.1 mmol/L. Results Among AHFS patients without diabetes presenting to the ED ( n = 9275), blood glucose >6.1 mmol/L ( n = 5252, 56.6%) was associated with increased risks of all-cause death [hazard ratio (HR) range: 1.26 (95% CI 1.05–1.50) to 1.50 (95% CI 1.11–2.02)], and cardiovascular death [HR range: 1.28 (95% CI 1.03–1.59) to 1.64 (95% CI 1.16–2.33)]. Among AHFS patients with diabetes ( n = 7249), presenting blood glucose >11.1 mmol/L ( n = 2286, 31.5%) was associated with increased risks of all-cause death (HR 1.48, 95% CI 1.10–2.00) and diabetes-related hospitalizations (HR 1.39, 95% CI; 1.20–1.61). Presentation blood glucose >9.4 mmol/L was associated with increased risks of hospitalization for HF or cardiovascular causes [HR range: 1.09 (95% CI 1.02–1.17) to 1.15 (95% CI 1.07–1.24)] in all patients. With higher presentation blood glucose, the risk of incident diabetes diagnosis increased, with adjusted HRs of 1.61 (>6.1–7.8 mmol/L) to 3.61 (>11.1 mmol/L) among those without the condition at baseline (all P < 0.001). Conclusions Mildly elevated presentation blood glucose was associated with early death, future diabetes, and hospitalizations for diabetes, HF, and cardiovascular causes among patients with AHFS.

Aims To study the relation between body mass index (BMI) in young men and risk of early hospitalization with heart failure. Methods and results In a prospective cohort study, men from the Swedish Conscript Registry investigated 1968–2005 (n = 1 610 437; mean age, 18.6 years were followed 5–42 years (median, 23.0 years; interquartile range, 15.0–32.0), 5492 first hospitalizations for heart failure occurred (mean age at diagnosis, 46.6 (SD 8.0) years). Compared with men with a body mass index (BMI) of 18.5–20.0 kg/m2, men with a BMI 20.0–22.5 kg/m2 had an hazard ratio (HR) of 1.22 (95% CI, 1.10–1.35), after adjustment for age, year of conscription, comorbidities at baseline, parental education, blood pressure, IQ, muscle strength, and fitness. The risk rose incrementally with increasing BMI such that men with a BMI of 30–35 kg/m2 had an adjusted HR of 6.47 (95% CI, 5.39–7.77) and those with a BMI of ≥35 kg/m2 had an HR of 9.21 (95% CI, 6.57–12.92). The multiple-adjusted risk of heart failure per 1 unit increase in BMI ranged from 1.06 (95% CI, 1.02–1.11) in heart failure associated with valvular disease to 1.20 (95% CI, 1.18–1.22) for cases associated with coronary heart disease, diabetes, or hypertension. Conclusion We found a steeply rising risk of early heart failure detectable already at a normal body weight, increasing nearly 10-fold in the highest weight category. Given the current obesity epidemic, heart failure in the young may increase substantially in the future and physicians need to be aware of this.

Aims The globalization of clinical trials has highlighted geographic variations in patient characteristics, event rates, and treatment effects. We investigated these further in PARADIGM-HF, the largest and most globally representative trial in heart failure (HF) to date. Methods and results We looked at five regions: North America (NA) 602 (8%), Western Europe (WE) 1680 (20%), Central/Eastern Europe/Russia (CEER) 2762 (33%), Latin America (LA) 1433 (17%), and Asia-Pacific (AP) 1487 (18%). Notable differences included: WE patients (mean age 68 years) and NA (65 years) were older than AP (58 years) and LA (63 years) and had more coronary disease; NA and CEER patients had the worst signs, symptoms, and functional status. North American patients were the most likely to have a defibrillating-device (54 vs. 2% AP) and least likely prescribed a mineralocorticoid receptor antagonist (36 vs. 65% LA). Other evidence-based therapies were used most frequently in NA and WE. Rates of the primary composite outcome of cardiovascular (CV) death or HF hospitalization (per 100 patient-years) varied among regions: NA 13.6 (95% CI 11.7–15.7) WE 9.6 (8.6–10.6), CEER 12.3 (11.4–13.2), LA 11.2 (10.0–12.5), and AP 12.5 (11.3–13.8). After adjustment for prognostic variables, relative to NA, the risk of CV death was higher in LA and AP and the risk of HF hospitalization lower in WE. The benefit of sacubitril/valsartan was consistent across regions. Conclusion There were many regional differences in PARADIGM-HF, including in age, symptoms, comorbidity, background therapy, and event-rates, although these did not modify the benefit of sacubitril/valsartan. Clinical trial registration URL http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Aims Patients with chronic heart failure (CHF) show impaired health-related quality of life (HRQoL), an important target for therapeutic intervention. Impaired iron homeostasis may be one mechanism underlying the poor physical condition of CHF patients. This detailed subanalysis of the previously published FAIR-HF study evaluated baseline HRQoL in iron-deficient patients with CHF and the effect of intravenous ferric carboxymaltose (FCM) on HRQoL. Methods and results FAIR-HF randomized 459 patients with reduced left ventricular ejection fraction and iron deficiency, with or without anaemia, to FCM or placebo (2:1). Health-related quality of life was assessed at baseline and after 4, 12, and 24 weeks of therapy using the generic EQ-5D questionnaire and disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ). Baseline mean Visual Analogue Scale (VAS) score was 54.3 ± 16.4 and KCCQ overall summary score was 52.4 ± 18.8. Ferric carboxymaltose significantly improved VAS and KCCQ (mean differences from baseline in KCCQ overall, clinical and total symptom scores, P < 0.001 vs. placebo) at all time points. At Week 24, significant improvement vs. placebo was observed in four of the five EQ-5D dimensions: mobility ( P = 0.004), self-care ( P < 0.001), pain/discomfort ( P = 0.006), anxiety/depression ( P = 0.012), and usual activity ( P = 0.035). Ferric carboxymaltose improved all KCCQ domain mean scores from Week 4 onward ( P ≤ 0.05), except for self-efficacy and social limitation. Effects were present in both anaemic and non-anaemic patients. Conclusions HRQoL is impaired in iron-deficient patients with CHF. Intravenous FCM significantly improved HRQoL after 4 weeks, and throughout the remaining study period. The positive effects of FCM were independent of anaemia status.

Aims: Remote management of heart failure using implantable electronic devices (REM-HF) aimed to assess the clinical and cost-effectiveness of remote monitoring (RM) of heart failure in patients with cardiac implanted electronic devices (CIEDs).Methods and results: Between 29 September 2011 and 31 March 2014, we randomly assigned 1650 patients with heart failure and a CIED to active RM or usual care (UC). The active RM pathway included formalized remote follow-up protocols, and UC was standard practice in nine recruiting centres in England. The primary endpoint in the time to event analysis was the 1st event of death from any cause or unplanned hospitalization for cardiovascular reasons. Secondary endpoints included death from any cause, death from cardiovascular reasons, death from cardiovascular reasons and unplanned cardiovascular hospitalization, unplanned cardiovascular hospitalization, and unplanned hospitalization. REM-HF is registered with ISRCTN (96536028). The mean age of the population was 70 years (range 23–98); 86% were male. Patients were followed for a median of 2.8 years (range 0–4.3 years) completing on 31 January 2016. Patient adherence was high with a drop out of 4.3% over the course of the study. The incidence of the primary endpoint did not differ significantly between active RM and UC groups, which occurred in 42.4 and 40.8% of patients, respectively [hazard ratio 1.01; 95% confidence interval (CI) 0.87–1.18; P = 0.87]. There were no significant differences between the two groups with respect to any of the secondary endpoints or the time to the primary endpoint components.Conclusion: Among patients with heart failure and a CIED, RM using weekly downloads and a formalized follow up approach does not improve outcomes.

Aims Although cardiac resynchronization therapy (CRT) is effective in patients with systolic heart failure (HF) and a wide QRS interval, a substantial proportion of patients remain non-responsive. The SonR contractility sensor embedded in the right atrial lead enables individualized automatic optimization of the atrioventricular (AV) and interventricular (VV) timings. The RESPOND-CRT study investigated the safety and efficacy of the contractility sensor system in HF patients undergoing CRT. Methods and results RESPOND-CRT was a prospective, randomized, double-blinded, multicentre, non-inferiority trial. Patients were randomized (2:1, respectively) to receive weekly, automatic CRT optimization with SonR vs. an Echo-guided optimization of AV and VV timings. The primary efficacy endpoint was the rate of clinical responders (patients alive, without adjudicated HF-related events, with improvement in New York Heart Association class or quality of life), at 12 months. The study randomized 998 patients. Responder rates were 75.0% in the SonR arm and 70.4% in the Echo arm (mean difference, 4.6%; 95% CI, −1.4% to 10.6%; P

© The Author 2017. Aims To determine if an intensified form of heart failure management programme (INT-HF-MP) based on individual profiling is superior to standard management (SM) in reducing health care costs during 12-month follow-up (primary endpoint). Methods and results A multicentre randomized trial involving 787 patients (full analysis set) discharged from four tertiary hospitals with chronic HF who were randomized to SM (n = 391) or INT-HF-MP (n = 396). Mean age was 74 ± 12 years, 65% had HF with a reduced ejection fraction (31.4 ± 8.9%) and 14% were remote-dwelling. Study groups were well matched. According to Green, Amber, Red Delineation of rIsk And Need in HF (GARDIAN-HF) profiling, regardless of location, patients in the INT-HF-MP received a combination of face-to-face (home visits) and structured telephone support (STS); only 9% ('low risk') were designated to receive the same level of management as the SM group. The median cost in 2017 Australian dollars (A$1 equivalent to ∼EUR e0.7) of applying INT-HF-MP was significantly greater than SM ($152 vs. $121 per patient per month; P < 0.001), However, at 12 months, there was no difference in total health care costs for the INT-HF-MP vs. SM group (median $1579, IQR $644 to $3717 vs. $1450, IQR $564 to $3615 per patient per month, respectively). This reflected minimal differences in all-cause mortality (17.7% vs. 18.4%; P = 0.848) and recurrent hospital stay (18.6 ± 26.5 vs. 16.6 ± 24.8 days; P = 0.199) between the INT-HF-MP and SM groups, respectively. Conclusion During 12-months follow-up, an INT-HF-MP did not reduce healthcare costs or improve health outcomes relative to SM.

Aim The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in iron-deficient patients with heart failure (HF). Methods and results CONFIRM-HF was a multi-centre, double-blind, placebo-controlled trial that enrolled 304 ambulatory symptomatic HF patients with left ventricular ejection fraction ≤45%, elevated natriuretic peptides, and iron deficiency (ferritin

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 ligible 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 years), and left ventricular ejection fraction (LVEF, 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 [0.98 (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

Aims Takotsubo syndrome (TTS) is typically provoked by negative stressors such as grief, anger, or fear leading to the popular term 'broken heart syndrome'. However, the role of positive emotions triggering TTS remains unclear. The aim of the present study was to analyse the prevalence and characteristics of patients with TTS following pleasant events, which are distinct from the stressful or undesirable episodes commonly triggering TTS. Methods and results Takotsubo syndrome patients with preceding pleasant events were compared to those with negative emotional triggers from the International Takotsubo Registry. Of 1750 TTS patients, we identified a total of 485 with a definite emotional trigger. Of these, 4.1% (n = 20) presented with pleasant preceding events and 95.9% (n = 465) with unequivocal negative emotional events associated with TTS. Interestingly, clinical presentation of patients with 'happy heart syndrome' was similar to those with the 'broken heart syndrome' including symptoms such as chest pain [89.5% (17/19) vs. 90.2% (412/457), P = 1.0]. Similarly, electrocardiographic parameters, laboratory findings, and 1-year outcome did not differ. However, in a post hoc analysis, a disproportionate higher prevalence of midventricular involvement was noted in 'happy hearts' compared with 'broken hearts' (35.0 vs. 16.3%, P = 0.030). Conclusion Our data illustrate that TTS can be triggered by not only negative but also positive life events. While patient characteristics were similar between groups, the midventricular TTS type was more prevalent among the 'happy hearts' than among the 'broken hearts'. Presumably, despite their distinct nature, happy and sad life events may share similar final common emotional pathways, which can ultimately trigger TTS. OA hybrid - CA extern

Item does not contain fulltext 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 Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin. Methods and results Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution. Conclusion Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.

Aims Dronedarone is a new multichannel blocking antiarrhythmic drug for treatment of atrial fibrillation (AF). In patients with recently decompensated congestive heart failure (CHF) and depressed LV function, the drug was associated with excess mortality compared with a placebo group. The present study aimed to analyse in detail the effects of dronedarone on mortality and morbidity in AF patients CHF. Methods and results We performed a post hoc analysis of ATHENA, a large placebo-controlled outcome trial in 4628 patients with paroxysmal or persistent AF, to evaluate the relationship between clinical outcomes and dronedarone therapy in patients with stable CHF. The primary outcome was time to first cardiovascular (CV) hospitalization or death. There were 209 patients with NYHA class II/III CHF and a left ventricular ejection fraction ≤0.40 at baseline (114 placebo, 95 dronedarone patients). A primary outcome event occurred in 59/114 placebo patients compared with 42/95 dronedarone patients [hazard ratio (HR) 0.78, 95% CI = 0.52–1.16]. Twenty of 114 placebo patients and 12/95 dronedarone patients died during the study (HR 0.71, 95% CI = 0.34–1.44). Fifty-four placebo and 42 dronedarone patients were hospitalized for an intermittent episode of NYHA class IV CHF (HR = 0.78, 95% CI = 0.52–1.17). Conclusion In this post-hoc analysis of ATHENA patients with AF and stable CHF, dronedarone did not increase mortality and showed a reduction of CV hospitalization or death similar to the overall population. However, in the light of the ANtiarrhythmic trial with DROnedarone in Moderate to severe CHF Evaluating morbidity DecreAse study, dronedarone should be contraindicated in patients with NYHA class IV or unstable NYHA classes II and III CHF.

AIMS: Thiazolidinediones are insulin sensitizers, and are associated with fluid retention and increased risk of heart failure (HF) in people with type 2 diabetes. We assessed fatal and non-fatal HF events and their outcome, and identified HF predictors in the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial population. METHODS AND RESULTS: In a multicentre, open-label study, we randomized 4447 people with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA(1c) of 7.9% to add-on rosiglitazone (n = 2220) or to a combination of metformin and sulfonylurea (n = 2227) and followed them over 5.5 years on average. Heart failure hospitalizations and deaths were adjudicated by a Clinical Endpoint Committee using pre-specified criteria. Independent predictors of HF events were identified out of a group of 30 pre-specified clinical, demographic, and biological variables. In the rosiglitazone group, the risk of HF death or hospitalization was doubled: HR = 2.10 (95% CI, 1.35-3.27): the excess HF event rate was 2.6 (1.1-4.1) per 1000 person-years. An excess in HF deaths was observed (10 vs. two), including four HF deaths as first HF events. By contrast, there was no increase in cardiovascular mortality or hospitalization (HR = 0.99, 95% CI, 0.85-1.16) or in cardiovascular deaths (60 vs. 71). Independent predictors of HF were rosiglitazone assignment, age, urinary albumin : creatinine ratio, body mass index, and systolic blood pressure at baseline. A history of previous cardiovascular disease was not predictive of HF. Duration of HF hospitalization and rate of HF re-hospitalization were similar in the two groups. CONCLUSION: These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that this agent should not continue to be used in people developing symptomatic HF while using the medication. Close follow-up for the risk of HF should be offered to elderly people, people with markedly increased body mass index, people with microalbuminuria/proteinuria, and people with increased systolic blood pressure.

Aims Clinical parameters are weak predictors of outcome in patients with idiopathic dilated cardiomyopathy (IDC). We assessed the prognostic value of cardiac magnetic resonance (CMR) parameters in addition to conventional clinical and electrocardiographic characteristics. Methods and results One hundred and forty-one IDC patients were studied. QRS and QTc intervals were measured in 12-lead surface electrocardiogram. Patients were followed for median 1339 days, including 483 patient-years. The primary endpoint—cardiac death or sudden death—occurred in 25 (18%) patients, including 16 patients with cardiac death, 3 patients with sudden cardiac death (SCD), and 6 patients with ICD shock. Late gadolinium enhancement (LGE) was detected in 36 patients (26%). Kaplan–Meier survival analysis displayed QRS >110 ms (P = 0.010), the presence of LGE (P = 0.037), and diabetes mellitus (P < 0.001) as significant parameters for a worse outcome. Multivariable analysis revealed cardiac index (P < 0.001), right ventricular end-diastolic volume index (RVEDVI) (P = 0.006) derived from CMR imaging, the presence of diabetes mellitus (P = 0.006), and QRS >110 ms (P = 0.045) as significant predictors for the primary endpoint. Conclusion Cardiac index and RVEDVI derived from CMR imaging in addition to QRS duration >110 ms from conventional surface ECG and diabetes mellitus provide prognostic impact for cardiac death and SCD in patients with IDC.

Aims To identify risk factors for left ventricular (LV) dysfunction in right ventricular (RV) pacing in the young. Methods and results Left ventricular function was evaluated in 82 paediatric patients with either non-surgical (n = 41) or surgical (n= 41) complete atrioventricular block who have been 100% RV paced for a mean period of 7.4 years. Left ventricular shortening fraction (SF) decreased from a median (range) of 39 (24–62)% prior to implantation to 32 (8–49)% at last follow-up (P < 0.05). Prevalence of a combination of LV dilatation (LV end-diastolic diameter >+2z-values) and dysfunction (SF < 0.26) was found to increase from 1.3% prior to pacemaker implantation to 13.4% (11/82 patients) at last follow-up (P = 0.01). Ten of these 11 patients had progressive LV remodelling and 8 of 11 were symptomatic. The only significant risk factor for the development of LV dilatation and dysfunction was the presence of epicardial RV free wall pacing (OR = 14.3, P < 0.001). Other pre-implantation demographic, diagnostic, and haemodynamic factors including block aetiology, pacing variables, and pacing duration did not show independent significance. Conclusion Right ventricular pacing leads to pathologic LV remodelling in a significant proportion of paediatric patients. The major independent risk factor is the presence of epicardial RV free wall pacing, which should be avoided whenever possible.

Aims To investigate whether genetic variants of the histidine-rich calcium (HRC)-binding protein are associated with idiopathic dilated cardiomyopathy (DCM) and its progression. Methods and results We screened 123 idiopathic DCM patients and 96 healthy individuals by single-strand conformation polymorphism analysis and direct sequencing for genetic variants in HRC. Six polymorphisms were detected: Leu35Leu (A/G), Ser43Asn (G/A), Ser96Ala (T/G), Glu202_Glu203insGlu (−/GAG), Asp261del (GAT/−), and an in-frame insertion of 51 amino acids at His321. The analysis of their frequencies did not reveal any significant correlation with DCM development. However, the Ser96Ala polymorphism exhibited a statistically significant correlation with the occurrence of life-threatening ventricular arrhythmias. During a follow-up of 4.02 ± 2.4 years, the risk for ventricular arrhythmias was higher (HR, 9.620; 95% CI, 2.183–42.394; P = 0.003) in the Ala/Ala patients, compared with Ser/Ser homozygous patients. On multivariable Cox regression analysis, the Ser96Ala polymorphism was the only significant genetic arrythmogenesis predictor in DCM patients (HR, 4.191; 95% CI, 0.838–20.967; P = 0.018). Conclusion The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM.

Aims The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events.\ud Methods and results We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for

This editorial refers to ‘Heart failure in young adults: 20-year trends in hospitalizations, aetiology, and case fatality in Sweden’, by A. Barasa et al. doi:10.1093/eurheartj/eht278 In recent years the numbers of observational reports in the medical field have exploded. Several reasons might explain such a huge increase in observational clinical research. First, the increasing expectations of people regarding their national health systems associated with their exponential cost and, consequently, the need to know how the declining resources are used. Secondly, understanding the current epidemiology of diseases and therapies to make reasonable estimates of the needs for care and expenditure in the future. Thirdly, to allow physicians and scientists to learn more about the incidence and course of diseases by observing ‘clinical practice’ What is ‘clinical practice’? Clarifying this is important in order to interpret the observational findings correctly. As elegantly reported by Gabbay et al., 1 the majority of clinicians rarely access and use explicit evidence from research or other sources directly. They instead rely on ‘mindlines’ generated by a number of sources of varying degrees of reliabitiy, collectively reinforced, resulting in individual ‘internalized, tacit, guidelines’. These can be far removed from the official recommendations; however, they guide the physician in his clinical practice. A similar process also of course applies to the patient; mixing information obtained from different sources leads to individual beliefs guiding patient behaviour (i.e. acceptance of treatment and adherence both to prescribed medications and an appropriate lifestyle over time). All this results in so-called ‘clinical practice’, which is the object of observational medical research. On the therapeutic front, clinical practice lies in both physician prescriptions (adherence to guideline recommendations) and patient …

Background We developed and validated a heart failure (HF) risk score combining daily measurements of multiple device-derived parameters. Methods Heart failure patients from clinical studies with implantable devices were used to form two separate data sets. Daily HF scores were estimated by combining changes in intra-thoracic impedance, atrial fibrillation (AF) burden, rapid rate during AF, %CRT pacing, ventricular tachycardia, night heart rate, heart rate variability, and activity using a Bayesian model. Simulated monthly follow-ups consisted of looking back at the maximum daily HF risk score in the preceding 30 days, categorizing the evaluation as high, medium, or low risk, and evaluating the occurrence of HF hospitalizations in the next 30 days. We used an Anderson–Gill model to compare survival free from HF events in the next 30 days based on risk groups. Results The development data set consisted of 921 patients with 9790 patient-months of data and 91 months with HF hospitalizations. The validation data set consisted of 1310 patients with 10 655 patient-months of data and 163 months with HF hospitalizations. In the validation data set, 10% of monthly evaluations in 34% of the patients were in the high-risk group. Monthly diagnostic evaluations in the high-risk group were 10 times (adjusted HR: 10.0; 95% CI: 6.4–15.7, P < 0.001) more likely to have an HF hospitalization (event rate of 6.8%) in the next 30 days compared with monthly evaluations in the low-risk group (event rate of 0.6%). Conclusion An HF score based on implantable device diagnostics can identify increased risk for HF hospitalization in the next 30 days.

Aims:\ud The incidence and predictors of stroke in patients with heart failure and preserved ejection fraction (HF-PEF), but without atrial fibrillation (AF), are unknown. We described the incidence of stroke in HF-PEF patients with and without AF and predictors of stroke in those without AF.\ud Methods and results:\ud We pooled data from the CHARM-Preserved and I-Preserve trials. Using Cox regression, we derived a model for stroke in patients without AF in this cohort and compared its performance with a published model in heart failure patients with reduced ejection fraction (HF-REF)—predictive variables: age, body mass index, New York Heart Association class, history of stroke, and insulin-treated diabetes. The two stroke models were compared and Kaplan–Meier curves for stroke estimated. The risk model was validated in a third HF-PEF trial. Of the 6701 patients, 4676 did not have AF. Stroke occurred in 124 (6.1%) with AF and in 171 (3.7%) without AF (rates 1.80 and 1.00 per 100 patient-years, respectively). There was no difference in performance of the stroke model derived in the HF-PEF cohort and the published HF-REF model (c-index 0.71, 95% confidence interval 0.57–0.84 vs. 0.73, 0.59–0.85, respectively) as the predictive variables overlapped. The model performed well in the validation cohort (0.86, 0.62–0.99). The rate of stroke in patients in the upper third of risk approximated to that in patients with AF (1.60 and 1.80 per 100 patient-years, respectively).\ud Conclusions:\ud A small number of clinical variables identify a subset of patients with HF-PEF, but without AF, at elevated risk of stroke.

Aims Threshold crossings of impedance trends detected by implanted devices have been associated with clinically relevant heart failure events, but long-term prognosis of such events has not been demonstrated. The aim of this study is to examine the relationship between alterations in intrathoracic impedance and mortality risk in patients with implantable devices. Methods and results We reviewed remote monitoring data in the de-identified Medtronic CareLink® Discovery Link that captured intrathoracic impedance trends for >6 months. The initial 6 months of the cardiac and impedance trends were used as the observation period to create the patient groups and cross-referenced with the Social Security Death Index for mortality data. In our study cohort of 21 217 patients, 36% experienced impedance threshold crossing within the initial 6 months of monitoring (defined as the ‘early threshold crossing’ group). Patients with early threshold crossings demonstrated an increased risk of age- and gender-adjusted all-cause mortality [hazard ratio (HR) 2.15, 95% confidence interval (CI) 1.95–2.38, P < 0.0001]. Increased mortality risk remained significant when analysed in subgroups of patients without defibrillator shock (HR 2.10, 95% CI 1.90–2.34, P < 0.0001, n = 1621) or within those patients without device-detectable atrial fibrillation (AF) during the initial 6 months of monitoring (HR 2.09, 95% CI 1.86–2.34, P < 0.0001, n = 17 235). Both the number and the duration of early threshold crossings of impedance trends detectable by implanted devices were associated with increased mortality risk. Furthermore, the improvement of altered impedance trends portends more favourable prognosis. Conclusions Threshold crossing of impedance trends detectable by implanted devices is associated with relatively increased mortality risk even after adjusted for demographic, device-detected AF, or defibrillator shocks.

Aims Person-centred care (PCC) emphasizes a partnership in care between patients and healthcare professionals and is advocated by WHO as a key component of quality health care. We evaluated outcomes of PCC in hospitalized patients with chronic heart failure (CHF) with respect to the length of hospital stay (LOS), activities of daily living (ADL), health-related quality of life (HRQL) and 6-month readmission rate. Methods and results During 2008–2010, 248 consecutive patients hospitalized for symptoms of worsening CHF were enrolled in a controlled before and after designed study. A Usual care group (n= 123) was recruited according to pre-defined criteria to map usual CHF care and assess outcomes at five designated hospital wards. Based on the mapping, a panel of in-house clinicians and researchers developed measures aimed at aligning usual care with basic PCC principles. These measures were incorporated into a study protocol to guide care procedures at the same five wards. Person-centred care was then implemented at these wards and evaluated in 125 patients. Both length of hospital stay and 6-month readmission were extracted from patient records. Activities of daily living were evaluated at baseline and discharge and HRQL was evaluated at baseline and after 3 months. In the analysis of all patients, the LOS was reduced by 1 day (P= 0.16) while retaining ADL (P= 0.07). When PCC was fully implemented (per protocol analysis), LOS was reduced by 2.5 days (P= 0.01) and the ADL-level better preserved (P= 0.04). Health-related quality of life and time-to-first readmission did not differ. Conclusion In this proof-of-concept study, our findings suggest that a fully implemented PCC approach shortens hospital stay and maintains functional performance in patients hospitalized for worsening CHF, without increasing risk for readmission or jeopardizing patients' HRQL.

AIMS: Cardiotrophin-1 (CT-1) is a cytokine that induces hypertrophy in cardiomyocytes and is associated with left ventricular hypertrophy (LVH) in hypertensive patients. The objective of this study was to evaluate whether plasma CT-1 is associated with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: The study was performed in 124 patients with HCM. All patients underwent a full clinical evaluation and an echocardiogram. Left ventricular hypertrophy was evaluated by the measurement of the maximal LV wall thickness and the Spirito's LVH score. Plasma CT-1 was measured by an enzyme-linked immunosorbent assay. Compared with controls, patients with HCM exhibited higher (P < 0.001) plasma CT-1 levels. Significant correlations were found between CT-1 and maximal LV wall thickness (r = 0.284, P = 0.001) and the Spirito's LVH score (r = 0.287, P = 0.006) in HCM patients. In addition, the levels of CT-1 were higher (P = 0.02) in patients with severe LVH (maximal LV wall thickness ≥30 mm) than in patients with mild or moderate LVH (maximal LV wall thickness

Aims Hypertrophic cardiomyopathy (HCM) is an important cause of heart failure-related disability over a wide range of ages. Profiles of severe progressive heart failure symptoms and death, or heart transplantation deserve more complete definition within large patient cohorts. Methods and results Clinical and morphological features of heart failure were assessed in 293 consecutive HCM patients over a median follow-up of 6 (inter-quartile range 2–11) years. Gross and histopathological features were analysed in 12 patients for whom the heart was available for inspection. Of the 293 patients, 50 (17%) developed severe progressive heart failure, including 18 who died or were transplanted. Three profiles of heart failure were identified predominantly associated with: (i) end-stage systolic dysfunction (ejection fraction

Aims The aim of this study was to determine whether growth differentiation factor-15 (GDF-15) predicts mortality and morbidity after cardiac resynchronization therapy (CRT). Growth differentiation factor-15, a transforming growth factor-β-related cytokine which is up-regulated in cardiomyocytes via multiple stress pathways, predicts mortality in patients with heart failure treated pharmacologically. Methods and results Growth differentiation factor-15 was measured before and 360 days (median) after implantation in 158 patients with heart failure [age 68 ± 11 years (mean ± SD), left ventricular ejection fraction (LVEF) 23.1 ± 9.8%, New York Class Association (NYHA) class III ( n = 117) or IV ( n = 41), and QRS 153.9 ± 28.2 ms] undergoing CRT and followed up for a maximum of 5.4 years for events. In a stepwise Cox proportional hazards model with bootstrapping, adopting log GDF-15, log NT pro-BNP, LVEF, and NYHA class as independent variables, only log GDF-15 [hazard ratio (HR), 3.76; P = 0.0049] and log NT pro-BNP (HR, 2.12; P = 0.0171) remained in the final model. In the latter, the bias-corrected slope was 0.85, the optimism ( O ) was −0.06, and the c -statistic was 0.74, indicating excellent internal validity. In univariate analyses, log GDF-15 [HR, 5.31; 95% confidence interval (CI), 2.31–11.9; likelihood ratio (LR) χ 2 = 14.6; P < 0.0001], NT pro-BNP (HR, 2.79; 95% CI, 1.55–5.26; LR χ 2 = 10.4; P = 0.0004), and the combination of both biomarkers (HR, 7.03; 95% CI, 2.91–17.5; LR χ 2 = 19.1; P < 0.0001) emerged as significant predictors. The biomarker combination was associated with the highest LR χ 2 for all endpoints. Conclusion Pre-implant GDF-15 is a strong predictor of mortality and morbidity after CRT, independent of NT pro-BNP. The predictive value of these analytes is enhanced by combined measurement.

Aims To investigate the effects of cardiac resynchronization therapy (CRT) on survival in heart failure (HF) patients with permanent atrial fibrillation (AF) and the role of atrio-ventricular junction (AVJ) ablation in these patients. Methods and results Data from 1285 consecutive patients implanted with CRT devices are presented: 1042 patients were in sinus rhythm (SR) and 243 (19%) in AF. Rate control in AF was achieved by either ablating the AVJ in 118 patients (AVJ-abl) or prescribing negative chronotropic drugs (AF-Drugs). Compared with SR, patients with AF were significantly older, more likely to be non-ischaemic, with higher ejection fraction, shorter QRS duration, and less often received ICD back-up. During a median follow-up of 34 months, 170/1042 patients in SR and 39/243 in AF died (mortality: 8.4 and 8.9 per 100 person-year, respectively). Adjusted hazard ratios were similar for all-cause and cardiac mortality [0.9 (0.57–1.42), P = 0.64 and 1.00 (0.60–1.66) P = 0.99, respectively]. Among AF patients, only 11/118 AVJ-abl patients died vs. 28/125 AF-Drugs patients (mortality: 4.3 and 15.2 per 100 person-year, respectively, P < 0.001). Adjusted hazard ratios of AVJ-abl vs. AF-Drugs was 0.26 [95% confidence interval (CI) 0.09–0.73, P = 0.010] for all-cause mortality, 0.31 (95% CI 0.10–0.99, P = 0.048) for cardiac mortality, and 0.15 (95% CI 0.03–0.70, P = 0.016) for HF mortality. Conclusion Patients with HF and AF treated with CRT have similar mortality compared with patients in SR. In AF, AVJ ablation in addition to CRT significantly improves overall survival compared with CRT alone, primarily by reducing HF death.