Journal: Eur J Heart Fail

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Abstract

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC.

Frantz S, Falcao-Pires I, Balligand JL, Bauersachs J, ... Varricchi G, Heymans S
Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.

Eur J Heart Fail: 14 Jan 2018; epub ahead of print
Frantz S, Falcao-Pires I, Balligand JL, Bauersachs J, ... Varricchi G, Heymans S
Eur J Heart Fail: 14 Jan 2018; epub ahead of print | PMID: 29333691
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Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy.

Díez J
Natriuretic peptides (NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure (CHF), countering renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial (ANP) or brain (BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system (NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter-regulatory hormones of the RAAS and SNS, and endothelin-1 become over-activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF.

Eur J Heart Fail: 20 Oct 2016; epub ahead of print
Díez J
Eur J Heart Fail: 20 Oct 2016; epub ahead of print | PMID: 27766748
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Heart and brain interaction in patients with heart failure: overview and proposal for a taxonomy. A position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association.

Doehner W, Ural D, Haeusler KG, Čelutkienė J, ... Coats AJS, Ruschitzka F
Heart failure (HF) is a complex clinical syndrome with multiple interactions between the failing myocardium and cerebral (dys-)functions. Bi-directional feedback interactions between the heart and the brain are inherent in the pathophysiology of HF: (i) the impaired cardiac function affects cerebral structure and functional capacity, and (ii) neuronal signals impact on the cardiovascular continuum. These interactions contribute to the symptomatic presentation of HF patients and affect many co-morbidities of HF. Moreover, neuro-cardiac feedback signals significantly promote aggravation and further progression of HF and are causal in the poor prognosis of HF. The diversity and complexity of heart and brain interactions make it difficult to develop a comprehensive overview. In this paper a systematic approach is proposed to develop a comprehensive atlas of related conditions, signals and disease mechanisms of the interactions between the heart and the brain in HF. The proposed taxonomy is based on pathophysiological principles. Impaired perfusion of the brain may represent one major category, with acute (cardio-embolic) or chronic (haemodynamic failure) low perfusion being sub-categories with mostly different consequences (i.e. ischaemic stroke or cognitive impairment, respectively). Further categories include impairment of higher cortical function (mood, cognition), of brain stem function (sympathetic over-activation, neuro-cardiac reflexes). Treatment-related interactions could be categorized as medical, interventional and device-related interactions. Also interactions due to specific diseases are categorized. A methodical approach to categorize the interdependency of heart and brain may help to integrate individual research areas into an overall picture.

Eur J Heart Fail: 26 Dec 2017; epub ahead of print
Doehner W, Ural D, Haeusler KG, Čelutkienė J, ... Coats AJS, Ruschitzka F
Eur J Heart Fail: 26 Dec 2017; epub ahead of print | PMID: 29280256
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Abstract

Relevance of cardiac parvovirus B19 in myocarditis and dilated cardiomyopathy: review of the literature.

Verdonschot J, Hazebroek M, Merken J, Debing Y, ... Brunner-La Rocca HP, Heymans S
Over the last decade, parvovirus B19 (B19V) has frequently been linked to the pathogenesis of myocarditis (MC) and its progression towards dilated cardiomyopathy (DCM). The exact role of the presence of B19V and its load remains controversial, as this virus is also found in the heart of healthy subjects. Moreover, the prognostic relevance of B19V prevalence in endomyocardial biopsies still remains unclear. As a result, it is unclear whether the presence of B19V should be treated. This review provides an overview of recent literature investigating the presence of B19V and its pathophysiological relevance in MC and DCM, as well as in normal hearts. In brief, no difference in B19V prevalence is observed between MC/DCM and healthy control hearts. Therefore, the question remains open whether and how cardiac B19V may be of pathogenetic importance. Findings suggest that B19V is aetiologically relevant either in the presence of other cardiotropic viruses, or when B19V load is high and/or actively replicating, which both may maintain myocardial (low-grade) inflammation. Therefore, future studies should focus on the prognostic relevance of the viral load, replicative status and virus co-infections. In addition, the immunogenetic background of MC/DCM patients that makes them susceptible to develop heart failure upon presence of B19V should be more thoroughly investigated.

Eur J Heart Fail: 16 Oct 2016; epub ahead of print
Verdonschot J, Hazebroek M, Merken J, Debing Y, ... Brunner-La Rocca HP, Heymans S
Eur J Heart Fail: 16 Oct 2016; epub ahead of print | PMID: 27748022
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Abstract

Determinants and prognostic implications of the negative diastolic pulmonary pressure gradient in patients with pulmonary hypertension due to left heart disease.

Nagy AI, Venkateshvaran A, Merkely B, Lund LH, Manouras A
The diastolic pulmonary pressure gradient (DPG) has recently been introduced as a specific marker of combined pre-capillary pulmonary hypertension (Cpc-PH) in left heart disease (LHD). However, its diagnostic and prognostic superiority compared with traditional haemodynamic indices has been challenged lately. Current recommendations explicitly denote that in the normal heart, DPG values are greater than zero, with DPG ≥7 mmHg indicating Cpc-PH. However, clinicians are perplexed by the frequent observation of DPG <0 mmHg (DPGNEG ), as its physiological explanation and clinical impact are unclear to date. We hypothesized that large V-waves in the pulmonary artery wedge pressure (PAWP) curve yielding asymmetric pressure transmission might account for DPGNEG and undertook this study to clarify the physiological and prognostic implications of DPGNEG .

Eur J Heart Fail: 16 Oct 2016; epub ahead of print
Nagy AI, Venkateshvaran A, Merkely B, Lund LH, Manouras A
Eur J Heart Fail: 16 Oct 2016; epub ahead of print | PMID: 27748008
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Abstract

Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes.

Fitchett DH, Udell JA, Inzucchi SE
Diabetes is a major risk factor for heart failure (HF). Patients with diabetes have a high incidence of both clinical HF and subclinical LV dysfunction. Although intensive glucose lowering does not appear to impact on HF outcomes, the choice of glucose-lowering agents plays an important role in the development of HF and related cardiovascular outcomes. Whilst metformin and insulin appear to have little impact on HF progression, the role of sulphonylurea agents in this patient population remains uncertain. Thiazolidinediones (TZDs) are associated with a significant risk of HF progression and are best avoided in patients at risk. The incretin-based therapies (GLP agonists and DPP-4 inhibitors) are generally not associated with any HF interaction. However, a small increase in HF admissions was observed with the DPP-4 inhibitor saxagliptin. The GLP-1 agonist liraglutide was recently shown to reduce cardiovascular and all-cause mortality, yet hospitalization for HF was not significantly reduced. The SGLT2 inhibitor empagliflozin was shown to reduce HF admissions and cardiovascular mortality in patients with prior cardiovascular disease including HF. These recent data showing improved outcomes with a glucose-lowering category provide a novel strategy to improve survival and reduce morbidity in diabetic patients at high cardiovascular disease risk.

Eur J Heart Fail: 21 Sep 2016; epub ahead of print
Fitchett DH, Udell JA, Inzucchi SE
Eur J Heart Fail: 21 Sep 2016; epub ahead of print | PMID: 27653447
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Abstract

Direct cellular reprogramming for cardiac repair and regeneration.

Batty JA, Lima JA, Kunadian V
Heart failure is a major cause of morbidity and mortality, characterized by depletion of functioning cardiomyocytes, myocardial remodelling, and impaired contractile function. As the heart has a limited capacity for repair, and current treatments do not reverse myocardial attrition, novel regenerative strategies are imperative. Although cell delivery-based approaches remain promising, in situ reprogramming of endogenous cardiac fibroblasts (which are pathophysiologically implicated in cardiac remodelling) into functional cardiomyocytes may represent an advantageous approach. Several groups report successful in vitro and in vivo reprogramming of murine fibroblasts, using critical transcription factors, microRNA mimics, and small molecules, to cells demonstrating cardiomyocyte-like morphology, gene expression, and spontaneous contraction, which improve cardiac function in post-infarct models. Although proof-of-concept studies demonstrate reprogramming in human fibroblasts, significant barriers to therapeutic reprogramming remain. In this review, we evaluate the current status of reprogramming strategies for cardiac repair, and explore future perspectives within the context of clinical translation.

Eur J Heart Fail: 03 Dec 2015; epub ahead of print
Batty JA, Lima JA, Kunadian V
Eur J Heart Fail: 03 Dec 2015; epub ahead of print | PMID: 26635186
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Abstract

Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease.

Bramlage P, Swift S, Thoenes M, Minguet J, Ferrero C, Schmieder RE
Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next-generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease.

Eur J Heart Fail: 03 Dec 2015; epub ahead of print
Bramlage P, Swift S, Thoenes M, Minguet J, Ferrero C, Schmieder RE
Eur J Heart Fail: 03 Dec 2015; epub ahead of print | PMID: 26634965
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Abstract

Impact of diabetes mellitus on outcomes in patients with acute myocardial infarction and systolic heart failure.

Deedwania PC, Ahmed MI, Feller MA, Aban IB, ... Pitt B, Ahmed A
Aims: To determine independent associations of diabetes mellitus with outcomes in a propensity-matched cohort of patients with acute myocardial infarction (AMI) and systolic heart failure (HF). Methods and results: In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial, hospitalized AMI patients complicated by left ventricular ejection fraction ≤40% and symptoms of HF receiving standard therapy were randomized 3-14 days post-AMI to receive eplerenone 25-50 mg/day (n = 3319) or placebo (n = 3313). Of the 6632 patients, 2142 (32%) had a history of diabetes, who were older and sicker. Using propensity scores for diabetes, we assembled a cohort of 1119 pairs of patients with and without diabetes who were balanced on 64 baseline characteristics. Incident fatal or nonfatal recurrent AMI occurred in 136 (12%) and 87 (8%) of matched patients with and without diabetes, respectively, during 2.5 years of follow-up [hazard ratio (HR) when diabetes was compared with no-diabetes, 1.61; 95% confidence interval (CI), 1.23-2.10; P = 0.001]. Diabetes was associated with nonfatal AMI (HR, 1.68; 95% CI, 1.23-2.31; P = 0.001) but not with fatal AMI (HR, 1.42; 95% CI, 0.88-2.28; P = 0.146). Hazard ratios (95% CIs) for the association of diabetes with all-cause mortality, cardiovascular mortality, all-cause hospitalization, and cardiovascular hospitalization were 1.12 (0.93-1.37; P = 0.224), 1.11 (0.90-1.37; P = 0.318), 1.13 (1.00-1.27; P = 0.054), and 1.20 (1.01-1.44; P = 0.042), respectively. Conclusion: In post-AMI patients with systolic HF, diabetes mellitus is a significant independent risk factor for recurrent short-term nonfatal AMI, but had no association with fatal AMI.

Eur J Heart Fail: 11 Mar 2011; epub ahead of print
Deedwania PC, Ahmed MI, Feller MA, Aban IB, ... Pitt B, Ahmed A
Eur J Heart Fail: 11 Mar 2011; epub ahead of print | PMID: 21393298
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Abstract

Early drop in systolic blood pressure and worsening renal function in acute heart failure: renal results of Pre-RELAX-AHF.

Voors AA, Davison BA, Felker GM, Ponikowski P, ... Metra M, on behalf of the Pre-RELAX-AHF study group
Aims: We aimed to determine the relation between baseline systolic blood pressure (SBP), change in SBP, and worsening renal function (WRF) in acute heart failure (AHF) patients enrolled in the Pre-RELAX-AHF trial. Methods and results: The Pre-RELAX-AHF study enrolled 234 patients within 16 h of admission (median 7 h) for AHF and randomized them to relaxin given intravenous (i.v.) for 48 h or placebo. Blood pressure was measured at baseline, at 3, 6, 9, 12, 24, 36, and 48 h and at 3, 4, and 5 days after enrolment. Worsening renal function was defined as a serum creatinine increase of ≥0.3 mg/dL by Day 5. Worsening renal function was found in 68 of the 225 evaluable patients (30%). Patients with WRF were older (73.5 ± 9.4 vs. 69.1 ± 10.6 years; P= 0.003), had a higher baseline SBP (147.3 ± 19.9 vs. 140.8 ± 16.7 mmHg; P= 0.01), and had a greater early drop in SBP (37.9 ± 16.0 vs. 31.4 ± 12.2 mmHg; P= 0.004). In a multivariable model, higher age, higher baseline creatinine, and a greater early drop in SBP, but not baseline SBP, remained independent predictors of WRF. Furthermore, WRF was associated with a higher Day 60 (P= 0.01), and Day 180 (P= 0.003) mortality. Conclusions: Worsening renal function in hospitalized AHF patients is related to a poor clinical outcome and is predicted by a greater early drop in SBP. Trial registration clinicaltrials.gov identifier NCT00520806.

Eur J Heart Fail: 30 May 2011; epub ahead of print
Voors AA, Davison BA, Felker GM, Ponikowski P, ... Metra M, on behalf of the Pre-RELAX-AHF study group
Eur J Heart Fail: 30 May 2011; epub ahead of print | PMID: 21622980
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Abstract

Predicting heart failure decompensation using cardiac implantable electronic devices: a review of practices and challenges.

Hawkins NM, Virani SA, Sperrin M, Buchan IE, McMurray JJ, Krahn AD
Cardiac implantable electronic devices include remote monitoring tools intended to guide heart failure management. The monitoring focus has been on averting hospitalizations by predicting worsening heart failure. However, although device measurements including intrathoracic impedance correlate with risk of decompensation, they individually predict hospitalizations with limited accuracy. Current \'crisis detection\' methods involve repeatedly screening for impending decompensation, and do not adhere to the principles of diagnostic testing. Complex substrate, limited test performance, low outcome incidence, and long test to outcome times inevitably generate low positive and high negative predictive values. When combined with spectrum bias, the generalizability, incremental value, and cost-effectiveness of device algorithms are questionable. To avoid these pitfalls, remote monitoring may need to shift from crisis detection to health maintenance, keeping the patient within an ideal physiological range through continuous \'closed loop\' interaction and dynamic therapy adjustment. Test performance must also improve, possibly through combination with physiological sensors in different dimensions, static baseline characteristics, and biomarkers. Complex modelling may tailor monitoring to individual phenotypes, and thus realize a personalized medicine approach. Future randomized controlled trials should carefully consider these issues, and ensure that the interventions tested are generalizable to clinical practice.

Eur J Heart Fail: 13 Dec 2015; epub ahead of print
Hawkins NM, Virani SA, Sperrin M, Buchan IE, McMurray JJ, Krahn AD
Eur J Heart Fail: 13 Dec 2015; epub ahead of print | PMID: 26663507
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Abstract

Current state of knowledge on Takotsubo syndrome: a Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology.

Lyon AR, Bossone E, Schneider B, Sechtem U, ... Mebazaa A, Omerovic E
Takotsubo syndrome is an acute reversible heart failure syndrome that is increasingly recognized in modern cardiology practice. This Position Statement from the European Society of Cardiology Heart Failure Association provides a comprehensive review of the various clinical and pathophysiological facets of Takotsubo syndrome, including nomenclature, definition, and diagnosis, primary and secondary clinical subtypes, anatomical variants, triggers, epidemiology, pathophysiology, clinical presentation, complications, prognosis, clinical investigations, and treatment approaches. Novel structured approaches to diagnosis, risk stratification, and management are presented, with new algorithms to aid decision-making by practising clinicians. These also cover more complex areas (e.g. uncertain diagnosis and delayed presentation) and the management of complex cases with ongoing symptoms after recovery, recurrent episodes, or spontaneous presentation. The unmet needs and future directions for research in this syndrome are also discussed.

Eur J Heart Fail: 08 Nov 2015; epub ahead of print
Lyon AR, Bossone E, Schneider B, Sechtem U, ... Mebazaa A, Omerovic E
Eur J Heart Fail: 08 Nov 2015; epub ahead of print | PMID: 26548803
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Time-trends in treatment and cardiovascular events in patients with heart failure: a pharmacosurveillance study.

de Peuter OR, Lip GY, Souverein PC, Klungel OH, ... Büller HR, Kamphuisen PW
Aims: We assessed, in patients with a first hospitalization for heart failure (HF), the temporal relationship of the incidence of cardiovascular events, all-cause mortality, and cardiovascular drug treatment. Methods and results: Data were obtained from the PHARMO Record Linkage System, a population-based registry of pharmacy records linked with hospital discharge records in The Netherlands. Patients were selected based on a first hospital discharge diagnosis of documented HF. Two time-periods were compared: 1998-2002 and 2003-07. In each time-period, we analysed all prescribed cardiovascular medications, all-cause mortality, and cardiovascular events (rehospitalization for HF and ischaemic events) within the first year after hospitalization, and the occurrence of ischaemic events separately (myocardial infarction and ischaemic stroke). Cox-regression analysis was performed to calculate hazard ratios (HR) with 95% confidence intervals (CI). We identified 8276 patients in 1998-2002 and 9548 patients from 2003-07. There was an increase in almost all cardiovascular medication prescriptions in the second period: in particular, beta-blocker prescriptions rose from 36% in 1998-2002 to 55% in 2003-07. In the first year after hospitalization, there was no difference in all-cause mortality or any cardiovascular event (HR 1.00, 95%CI: 0.95-1.05), as a composite endpoint or when analysed separately. The incidence of ischaemic events decreased from 2.7 to 1.9% in the first and second time-period, respectively (HR 0.74, 95%CI: 0.61-0.90). Conclusion: Prescription of cardiovascular medications in patients with a first hospitalization for HF has increased in recent years, particularly for beta-blockers, and the incidence of ischaemic events may have decreased. There was no decrease in all-cause mortality or cardiovascular events.

Eur J Heart Fail: 03 Jan 2011; epub ahead of print
de Peuter OR, Lip GY, Souverein PC, Klungel OH, ... Büller HR, Kamphuisen PW
Eur J Heart Fail: 03 Jan 2011; epub ahead of print | PMID: 21193438
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Fluid status monitoring with a wireless network to reduce cardiovascular-related hospitalizations and mortality in heart failure: rationale and design of the OptiLink HF Study (Optimization of Heart Failure Management using OptiVol Fluid Status Monitoring and CareLink).

Brachmann J, Böhm M, Rybak K, Klein G, ... Drexler H, on behalf of the OptiLink HF Study Executive Board and Investigators
Aims: The Optimization of Heart Failure Management using OptiVol Fluid Status Monitoring and CareLink (OptiLink HF) study is designed to investigate whether OptiVol fluid status monitoring with an automatically generated wireless CareAlert notification via the CareLink Network can reduce all-cause death and cardiovascular hospitalizations in an HF population, compared with standard clinical assessment. Methods Patients with newly implanted or replacement cardioverter-defibrillator devices with or without cardiac resynchronization therapy, who have chronic HF in New York Heart Association class II or III and a left ventricular ejection fraction ≤35% will be eligible to participate. Following device implantation, patients are randomized to either OptiVol fluid status monitoring through CareAlert notification or regular care (OptiLink \'on\' vs. \'off\'). The primary endpoint is a composite of all-cause death or cardiovascular hospitalization. It is estimated that 1000 patients will be required to demonstrate superiority of the intervention group to reduce the primary outcome by 30% with 80% power. Conclusion: The OptiLink HF study is designed to investigate whether early detection of congestion reduces mortality and cardiovascular hospitalization in patients with chronic HF. The study is expected to close recruitment in September 2012 and to report first results in May 2014. ClinicalTrials.gov Identifier: NCT00769457.

Eur J Heart Fail: 10 May 2011; epub ahead of print
Brachmann J, Böhm M, Rybak K, Klein G, ... Drexler H, on behalf of the OptiLink HF Study Executive Board and Investigators
Eur J Heart Fail: 10 May 2011; epub ahead of print | PMID: 21555324
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Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology.

Harjola VP, Mebazaa A, Čelutkienė J, Bettex D, ... Yilmaz MB, Konstantinides S
Acute right ventricular (RV) failure is a complex clinical syndrome that results from many causes. Research efforts have disproportionately focused on the failing left ventricle, but recently the need has been recognized to achieve a more comprehensive understanding of RV anatomy, physiology, and pathophysiology, and of management approaches. Right ventricular mechanics and function are altered in the setting of either pressure overload or volume overload. Failure may also result from a primary reduction of myocardial contractility owing to ischaemia, cardiomyopathy, or arrhythmia. Dysfunction leads to impaired RV filling and increased right atrial pressures. As dysfunction progresses to overt RV failure, the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion. Ventricular interdependence results in impaired left ventricular filling, a decrease in left ventricular stroke volume, and ultimately low cardiac output and cardiogenic shock. Identification and treatment of the underlying cause of RV failure, such as acute pulmonary embolism, acute respiratory distress syndrome, acute decompensation of chronic pulmonary hypertension, RV infarction, or arrhythmia, is the primary management strategy. Judicious fluid management, use of inotropes and vasopressors, assist devices, and a strategy focusing on RV protection for mechanical ventilation if required all play a role in the clinical care of these patients. Future research should aim to address the remaining areas of uncertainty which result from the complexity of RV haemodynamics and lack of conclusive evidence regarding RV-specific treatment approaches.

Eur J Heart Fail: 20 Mar 2016; 18:226-41
Harjola VP, Mebazaa A, Čelutkienė J, Bettex D, ... Yilmaz MB, Konstantinides S
Eur J Heart Fail: 20 Mar 2016; 18:226-41 | PMID: 26995592
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The WHICH? trial: rationale and design of a pragmatic randomized, multicentre comparison of home- vs. clinic-based management of chronic heart failure patients.

Stewart S, Carrington MJ, Marwick T, Davidson PM, ... Scuffham PA, On behalf of the Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial Investigators
Aims: To describe the rationale and design of the Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial. Methods WHICH? is a pragmatic, multicentre, randomized controlled trial that seeks to determine if multidisciplinary management of chronic heart failure (CHF) patients post-acute hospitalization delivered in a patient\'s own home is superior to care delivered via a specialist CHF outpatient clinic. The composite primary endpoint is all-cause, unplanned recurrent hospitalization or death during 12-18 months of follow-up. Of 688 eligible patients, 280 patients (73% male and 66% principal diagnosis of CHF) with a mean age of 71 ± 14 years have been randomized to home- (n = 143) or clinic-based (n = 137) post-discharge management. This will provide 80% power (two-sided alpha of 0.05) to detect a 15% absolute difference in both the primary end-point and rate of all-cause hospital stay. Preliminary data suggest that the two groups are well matched in nearly all baseline socio-economic and clinical parameters. The majority of patients have significant co-morbidity, including hypertension (63%), coronary artery disease (55%), and atrial fibrillation (53%) with an accordingly high Charlson Index of Comorbidity Score (6.1 ± 2.4). Perspective Despite its relatively small size, the WHICH? trial is well placed to examine the relative impact of two of the most commonly applied forms of face-to-face management designed to reduce recurrent hospitalization and prolong survival in CHF patients.

Eur J Heart Fail: 27 May 2011; epub ahead of print
Stewart S, Carrington MJ, Marwick T, Davidson PM, ... Scuffham PA, On behalf of the Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial Investigators
Eur J Heart Fail: 27 May 2011; epub ahead of print | PMID: 21616952
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Abstract

Complementary role of copeptin and high-sensitivity troponin in predicting outcome in patients with stable chronic heart failure.

Tentzeris I, Jarai R, Farhan S, Perkmann T, ... Wojta J, Huber K
Aims: Copeptin, the C-terminal part of the vasopressin pro-hormone, is elevated after myocardial infarction and predicts adverse outcome. In the present study we investigated whether the complementary role of copeptin and cardiac troponin T (cTnT) could be used for identification of high-risk patients with chronic stable heart failure. Methods and results: We measured copeptin and high-sensitivity cTnT (hs-cTnT) levels in 172 consecutive patients with stable chronic heart failure. Patients were followed for all-cause mortality and hospitalization due to heart failure for a median of 1301 days (interquartile range: 707-1636). In univariate analysis, plasma copeptin showed a moderate but significant correlation with hs-cTnT (r= 0.40 P< 0.001), age (r= 0.36 P< 0.001), creatinine (r= 0.52 P< 0.001), and amino-terminal pro-B type natriuretic peptide (NT-proBNP; r= 0.42 P< 0.001). Both copeptin (P= 0.002) and hs-cTnT (P= 0.005) concentrations were significantly increased in patients with higher New York Heart Association classes. While 109 (58%) patients had hs-cTnT concentrations above normal (>14 pg/mL) 104 patients (55%) had copeptin concentrations above normal (16.4 pmol/L). In survival analysis, both elevated copeptin and hs-cTnT concentrations were significant predictors of outcome (P< 0.001 for both). The combination of both markers showed a graded and highly significant association with impaired clinical outcome, which was independent of plasma NT-proBNP levels (adjusted hazard ratios 1.40, 95% CI, 1.20-1.70; P< 0.001). Adding copeptin concentrations to a prediction model with NT-proBNP and hs-cTnT resulted in significant improvement in model performance (net reclassification improvement 0.208; P< 0.05). Conclusion: Our data suggest that the combined use of hs-cTnT and copeptin might predict clinical outcome of patients with chronic stable heart failure.

Eur J Heart Fail: 27 May 2011; epub ahead of print
Tentzeris I, Jarai R, Farhan S, Perkmann T, ... Wojta J, Huber K
Eur J Heart Fail: 27 May 2011; epub ahead of print | PMID: 21616953
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Left bundle branch block and mortality in patients with acute heart failure syndrome: a substudy of the EFICA cohort.

Huvelle E, Fay R, Alla F, Solal AC, Mebazaa A, Zannad F
Aims: In patients with chronic heart failure (CHF), left bundle branch block (LBBB) is associated with an increased risk of cardiovascular mortality. We aimed to investigate the association of LBBB with short- and long-term outcome in patients discharged after a de novo episode of acute heart failure (AHF) or AHF complicating a mild CHF. Methods and results: Patients with no history of New York Heart Association class III and IV CHF, who were admitted for a severe AHF episode and enrolled in the prospective observational EFICA study (n = 403), were included. Left bundle branch block prevalence was 16%. Patients with LBBB had a higher prevalence of dilated cardiomyopathy (23 vs. 10%, P < 0.005), a higher percentage of AHF episodes without identified precipitating factor (15 vs. 2%, P < 0.001), and were less likely to present increased markers of cardiac injury (41 vs. 56%, P = 0.04). The 4-week mortality was 24.8% with no difference between LBBB and no LBBB patients. Left bundle branch block was however an independent predictor of 1-year mortality in the 4-week survivors [hazards ratio (95% confidence interval) = 2.01 (1.12-3.64), P = 0.02]. Conclusion: Long-term outcome of patients surviving a severe episode of de novo AHF or AHF complicating a mild CHF is worsened by LBBB. These patients may constitute a subgroup at high risk in whom specific therapeutic solutions should be investigated.

Eur J Heart Fail: 23 Dec 2009; epub ahead of print
Huvelle E, Fay R, Alla F, Solal AC, Mebazaa A, Zannad F
Eur J Heart Fail: 23 Dec 2009; epub ahead of print | PMID: 20028696
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Abstract

Isolated left ventricular non-compaction in adults: clinical and echocardiographic features in 105 patients. Results from a French Registry.

Habib G, Charron P, Eicher JC, Giorgi R, ... Cohen-Solal A, On behalf of the Working Groups ‘Heart Failure and Cardiomyopathies’ and ‘Echocardiography’ of the French Society of Cardiology
Aims: The clinical features, prognosis, and even definition of left ventricular non-compaction (LVNC) are still the subject of much debate. The aim of this registry was to describe the clinical, echocardiographic, and prognostic features of LVNC in France. The main endpoint was to assess clinical and echocardiographic predictors of adverse outcome, defined as death or heart transplantation. Methods and results: Between 2004 and 2006, 154 suspected cases of LNVC were identified from a nationwide survey in France. The diagnosis of LVNC was confirmed in 105 cases by echocardiographic evaluation in a core laboratory. Clinical and echocardiographic data for the 105 cases of LVNC are presented. Left ventricular non-compaction was first detected from heart failure symptoms in 45 patients, rhythm disorders in 12, and familial screening in 8. Left ventricular ejection fraction (LVEF) was <30% in 46% of patients, but ≥50% in 16%. The latter had less symptoms of severe heart failure (11 vs. 54%, P = 0.001), but similar extension of the NC zone. During 2.33 ± 1.47 years of follow-up, several complications occurred, including severe heart failure in 33 patients, transplantation in 9, ventricular arrhythmia in 7, embolic events in 9, and death in 12. Factors associated with death or heart transplantation were NYHA 3 or 4 (HR = 6.69; P = 0.0007), high LV filling pressures (HR = 7.59; P = 0.001), LVEF (HR = 0.93; P = 0.006), and hospitalization for heart failure (HR = 13.55; P < 0.0001). Conclusion: In this large reported series of LVNC, we observed that: (i) Left ventricular non-compaction was detected by familial screening in asymptomatic patients in 8% of cases. (ii) Left ventricular non-compaction was frequently over-diagnosed by echocardiography. (iii) Patients identified as LVNC presented with a high risk of severe complications, transplantation or death and needed close follow-up.

Eur J Heart Fail: 03 Jan 2011; epub ahead of print
Habib G, Charron P, Eicher JC, Giorgi R, ... Cohen-Solal A, On behalf of the Working Groups ‘Heart Failure and Cardiomyopathies’ and ‘Echocardiography’ of the French Society of Cardiology
Eur J Heart Fail: 03 Jan 2011; epub ahead of print | PMID: 21193437
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Abstract

Prognostic importance of natriuretic peptides and atrial fibrillation in patients receiving cardiac resynchronization therapy.

Smit MD, Maass AH, Hillege HL, Wiesfeld AC, Van Veldhuisen DJ, Van Gelder IC
Aims: The aim of this study was to investigate the prognostic value of natriuretic peptides and atrial fibrillation (AF) on response to cardiac resynchronization therapy (CRT) and mortality. Methods and results: This study included 338 consecutive CRT patients. Response to CRT was defined as a reduction in left ventricular end-systolic volume of ≥15% in the absence of death at 6-month follow-up. During follow-up (27 ± 19 months), 139 patients (41%) had AF, being new onset in 40 patients (21%). Forty-two patients (12%) had permanent AF. Response to CRT was observed in 168 of 302 patients (56%): 60 of 123 patients (43%) with AF vs. 108 of 179 patients (60%) without AF (P = 0.047). Low baseline atrial natriuretic peptide (ANP) [odds ratio for log(2) ANP 0.49, 95% confidence interval (CI) 0.35-0.68, P < 0.001] and large left ventricular end-systolic volume (odds ratio for every 50 mL 1.40, 95% CI 1.09-1.79, P = 0.009) were independent predictors of response. Neither the presence of AF nor the increase in AF burden independently predicted response. Ninety patients (27%) died; 50 patients (36%) with AF vs. 40 patients (20%) without AF (log rank P = 0.029). Important predictors of all-cause mortality were new-onset AF (hazard ratio 8.11, 95% CI 3.31-19.85, P < 0.001), permanent AF (hazard ratio 3.19, 95% CI 1.61-6.30, P = 0.001), and baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) (hazard ratio for log(2) NT-proBNP 0.77, 95% CI 0.66-0.90, P = 0.001). Conclusion: In patients treated with CRT, lower ANP and larger left ventricular end-systolic volume were independent predictors of response. New-onset AF, permanent AF, and NT-proBNP were independently associated with increased all-cause mortality.

Eur J Heart Fail: 18 Feb 2011; epub ahead of print
Smit MD, Maass AH, Hillege HL, Wiesfeld AC, Van Veldhuisen DJ, Van Gelder IC
Eur J Heart Fail: 18 Feb 2011; epub ahead of print | PMID: 21330294
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Abstract

Incidence and clinical relevance of uncontrolled ventricular rate during atrial fibrillation in heart failure patients treated with cardiac resynchronization therapy.

Boriani G, Gasparini M, Landolina M, Lunati M, ... Santini M, on behalf of the ClinicalService cardiac centres
Aims: Uncontrolled ventricular rate (VR) during atrial fibrillation (AF) may cause clinical deterioration in heart failure (HF) patients who need continuous biventricular pacing to achieve cardiac resynchronization therapy (CRT). We aimed at evaluating the association between AF, uncontrolled VR, and sub-optimal CRT, defined as low biventricular pacing percentage (BIVP%). Methods and results: All 1404 patients had HF, New York Heart Association (NYHA) ≥II, left ventricular ejection fraction (LVEF) ≤35%, and QRS ≥120 ms, and received an implantable CRT defibrillator (CRT-D). Occurrence of AF, VR during AF and lifetime BIVP% were estimated from device data. Ventricular rate during AF was defined as uncontrolled in patients with mean VR>80 bpm and maximum VR>110 bpm. Over a median follow-up of 18 months, AF was detected in 443 of 1404 patients (32%). In this sub-group of AF patients, VR during AF was uncontrolled in 150 of 443 patients (34%). Multivariate Cox regression analysis showed that age [hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 1.00-1.06, P= 0.028], and uncontrolled VR [HR = 1.69 (CI = 1.01-2.83), P= 0.046] were the only independent predictors of clinical outcome, assessed by HF hospitalizations and death. The median lifetime BIVP% was 95% (25-75 percentile range 91-99%). Biventricular pacing percentage was significantly and inversely correlated to VR, decreasing by 7% for each 10 bpm increase in VR. Sub-optimal CRT, defined as BIVP% <95%, was predicted by the occurrence of persistent or permanent AF [odds ratio (OR) = 3.77, CI = 2.44-5.82, P< 0.001], and uncontrolled VR [OR = 2.25, CI = 1.35-3.73, P= 0.002]. Conclusion: Uncontrolled VR occurs in one-third of CRT-D patients, who experience AF, and is associated with HF hospitalizations and death and with sub-optimal CRT (lifetime BIVP%<95%).

Eur J Heart Fail: 11 May 2011; epub ahead of print
Boriani G, Gasparini M, Landolina M, Lunati M, ... Santini M, on behalf of the ClinicalService cardiac centres
Eur J Heart Fail: 11 May 2011; epub ahead of print | PMID: 21558331
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Abstract

Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure.

Pascual-Figal DA, Manzano-Fernández S, Boronat M, Casas T, ... Valdés M, Januzzi JL
Aim To investigate the use of biomarkers providing independent information regarding physiology in acutely decompensated heart failure (ADHF) for assessment of risk. Methods and results: This was a prospective study of 107 patients hospitalized with ADHF (mean age 72 ± 13 years, 44% male, left ventricular ejection fraction 47 ± 15%). Blood samples were collected on presentation to measure soluble (s)ST2, high-sensitivity troponin T (hsTnT), and amino-terminal pro-B type natriuretic peptide (NT-proBNP) levels. Clinical follow-up was obtained for all patients over a median period of 739 days, and all-cause mortality was registered. Concentrations of sST2 [per 10 ng/mL, hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.04-1.13; P< 0.001], hsTnT (per 0.1 ng/mL, HR 1.16, 95% CI 1.09-1.24; P< 0.001), and NT-proBNP (per 100 pg/mL, HR 1.01, 95% CI 1.003-1.01; P< 0.001) were each predictive of a higher risk of death. In bootstrapped models, each biomarker retained independent predictive value for mortality. Patients with all three biomarkers below their optimal cut-off at presentation were free of death (0%) during follow-up, whereas 53% of those with elevations of all three biomarkers had died. For each elevated marker (from 0 to 3) adjusted analysis suggested a tripling of the risk of death (for each elevated marker, HR 2.64, 95% CI 1.63-4.28, P< 0.001). Integrated discrimination analyses indicated that the use of these three markers in a multimarker approach uniquely improved prediction of death. Conclusions: Biomarkers reflecting remodelling (sST2), myonecrosis (hsTnT), and myocardial stretch (NT-proBNP) provide complementary prognostic information in patients with ADHF. When used together, these novel markers provide superior risk stratification.

Eur J Heart Fail: 09 May 2011; epub ahead of print
Pascual-Figal DA, Manzano-Fernández S, Boronat M, Casas T, ... Valdés M, Januzzi JL
Eur J Heart Fail: 09 May 2011; epub ahead of print | PMID: 21551163
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Abstract

Differential prognostic effect of systolic blood pressure on mortality according to left-ventricular function in patients with acute heart failure.

Núñez J, Núñez E, Fonarow GC, Sanchis J, ... Chorro FJ, Llàcer A
Aims: To evaluate the relationship between systolic blood pressure (SBP) and long-term mortality in patients with acute heart failure (AHF) stratified by ejection fraction (LVEF): reduced (< or =40%) vs. preserved (> or =50%). Methods and results: We studied 1049 consecutive patients admitted with AHF. Systolic blood pressure was determined in the emergency department. Left-ventricular ejection fraction was categorized as < or =40% (n = 288), 41-49% (n = 174), or > or =50% (n = 587). Cox regression analysis was used for multivariable analysis. Mean age and SBP were 73 +/- 11 years and 150 +/- 36 mmHg, respectively. During a median follow-up of 18 months, 290 deaths (33.1%) were identified. Higher SBP was associated with lower mortality. In multivariable analysis, a differential effect of SBP across LVEF status was documented (P-value for interaction = 0.036). In linear models, SBP was shown to be inversely related with mortality in both groups (per 10 mmHg decrease): HR((LVEF > or = 50%)): 1.06, CI 95% = 1.01-1.11; P = 0.016, and HR((LVEF < or = 40%)): 1.16, 95% CI = 1.08-1.25; P < 0.001). When SBP was modelled with restrictive cubic splines, an inverse and almost linear relationship with mortality was shown in patients with LVEF < or =40% (P < 0.001), whereas in patients with LVEF > or =50%, SBP followed a J-shape curve. Conclusion: In patients with AHF, SBP showed a differential prognostic effect on mortality according to LVEF status; when LVEF was < or =40%, SBP was linearly and inversely associated with mortality. Conversely, in patients with LVEF > or =50% this relationship showed a J-shape pattern.

Eur J Heart Fail: 21 Dec 2009; 12:38-44
Núñez J, Núñez E, Fonarow GC, Sanchis J, ... Chorro FJ, Llàcer A
Eur J Heart Fail: 21 Dec 2009; 12:38-44 | PMID: 20023043
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Abstract

Pharmacological treatment of hypertrophic cardiomyopathy: current practice and novel perspectives.

Ammirati E, Contri R, Coppini R, Cecchi F, Frigerio M, Olivotto I
Hypertrophic cardiomyopathy (HCM) is entering a phase of intense translational research that holds promise for major advances in disease-specific pharmacological therapy. For over 50 years, however, HCM has largely remained an orphan disease, and patients are still treated with old drugs developed for other conditions. While judicious use of the available armamentarium may control the clinical manifestations of HCM in most patients, specific experience is required in challenging situations, including deciding when not to treat. The present review revisits the time-honoured therapies available for HCM, in a practical perspective reflecting real-world scenarios. Specific agents are presented with doses, titration strategies, pros and cons. Peculiar HCM dilemmas such as treatment of dynamic outflow obstruction, heart failure caused by end-stage progression and prevention of atrial fibrillation and ventricular arrhythmias are assessed. In the near future, the field of HCM drug therapy will rapidly expand, based on ongoing efforts. Approaches such as myocardial metabolic modulation, late sodium current inhibition and allosteric myosin inhibition have moved from pre-clinical to clinical research, and reflect a surge of scientific as well as economic interest by academia and industry alike. These exciting developments, and their implications for future research, are discussed.

Eur J Heart Fail: 24 Apr 2016; epub ahead of print
Ammirati E, Contri R, Coppini R, Cecchi F, Frigerio M, Olivotto I
Eur J Heart Fail: 24 Apr 2016; epub ahead of print | PMID: 27109894
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Abstract

Myocardial fibrosis in isolated left ventricular non-compaction and its relation to disease severity.

Nucifora G, Aquaro GD, Pingitore A, Masci PG, Lombardi M
Aims: The aim of the present study was to evaluate the prevalence and extent of myocardial fibrosis in patients with isolated left ventricular non-compaction (LVNC) and to determine its relation to clinical status and LV systolic function. Methods and results: The cardiac magnetic resonance imaging (MRI) database of our institution was searched for all patients with a first diagnosis of isolated LVNC. The diagnosis of isolated LVNC was based on the presence of standard cardiac MRI and clinical criteria. For each patient, cine and contrast-enhanced cardiac MR images were analysed to evaluate LV systolic function and the prevalence and extent of late gadolinium enhancement (LGE), a surrogate of myocardial fibrosis. A total of 42 patients (mean age 46 ± 20 years, 62% male) were identified. Late gadolinium enhancement was observed in 23 (55%) patients with isolated LVNC, occupying 4.8 ± 6.7% of the LV mass. Both the presence and extent of LGE were significantly related to the number of abnormal clinical features (i.e. symptomatic status, resting electrocardiogram abnormalities, and 24 h Holter monitoring abnormalities; P< 0.001 and P= 0.001, respectively). Similarly, LGE was more prevalent and extensive in patients with LV ejection fraction (EF) <50% compared with patients with LVEF ≥50% (90 vs. 23%; P< 0.001 and 8.9 ± 7.6 vs. 1.1 ± 2.4%; P< 0.001, respectively). At multivariate analysis, both the presence and extent of LV LGE were independently related to LVEF (β = -0.63; P< 0.001 and β = -0.62; P< 0.001, respectively). Conclusion: Myocardial fibrosis is related to clinical disease severity and LV systolic dysfunction in isolated LVNC.

Eur J Heart Fail: 06 Jan 2011; epub ahead of print
Nucifora G, Aquaro GD, Pingitore A, Masci PG, Lombardi M
Eur J Heart Fail: 06 Jan 2011; epub ahead of print | PMID: 21208941
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Abstract

A new mechanism preventing proarrhythmia in chronic heart failure: rapid phase-III repolarization explains the low proarrhythmic potential of amiodarone in contrast to sotalol in a model of pacing-induced heart failure.

Frommeyer G, Milberg P, Witte P, Stypmann J, ... Fehr M, Eckardt L
Aims: Life-threatening arrhythmias are a major problem in chronic heart failure (CHF). The aim of the present study was to investigate the mechanism underlying the low proarrhythmic potential of amiodarone in a model of pacing-induced heart failure. Methods and results: Heart failure was induced in 35 female rabbits by rapid ventricular pacing, resulting in a significant decrease of ejection fraction. Thirty-four rabbits were sham-operated. In 17 of 35 CHF-rabbits and 20 of 34 \'sham\'-rabbits, amiodarone (50 mg/kg/day) was fed for 6 weeks. Eight monophasic action potentials and a simultaneously recorded 12-lead electrocardiogram showed prolongation of QT-interval and action potential duration (APD(90)) in all failing hearts (P< 0.05). Amiodarone pre-treatment led to a prolongation of APD(90) (+19 ms) as compared with sham-controlled hearts but showed only a marginal effect on APD(90) in failing hearts. Infusion of sotalol (50-100 µM) led to a significant prolongation of APD(90) in sham and a further prolongation of APD(90) in failing hearts [+55 ms (50 µM); +70 ms (100 µM); P< 0.01 as compared with sham hearts]. Sotalol led to a triangular action potential configuration in sham and failing hearts, whereas amiodarone did not cause triangularization but caused a rapid phase-III repolarization. Moreover, amiodarone did not increase dispersion of repolarization either in sham or in failing hearts. Infusion of sotalol led to a significant increase in dispersion of repolarization in sham (+29 ms) and a further increase in failing hearts (+67 ms; P< 0.05). Conclusion: Chronic amiodarone results in a rapid phase-III-repolarization and does not increase dispersion of repolarization. These electrophysiological findings are present in healthy hearts and are preserved in heart failure. This contributes to the low proarrhythmic potential of amiodarone in heart failure.

Eur J Heart Fail: 29 Aug 2011; epub ahead of print
Frommeyer G, Milberg P, Witte P, Stypmann J, ... Fehr M, Eckardt L
Eur J Heart Fail: 29 Aug 2011; epub ahead of print | PMID: 21873342
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Abstract

Which components of heart failure programmes are effective? A systematic review and meta-analysis of the outcomes of structured telephone support or telemonitoring as the primary component of chronic heart failure management in 8323 patients: Abridged Cochrane Review.

Inglis SC, Clark RA, McAlister FA, Stewart S, Cleland JG
Aims: Telemonitoring (TM) and structured telephone support (STS) have the potential to deliver specialized management to more patients with chronic heart failure (CHF), but their efficacy is still to be proven. The aim of this meta-analysis was to review randomized controlled trials (RCTs) of TM or STS for all-cause mortality and all-cause and CHF-related hospitalizations in patients with CHF, as a non-invasive remote model of a specialized disease-management intervention. Methods and results: We searched all relevant electronic databases and search engines, hand-searched bibliographies of relevant studies, systematic reviews, and meeting abstracts. Two reviewers independently extracted all data. Randomized controlled trials comparing TM or STS to usual care in patients with CHF were included. Studies that included intensified management with additional home or clinic-visits were excluded. Primary outcomes (mortality and hospitalizations) were analysed; secondary outcomes (cost, length of stay, and quality of life) were tabulated. Thirty RCTs of STS and TM were identified (25 peer-reviewed publications (n= 8323) and five abstracts (n= 1482)). Of the 25 peer-reviewed studies, 11 evaluated TM (2710 participants), 16 evaluated STS (5613 participants) with two testing both STS and TM in separate intervention arms compared with usual care. Telemonitoring reduced all-cause mortality {risk ratio (RR) 0.66 [95% confidence interval (CI) 0.54-0.81], P< 0.0001 }and STS showed a similar, but non-significant trend [RR 0.88 (95% CI 0.76-1.01), P= 0.08]. Both TM [RR 0.79 (95% CI 0.67-0.94), P= 0.008], and STS [RR 0.77 (95% CI 0.68-0.87), P< 0.0001] reduced CHF-related hospitalizations. Both interventions improved quality of life, reduced costs, and were acceptable to patients. Improvements in prescribing, patient-knowledge and self-care, and functional class were observed. Conclusion: Telemonitoring and STS both appear effective interventions to improve outcomes in patients with CHF. Systematic Review Number: Cochrane Database of Systematic Reviews. 2008:Issue 3. Art. No.: CD007228. DOI: 10.1002/14651858.CD007228.

Eur J Heart Fail: 07 Jul 2011; epub ahead of print
Inglis SC, Clark RA, McAlister FA, Stewart S, Cleland JG
Eur J Heart Fail: 07 Jul 2011; epub ahead of print | PMID: 21733889
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Abstract

Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome.

Karlström P, Alehagen U, Boman K, Dahlström U, On behalf of the UPSTEP-study group
Aim To determine whether brain natriuretic peptide (BNP)-guided heart failure (HF) treatment improves morbidity and/or mortality when compared with conventional treatment. Methods and results: UPSTEP was an investigator-initiated, randomized, parallel group, multicentre study with a PROBE design. Symptomatic patients with worsening HF, New York Heart Association class II-IV, ejection fraction <40% and elevated BNP levels, were included. All patients (n= 279) were treated according to recommended guidelines and randomized to BNP-guided (BNP) or to conventional (CTR) HF treatment. The goal was to reduce BNP levels to <150 ng/L in younger patients and <300 ng/L in elderly patients, respectively. The primary outcome was a composite of death due to any cause, need for hospitalization and worsening HF. The study groups were well matched, including for BNP concentration at entry (mean: 808 vs. 899 ng/L; P= 0.34). There were no significant differences between the groups regarding either the primary outcome (P = 0.18) or any of the secondary endpoints. There were no differences for the pre-specified analyses; days out of hospital, and younger vs. elderly. A subgroup analysis comparing treatment responders (>30% decrease in baseline BNP value) vs. non-responders found improved survival among responders (P< 0.0001 for the primary outcome), and all of the secondary endpoints were also improved. Conclusions: Morbidity and mortality were not improved by HF treatment guided by BNP levels. However, BNP responders had a significantly better clinical outcome than non-responders. Future research is needed to elucidate the responsible pathophysiological mechanisms in this sub-population.

Eur J Heart Fail: 30 Jun 2011; epub ahead of print
Karlström P, Alehagen U, Boman K, Dahlström U, On behalf of the UPSTEP-study group
Eur J Heart Fail: 30 Jun 2011; epub ahead of print | PMID: 21715446
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Abstract

Directionality of blood pressure response to standing may determine development of heart failure: prospective cohort study.

Fedorowski A, Hedblad B, Engström G, Melander O
Aims: To study the prospective relationship of blood pressure response during orthostatic challenge with incidence of heart failure (HF). Methods and results: In a Swedish prospective cohort study (the Malmö Preventive Project), we followed up 32 669 individuals (68.2% men; mean age, 46 years) over a period of 24 years. Incidence of first hospitalization due to new-onset HF was related to early (60-120 s) postural changes in systolic and diastolic blood pressure (ΔSBP and ▵DBP), and mean arterial pressure (ΔMAP), using Cox proportional hazards models. Hazard ratio of incident HF increased across descending quartiles of ΔSBP from the first (and reference) quartile (+8.5 ± 4.9 mmHg), through the second (neutral response), to the third and fourth quartiles (-5.0 ± 0.1 and -13.7 ± 6.1 mmHg, respectively; P for linear trend=0.009). A pronounced hypotensive SBP response (fourth quartile) conferred the highest risk of new-onset HF [hazard ratio (HR), 1.31; 95% confidence interval (CI), 1.11-1.53]. A similar pattern was observed with regard to ΔMAP, where the first (and reference) quartile with a marked positive MAP response (+7.7 ± 3.1 mmHg) had the lowest, and the fourth quartile with a hypotensive MAP response (-5.2 ± 3.4 mmHg) had the highest HF risk (HR for fourth vs. first quartile: 1.37; 95% CI, 1.17-1.62). In a continuous model, the risk of incident HF conferred by negative ΔSBP matched that of resting SBP (HR per 10 mmHg difference: 1.17; 95% CI, 1.11-1.23, and 1.17, 1.14-1.20, respectively), whereas MAP drop was the strongest individual predictor of HF development (HR 1.26, 95% CI, 1.21-1.31). Conclusion: Early increase of blood pressure in response to orthostatic challenge signals reduced the risk of HF development.

Eur J Heart Fail: 16 Mar 2011; epub ahead of print
Fedorowski A, Hedblad B, Engström G, Melander O
Eur J Heart Fail: 16 Mar 2011; epub ahead of print | PMID: 21406482
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Abstract

Microvascular tissue perfusion is impaired in acutely decompensated heart failure and improves following standard treatment.

Lauten A, Ferrari M, Goebel B, Rademacher W, ... Figulla HR, Jung C
Aims: Acutely decompensated heart failure (ADHF) leads to neurohumoral activation potentially affecting vascular tone and organ perfusion and may be linked to unfavourable outcome. Global haemodynamic, clinical, and laboratory parameters may severely underestimate tissue hypoperfusion. Therefore, the purpose of this study was to evaluate microvascular flow index (MFI) in patients with ADHF and to assess the effect of standard pharmacological therapy using Sidestream Dark Field (SDF) imaging. Methods and results: Twenty-seven patients (mean age 75.5 ± 10.1 years, 48% male) with ADHF in New York Heart Association functional class ≥III were included. Serum markers of neurohumoral activation [brain natriuretic peptide (BNP)], endothelin-1 (ET-1), noradrenaline (NA), and echocardiographic parameters of left ventricle-function were determined at hospital admission and the day before discharge. Using SDF imaging, MFI was evaluated at both time-points in semi-quantitative vessel categories (small: 10-25 μm; medium: 26-50 μm; and large: 51-100 μm). At admission, increased serum levels of BNP, NA, and ET-1 and a severely reduced MFI were observed in association with ADHF. Serum levels of BNP, NA, and ET-1 decreased significantly with standard pharmacological therapy (BNP: 2163 ± 1577 vs.1006 ± 945 pg/mL, P< 0.05; NA: 349 ± 280 to 318 ± 265 pg/mL, P< 0.05; ET-1: 5.08 ± 0.72 to 4.81 ± 0.59 pg/mL; P< 0.01). Standard pharmacological treatment also had a profound impact on tissue perfusion by significantly improving median MFI in small [2.6; inter-quartile range (IQR) 2.3-2.9 vs. 2.9; IQR 2.8-3.0; P= 0.01) and medium-sized (2.0; IQR 1.9-2.5 vs. 2.7; IQR 2.5-2.8; P< 0.01) vessels. Conclusion: In patients with ADHF, microvascular tissue perfusion is impaired even when global haemodynamic or laboratory signs of hypoperfusion are absent. Effective pharmacological treatment to decrease neurohumoral activation significantly improves microflow. Hypoperfusion in ADHF is potentially linked to neurohumoral activation with increased plasma levels of vasoconstrictors and sympatho-adrenergic activity.

Eur J Heart Fail: 05 May 2011; epub ahead of print
Lauten A, Ferrari M, Goebel B, Rademacher W, ... Figulla HR, Jung C
Eur J Heart Fail: 05 May 2011; epub ahead of print | PMID: 21543374
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Abstract

Augmentation of left ventricular mechanics by recirculation-mediated AAV2/1-SERCA2a gene delivery in experimental heart failure.

Mariani JA, Smolic A, Preovolos A, Byrne MJ, Power JM, Kaye DM
Aims: Down-regulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) is a key molecular abnormality in heart failure (HF), which is not currently addressed by specific pharmacotherapy. We sought to evaluate, in detail, the impact of augmented SERCA2a expression on left ventricular (LV) mechanics in a large animal model of HF. Methods and results: Heart failure was induced in adult sheep by rapid pacing (180 b.p.m.) for 1 month, followed by delivery of adeno-associated virus (AAV) 2/1-SERCA, using a percutaneous, recirculating system for gene delivery over a 10 min period. Left ventricular mechanics was investigated by echocardiography and conductance catheter measurements in sheep receiving AAV2/1-SERCA2a after a further 4 weeks of pacing in comparison with untreated HF controls. Left ventricular function was significantly improved in the AAV2/1-SERCA2a-treated group, despite continued pacing, as measured by fractional shortening (delta absolute FS, control -4.2 ± 1.5% vs. treatment 4.4 ± 1.5%; P < 0.01) and conductance catheterization (delta Ees, control -1.22 ± 0.60 vs. treatment 0.65 ± 0.51; P < 0.05). Western blots showed an increase in SERCA protein in AAV2/1-SERCA2a-treated animals, and an analysis of gene delivery showed no evidence of regional myocardial heterogeneity in the distribution of AAV2/1-SERCA. Conclusion: In a large animal model, AAV2/1-mediated SERCA2a gene delivery using percutaneous, recirculating cardiac delivery leads to improved LV function.

Eur J Heart Fail: 03 Feb 2011; epub ahead of print
Mariani JA, Smolic A, Preovolos A, Byrne MJ, Power JM, Kaye DM
Eur J Heart Fail: 03 Feb 2011; epub ahead of print | PMID: 21289077
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Abstract

Global and regional putamen volume loss in patients with heart failure.

Kumar R, Nguyen HD, Ogren JA, Macey PM, ... Harper RM, Woo MA
Aims: Heart failure (HF) is accompanied by diminished cognitive, motor, learning, emotional, and planning deficits, which are associated with increased morbidity and mortality. A basal ganglia structure, the putamen, serves many functions that are affected in HF, but its global or localized structural integrity is unknown. Our aim was to evaluate global and regional putamen volume differences in HF over control subjects. Methods and results: We collected two high-resolution T1-weighted scans from 16 HF patients (age, 54.1 ± 8.3 years; 12 males; left ventricular ejection fraction, 27.8 ± 6.8%) and 32 control subjects (52.4 ± 7.3 years; 24 males) using a 3.0 T magnetic resonance imaging scanner. After realigning, averaging, and reorienting the T1-weighted volumes into a common space, the structures were manually outlined, tracings were normalized for head size, volumes calculated, and surface models generated. Demographic data were compared between groups with χ(2) and independent samples t-tests, global putamen volumes were evaluated using independent samples t-tests, and regional differences were examined with surface morphometry. No significant differences in age or sex appeared between groups, but body mass index differed significantly (P = 0.008). Heart failure patients showed significantly lower left (controls vs. HF; 4842.1 ± 740.0 vs. 4224.1 ± 894.4 mm(3), P = 0.014) and right (4769.3 ± 651.9 vs. 4193.7 ± 876.2 mm(3), P = 0.014) global putamen volumes than controls, with localized reductions in bilateral rostral, mid-dorsal, and medial-caudal regions (left, P < 0.003; right, P < 0.0002). Conclusion: Putamen structures showed global and localized volume reductions in HF over controls. The localized volume losses suggest deficits in motor and neuropsychological functions, which are evident in HF subjects, and may be due to hypoxic and ischaemic processes targeting these areas.

Eur J Heart Fail: 11 Mar 2011; epub ahead of print
Kumar R, Nguyen HD, Ogren JA, Macey PM, ... Harper RM, Woo MA
Eur J Heart Fail: 11 Mar 2011; epub ahead of print | PMID: 21393297
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Abstract

Decreasing trends in the incidence of heart failure after acute myocardial infarction from 1993-2004: a study of 175 216 patients with a first acute myocardial infarction in Sweden.

Shafazand M, Rosengren A, Lappas G, Swedberg K, Schaufelberger M
Aims: To investigate temporal trends in the risk of heart failure (HF) complicating acute myocardial infarction (AMI) and to determine whether these trends differ by gender or age. Methods and results: The national Swedish hospital discharge and death registries from 1993 to 2004 were used to calculate age- and gender-specific trends for a first episode of HF within 3 years in 175 216 patients aged 35-84 and hospitalized with a first AMI. Overall, 14.4% of patients aged 35-64 and 31.5% of those aged 65-84 with AMI in 1993-1995 had a hospital diagnosis of HF within 3 years (including the index admission). Corresponding figures for patients with AMI from 2002 to 2004 were 11.5 and 28.0%, respectively. In multivariable analyses, the risk of HF decreased by 4% per year. Having had a stroke before admission increased HF risk by 37%, diabetes increased the risk by 76% and atrial fibrillation by 80%. Patients with any kind of valvular disease had a more than doubled risk. Women had a 6% higher incidence of HF than men, whereas men with an index admission for AMI who did not develop HF had higher mortality than women. Conclusions: In this national sample, we observed a steady decrease in the risk of being hospitalized with HF after an AMI. However, the 3-year risk of HF remains high, with nearly one-third of AMI patients aged 65-84 developing HF within 3 years.

Eur J Heart Fail: 01 Dec 2010; epub ahead of print
Shafazand M, Rosengren A, Lappas G, Swedberg K, Schaufelberger M
Eur J Heart Fail: 01 Dec 2010; epub ahead of print | PMID: 21118860
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Abstract

Body mass indices and outcome in patients with chronic heart failure.

Futter JE, Cleland JG, Clark AL
Aims: There is an inverse relation between body mass and mortality in large populations of patients with chronic heart failure with a broad range of disease severity. The best measure of body size to describe the relation is not clear. Methods and results: Patients with chronic heart failure (n = 2271, age 71.9 ± 11.3 years; 74.6% male) due to left ventricular systolic dysfunction were followed for a median of 1785 days (inter-quartile range, 874-2311 days) in survivors. We measured body mass index (BMI: weight/height(2)), ponderal index (PI: weight/height(3)), and body surface area (BSA). In a subset of 1025 patients, we also calculated the \'Charles index\' [weight/(waist(2) × height)] together with bioimpedance data. During follow-up, 912 patients died. Measures of body mass were strong univariable predictors of outcome, and BSA (χ(2) = 71.3) was the strongest predictor followed by height (χ(2) = 68.6), weight (χ(2) = 57.4), then BMI (χ(2) = 15.2). The larger the patient\'s size, the lower the risk of mortality. Body surface area was the single strongest predictor of outcome in a multivariable model including 14 variables. In the subset with bioimpedance data, basal metabolic rate, BSA, weight, BMI, percentage body fat, fat mass, PI, and fat-free mass were all univariable predictors of outcome. Conclusion: Measures of body size are strongly related to outcome in patients with chronic heart failure. Body surface area is a stronger predictor of mortality than other measures of body habitus, irrespective of height correction. The greater the overall bulk of the body, the better the survival.

Eur J Heart Fail: 08 Dec 2010; epub ahead of print
Futter JE, Cleland JG, Clark AL
Eur J Heart Fail: 08 Dec 2010; epub ahead of print | PMID: 21138908
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Abstract

Economic impact of remote patient monitoring: an integrated economic model derived from a meta-analysis of randomized controlled trials in heart failure.

Klersy C, De Silvestri A, Gabutti G, Raisaro A, ... Regoli F, Auricchio A
Aims: To assess the cost-effectiveness and the cost utility of remote patient monitoring (RPM) when compared with the usual care approach based upon differences in the number of hospitalizations, estimated from a meta-analysis of randomized clinical trials (RCTs). Methods and results: We reviewed the literature published between January 2000 and September 2009 on multidisciplinary heart failure (HF) management, either by usual care or RPM to retrieve the number of hospitalizations and length of stay (LOS) for HF and for any cause. We performed a meta-analysis of 21 RCTs (5715 patients). Remote patient monitoring was associated with a significantly lower number of hospitalizations for HF [incidence rate ratio (IRR): 0.77, 95% CI 0.65-0.91, P < 0.001] and for any cause (IRR: 0.87, 95% CI: 0.79-0.96, P = 0.003), while LOS was not different. Direct costs for hospitalization for HF were approximated by diagnosis-related group (DRG) tariffs in Europe and North America and were used to populate an economic model. The difference in costs between RPM and usual care ranged from €300 to €1000, favouring RPM. These cost savings combined with a quality-adjusted life years (QALYs) gain of 0.06 suggest that RPM is a \'dominant\' technology over existing standard care. In a budget impact analysis, the adoption of an RPM strategy entailed a progressive and linear increase in costs saved. Conclusions: The novel cost-effectiveness data coupled with the demonstrated clinical efficacy of RPM should encourage its acceptance amongst clinicians and its consideration by third-party payers. At the same time, the scientific community should acknowledge the lack of prospectively and uniformly collected economic data and should request that future studies incorporate economic analyses.

Eur J Heart Fail: 03 Jan 2011; epub ahead of print
Klersy C, De Silvestri A, Gabutti G, Raisaro A, ... Regoli F, Auricchio A
Eur J Heart Fail: 03 Jan 2011; epub ahead of print | PMID: 21193439
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Abstract

Towards a re-definition of \'cardiac hypertrophy\' through a rational characterization of left ventricular phenotypes: a position paper of the Working Group \'Myocardial Function\' of the ESC.

Knöll R, Iaccarino G, Tarone G, Hilfiker-Kleiner D, ... Sugden PH, Balligand JL
Many primary or secondary diseases of the myocardium are accompanied with complex remodelling of the cardiac tissue that results in increased heart mass, often identified as cardiac \'hypertrophy\'. Although there have been numerous attempts at defining such \'hypertrophy\', the present paper delineates the reasons as to why current definitions of cardiac hypertrophy remain unsatisfying. Based on a brief review of the underlying pathophysiology and tissue and cellular events driving myocardial remodelling with or without changes in heart dimensions, as well as current techniques to detect such changes, we propose to restrict the use of the currently popular term \'hypertrophy\' to cardiac myocytes that may or may not accompany the more complex tissue rearrangements leading to changes in shape or size of the ventricles, more broadly referred to as \'remodelling\'. We also discuss the great potential of genetically modified (mouse) models as tools to define the molecular pathways leading to the different forms of left ventricle remodelling. Finally, we present an algorithm for the stepwise assessment of myocardial phenotypes applicable to animal models using well-established imaging techniques and propose a list of parameters most suited for a critical evaluation of such pathophysiological phenomena in mouse models. We believe that this effort is the first step towards a much auspicated unification of the terminology between the experimental and the clinical cardiologists.

Eur J Heart Fail: 28 Jun 2011; epub ahead of print
Knöll R, Iaccarino G, Tarone G, Hilfiker-Kleiner D, ... Sugden PH, Balligand JL
Eur J Heart Fail: 28 Jun 2011; epub ahead of print | PMID: 21708908
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Abstract

Quality of life is impaired similarly in heart failure patients with preserved and reduced ejection fraction.

Hoekstra T, Lesman-Leegte I, van Veldhuisen DJ, Sanderman R, Jaarsma T
Aims: To compare quality of life (QoL) in heart failure (HF) patients with preserved ejection fraction (HF-PEF) and HF patients with reduced ejection fraction (HF-REF) in a well-defined HF population. Methods and results: Patients with HF-PEF [left ventricular ejection fraction (LVEF) ≥40%] were matched by age and gender to patients with HF-REF (LVEF <40%). In the current study, we only included HF patients with a B-type natriuretic peptide level (BNP) >100 pg/mL. Quality of life was assessed by Cantril\'s Ladder of Life, RAND-36, and the Minnesota Living with Heart Failure questionnaire, and impairment of QoL was adjusted for by BNP as a marker for severity of HF. We examined a total of 290 HF patients, of whom 145 had HF-PEF (41% female; age 72 ± 10; LVEF 51 ± 8%) and 145 had HF-REF (41% female; age 73 ± 10, LVEF 26 ± 7%). All HF patients reported markedly low scores of QoL, both on the general and disease-specific QoL questionnaires. Quality of life between patients with HF-PEF and HF-REF did not differ significantly. When adjusting the QoL scores for BNP, an association between QoL and LVEF was not found, i.e. patients with HF-PEF and HF-REF with similar BNP levels had the same impairment in QoL. Conclusion: Quality of life is similarly impaired in patients with HF-PEF as in HF-REF. These findings further support the need for more pharmacological and non-pharmacological studies in patients with HF-PEF. Trial registration number: NCT 98675639.

Eur J Heart Fail: 29 Jun 2011; epub ahead of print
Hoekstra T, Lesman-Leegte I, van Veldhuisen DJ, Sanderman R, Jaarsma T
Eur J Heart Fail: 29 Jun 2011; epub ahead of print | PMID: 21712287
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Abstract

Short- and long-term treatment of dilutional hyponatraemia with satavaptan, a selective arginine vasopressin V2-receptor antagonist: the DILIPO study.

Aronson D, Verbalis JG, Mueller M, Krum H, on behalf of the DILIPO investigators
Aims: Arginine vasopressin (AVP) V(2) receptor antagonism is a new approach to the management of hyponatraemia in congestive heart failure (CHF). The aim of this study was to investigate the efficacy and safety of satavaptan, an oral AVP V(2)-receptor antagonist, in patients with dilutional hyponatraemia. Methods and results: A total of 118 patients (90 with CHF) with dilutional hyponatraemia (serum sodium 115-132 mmol/L) were randomized to double-blind treatment with placebo or to 25 or 50 mg/day of satavaptan for 4 days, followed by non-comparative open-label satavaptan therapy for up to 343 days. The response rate (sodium ≥135 mmol/L and/or an increase in ≥5 mmol/L above baseline) was significantly higher with satavaptan 50 mg than with placebo (61.0 vs. 26.8%; P= 0.0035), with a trend towards significance with satavaptan 25 mg (48.6%, P= 0.0599). Median times to response were 3.30 and 2.79 days with satavaptan 25 and 50 mg/day, respectively, both shorter than placebo (>4 days; P= 0.0278 and P= 0.0004, respectively). Satavaptan therapy was effective in CHF patients, with response rates higher with both satavaptan 25 mg/day (53.6%) and 50 mg/day (57.1%) than with placebo (23.5%; P= 0.019 and P= 0.009, respectively). Sodium responses were maintained during open-label therapy after a temporary study drug discontinuation period. Higher rates of adverse events occurred with the 50 mg/day dose, including rapid correction of hyponatraemia. Conclusions: In patients with dilutional hyponatraemia, V(2) receptor antagonism with satavaptan was effective in increasing serum sodium concentrations. The long-term open-label treatment results demonstrate sustained efficacy of satavaptan in maintaining normal sodium levels. Trial registration clinicaltrials.gov Identifier: NCT00274326.

Eur J Heart Fail: 04 Jan 2011; epub ahead of print
Aronson D, Verbalis JG, Mueller M, Krum H, on behalf of the DILIPO investigators
Eur J Heart Fail: 04 Jan 2011; epub ahead of print | PMID: 21199833
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Abstract

To die with or from heart failure: a difference that counts: Why official vital statistics are unsuitable for studying mortality in heart failure patients.

Engelfriet PM, Hoogenveen RT, Boshuizen HC, van Baal PH
Aims: Mortality attributed to a disease is an important public health measure of the \'burden\' of that disease. A discrepancy has been noted between the high mortality rates associated with heart failure (HF) and the share of deaths ascribed to HF in official mortality statistics. It was our main aim to estimate excess mortality associated with HF and use the estimates to better understand the burden of HF. Methods and results: Excess mortality was defined as the difference in mortality rates between individuals with and those without HF. An epidemiological model was formulated that allowed deriving age-specific excess mortality rates in HF patients from HF incidence and prevalence. Incidence and prevalence were estimated from yearly collected cross-sectional data from four nationally representative General Practice registries in the Netherlands. The year 2007 was chosen as a reference. Next, excess mortality rates were used to calculate numbers of deaths among HF patients and compare the figures with national cause-of-death statistics. The latter were found to be more than three times smaller than the former (roughly 6000 vs. 21 000). Further, by applying HF prevalence and mortality rates to a life table of the Dutch population, average numbers of life years lost due to HF were calculated to be 6.9 years. Conclusion: National mortality statistics strongly underestimate the number of deaths associated with HF. Moreover, the high mortality rate in HF patients amounts to a remarkably large number of life years lost given the advanced age of disease onset.

Eur J Heart Fail: 10 Jan 2011; epub ahead of print
Engelfriet PM, Hoogenveen RT, Boshuizen HC, van Baal PH
Eur J Heart Fail: 10 Jan 2011; epub ahead of print | PMID: 21216785
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Abstract

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency.

Anker SD, Schroeder S, Atar D, Bax JJ, ... Voors AA, Ruschitzka F
Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient\'s burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research.

Eur J Heart Fail: 12 Apr 2016; epub ahead of print
Anker SD, Schroeder S, Atar D, Bax JJ, ... Voors AA, Ruschitzka F
Eur J Heart Fail: 12 Apr 2016; epub ahead of print | PMID: 27071916
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Abstract

The effect of ventricular assist devices on long-term post-transplant outcomes: a systematic review of observational studies.

Alba AC, McDonald M, Rao V, Ross HJ, Delgado DH
Aims: Ventricular assist device (VAD) therapy is widely used as a bridge to cardiac transplant. Studies addressing the effect of VADs on post-transplant outcomes have shown conflicting results. It is imperative to review this evidence to inform clinical decision making and future research. Our aim was to systematically evaluate the effect of VAD therapy on long-term post-transplant outcomes in heart transplant recipients. Methods and results: We searched online databases (Medline, PubMed, Embase, and CINAHL) and references of included articles. Comparative studies evaluating the effect of VADs on post-transplant outcomes in adults were included and study results were meta-analysed using random-effects models. We conducted subgroup analyses to assess the effect estimate of extra- vs. intra-corporeal VADs and to evaluate the impact of transplant era and listing status. Overall, we identified 31 observational studies. One-year post-transplant mortality in recipients bridged with an extra-corporeal VAD was significantly higher than in non-bridged recipients (RR 1.8, 95% CI 1.53-2.13, I(2)= 1%), while patients supported with an intra-corporeal VAD had similar mortality to non-bridged recipients (RR 1.08, 95% CI 0.95-1.22, I(2)= 0%). The risks of rejection within the first post-transplant year and coronary allograft vasculopathy were not significantly different between patients with or without VAD support prior to transplant. Publication bias was low; however, the risk of bias across studies was moderate to high. Conclusion: Intra-corporeal VAD support does not have a deleterious impact on post-transplant outcomes. However, post-transplant survival may be poorer in the subgroup of patients supported with extra-corporeal devices. Studies with greater methodological rigour are warranted.

Eur J Heart Fail: 09 May 2011; epub ahead of print
Alba AC, McDonald M, Rao V, Ross HJ, Delgado DH
Eur J Heart Fail: 09 May 2011; epub ahead of print | PMID: 21551162
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Abstract

Increased serum high-mobility group box-1 and cleaved receptor for advanced glycation endproducts levels and decreased endogenous secretory receptor for advanced glycation endproducts levels in diabetic and non-diabetic patients with heart failure.

Wang LJ, Lu L, Zhang FR, Chen QJ, De Caterina R, Shen WF
Aims: High-mobility group box-1 (HMGB1) is a ligand for the receptor for advanced glycation endproducts (RAGE). An HMGB1-RAGE interaction has been implicated in cardiac dysfunction. We assessed the association of HMGB1 and RAGE isoforms with heart failure (HF) in diabetic and non-diabetic patients. Methods and results: We assayed serum levels of HMGB1, cleaved RAGE (cRAGE), endogenous secretory RAGE (esRAGE), high-sensitivity C-reactive protein (hsCRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) in parallel with assessment of left ventricular volumes and function in 125 diabetic and 222 non-diabetic Chinese patients with chronic HF. Of the total, 79 diabetic patients without HF and 220 normal subjects served as diabetic and normal controls, respectively. Serum HMGB1, cRAGE, hsCRP, and NT-proBNP levels were higher and, in contrast, esRAGE levels lower in HF patients than in subjects without HF (for all; P < 0.01), with higher levels of cRAGE and hsCRP in diabetic HF vs. non-diabetic HF patients (P < 0.01). For HF patients-with or without diabetes-HMGB1 levels correlated positively with left ventricular end-diastolic and end-systolic volumes (r = 0.267 and r = 0.321, respectively) and NT-proBNP values (r = 0.497), and were inversely related to ejection fraction (r = -0.461; all P < 0.001). Serum cRAGE levels correlated with NT-proBNP values (r = 0.451) and New York Heart Association functional class (r = 0.402; both P < 0.001). Multivariable regression analysis revealed that HMGB1, cRAGE, and esRAGE were consistently associated with HF in diabetic and non-diabetic patients. Conclusion: Heart failure patients have increased serum HMGB1 and cRAGE and decreased esRAGE levels, and these are related to the severity of HF in both diabetic and non-diabetic patients. Such associations are worth further investigation.

Eur J Heart Fail: 26 Jan 2011; epub ahead of print
Wang LJ, Lu L, Zhang FR, Chen QJ, De Caterina R, Shen WF
Eur J Heart Fail: 26 Jan 2011; epub ahead of print | PMID: 21266376
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Abstract

EURObservational Research Programme: a worldwide registry on peripartum cardiomyopathy (PPCM) in conjunction with the Heart Failure Association of the European Society of Cardiology Working Group on PPCM.

Sliwa K, Hilfiker-Kleiner D, Mebazaa A, Petrie MC, ... McMurray JJ, Pieske B
The EURObservational Research Programme is a rolling programme of cardiovascular registries and surveys of the European Society of Cardiology (ESC). These registries will provide information on the nature of cardiovascular disease and its management. This manuscript provides an update on new literature on peripartum cardiomyopathy (PPCM), published since the 2010 Position Statement from the Heart Failure Association of the European Society of Cardiology Working Group on PPCM, and describes a new registry on this under-recognized condition. Peripartum cardiomyopathy is an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of the pregnancy, or in the months following delivery, where no other cause for heart failure is found.

Eur J Heart Fail: 03 Mar 2014; epub ahead of print
Sliwa K, Hilfiker-Kleiner D, Mebazaa A, Petrie MC, ... McMurray JJ, Pieske B
Eur J Heart Fail: 03 Mar 2014; epub ahead of print | PMID: 24591060
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Abstract

Acute kidney injury and outcomes in acute decompensated heart failure: evaluation of the RIFLE criteria in an acutely ill heart failure population.

Hata N, Yokoyama S, Shinada T, Kobayashi N, ... Kurihara O, Takahashi Y
Aims: The clinical course including the outcome of acute decompensated heart failure (ADHF) correlates with renal dysfunction, but the evaluation of renal function has not yet been standardized. We therefore investigated the relationship between the prognosis of ADHF and acute kidney injury (AKI) evaluated using the risk, injury, failure, loss, end stage (RIFLE) criteria. Methods and results: This study assessed 376 consecutive patients with ADHF admitted to the intensive care unit (ICU) (mean age 71.6 years; 238 male). The underlying aetiology was ischaemic heart disease, hypertensive heart disease, cardiomyopathy, valvular diseases, and \'other\' in 124, 70, 60, 107, and 15 patients, respectively. We defined AKI according to the RIFLE criteria, and the most severe RIFLE classifications during hospitalization were adopted to assess patient outcomes. The in-hospital mortality was significantly higher among patients with AKI (29 of 275; 10.5%) than in those without AKI (1 of 101; 1.0%, P = 0.0010). Both ICU and hospital stays were longer for patients with AKI (8.8 +/- 15.4 vs. 48.6 +/- 47.6 days), than for patients without (5.0 +/- 2.8 vs. 25.7 +/- 16.8 days, P < 0.05 and P < 0.001). Conclusion: Acute kidney injury evaluated by the RIFLE criteria was associated with a poorer outcome for patients with ADHF.

Eur J Heart Fail: 21 Dec 2009; 12:32-7
Hata N, Yokoyama S, Shinada T, Kobayashi N, ... Kurihara O, Takahashi Y
Eur J Heart Fail: 21 Dec 2009; 12:32-7 | PMID: 20023042
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Abstract

Relationship between cardioscopic images and histological changes in the left ventricle of patients with idiopathic myocarditis.

Uchida Y, Uchida Y, Sakurai T, Kanai M, ... Nakagawa O, Hiruta N
Aims: Endomyocardial biopsy is essential for definite diagnosis of idiopathic myocarditis. However, since endomyocardial biopsy is guided by fluoroscopy, whether or not the diseased myocardium is biopsied depends on chance, and this may lead to misdiagnosis. If the endocardial surface represents changes indicative of stages of myocarditis, staging of myocarditis and targeted cardioscope-guided biopsy could be used for accurate histological diagnosis. Methods and results: The relationship between left ventricular endocardial surface colour observed by cardioscopy and biopsy findings were examined in 78 patients with suspected idiopathic myocarditis. Of these, 59 patients were diagnosed histologically as idiopathic myocarditis. Endocardial colour was classified into red, milky white, purple, yellowish brown, or white. Biopsied specimens with red and milky white wall segments exhibited histological changes compatible with acute myocarditis; purple segments, active chronic myocarditis; and yellowish brown and white segments, inactive chronic myocarditis. The sensitivity, specificity, and predictive value of red and milky white colours for detecting acute myocarditis were 100, 100, and 100%, respectively; of purple for detecting active chronic myocarditis were 83, 92, and 78%, respectively; and yellowish brown and white for detecting inactive chronic myocarditis were 82, 74, and 53, respectively. Conclusion: Red and milky white endocardial surface colours predicted histological acute myocarditis, and purple predicted active chronic myocarditis. However, yellowish brown and white colours did not predict inactive chronic myocarditis.

Eur J Heart Fail: 24 Jan 2011; epub ahead of print
Uchida Y, Uchida Y, Sakurai T, Kanai M, ... Nakagawa O, Hiruta N
Eur J Heart Fail: 24 Jan 2011; epub ahead of print | PMID: 21257727
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Abstract

Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure.

Waldmüller S, Erdmann J, Binner P, Gelbrich G, ... Scheffold T, on behalf of the German Competence Network Heart Failure
Aims: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be due to mutations in the genes encoding β-myosin heavy chain (MYH7) or cardiac myosin-binding protein C (MYBPC3). The aim of the present study was to determine the prevalence and spectrum of mutations in both genes in German HCM and DCM patients and to establish novel genotype-to-phenotype correlations. Methods and results: Coding exons and intron flanks of the two genes MYH7 and MYBPC3 of 236 patients with HCM and 652 patients with DCM were sequenced by conventional and array-based means. Clinical records were established following standard protocols. Mutations were detected in 41 and 11% of the patients with HCM and DCM, respectively. Differences were observed in the frequency of splice site and frame-shift mutations in the gene MYBPC3, which occurred more frequently (P< 0.02, P< 0.001, respectively) in HCM than in DCM, suggesting that cardiac myosin-binding protein C haploinsufficiency predisposes to hypertrophy rather than to dilation. Additional novel genotype-to-phenotype correlations were found in HCM, among these a link between MYBPC3 mutations and a particularly large thickness of the interventricular septum (P= 0.04 vs. carriers of a mutation in MYH7). Interestingly, this correlation and a link between MYH7 mutations and a higher degree of mitral valve regurgitation held true for both HCM and DCM, indicating that the gene affected by a mutation may determine the magnitude of structural and functional alterations in both HCM and DCM. Conclusion: A large clinical-genetic study has unravelled novel genotype-to-phenotype correlations in HCM and DCM which warrant future investigation of both the underlying mechanisms and the prognostic use.

Eur J Heart Fail: 13 Jul 2011; epub ahead of print
Waldmüller S, Erdmann J, Binner P, Gelbrich G, ... Scheffold T, on behalf of the German Competence Network Heart Failure
Eur J Heart Fail: 13 Jul 2011; epub ahead of print | PMID: 21750094
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Clinical trials update from the American College of Cardiology Meeting 2011: STICH, NorthStar, TARGET, and EVEREST II.

Cleland JG, Coletta AP, Freemantle N, Clark AL
This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the annual American College of Cardiology meeting held in New Orleans in 2011. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. The STICH trial failed to show a benefit of revascularization on all-cause mortality in patients with HF and coronary artery disease; however, cardiovascular deaths were reduced compared with medical therapy alone. Results from the NorthStar study suggest that patients with clinically stable systolic HF, who are on optimal medical therapy, including those with elevated amino-terminal B-type natriuretic peptide levels, may not benefit from long-term follow-up in an HF clinic. Results from the TARGET study demonstrate that targeted left ventricular lead placement using speckle tracking echocardiography is feasible in patients undergoing implantation of a cardiac resynchronization therapy device and is associated with an enhanced response. Two-year follow-up data from EVEREST II show that although a catheter-based mitral valve repair procedure using the MitraClip(®) system was less effective at reducing mitral regurgitation than conventional surgery, similar improvements in clinical outcomes were observed with fewer short-term adverse events.

Eur J Heart Fail: 29 Jun 2011; 13:805-8
Cleland JG, Coletta AP, Freemantle N, Clark AL
Eur J Heart Fail: 29 Jun 2011; 13:805-8 | PMID: 21712293
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Abstract

Heart Failure Association of the European Society of Cardiology heart failure nurse curriculum.

Riley JP, Astin F, Crespo-Leiro MG, Deaton CM, ... Filippatos G, Anker SD
Recent advances in care and management of heart failure have improved outcome, largely as a result of the developing evidence basis for medications, implantable devices and the organization of heart failure follow-up. Such developments have also increased the complexity of delivering and coordinating care. This has led to a change to the way in which heart failure services are organized and to the traditional role of the heart failure nurse. Nurses in many countries now provide a range of services that include providing care for patients with acute and with chronic heart failure, working in and across different sectors of care (inpatient, outpatient, community care, the home and remotely), organising care services around the face-to-face and the remote collection of patient data, and liaising with a wide variety of health-care providers and professionals. To support such advances the nurse requires a skill set that goes beyond that of their initial education and training. The range of nurses\' roles across Europe is varied. So too is the nature of their educational preparation. This heart failure nurse curriculum aims to provide a framework for use in countries of the European Society of Cardiology. Its modular approach enables the key knowledge, skills, and behaviours for the nurse working in different care settings to be outlined and so facilitate nursing staff to play a fuller role within the heart failure team.

Eur J Heart Fail: 24 May 2016; epub ahead of print
Riley JP, Astin F, Crespo-Leiro MG, Deaton CM, ... Filippatos G, Anker SD
Eur J Heart Fail: 24 May 2016; epub ahead of print | PMID: 27220672
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Abstract

Bi treatment with hydralazine/nitrates vs. placebo in Africans admitted with acute HEart Failure (BA-HEF).

Sliwa K, Damasceno A, Davison BA, Mayosi BM, ... Edwards C, Cotter G
Patients with acute heart failure in Africa are rarely being treated with a hydralazine/nitrates combination. Therefore the effect of this treatment was studied here Methods and results: The study was planned to enrol 500 patients during an acute heart failure (HF) admission, from nine sub-Saharan African countries. Patients were randomized in a double-blind manner to receive 50 mg hydralazine/20 mg isosorbide dinitrate (HYIS) t.i.d. or matching placebo for 24 weeks followed by open label HYIS for all patients. The study was terminated after 147 patients were enrolled due mostly to issues with recruitment into a prospective, placebo-controlled study. Most patients were recruited from Mozambique, South Africa, Kenya, and Uganda. The primary endpoint of death or HF readmission through 24 weeks was neutral [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.48-2.27, P = 0.90] in the 133 randomized patients included in the analyses. There were non-signficant effects in favour of HYIS in secondary endpoints including change in dyspnoea severity at day 7 or discharge, decrease in systolic blood pressure, greater decrease in weight, and increase in 6-min walk test distance at week 24. There were also small changes in echocardiographic indices of cardiac size and function in favour or HYIS, but none was significant.

Eur J Heart Fail: 20 May 2016; epub ahead of print
Sliwa K, Damasceno A, Davison BA, Mayosi BM, ... Edwards C, Cotter G
Eur J Heart Fail: 20 May 2016; epub ahead of print | PMID: 27206810
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Abstract

Sleep-disordered breathing in heart failure.

Pearse SG, Cowie MR
Sleep-disordered breathing-comprising obstructive sleep apnoea (OSA), central sleep apnoea (CSA), or a combination of the two-is found in over half of heart failure (HF) patients and may have harmful effects on cardiac function, with swings in intrathoracic pressure (and therefore preload and afterload), blood pressure, sympathetic activity, and repetitive hypoxaemia. It is associated with reduced health-related quality of life, higher healthcare utilization, and a poor prognosis. Whilst continuous positive airways pressure (CPAP) is the treatment of choice for patients with daytime sleepiness due to OSA, the optimal management of CSA remains uncertain. There is much circumstantial evidence that the treatment of OSA in HF patients with CPAP can improve symptoms, cardiac function, biomarkers of cardiovascular disease, and quality of life, but the quality of evidence for an improvement in mortality is weak. For systolic HF patients with CSA, the CANPAP trial did not demonstrate an overall survival or hospitalization advantage for CPAP. A minute ventilation-targeted positive airway therapy, adaptive servoventilation (ASV), can control CSA and improves several surrogate markers of cardiovascular outcome, but in the recently published SERVE-HF randomized trial, ASV was associated with significantly increased mortality and no improvement in HF hospitalization or quality of life. Further research is needed to clarify the therapeutic rationale for the treatment of CSA in HF. Cardiologists should have a high index of suspicion for SDB in those with HF, and work closely with sleep physicians to optimize patient management.

Eur J Heart Fail: 11 Feb 2016; epub ahead of print
Pearse SG, Cowie MR
Eur J Heart Fail: 11 Feb 2016; epub ahead of print | PMID: 26869027
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Abstract

Heart failure registry: a valuable tool for improving the management of patients with heart failure.

Jonsson A, Edner M, Alehagen U, Dahlström U
Aims: Guidelines on how to diagnose and treat patients with heart failure (HF) are published regularly. However, many patients do not fulfil the diagnostic criteria and are not treated with recommended drugs. The Swedish Heart Failure Registry (S-HFR) is an instrument which may help to optimize the handling of HF patients. Methods and results: The S-HFR is an Internet-based registry in which participating centres (units) can record details of their HF patients directly online and transfer data from standardized forms or from computerized patient documentation. Up to December 2007, 16,117 patients from 78 units had been included in the S-HFR. Of these, 10,229 patients had been followed for at least 1 year, and 2133 deaths were recorded. Online reports from the registry showed that electrocardiograms were available for 97% of the patients. Sinus rhythm was found in 51% of patients and atrial fibrillation in 38%. Echocardiography was performed in 83% of the patients. Overall, 77% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, 80% were on beta-blockers, 34% on aldosterone antagonists, and 83% on diuretics. Conclusion: The S-HFR is a valuable tool for improving the management of patients with HF, since it enables participating centres to focus on their own potential for improving diagnoses and medical treatment, through the online reports provided.

Eur J Heart Fail: 21 Dec 2009; 12:25-31
Jonsson A, Edner M, Alehagen U, Dahlström U
Eur J Heart Fail: 21 Dec 2009; 12:25-31 | PMID: 20023041
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Abstract

Kidney injury molecule-1 and N-acetyl-ss-D-glucosaminidase in chronic heart failure: possible biomarkers of cardiorenal syndrome.

Jungbauer CG, Birner C, Jung B, Buchner S, ... Riegger G, Luchner A
Aims: Patients with chronic heart failure are often characterized by impaired renal function, also referred to as cardiorenal syndrome (CRS). The aim of this study was to assess whether novel markers of kidney injury are elevated in chronic heart failure and CRS. Methods and results: The new renal biomarkers kidney injury molecule-1 (KIM-1), N-acetyl-ß-d-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) were assessed from urine samples of 173 individuals. Patients with chronic heart failure (n= 150) were characterized by decreased ejection fraction (32 ± 9% vs. controls 62 ± 4%, P < 0.001) and increased plasma N-terminal pro-brain natriuretic peptide (median 1460 pg/mL, interquartile range (IQR) 630-3000 pg/mL vs. controls 56, IQR 25-64l pg/mL, P < 0.001). Urinary analysis showed that KIM-1 was significantly elevated in heart failure patients compared with healthy controls (1100, IQR 620-1920 vs. 550, IQR 320-740 ng/g urinary creatinine, P < 0.001). Further, KIM-1 increased significantly with decreasing left ventricular function (r = -0.37, P < 0.001) and severity of New York Heart Association (NYHA)-class (r = 0.5, P < 0.001). N-acetyl-ß-d-glucosaminidase showed a weaker response but correlated significantly with left ventricular dysfunction (r = -0.18, P= 0.015) and more severe clinical condition (r = 0.22, P= 0.04). In contrast, NGAL showed no significant correlation. Kidney injury molecule-1 and NAG were also predictors of all-cause mortality and the composite of all-cause mortality and rehospitalization for heart failure (all P < 0.05). Conclusions: Kidney injury molecule-1 and NAG are elevated in symptomatic heart failure. This finding may be present in patients with apparently normal kidney function and indicates tubular injury in chronic heart failure. Kidney injury molecule-1 and NAG are potential markers of CRS with additional prognostic value.

Eur J Heart Fail: 17 Aug 2011; epub ahead of print
Jungbauer CG, Birner C, Jung B, Buchner S, ... Riegger G, Luchner A
Eur J Heart Fail: 17 Aug 2011; epub ahead of print | PMID: 21846754
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Abstract

Multicentre study using strain delay index for predicting response to cardiac resynchronization therapy (MUSIC study).

Lim P, Donal E, Lafitte S, Derumeaux G, ... Grimm RA, Gueret P
Aims: Strain delay index (SDI) allows quantification of the wasted contraction or gain of myocardial contractility expected after cardiac resynchronization therapy (CRT). The present multicentre prospective study aimed to assess the accuracy of the SDI in predicting responses to CRT in real-life patients with wide and narrow (<130 ms) QRS complexes. Methods and results: Implantation of a CRT device was performed in 235 heart failure patients and echocardiography data were analysable in 80% (n= 189) of patients (age 65 ± 12 years, left ventricular ejection fraction = 26 ± 8%, 63 ischaemic, 51 with narrow QRS complexes). Mechanical dyssynchrony before CRT was quantified by the 12-segment standard deviation of peak longitudinal strain by speckle tracking (12SD-ε, 12 standard deviation of time to peak strain by speckle tracking), and SDI, defined as the sum of difference between end-systolic and peak-ε across the 16 segments. Response to CRT was defined as an end-systolic volume reduction (ESVR) at 6 months >15%. After CRT, ESVR>15% was observed in 60% (n= 114/189) of patients, and was greater in non-ischaemic (68 vs. 44%, P= 0.003) and wide QRS patients (65 vs. 49%, P= 0.04). Correlation between 12SD-ε and ESVR was poor (r = 0.18, P= 0.01). In contrast, SDI correlated with reverse remodelling (r = 0.61, P< 0.0001 for all) in both wide and narrow QRS patients and ischaemic and non-ischaemic patients. Decrease in SDI after CRT was greater in responders and correlated with ESVR. Finally, SDI > 25% identified responders to CRT (positive and negative predictive value of 80 and 84%, respectively) with 6% inter-observer variability. Conclusion: The present multicentre study suggests that SDI may identify responders to CRT in ischaemic and non-ischaemic patients.

Eur J Heart Fail: 03 Aug 2011; epub ahead of print
Lim P, Donal E, Lafitte S, Derumeaux G, ... Grimm RA, Gueret P
Eur J Heart Fail: 03 Aug 2011; epub ahead of print | PMID: 21810831
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Abstract

Reframing the association and significance of co-morbidities in heart failure.

Triposkiadis F, Giamouzis G, Parissis J, Starling RC, ... Butler J, Filippatos G
Several co-existing diseases and/or conditions (co-morbidities) are present in patients with heart failure (HF), with diverse clinical relevance. Multiple mechanisms may underlie the co-existence of HF and co-morbidities, including direct causation, associated risk factors, heterogeneity, and independence. The complex inter-relationship of co-morbidities and their impact on the cardiovascular system contribute to the features of HF, both with reduced (HFrEF) and preserved ejection fraction (HFpEF). The purpose of this work is to provide an overview of the contribution of major cardiac and non-cardiac co-morbidities to HF development and outcomes, in the context of both HFpEF and HFrEF. Accordingly, epidemiological evidence linking co-morbidities to HF and the effect of prevalent and incident co-morbidities on HF outcome will be reviewed.

Eur J Heart Fail: 29 Jun 2016; epub ahead of print
Triposkiadis F, Giamouzis G, Parissis J, Starling RC, ... Butler J, Filippatos G
Eur J Heart Fail: 29 Jun 2016; epub ahead of print | PMID: 27358242
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Abstract

Associations of albuminuria in patients with chronic heart failure: findings in the ALiskiren Observation of heart Failure Treatment study.

Jackson CE, Macdonald MR, Petrie MC, Solomon SD, ... McMurray JJ, For the ALiskiren Observation of heart Failure Treatment (ALOFT) investigators
Aims: To examine the relationships between baseline characteristics and urinary albumin excretion in the extensively phenotyped patients in the ALiskiren Observation of heart Failure Treatment (ALOFT) study. Methods and results: Urinary albumin creatinine ratio (UACR) was available in 190 of 302 (63%) patients randomized in ALOFT. Of these, 107 (56%) had normal albumin excretion, 63 (33%) microalbuminuria, and 20 (11%) macroalbuminuria. Compared with patients with normoalbuminuria, those with microalbuminuria had a greater prevalence of diabetes (48 vs. 26%, P = 0.005) and a lower estimated glomerular filtration rate (eGFR) (60.7 vs. 68.3 mL/min/1.73 m(2), P = 0.01). Patients with macroalbuminuria had additional differences from those with a normal UACR, including younger age (63 vs. 69 years, P = 0.02), higher glycated haemoglobin (HbA1c; 7.9 vs. 6.2%, P < 0.001), and different echocardiographic findings. Of the non-diabetic patients, 28% had microalbuminuria and 7% had macroalbuminuria. Independent predictors of UACR in these patients included N-terminal pro B-type natriuretic peptide (NT-proBNP), HbA1c, and left ventricular diastolic dimension. Increased UACR was not associated with markers of inflammation or of renin angiotensin aldosterone system activation and was not reduced by aliskiren. Conclusions: Increased UACR is common in patients with heart failure, including non-diabetics. Urinary albumin creatinine ratio is independently associated with HbA1c and NT-proBNP, even in non-diabetic patients. Clinical Trial registration: ClinicalTrials.gov NCT00219011.

Eur J Heart Fail: 04 Apr 2011; epub ahead of print
Jackson CE, Macdonald MR, Petrie MC, Solomon SD, ... McMurray JJ, For the ALiskiren Observation of heart Failure Treatment (ALOFT) investigators
Eur J Heart Fail: 04 Apr 2011; epub ahead of print | PMID: 21459891
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Abstract

Intercellular communication lessons in heart failure.

Bang C, Antoniades C, Antonopoulos AS, Eriksson U, ... Speer T, Thum T
Cell-cell or inter-organ communication allows the exchange of information and messages, which is essential for the coordination of cell/organ functions and the maintenance of homeostasis. It has become evident that dynamic interactions of different cell types play a major role in the heart, in particular during the progression of heart failure, a leading cause of mortality worldwide. Heart failure is associated with compensatory structural and functional changes mostly in cardiomyocytes and cardiac fibroblasts, which finally lead to cardiomyocyte hypertrophy and fibrosis. Intercellular communication within the heart is mediated mostly via direct cell-cell interaction or the release of paracrine signalling mediators such as cytokines and chemokines. However, recent studies have focused on the exchange of genetic information via the packaging into vesicles as well as the crosstalk of lipids and other paracrine molecules within the heart and distant organs, such as kidney and adipose tissue, which might all contribute to the pathogenesis of heart failure. In this review, we discuss emerging communication networks and respective underlying mechanisms which could be involved in cardiovascular disease conditions and further emphasize promising therapeutic targets for drug development.

Eur J Heart Fail: 22 Sep 2015; epub ahead of print
Bang C, Antoniades C, Antonopoulos AS, Eriksson U, ... Speer T, Thum T
Eur J Heart Fail: 22 Sep 2015; epub ahead of print | PMID: 26398116
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Abstract

Heart Failure Association of the European Society of Cardiology Specialist Heart Failure Curriculum.

McDonagh TA, Gardner RS, Lainscak M, Nielsen OW, ... Filippatos G, Anker SD
It is well established that organized care of heart failure patients, including specialist management by cardiologists, improves patient outcomes. In response to this, other national training bodies (the UK and the USA) have developed heart failure subspecialty curricula within their Cardiology Training Curricula. In addition, European Society of Cardiology (ESC) subspecialty curricula exist for Interventional Cardiology and Heart Rhythm Management. The purpose of this heart failure curriculum is to provide a framework which can be used as a blueprint for training across Europe. This blueprint mirrors other ESC curricula. Each section has three components: the knowledge required, the skills which are necessary, and the professionalism (attitudes and behaviours) which should be attained. The programme is designed to last 2 years. The first year is devoted to the specialist heart failure module. The second year allows completion of the optional modules of advanced imaging, device therapy for implanters, cardiac transplantation, and mechanical circulatory support. The second year can also be devoted to continuation of specialist heart failure training and/or research for those not wishing to continue with the advanced modules.

Eur J Heart Fail: 26 Jan 2014; epub ahead of print
McDonagh TA, Gardner RS, Lainscak M, Nielsen OW, ... Filippatos G, Anker SD
Eur J Heart Fail: 26 Jan 2014; epub ahead of print | PMID: 24464608
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Abstract

The Heart Failure Revascularisation Trial (HEART).

Cleland JG, Calvert M, Freemantle N, Arrow Y, ... Pennell DJ, Senior R
Aims: Revascularization is frequently advocated to improve ventricular function and prognosis for patients with heart failure due to coronary artery disease, especially when there is evidence of extensive myocardial viability. Methods and results: Patients with heart failure, coronary artery disease, and a left ventricular (LV) ejection fraction <35%, who had a substantial volume of viable myocardium with contractile dysfunction assessed by any standard imaging technique, were randomly assigned to a strategy of conservative management vs. angiography with the intent of percutaneous or surgical revascularization. Patients requiring revascularization for angina or too frail for surgery were excluded. Only 138 of the planned 800 patients were enrolled because of withdrawal of funding due to slow recruitment. Also, a larger trial (The Surgical Treatment for Ischemic Heart Failure Trial) addressing a similar question became available, which investigators were encouraged to join. Of 69 patients assigned to the invasive strategy, 6 refused angiography, 2 died as a result of the diagnostic procedure, 14 were considered unsuitable for revascularization, 2 refused surgery, and 45 had revascularization. After a median follow-up of 59 (inter-quartile range: 33-63) months, there were 51 (37%) deaths; 25 (37%) in those assigned to the conservative strategy, and 26 (38%) in those assigned to the invasive strategy, 13 (29%) of whom had been revascularized. Conclusion: A conservative management strategy may not be inferior to one of coronary arteriography with the intent to revascularize in patients with heart failure, LV systolic dysfunction, and extensive myocardial viability. However, this study was underpowered and, further, larger trials are required to settle this issue. Clinical trials Registration No: ISRCTN86284615.

Eur J Heart Fail: 15 Dec 2010; epub ahead of print
Cleland JG, Calvert M, Freemantle N, Arrow Y, ... Pennell DJ, Senior R
Eur J Heart Fail: 15 Dec 2010; epub ahead of print | PMID: 21156659
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Abstract

Characterization of heart failure patients with preserved ejection fraction: A comparison between ADHERE-US registry and ADHERE-International registry.

West R, Liang L, Fonarow GC, Kociol R, ... O\'Connor CM, Hernandez AF
Aims: To characterize geographic differences in clinical characteristics and care of patients hospitalized with heart failure and preserved ejection fraction (HF-PEF). Methods and results: Using data on 61 182 admissions in 307 US hospitals from March 2004 to March 2006 from the Acute Decompensated Heart Failure National Registry (ADHERE)-United States (US) database and 10 904 admissions in 70 hospitals from 10 countries from March 2005 to January 2009 from the ADHERE-International (I) database composed of countries in Asia-Pacific and Latin-American regions, we compared characteristics, treatments, length of stay, and in-hospital mortality between patients with PEF (left ventricular EF ≥ 40%). There were 26 258 (49.6%) admissions with HF-PEF in the ADHERE-US and 4206 (45.7%) in ADHERE-I. The USA cohort was older [median 77.2 years (25th, 75th, 66.5, and 84.4) vs. 71.0 (59.0, 79.0), P< 0.001] and more likely to be female (61.8 vs. 54.7%, P< 0.001). The international cohort had a longer length of stay [median 6.0 days (4.0, 10.0)] vs. 4.0 days [3.0, 7.0], P< 0.001) and higher use of inotropes (12.5 vs. 4.8%, P< 0.001). At discharge, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and diuretics were prescribed more in the USA (57.6 vs. 54.4%, P< 0.001; 63.0 vs. 35.5%, P< 0.001; 78.2 vs. 76.2%, P< 0.001); digoxin was prescribed more outside the USA (26.0 vs. 17.7%, P< 0.001). After adjusting for baseline characteristics, 7-day inpatient mortality was similar between the international and the USA cohorts [hazard ratio 0.80, 95% CI (0.61-1.05); P= 0.11]. Conclusions: Clinical characteristics, inpatient interventions, discharge therapies, and length of stay vary significantly for HF-PEF patients across geographic regions. This has important implications for global clinical trials and outcome studies in HF.

Eur J Heart Fail: 29 Jun 2011; epub ahead of print
West R, Liang L, Fonarow GC, Kociol R, ... O'Connor CM, Hernandez AF
Eur J Heart Fail: 29 Jun 2011; epub ahead of print | PMID: 21712289
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Abstract

Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document.

Zannad F, Garcia AA, Anker SD, Armstrong PW, ... Zalewski A, McMurray JJ
Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g. all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group\'s recommendations for achieving common views on heart failure endpoints in clinical trials.

Eur J Heart Fail: 20 Jun 2013; epub ahead of print
Zannad F, Garcia AA, Anker SD, Armstrong PW, ... Zalewski A, McMurray JJ
Eur J Heart Fail: 20 Jun 2013; epub ahead of print | PMID: 23787718
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Abstract

The effect of cardiac resynchronization therapy on left ventricular diastolic function assessed with speckle-tracking echocardiography.

Shanks M, Antoni ML, Hoke U, Bertini M, ... Bax JJ, Delgado V
Aims: Changes in left ventricular (LV) diastolic function after cardiac resynchronization therapy (CRT) in relation to LV reverse remodelling and heart failure aetiology have not been extensively characterized. The aims of the study were to evaluate changes in LV diastolic function with speckle-tracking echocardiography in relation to: (i) cardiac resynchronization therapy response (LV remodelling) and (ii) heart failure aetiology. Methods and results: A total of 192 heart failure patients undergoing CRT implantation were evaluated. Speckle-tracking echocardiography was performed before and 6 months after implantation and reliable analysis was obtained in 188 patients. Left ventricular diastolic function was assessed by measuring diastolic strain rate during the isovolumic relaxation period (SR(IVR)) and by calculating the ratio of peak transmitral E-wave to SR(IVR) (E/SR(IVR)). Changes in LV diastolic parameters were evaluated in responders and non-responders and in patients with ischaemic and non-ischaemic cardiomyopathy. Response to CRT was defined as ≥15% reduction in LV end-systolic volume at 6 months follow-up. One-hundred and nine patients (58%) were defined as responders. Significant improvements in LV diastolic performance were observed in responders with improvement in SR(IVR) (from 0.14 ± 0.08 to 0.18 ± 0.12 s(-1), P= 0.001) and E/SR(IVR) (from 834 ± 840 to 641 ± 612, P= 0.04). In addition, LV relaxation improved in patients with non-ischaemic aetiology (SR(IVR): from 0.15 ± 0.08 to 0.19 ± 0.13 s(-1), P= 0.004). In contrast, LV relaxation did not improve in non-responders and in patients with ischaemic heart disease. Conclusions: Novel diastolic strain rate indices are useful for evaluating changes in LV diastolic function after CRT. Improvement in diastolic function was only observed in responders to CRT and patients with non-ischaemic aetiology.

Eur J Heart Fail: 29 Aug 2011; epub ahead of print
Shanks M, Antoni ML, Hoke U, Bertini M, ... Bax JJ, Delgado V
Eur J Heart Fail: 29 Aug 2011; epub ahead of print | PMID: 21873339
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Abstract

Selection of a mineralocorticoid receptor antagonist for patients with hypertension or heart failure.

Iqbal J, Parviz Y, Pitt B, Newell-Price J, Al-Mohammad A, Zannad F
Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post-infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co-morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence-based approach with personalized medicine.

Eur J Heart Fail: 26 Jan 2014; epub ahead of print
Iqbal J, Parviz Y, Pitt B, Newell-Price J, Al-Mohammad A, Zannad F
Eur J Heart Fail: 26 Jan 2014; epub ahead of print | PMID: 24464876
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Abstract

Comparative analysis of the therapeutic effects of long-acting and short-acting loop diuretics in the treatment of chronic heart failure using 123I-metaiodobenzylguanidine scintigraphy.

Hisatake S, Nanjo S, Fujimoto S, Yamashina S, ... Nakano H, Yamazaki J
Aims: Loop diuretics are essential for the treatment of chronic heart failure (CHF) but short-acting diuretics are reported to induce sympathetic nervous system (SNS) activation. This study was performed to compare therapeutic effects of two loop diuretics, long-acting azosemide and short-acting furosemide, using (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy. Methods and results: Twenty-two patients with New York Heart Association class II-III heart failure and left ventricular dysfunction, who required treatment with a loop diuretic, were included. In this crossover study, 11 patients were randomized to azosemide treatment first and the remaining 11 patients to furosemide. Treatments were administered for 6 months and then patients were crossed over to the second treatment. (123)I-MIBG scintigraphy was performed before and 6 months after the start of treatment with each loop diuretic. Early and delayed images were obtained 20 min and 4 h after administration of (123)I-MIBG, respectively; and the heart/mediastinum (H/M) ratio and washout rate (WR) were measured. In addition, left ventricular ejection fraction (LVEF), levels of brain natriuretic peptide (BNP), and norepinephrine were measured before and 6 months after the start of treatment. No differences were observed between the two groups in terms of concomitant medication, cause of heart failure, H/M ratio, WR, BNP, norepinephrine, or LVEF. The azosemide group exhibited a significant increase in delayed image H/M ratio, and a significant decrease in WR and norepinephrine after the final administration compared with the furosemide group. Conclusion: This study indicates that azosemide suppresses SNS activation compared with furosemide in patients with CHF, suggesting that long-acting loop diuretics may have more beneficial effects on the prognosis of CHF.

Eur J Heart Fail: 23 May 2011; epub ahead of print
Hisatake S, Nanjo S, Fujimoto S, Yamashina S, ... Nakano H, Yamazaki J
Eur J Heart Fail: 23 May 2011; epub ahead of print | PMID: 21602550
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Abstract

Red blood cell distribution width and 1-year mortality in acute heart failure.

van Kimmenade RR, Mohammed AA, Uthamalingam S, van der Meer P, Felker GM, Januzzi JL
Aims: Red blood cell distribution width (RDW) predicts mortality in chronic heart failure (HF) and stable coronary artery disease. The prognostic value of RDW in more acute settings such as acute HF, and its relative prognostic value compared with more established measures such as N-terminal pro-brain natriuretic peptide (NT-proBNP), remains unknown. Methods and results: In a cohort of 205 patients with acute HF, independent predictors of RDW were identified using linear regression analysis. The association between RDW and 1-year survival in the context of other predictors was assessed using Cox\'s proportional hazards analysis. Red blood cell distribution width was elevated in 67 (32.7%) patients; RDW was independently associated with haematological variables such as haemoglobin (P < 0.001) as well as the use of loop diuretics (P = 0.006) and beta-blockers (P = 0.015) on presentation, but not with nutritional deficiencies, recent transfusion, or inflammatory variables. Log-transformed RDW values independently predicted mortality in multivariable Cox\'s proportional hazards analysis (hazards ratio, 1.03; 95% confidence interval, 1.00-1.06; P = 0.04); when stratified on the basis of RDW and NT-proBNP status, the combination provided additional prognostic information. Conclusion: Red blood cell distribution width is frequently elevated among patients with acute HF and does not appear to be associated with nutritional status, transfusion history, or inflammation. Red blood cell distribution width independently predicts 1-year mortality in acute HF. The value of RDW appears additive to other established prognostic variables such as NT-proBNP.

Eur J Heart Fail: 22 Dec 2009; epub ahead of print
van Kimmenade RR, Mohammed AA, Uthamalingam S, van der Meer P, Felker GM, Januzzi JL
Eur J Heart Fail: 22 Dec 2009; epub ahead of print | PMID: 20026456
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Abstract

Mitral annular plane systolic excursion on exercise: a simple diagnostic tool for heart failure with preserved ejection fraction.

Wenzelburger FW, Tan YT, Choudhary FJ, Lee ES, Leyva F, Sanderson JE
Aims: Current guidelines for the diagnosis of heart failure with normal or preserved ejection fraction (HFpEF) are based on measurements at rest. However, in HFpEF ventricular dysfunction is more apparent on exercise. We hypothesized that Mitral annular plane systolic excursion (MAPSE) which is easy to acquire on exercise could be used to detect occult left ventricular (LV) impairment. Methods and results: Cardiopulmonary exercise testing and 2D-Doppler echocardiography were performed at rest and on exercise. MAPSE was assessed by using M-mode (apical four-chamber view). Sixty-two patients with HFpEF [LV ejection fraction (LVEF)=60 ± 7%] with reduced VO(2) max (18.6 ± 5.2 mL/min/kg) and 36 control subjects (LVEF=62 ± 7%, VO(2) max 29.4 ± 4.8 mL/min/kg) were studied. MAPSE at rest was significantly lower in patients (10.9 ± 2.1 vs. 12.1 ± 2.2 mm in controls, P= 0.008) which was even more pronounced on exercise (12.0 ± 2.2 mm and 16.2 ± 2.7 mm, respectively, P< 0.001). At rest MAPSE correlated with longitudinal strain (r = 0.432, P= 0.001), peak systolic myocardial velocity (r = 0.545, P< 0.001), and early diastolic myocardial velocity (r = 0.322, P= 0.02) and on exercise with LV apical rotation (r = 0.582, P< 0.001), longitudinal strain (r = 0.589, P< 0.001), and myocardial tissue velocities (P< 0.001). The area under the receiver operating characteristic curve for MAPSE was 0.655 (confidence interval 0.540-0.770) at rest and 0.901 (confidence interval 0.835-0.967) on exercise, to differentiate between patients and controls. Conclusion: Mitral annular plane systolic excursion at rest and on exercise correlates well with more sophisticated measurements of ventricular function in HFpEF patients. It is potentially a useful and easily acquired measurement, especially on exercise, for the diagnosis of HFpEF.

Eur J Heart Fail: 02 Aug 2011; epub ahead of print
Wenzelburger FW, Tan YT, Choudhary FJ, Lee ES, Leyva F, Sanderson JE
Eur J Heart Fail: 02 Aug 2011; epub ahead of print | PMID: 21807660
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Abstract

Decongestion in acute heart failure.

Mentz RJ, Kjeldsen K, Rossi GP, Voors AA, ... O\'Connor C, Felker GM
Congestion is a major reason for hospitalization in acute heart failure (HF). Therapeutic strategies to manage congestion include diuretics, vasodilators, ultrafiltration, vasopressin antagonists, mineralocorticoid receptor antagonists, and potentially also novel therapies such as gut sequesterants and serelaxin. Uncertainty exists with respect to the appropriate decongestion strategy for an individual patient. In this review, we summarize the benefit and risk profiles for these decongestion strategies and provide guidance on selecting an appropriate approach for different patients. An evidence-based initial approach to congestion management involves high-dose i.v. diuretics with addition of vasodilators for dyspnoea relief if blood pressure allows. To enhance diuresis or overcome diuretic resistance, options include dual nephron blockade with thiazide diuretics or natriuretic doses of mineralocorticoid receptor antagonists. Vasopressin antagonists may improve aquaresis and relieve dyspnoea. If diuretic strategies are unsuccessful, then ultrafiltration may be considered. Ultrafiltration should be used with caution in the setting of worsening renal function. This review is based on discussions among scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from 30 November to 1 December 2012.

Eur J Heart Fail: 05 Mar 2014; epub ahead of print
Mentz RJ, Kjeldsen K, Rossi GP, Voors AA, ... O'Connor C, Felker GM
Eur J Heart Fail: 05 Mar 2014; epub ahead of print | PMID: 24599738
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Abstract

Sex differences in cardiomyopathies.

Meyer S, van der Meer P, van Tintelen JP, van den Berg MP
Cardiomyopathies are a heterogeneous group of heart muscle diseases with a variety of specific phenotypes. According to the contemporary European Society of Cardiology classification, they are classified into hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), restrictive (RCM), and unclassified cardiomyopathies. Each class is aetiologically further categorized into inherited (familial) and non-inherited (non-familial) forms. There is substantial evidence that biological sex is a strong modulator of the clinical manifestation of these cardiomyopathies, and sex-specific characteristics are detectable in all classes. For the clinician, it is important to know the sex-specific aspects of clinical disease expression and the potential modes of inheritance or the hereditary influences underlying the development of cardiomyopathies, since these may aid in diagnosing such diseases in both sexes.

Eur J Heart Fail: 26 Jan 2014; epub ahead of print
Meyer S, van der Meer P, van Tintelen JP, van den Berg MP
Eur J Heart Fail: 26 Jan 2014; epub ahead of print | PMID: 24464619
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Abstract

Cell-based therapies for cardiac repair: a meeting report on scientific observations and European regulatory viewpoints.

Schüssler-Lenz M, Beuneu C, Menezes-Ferreira M, Jekerle V, ... Zeiher A, Salmikangas P
In the past decade, novel cell-based products have been studied in patients with acute and chronic cardiac disease to assess whether these therapies are efficacious in improving heart function and preventing the development of end-stage heart failure. Cardiac indications studied include acute myocardial infarction (AMI), refractory angina, and chronic heart failure (CHF). Increased clinical activity, experience, and multiple challenges faced by developers have been recognized at the regulatory level. In May 2014, the Committee for Advanced Therapies (CAT) discussed in an expert meeting various cell-based medicinal products developed for cardiac repair, with a focus on non-manipulated bone marrow cells, sorted bone marrow or apheresis, and expanded cells, applied to patients with AMI or CHF. The intention was to share information, both scientific and regulatory, and to examine the challenges and opportunities in this field. These aspects were considered from the quality, and non-clinical and clinical perspectives, including current imaging techniques, with a focus on AMI and CHF. The scope of this overview is to present the European regulatory viewpoint on cell-based therapies for cardiac repair in the context of scientific observations.

Eur J Heart Fail: 15 Oct 2015; epub ahead of print
Schüssler-Lenz M, Beuneu C, Menezes-Ferreira M, Jekerle V, ... Zeiher A, Salmikangas P
Eur J Heart Fail: 15 Oct 2015; epub ahead of print | PMID: 26470631
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Abstract

The kidney in congestive heart failure: \'are natriuresis, sodium, and diuretics really the good, the bad and the ugly?\'

Verbrugge FH, Dupont M, Steels P, Grieten L, ... Tang WH, Mullens W
This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron\'s function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction-although not by conventional GFR measurements-is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function.

Eur J Heart Fail: 26 Jan 2014; epub ahead of print
Verbrugge FH, Dupont M, Steels P, Grieten L, ... Tang WH, Mullens W
Eur J Heart Fail: 26 Jan 2014; epub ahead of print | PMID: 24464967
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Abstract

Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study.

Krum H, Massie B, Abraham WT, Dickstein K, ... Armbrecht J, on behalf of the ATMOSPHERE Investigators
Aims: The renin-angiotensin-aldosterone system (RAAS) represents a key therapeutic target in heart failure (HF) management. However, conventional agents that block this system induce a reflex increase in plasma renin activity (PRA), which may lead to RAAS \'escape\'. Direct renin inhibitors (DRIs) have been developed that decrease PRA and thus may provide a greater RAAS blockade. Aliskiren is the first orally active DRI. Plasma levels of B-type natriuretic peptide (BNP) have been observed to be reduced with aliskiren compared with placebo. The aim of the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE) study is to evaluate the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on cardiovascular death and HF hospitalization in patients with chronic systolic HF, NYHA functional class II-IV symptoms, and elevated plasma levels of BNP. Methods Patients tolerant to at least 10 mg or equivalent of enalapril will undergo an open-label run-in period where they receive enalapril then aliskiren. Approximately 7000 patients tolerating this run-in period will then be randomized 1:1:1 to aliskiren monotherapy, enalapril monotherapy, or the combination. The primary endpoints of ATMOSPHERE are (i) whether the aliskiren/enalapril combination is superior to enalapril monotherapy in delaying time to first occurrence of cardiovascular death or HF hospitalization and (ii) whether aliskiren monotherapy is superior or at least non-inferior to enalapril monotherapy on this endpoint. Perspective The ATMOSPHERE study will definitively determine the role of a DRI strategy additional to or as an alternative to conventional RAAS blockade in patients with chronic systolic HF.

Eur J Heart Fail: 20 Dec 2010; 13:107-114
Krum H, Massie B, Abraham WT, Dickstein K, ... Armbrecht J, on behalf of the ATMOSPHERE Investigators
Eur J Heart Fail: 20 Dec 2010; 13:107-114 | PMID: 21169387
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Abstract

Parathyroid hormone and vitamin D--markers for cardiovascular and all cause mortality in heart failure.

Schierbeck LL, Jensen TS, Bang U, Jensen G, Køber L, Jensen JE
Aims: To investigate levels of vitamin D and parathyroid hormone (PTH) in a population of heart failure (HF) patients, and to evaluate whether vitamin D and PTH are related to prognosis. Methods and results: This was a prospective study of 148 HF outpatients (mean age 68 years, 102 men) with follow-up for mortality after 3&frac12; years. Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), PTH, 25-hydroxyvitamin D (25-OHD), and several other biomarkers were examined. Mortality and cardiovascular mortality were analysed in multivariable regression analyses adjusting for other independent prognostic variables. Vitamin D deficiency (≤50 nmol/L) was prevalent in 43% of the population; 26% had elevated PTH levels; none had primary hyperparathyroidism. We found a strong and independent significant association of both PTH and vitamin D to mortality, which was independent of other clinically important parameters [NT-proBNP, estimated glomerular filtration rate (eGFR), age, and left ventricular ejection fraction (LVEF)]. Both PTH and vitamin D were also significantly associated with all cause mortality. In an adjusted model, we found a hazard ratio of 1.9 (confidence interval 1.1-3.4) for vitamin D deficiency and 2.0 (1.0-3.8) for the upper median of PTH, respectively. Conclusion: In this relatively small prospective study, PTH and vitamin D were independently associated with all cause and cardiovascular mortality in patients with HF. This was independent of other known risk factors such as eGFR, LVEF, NT-proBNP, and age.

Eur J Heart Fail: 18 Mar 2011; epub ahead of print
Schierbeck LL, Jensen TS, Bang U, Jensen G, Køber L, Jensen JE
Eur J Heart Fail: 18 Mar 2011; epub ahead of print | PMID: 21415099
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Abstract

Myocardial damage in patients with sarcoidosis and preserved left ventricular systolic function: an observational study.

Patel AR, Klein MR, Chandra S, Spencer KT, ... Sweiss NJ, Beshai JF
Aims: Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) is a valuable test to detect myocardial damage in patients with sarcoidosis; however, the clinical significance of LGE in sarcoidosis patients with preserved left ventricular ejection fraction (LVEF) is not defined. We aim to characterize the prevalence of LGE, its associated cardiac findings, and its clinical implications in sarcoidosis patients with preserved LVEF. Methods and results: One hundred and fifty-two patients with biopsy proven extra-cardiac sarcoidosis, no known cardiac sarcoidosis, and LVEF ≥50% referred for LGE-CMR were included in this observational study. The presence of LGE in the left ventricular myocardium was considered diagnostic for cardiac sarcoidosis. The cohort was divided into two groups based on the presence or absence of LGE. Twenty-nine patients (19%) had LGE involving 11 ± 9% of the left ventricle. The modified Japanese Ministry of Health and Welfare (JMHW) criteria for diagnosing cardiac sarcoidosis only had a sensitivity of 52% and specificity of 83% for identifying myocardial LGE in these patients. Compared with those patients without LGE, those with LGE had a higher heart rate (84 ± 19 vs. 76 ± 18 b.p.m., P= 0.002), greater prevalence of an abnormal electrocardiogram (76 vs. 31%, P< 0.001), diastolic dysfunction (67 vs. 33%, P= 0.05), reduced right ventricular ejection fraction (49 ± 8 vs. 55 ± 6%, P= 0.012), and evidence of non-sustained ventricular tachycardia (33 vs. 6%). Conclusions: In patients with sarcoidosis and preserved systolic function, myocardial damage is commonly present and may increase the risk of ventricular tachy-arrhythmias. The JMHW Criteria were neither sensitive nor specific for predicting the presence of myocardial LGE.

Eur J Heart Fail: 03 Aug 2011; epub ahead of print
Patel AR, Klein MR, Chandra S, Spencer KT, ... Sweiss NJ, Beshai JF
Eur J Heart Fail: 03 Aug 2011; epub ahead of print | PMID: 21810833
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Abstract

The furosemide diagnostic test in suspected slow-onset heart failure: popular but not useful.

Kelder JC, Cramer MJ, Rutten FH, Plokker HW, Grobbee DE, Hoes AW
Aims: Early, slow-onset heart failure is difficult to diagnose from just signs and symptoms. The physician needs ancillary diagnostic tests. The \'loop-diuretic test\' or \'furosemide test\', characterized as weight loss and alleviation of symptoms after a short course of a loop-diuretic, could be a candidate. The furosemide test is not formally mentioned in the guidelines and no evidence could be found in the literature. We asked general practitioners (GPs) about their actual use of the furosemide test and studied the diagnostic accuracy in patients with suspected heart failure. Methods and results: General practitioners completed a questionnaire about their use of the furosemide test. We then performed a diagnostic accuracy study among a representative and consecutive sample of patients suspected of new, slow-onset heart failure by the GP and who were referred to the rapid access heart failure diagnostic facility of one hospital. All patients underwent a standardized diagnostic work-up including echocardiography. The reference standard for the diagnosis of heart failure was the decision of an expert panel. Forty of the 54 GPs had actually used the furosemide test in the past year and 70% considered the test to be useful. Forty seven patients underwent the furosemide test and 12 (25%) were diagnosed with heart failure. None of the effects of the test (weight loss, alleviation of symptoms) was significantly associated with heart failure. Conclusion: We cannot support the use of the furosemide test as an ancillary diagnostic test in patients suspected of new, slow-onset heart failure.

Eur J Heart Fail: 04 Mar 2011; epub ahead of print
Kelder JC, Cramer MJ, Rutten FH, Plokker HW, Grobbee DE, Hoes AW
Eur J Heart Fail: 04 Mar 2011; epub ahead of print | PMID: 21372044
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Abstract

Myocarditis as a precipitating factor for heart failure: evaluation and 1-year follow-up using cardiovascular magnetic resonance and endomyocardial biopsy.

Mavrogeni S, Spargias C, Bratis C, Kolovou G, ... Pavlides G, Cokkinos D
Aims: The aim of this study was to evaluate myocarditis as a precipitating factor for heart failure using cardiovascular magnetic resonance (CMR) and endomyocardial biopsy Methods and results: Eighty-five patients with suspected myocarditis and 20 controls were evaluated. Seventy-one patients with positive CMR were referred for endomyocardial biopsy and re-evaluation after 1 year. Cardiovascular magnetic resonance was performed using STIR T2-weighted (T2W), early T1-weighted (EGE), and late gadolinium-enhanced (LGE) images. Immunohistological and polymerase chain reaction (PCR) analysis of myocardial specimens was employed. In patients with myocarditis, T2 and EGE were increased compared with controls (2.6 ± 0.9 vs. 1.57 ± 0.13, P < 0.001 and 7.9 ± 5.5 vs. 3.59 ± 0.08, P < 0.001, respectively). Late gadolinium enhancement was found in all myocarditis patients. Endomyocardial biopsy performed in 50 of 71 patients with positive CMR showed positive immunohistology in 48% and presence of infectious genomes in 80% (mainly Chlamydia, Herpes, and Parvovirus B19). Left ventricular ejection fraction (LVEF) was significantly decreased compared with controls (47.7 ± 19.2 vs. 64 ± 0.2, P < 0.001). After 1 year, CMR showed normalization of T2 and EGE, and decreased LGE. Left ventricular ejection fraction increased in 36.5% of patients, remained stable in 56.5% and decreased in 7% of patients, in whom biopsy showed persistence of the initial infective agents. A negative correlation was identified between EGE, LGE, and LVEF. Patients with positive biopsies had lower LVEFs. Conclusion: In a Greek population with myocarditis, Chlamydia with viruses was a common finding. Cardiovascular magnetic resonance and PCR proved useful for the detection of myocarditis; EGE and LGE had the best correlation for the development of heart failure. Persistence of the initially detected infective agents was identified in patients who deteriorated further.

Eur J Heart Fail: 02 Jun 2011; epub ahead of print
Mavrogeni S, Spargias C, Bratis C, Kolovou G, ... Pavlides G, Cokkinos D
Eur J Heart Fail: 02 Jun 2011; epub ahead of print | PMID: 21632580
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Abstract

Renal denervation in heart failure with normal left vetricular ejection fraction. Rationale and design of the DIASTOLE (DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection fraction) trial.

Verloop WL, Beeftink MM, Nap A, Bots ML, ... Allaart CP, Voskuil M
AimIncreasing evidence suggests an important role for hyperactivation of the sympathetic nervous system (SNS) in the clinical phenomena of heart failure with normal LVEF (HFNEF) and hypertension. Moreover, the level of renal sympathetic activation is directly related to the severity of heart failure. Since percutaneous renal denervation (pRDN) has been shown to be effective in modulating elevated SNS activity in patients with hypertension, it can be hypothesized that pRDN has a positive effect on HFNEF. The DIASTOLE trial will investigate whether renal sympathetic denervation influences parameters of HFNEF.MethodsDIASTOLE is a multicentre, randomized controlled trial. Sixty patients, diagnosed with HFNEF and treated for hypertension, will be randomly allocated in a 1:1 ratio to undergo renal denervation on top of medical treatment (n = 30) or to maintain medical treatment alone (n = 30). The primary objective is to investigate the efficacy of pRDN by means of pulsed wave Doppler echocardiographic parameters. Secondary objectives include safety of pRDN and a comparison of changes in the following parameters after pRDN: LV mass, LV volume, LVEF, and left atrial volume as determined by magnetic resonance imaging. Also, MIBG (metaiodobenzylguanidine) uptake and washout, BNP levels, blood pressure, heart rate variability, exercise capacity, and quality of life will be assessed.PerspectiveDIASTOLE is a randomized controlled trial evaluating renal denervation as a treatment option for HFNEF. The results of the current trial will provide important information regarding the treatment of HFNEF, and therefore may have major impact on future therapeutic strategies.Trail registrationNCT01583881.

Eur J Heart Fail: 24 Jul 2013; epub ahead of print
Verloop WL, Beeftink MM, Nap A, Bots ML, ... Allaart CP, Voskuil M
Eur J Heart Fail: 24 Jul 2013; epub ahead of print | PMID: 23883653
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Abstract

Prognostic electrocardiographic parameters in patients with suspected myocarditis.

Ukena C, Mahfoud F, Kindermann I, Kandolf R, Kindermann M, Böhm M
Aims: The objective of this study was to investigate the prognostic value of electrocardiographic (ECG) parameters for outcome in patients acutely admitted with myocarditis without previous heart failure who underwent endomyocardial biopsy. Methods and results: Between 1995 and 2009, 186 consecutive patients (age: 43.4 ± 13.9 years) acutely admitted with clinically suspected myocarditis were enrolled and followed up for a mean of 55.1 ± 105.1 months. Electrocardiograms recorded before myocardial biopsy were analysed for rhythm, conduction times, signs of hypertrophy, and repolarization abnormalities. The primary endpoint was time to cardiac death or heart transplantation. The mean QRS duration was 90.3 ± 24.3 ms; 158 patients had a normal QRS duration (<120 ms) and 21 patients had a prolonged QRS duration (≥120 ms). During follow-up, 15.8% of patients with a normal QRS duration reached the primary endpoint compared with 42.8% of patients with a prolonged baseline QRS duration [hazard ratio (HR) 3.43; 95% confidence interval (CI) 1.78-6.01; P < 0.001]. The increased risk predicted by a prolonged QRS duration was robust after adjusting for covariates (HR 2.83; CI 1.07-7.49; P = 0.012). A QTc prolongation ≥440 ms (P = 0.011), an abnormal QRS axis (P = 0.012), and premature ventricular beats (P = 0.018) were significant monovariate predictors but did not prove to be independent predictors for survival in multivariate analysis. Q-waves and repolarization abnormalities were neither associated with the primary endpoint nor with immunohistological signs of inflammation. Other ECG parameters were not significantly related to outcome. Conclusion: A prolonged QRS duration is an independent predictor for cardiac death or heart transplantation in patients with suspected myocarditis.

Eur J Heart Fail: 17 Jan 2011; epub ahead of print
Ukena C, Mahfoud F, Kindermann I, Kandolf R, Kindermann M, Böhm M
Eur J Heart Fail: 17 Jan 2011; epub ahead of print | PMID: 21239404
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Abstract

Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use.

D\'Elia E, Vaduganathan M, Gori M, Gavazzi A, Butler J, Senni M
Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome characterized by cardiovascular, metabolic, and pro-inflammatory diseases associated with advanced age and extracardiac comorbidities. All of these conditions finally lead to impairment of myocardial structure and function. The large phenotypic heterogeneity of HFpEF from pathophysiological underpinnings presents a major hurdle to HFpEF therapy. The new therapeutic approach in HFpEF should be targeted to each HF phenotype, instead of the \'one-size-fits-all\' approach, which has not been successful in clinical trials. Unless the structural and biological determinants of the failing heart are deeply understood, it will be impossible to appropriately differentiate HFpEF patients, identify subtle myocardial abnormalities, and finally reverse abnormal cardiac function. Based on evidence from endomyocardial biopsies, some of the specific cardiac structural phenotypes to be targeted in HFpEF may be represented by myocyte hypertrophy, interstitial fibrosis, myocardial inflammation associated with oxidative stress, and coronary disease. Once the diagnosis of HFpEF has been established, a potential approach could be to use a panel of biomarkers to identify the main cardiac structural HFpEF phenotypes, guiding towards more appropriate therapeutic strategies. Accordingly, the purpose of this review is to investigate the potential role of biomarkers in identifying different cardiac structural HFpEF phenotypes and to discuss the merits of a biomarker-guided strategy in HFpEF.

Eur J Heart Fail: 22 Oct 2015; epub ahead of print
D'Elia E, Vaduganathan M, Gori M, Gavazzi A, Butler J, Senni M
Eur J Heart Fail: 22 Oct 2015; epub ahead of print | PMID: 26493383
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Abstract

Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation.

Ter Maaten JM, Damman K, Verhaar MC, Paulus WJ, ... Navis G, Voors AA
Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.

Eur J Heart Fail: 09 Feb 2016; epub ahead of print
Ter Maaten JM, Damman K, Verhaar MC, Paulus WJ, ... Navis G, Voors AA
Eur J Heart Fail: 09 Feb 2016; epub ahead of print | PMID: 26861140
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Abstract

A perspective on re-evaluating digoxin\'s role in the current management of patients with chronic systolic heart failure: targeting serum concentration to reduce hospitalization and improve safety profile.

Adams KF, Ghali JK, Herbert Patterson J, Stough WG, ... Mackowiak JI, van Veldhuisen DJ
Digoxin improves exercise tolerance and reduces hospitalizations in patients with systolic heart failure, but its use has declined progressively for the past two decades. The Digitalis Investigation Group trial showed that digoxin reduced hospitalizations but had a neutral effect on total mortality. There was evidence that mortality caused by worsening heart failure was less, but there was also a signal suggesting an increase in other cardiac (presumed arrhythmic) death. Use of digoxin has declined substantially and recent guideline recommendations have significantly de-emphasized the importance of this drug in the management of heart failure. Two developments suggest that re-evaluation of the contemporary role of digoxin in the management of heart failure with reduced ejection fraction is warranted. First, heart failure remains progressive, characterized by chronic debility, exercise intolerance, and frequent and costly hospitalizations, despite evidence-based drug and device therapies that prolong survival. Health economics have made reducing hospitalizations in patients with heart failure a major priority. Second, a strong association has emerged between serum concentration and the safety and efficacy of digoxin, which indicates a change in our approach to dosing this agent is needed. Experimental and clinical results suggest that optimizing therapeutic benefit and avoiding harm means dosing to achieve low serum digoxin concentrations (0.5-0.9 ng/mL). Digoxin is an inexpensive agent and the totality of evidence indicates that it reduces hospitalizations and improves symptoms safely when dosed to achieve low serum concentrations. These findings suggest digoxin should have a more prominent therapeutic role in patients with heart failure and reduced ejection fraction.

Eur J Heart Fail: 26 Feb 2014; epub ahead of print
Adams KF, Ghali JK, Herbert Patterson J, Stough WG, ... Mackowiak JI, van Veldhuisen DJ
Eur J Heart Fail: 26 Feb 2014; epub ahead of print | PMID: 24574198
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Abstract

Occurrence of late gadolinium enhancement is associated with increased left ventricular wall stress and mass in patients with non-ischaemic dilated cardiomyopathy.

Alter P, Rupp H, Adams P, Stoll F, ... Rominger MB, Maisch B
Aims: Occurrence of late gadolinium enhancement (LGE) as assessed by cardiac magnetic resonance (CMR) imaging has been attributed to various myocardial injuries. We hypothesized that LGE is associated with left ventricular (LV) wall stress. Methods and results: We examined 300 patients with suspected non-ischaemic dilated cardiomyopathy. Cardiac magnetic resonance was used to assess LV volume, mass, wall stress, and LGE. Increased LV end-diastolic wall stress (> 4 kPa) was found in 112 patients (37 %), and increased end-systolic wall stress (>18 kPa) in 121 patients (40%). Presence of LGE was observed in 93 patients (31%). End-diastolic (94 ± 43 vs. 79 ± 42 ml/m&sup2;, P = 0.006) and end-systolic LV volumes (62 ± 44 vs. 44 ± 37 ml/m&sup2;, P < 0.001) and LV mass (95 ± 34 vs. 78 ± 31 g/m&sup2;, P < 0.001) were increased in patients exhibiting LGE. In particular, LV end-diastolic and end-systolic wall stress were increased (4.5 ± 2.8 vs. 3.6 ± 3.0 kPa, P = 0.025; 19.6 ± 9.1 vs. 17.5 ± 8.2 kPa, P = 0.045). Late gadolinium enhancement was observed more frequently than would be expected from random occurrence in patients with increased end-diastolic (39 vs. 26%, P = 0.020) and end-systolic wall stress (41 vs. 24%, P = 0.002). Both normal end-diastolic and end-systolic wall stress had a high negative predictive value for LGE (75 and 76%). Conclusions: The present study shows that occurrence of LGE in cardiomyopathy is associated with increased LV wall stress and mass. Suspected causes are an increased capillary leakage by stretch, impaired contrast agent redistribution, or increased diffusion distances. It is proposed that LGE should be considered as a potential prognostic determinant of heart failure and severe arrhythmias.

Eur J Heart Fail: 01 Aug 2011; epub ahead of print
Alter P, Rupp H, Adams P, Stoll F, ... Rominger MB, Maisch B
Eur J Heart Fail: 01 Aug 2011; epub ahead of print | PMID: 21803756
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Abstract

Association of impaired left ventricular twisting-untwisting with vascular dysfunction, neurohumoral activation and impaired exercise capacity in hypertensive heart disease.

Ikonomidis I, Tzortzis S, Triantafyllidi H, Parissis J, ... Paraskevaidis I, Lekakis J
We investigated the association between left ventricular (LV) torsional deformation and vascular dysfunction, fibrosis, neurohumoral activation, and exercise capacity in patients with normal ejection fraction Methods and results: In 320 newly-diagnosed untreated hypertensive patients and 160 controls, we measured: pulse wave velocity (PWV); coronary flow reserve (CFR) by Doppler echocardiography; global longitudinal strain and strain rate, peak twisting, the percentage changes between peak twisting, and untwisting at mitral valve opening (%dpTw - UtwMVO ), at peak (%dpTw - UtwPEF ), and the end of early LV diastolic filling (%dpTw - UtwEDF ) by speckle tracking imaging; transforming growth factor (TGFb-1), metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloptoteinase-1(TIMP-1), markers of collagen synthesis, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Oxygen consumption (VO2 ), measured by means of cardiopulmonary exercise test, was assessed in a subset of 80 patients. The PWV, CFR, longitudinal strain and strain rate, %dpTw-UtwMVO , %dpTw-UtwPEF , and %dpTw-UtwEDF were impaired in hypertensive patients compared with controls. In multivariable analysis, CFR, PWV, LV mass, and systolic blood pressure were independent determinants of longitudinal strain, strain rate, and untwisting markers (P < 0.05). Increased TGFb-1 was related with increased collagen synthesis markers, TIMP-1 and MMP-9 and these biomarkers were associated with impaired longitudinal systolic strain rate, untwisting markers, CFR and PWV (P < 0.05). Delayed untwisting as assessed by reduced %dpTw - UtwEDF was related with increased NT-proBNP and reduced VO2 (P < 0.05).

Eur J Heart Fail: 06 Oct 2015; epub ahead of print
Ikonomidis I, Tzortzis S, Triantafyllidi H, Parissis J, ... Paraskevaidis I, Lekakis J
Eur J Heart Fail: 06 Oct 2015; epub ahead of print | PMID: 26443037
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Abstract

Increased catabolic activity in adipose tissue of patients with chronic heart failure.

Szabó T, Postrach E, Mähler A, Kung T, ... Boschmann M, Doehner W
Aims: Patients with chronic heart failure (CHF) have an increased catabolic state that affects both muscle and adipose tissue (AT), and may ultimately result in cardiac cachexia. Increased plasma levels of ANP might contribute to increased lipid mobilization and oxidation in CHF. We tested the hypothesis that increased plasma ANP levels are associated with an increased catabolic (lipolytic) state of white AT in patients with CHF. Methods and results: After an overnight fast, AT metabolism was studied by microdialysis in patients with CHF and healthy controls of a similar age and body composition (both n = 8). AT glycolytic and lipolytic activities were assessed at rest (fasting) and after an oral glucose load (oGL). Fasting and post-prandial profiles of serum glucose, insulin, and free fatty acids and of dialysate glucose did not differ significantly between patients and controls. In contrast, fasting dialysate lactate and glycerol levels were two-fold higher in patients vs. controls (lactate, 0.51 ± 0.10 and 0.26 ± 0.06 mmol/L, P < 0.01; glycerol, 116 ± 18 and 50 ± 8 µmol/L, P < 0.001), indicating increased AT glycolytic and lipolytic rates in patients. After an oGL, dialysate lactate increased ∼2- and 2.5-fold, whereas dialysate glycerol decreased by ∼60% and 50% in patients vs. controls, but metabolite levels were always significantly higher in patients vs. controls (all P < 0.05). Plasma ANP levels were increased in patients and significantly correlated with adipose tissue dialysate glycerol. Conclusion: In patients wiuth CHF, there is a direct correlation between plasma ANP levels and increased AT catabolic (lipolytic) state. This might contribute to AT wasting and the development of cardiac cachexia in patients with CHF.

Eur J Heart Fail: 21 May 2013; epub ahead of print
Szabó T, Postrach E, Mähler A, Kung T, ... Boschmann M, Doehner W
Eur J Heart Fail: 21 May 2013; epub ahead of print | PMID: 23696611
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Abstract

Circulating microRNAs as candidate markers to distinguish heart failure in breathless patients.

Ellis KL, Cameron VA, Troughton RW, Frampton CM, Ellmers LJ, Richards AM
Aims: Since their identification in the circulation, microRNAs have received considerable interest as putative biomarkers of cardiovascular disease. We have investigated the diagnostic utility of microRNAs in differentiating between patients with heart failure (HF) and non-HF-related breathlessness, and between HF with reduced (HF-REF) and preserved (HF-PEF) EF. Methods and results: MicroRNA profiling was performed on plasma from 32 HF and 15 COPD patients, as well as 14 healthy controls. Seventeen microRNAs were selected for validation in 44 HF, 32 COPD, 59 other breathless, and 15 controls. Cases of HF were split evenly between HF-REF and HF-PEF. Diagnostic utility was compared with NT-proBNP and high sensitivity troponin T (hs-troponin T). MiR-103 [area under the curve (AUC) = 0.642, P = 0.007], miR-142-3p (AUC = 0.668, P = 0.002), miR-199a-3p (AUC = 0.668, P = 0.002), miR-23a (AUC = 0.637, P = 0.010), miR-27b (AUC = 0.642, P = 0.008), miR-324-5p (AUC = 0.621, P = 0.023), and miR-342-3p (AUC = 0.644, P = 0.007) were associated with HF diagnosis in regression and receiver operating characteristic (ROC) analyses. Individually, NT-proBNP (AUC = 0.896, P = 9.68 × 10(-14)) and hs-troponin T (AUC = 0.750, P = 2.50 × 10(-6)) exhibited greater sensitivity and specificity. However, combining significantly associated microRNAs with NT-proBNP improved the AUC of NT-proBNP by 4.6% (P = 0.013). Four microRNAs, miR-103, miR-142-3p, miR-30b, and miR-342-3p, were differentially expressed between HF and controls, COPD, and other breathless patients (P = 0.002-0.030). Eight microRNAs that distinguished between HF-REF and HF-PEF in screening (P = 0.017-0.049) were not replicated in the validation. Conclusions: Four microRNAs distinguished between HF and exacerbation of COPD, other causes of dyspnoea, and controls. Seven were associated with HF diagnosis in regression and ROC analysis. Although individually NT-proBNP was far superior in predicting HF, combining microRNA levels with NT-proBNP may add diagnostic value.

Eur J Heart Fail: 21 May 2013; epub ahead of print
Ellis KL, Cameron VA, Troughton RW, Frampton CM, Ellmers LJ, Richards AM
Eur J Heart Fail: 21 May 2013; epub ahead of print | PMID: 23696613
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Abstract

Kicking the tyres of a heart failure trial: physician response to the approval of sacubitril/valsartan in the USA.

Packer M
Angiotensin receptor-neprilysin inhibition has been shown to be superior to target doses of an ACE inhibitor in reducing the risk of cardiovascular death and clinical disease progression in patients with chronic heart failure and a reduced EF. Nevertheless, although sacubitril/valsartan has been available in the USA for a year, uptake of the drug by practitioners has been slow, in part because of misconceptions about the pivotal trial that demonstrated its efficacy in heart failure (PARADIGM-HF). This review addresses questions that have been raised in the USA about the design of the trial as well as the patients who were studied, the replicability and applicability of the results, and the safety of neprilysin inhibition. The totality of evidence indicates that the PARADIGM-HF trial used an appropriate comparator; enrolled patients typical of those seen in the community with mild to moderate symptoms; yielded highly persuasive and replicable results; and demonstrated benefits that are applicable to patients taking subtarget doses of ACE inhibitors and ARBs. Regulatory review in the USA concluded that the established advantages of sacubitril/valsartan on cardiovascular death and disease progression outweighed hypothetical uncertainties about the long-term effects of neprilysin inhibition in patients who might not have survived without the drug. Accordingly, both the new US and European Society of Cardiology heart failure guidelines recommend sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in patients with chronic heart failure who are currently receiving an ACE inhibitor or ARB.

Eur J Heart Fail: 10 Aug 2016; epub ahead of print
Packer M
Eur J Heart Fail: 10 Aug 2016; epub ahead of print | PMID: 27510447
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Abstract

Renal denervation and heart failure.

Böhm M, Ewen S, Kindermann I, Linz D, Ukena C, Mahfoud F
Renal denervation has been developed in order to lower systolic blood pressure in resistant hypertension by a reduction in renal afferent and efferent sympathetic nerve activity. In heart failure sympathetic activation, in particular, renal norepinephrine release is closely associated with morbidity and mortality. Initial studies have shown that renal denervation is able to reduce not only blood pressure but also heart rate, and is associated with a reduction in myocardial hypertrophy, improved glucose tolerance, and ameliorated microalbuminuria. Since some experimental and observational data suggest an antiarrhythmic effect, it is possible that renal denervation might also play a therapeutic role in arrhythmias often occurring in chronic heart failure. The first proof-of-concept studies are planned to evaluate the clinical effect of this pathophysiologically plausible method, which might be able to change clinical practice.

Eur J Heart Fail: 18 Mar 2014; epub ahead of print
Böhm M, Ewen S, Kindermann I, Linz D, Ukena C, Mahfoud F
Eur J Heart Fail: 18 Mar 2014; epub ahead of print | PMID: 24644008
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Abstract

Renin-angiotensin system blockade in heart failure patients on long-term haemodialysis in Taiwan.

Tang CH, Chen TH, Wang CC, Hong CY, Huang KC, Sue YM
Aims: Heart failure is among the most frequent complications of patients on long-term haemodialysis. The benefits of renin-angiotensin system (RAS) blockade on the outcomes of these patients have yet to be determined. Methods and results: We conducted a nationwide observational study using data from the Taiwan National Health Insurance claims database, between 1999 and 2010. We enrolled patients aged ≥35 years with new-onset heart failure [diagnosed by International Classification of Diseases, 9th revision, clinical modification (ICD-9-CM) codes] under treatment with medications. New users of a RAS blocker (RASB; i.e. an ACE inhibitor or an ARB used as monotherapy or dual therapy) were selected to compare with non-RASB users. We used Cox proportional hazards regression with and without propensity score adjustment to compare the risk of 3-year all-cause and cardiovascular mortality. Stratified analyses and RASB therapy duration as a time-dependent covariate were also performed. In all, 4771 were treated with an RASB (n = 3024) or without an RASB (n = 1747). RASB users had a higher prevalence of hypertension and diabetes, and a higher number of hospitalization. Among RASB users, 1148 deaths (38.0%) occurred during 5272 person-years of follow-up compared with 734 deaths (42.0%) among non-RASB users during 2683 person-years of follow-up. Three-year mortality rates were 45.4% and 49.1% for patients receiving and those not receiving an RASB, respectively (log-rank test, P < 0.001). Adjusted hazard analysis revealed that RASB therapeutic effects remained significant on all-cause [hazard ratio (HR) 0.8; 95% confidence interval (CI) 0.72-0.89; P < 0.001] and cardiovascular mortality (HR 0.76; 95% CI 0.64-0.90; P < 0.01). Conclusions: RASB therapy reduced all-cause and cardiovascular mortality in heart failure patients on long-term haemodialysis.

Eur J Heart Fail: 13 May 2013; epub ahead of print
Tang CH, Chen TH, Wang CC, Hong CY, Huang KC, Sue YM
Eur J Heart Fail: 13 May 2013; epub ahead of print | PMID: 23671265
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Abstract

Left atrial expansion index predicts all-cause mortality and heart failure admissions in dyspnoea.

Hsiao SH, Chiou KR
Aims: The power of left atrial (LA) parameters for predicting adverse events in relatively low-risk groups is not fully understood. This study investigated whether the LA expansion index predicts heart failure (HF) and all-cause mortality in subjects with dyspnoea. Methods and results: Echocardiography was performed to identify causes of dypnoea in 1735 patients. The LA expansion index was calculated as (Volmax - Volmin) × 100%/Volmin, where Volmax was defined as the maximal LA volume and Volmin was defined as the minimal LA volume. The endpoints were 2-year frequencies of HF hospitalization and all-cause mortality. Over a median follow-up of 2.7 years, 91 participants reached endpoints. Rates of adverse events were exponentially proportional to the LA expansion index. For predicting adverse events, the LA expansion index was better than the maximal indexed LA volume and tissue Doppler parameters. Hospitalization for HF was independently associated with age, LVEF, pulmonary artery systolic pressure, LA expansion index, and history of prior HF. All-cause mortality was associated with age, pulmonary artery systolic pressure, and LA expansion index. Compared with the highest quartile of the LA expansion index, the lowest quartile had a 3.1-fold higher hazard of HF events and a 17.8-fold higher hazard of all-cause mortality. Conclusions: The LA expansion index predicts adverse events in patients with dyspnoea. The prognostic power of the index exceeds that of other well-established echocardiographic parameters such as E/e\' and maximal indexed LA volume.Trial registrationNCT01171040.

Eur J Heart Fail: 23 May 2013; epub ahead of print
Hsiao SH, Chiou KR
Eur J Heart Fail: 23 May 2013; epub ahead of print | PMID: 23703107
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Abstract

Targeting myocardial remodelling to develop novel therapies for heart failure: A position paper from the Working Group on Myocardial Function of the European Society of Cardiology.

Tarone G, Balligand JL, Bauersachs J, Clerk A, ... Thum T, Tocchetti CG
The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/endoplasmic Ca(2 +) ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications.

Eur J Heart Fail: 17 Mar 2014; epub ahead of print
Tarone G, Balligand JL, Bauersachs J, Clerk A, ... Thum T, Tocchetti CG
Eur J Heart Fail: 17 Mar 2014; epub ahead of print | PMID: 24639064
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Abstract

Serial measurement of galectin-3 in patients with chronic heart failure: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study.

Motiwala SR, Szymonifka J, Belcher A, Weiner RB, ... Bhardwaj A, Januzzi JL
Aims: Galectin-3 is a prognostic heart failure (HF) biomarker that may mediate cardiac fibrosis. We examined the value of serial galectin-3 measurement for prognosis and response to therapy in chronic HF. Methods and results: A total of 151 subjects with LV systolic dysfunction (LVSD) were followed through 908 visits over 10 ± 3 months. The amount of time spent with a galectin-3 level ≤ 20.0 ng/mL and changes between baseline and subsequent values were considered across visits, and used to assess risk for adverse cardiovascular (CV) events and associations with LV remodelling. Medication effects on galectin-3 were examined. Median galectin-3 values at baseline, 3 months, and 6 months were higher in patients with CV events (21.7 vs. 18.4 ng/mL, P = 0.03; 21.7 vs. 16.5 ng/mL, P = 0.03; 23.2 vs. 16.0 ng/mL, P = 0.007). Galectin-3 concentration changed in 35.2% of subjects during study procedures; time spent at ≤ 20.0 ng/mL was significantly associated with a lower rate of CV events, independently predicted fewer CV events even adjusted for relevant variables including study allocation, NT-proBNP, and renal function [odds ratio (OR) = 0.90; P = 0.05], and predicted increase in LV ejection fraction (OR = 1.20; P = 0.04). Serial galectin-3 measurement at 6 months added prognostic value beyond the baseline level (P = 0.02). There were no significant effects of medications on galectin-3 levels. Conclusion: In chronic HF due to LVSD, serial galectin-3 measurement adds incremental prognostic information and predicts LV remodelling. In this study, HF therapies had no clear effects on galectin-3 levels.

Eur J Heart Fail: 12 May 2013; epub ahead of print
Motiwala SR, Szymonifka J, Belcher A, Weiner RB, ... Bhardwaj A, Januzzi JL
Eur J Heart Fail: 12 May 2013; epub ahead of print | PMID: 23666680
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Abstract

Clinicians\' attitudes regarding withdrawal of left ventricular assist devices in patients approaching the end of life.

Swetz KM, Cook KE, Ottenberg AL, Chang N, Mueller PS
Aims: Left ventricular assist devices (LVADs) are implanted to support the circulation of patients with advanced heart failure. Patients approaching death, or their surrogates, may request withdrawal of LVAD support. We sought to study the attitudes and practices of heart failure clinicians regarding withdrawal of LVAD support in patients approaching death. Methods and results: Using internet-based and secure methods, we surveyed members of the European Society of Cardiology-Heart Failure Association (ESC-HFA), the International Society for Heart and Lung Transplantation (ISHLT), and the Heart Failure Society of America (HFSA) to assess their attitudes and practices regarding LVAD withdrawal for patients approaching death. The results indicated that clinicians have varied attitudes and practices regarding withdrawing LVAD support in these patients. Furthermore, ESC-HFA clinicians (primarily European) and ISHLT and HFSA clinicians (primarily North American) differed in their attitudes and practices regarding withdrawal of LVAD support, particularly its ethical and legal permissibility. For example, more European clinicians than North American clinicians regarded withdrawing LVAD support as a form of euthanasia. Conclusion: Opinions and level of comfort with LVAD withdrawal vary among clinicians. Clinicians should be aware of suggested approaches or guidelines for managing requests for withdrawal of LVAD therapy.

Eur J Heart Fail: 06 Jun 2013; epub ahead of print
Swetz KM, Cook KE, Ottenberg AL, Chang N, Mueller PS
Eur J Heart Fail: 06 Jun 2013; epub ahead of print | PMID: 23744792
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This program is still in alpha version.