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Background and Aims: In chronic ischaemic heart failure, revascularisation strategies control symptoms but are less effective in improving left ventricular ejection fraction (LVEF). The aim of this trial is to investigate the safety of cardiac shockwave therapy (SWT) as a novel treatment option and its efficacy in increasing cardiac function by inducing angiogenesis and regeneration in hibernating myocardium., Methods: In this single-blind, parallel-group, sham-controlled trial (cardiac shockwave therapy for ischemic heart failure, CAST-HF; NCT03859466) patients with LVEF ≤40% requiring surgical revascularisation were enrolled. Patients were randomly assigned to undergo direct cardiac SWT or sham treatment in addition to coronary bypass surgery. The primary efficacy endpoint was the improvement in LVEF measured by cardiac magnetic resonance imaging from baseline to 360 days., Results: Overall, 63 patients were randomized, out of which 30 patients of the SWT group and 28 patients of the Sham group attained 1-year follow-up of the primary endpoint. Greater improvement in LVEF was observed in the SWT group (Δ from baseline to 360 days: SWT 11.3%, SD 8.8; Sham 6.3%, SD 7.4, P = .0146). Secondary endpoints included the 6-minute walking test, where patients randomized in the SWT group showed a greater Δ from baseline to 360 days (127.5 m, SD 110.6) than patients in the Sham group (43.6 m, SD 172.1) (P = .028) and Minnesota Living with Heart Failure Questionnaire score on day 360, which was 11.0 points (SD 19.1) for the SWT group and 17.3 points (SD 15.1) for the Sham group (P = .15). Two patients in the treatment group died for non-device-related reasons., Conclusions: In conclusion, the CAST-HF trial indicates that direct cardiac SWT, in addition to coronary bypass surgery improves LVEF and physical capacity in patients with ischaemic heart failure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Iron deficiency (ID) is a frequent comorbidity in patients with acute (AHF) and chronic heart failure (CHF) associated with morbidity and death. We aimed to better characterize iron homeostasis in patients with heart failure applying different biomarkers and to evaluate the accuracy of current ID definition by the European Society of Cardiology/American College of Cardiology/American Heart Association to indicate tissue iron availability and demand., Methods and Results: We performed a retrospective cohort study investigating 277 patients with AHF and 476 patients with CHF between February 2021 and May 2022. Patients with AHF had more advanced ID than patients with CHF, reflected by increased soluble transferrin receptor and soluble transferrin receptor-ferritin index, and lower ferritin, serum iron, transferrin saturation, hepcidin, and reticulocyte hemoglobin. Decreased iron availability or increased tissue iron demand, reflected by increased soluble transferrin receptor-ferritin index and decreased reticulocyte hemoglobin, was found in 84.1% (AHF) and 28.0% (CHF) with absolute ID and in 50.0% (AHF) and 10.5% (CHF) with combined ID according to the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition. Low hepcidin expression as an indicator of systemic ID was found in 91.1% (AHF) and 80.4% (CHF) of patients with absolute ID and in 32.3% (AHF) and 18.8% (CHF) of patients with combined ID. ID definitions with higher specificity reduce the need for iron supplementation by 25.5% in patients with AHF and by 65.6% in patients with CHF., Conclusions: Our results suggest that the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition might overestimate true ID, particularly in CHF. More stringent thresholds for ID could more accurately identify patients with heart failure with reduced tissue iron availability who benefit from intravenous iron supplementation.

Objective: Clinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality., Methods: Using data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects., Results: For the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR 5%-points lower LVEF =1.07, 95% CI 1.04 to 1.10; p interaction =0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HR indirect effect of 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF., Conclusions: The direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: The LeoDOR trial explored the efficacy and safety of intermittent levosimendan therapy in the vulnerable phase following a hospitalization for acute heart failure (HF)., Methods and Results: In this prospective multicentre, double-blind, two-armed trial, patients with advanced HF were randomized 2:1 at the end of an index hospitalization for acute HF to intermittent levosimendan therapy or matching placebo for 12 weeks. All patients had left ventricular ejection fraction (LVEF) ≤30% during index hospitalization. Levosimendan was administered according to centre preference either as 6 h infusion at a rate of 0.2 μg/kg/min every 2 weeks, or as 24 h infusion at a rate of 0.1 μg/kg/min every 3 weeks. The primary efficacy assessment after 14 weeks was based on a global rank score consisting of three hierarchical groups. Secondary clinical endpoints included the composite risk of tiers 1 and 2 at 14 and 26 weeks, respectively. Due to the COVID-19 pandemic, the planned number of patients could not be recruited. The final modified intention-to-treat analysis included 145 patients (93 in the combined levosimendan arm, 52 in the placebo arm), which reduced the statistical power to detect a 20% risk reduction in the primary endpoint to 60%. Compared with placebo, intermittent levosimendan had no significant effect on the primary endpoint: the mean rank score was 72.55 for the levosimendan group versus 73.81 for the placebo group (p = 0.863). However, there was a signal towards a higher incidence of the individual clinical components of the primary endpoint in the levosimendan group versus the placebo group both after 14 weeks (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.12-7.68; p = 0.021) and 26 weeks (HR 1.64, 95% CI 0.87-3.11; p = 0.122)., Conclusions: Among patients recently hospitalized with HF and reduced LVEF, intermittent levosimendan therapy did not improve post-hospitalization clinical stability., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Coronary artery disease (CAD) remains a severe socio-economic burden in the Western world. Coronary obstruction and subsequent myocardial ischemia result in the progressive replacement of contractile myocardium with dysfunctional, fibrotic scar tissue. Post-infarctional remodelling is causal for the concomitant decline of left-ventricular function and the fatal syndrome of heart failure. Available neurohumoral treatment strategies aim at the improvement of symptoms. Despite extensive research, therapeutic options for myocardial regeneration, including (stem)-cell therapy, gene therapy, cellular reprogramming or tissue engineering, remain purely experimental. Thus, there is an urgent clinical need for novel treatment options for inducing myocardial regeneration and improving left-ventricular function in ischemic cardiomyopathy. Shockwave therapy (SWT) is a well-established regenerative tool that is effective for the treatment of chronic tendonitis, long-bone non-union and wound-healing disorders. In preclinical trials, SWT regenerated ischemic myocardium via the induction of angiogenesis and the reduction of fibrotic scar tissue, resulting in improved left-ventricular function., Methods: In this prospective, randomized controlled, single-blind, monocentric study, 80 patients with reduced left-ventricular ejection fraction (LVEF≤ 40%) are subjected to coronary-artery bypass-graft surgery (CABG) surgery and randomized in a 1:1 ratio to receive additional cardiac SWT (intervention group; 40 patients) or CABG surgery with sham treatment (control group; 40 patients). This study aims to evaluate (1) the safety and (2) the efficacy of cardiac SWT as adjunctive treatment during CABG surgery for the regeneration of ischemic myocardium. The primary endpoints of the study represent (1) major cardiac events and (2) changes in left-ventricular function 12 months after treatment. Secondary endpoints include 6-min walk test distance, improvement of symptoms and assessment of quality of life., Discussion: This study aims to investigate the safety and efficacy of cardiac SWT during CABG surgery for myocardial regeneration. The induction of angiogenesis, decrease of fibrotic scar tissue formation and, thus, improvement of left-ventricular function could lead to improved quality of life and prognosis for patients with ischemic heart failure. Thus, it could become the first clinically available treatment strategy for the regeneration of ischemic myocardium alleviating the socio-economic burden of heart failure., Trial Registration: ClinicalTrials.gov NCT03859466. Registered on 1 March 2019., (© 2022. The Author(s).)

Hospitalization for acute heart failure (HF) is associated with a substantial morbidity burden and with associated healthcare costs and an increased mortality risk. However, few if any major medical innovations have been witnessed in this area in recent times. Levosimendan is a first-in-class calcium sensitizer and potassium channel opener indicated for the management of acute HF. Experience in several clinical studies has indicated that administration of intravenous levosimendan in intermittent cycles may reduce hospitalization and mortality rates in patients with advanced HF; however, none of those trials were designed or powered to give conclusive insights into that possibility. This paper describes the rationale and protocol of LeoDOR (levosimendan infusions for patients with advanced chronic heart failure), a randomized, double-blind, placebo-controlled, international, multicentre trial that will explore the efficacy and safety of intermittent levosimendan therapy, in addition to optimized standard therapy, in patients following hospitalization for acute HF. Salient features of LeoDOR include the use of two treatment regimens, in order to evaluate the effects of different schedules and doses of levosimendan during a 12 week treatment phase, and the use of a global rank primary endpoint, in which all patients are ranked across three hierarchical groups ranging from time to death or urgent heart transplantation or implantation of a ventricular assist device to time to rehospitalization and, lastly, time-averaged proportional change in N-terminal pro-brain natriuretic peptide. Secondary endpoints include changes in HF symptoms and functional status at 14 weeks., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: There are few data on the role of liver dysfunction in patients with end-stage heart failure supported by mechanical circulatory support. The aim of our study was to investigate predictors for acute liver failure in patients with end-stage heart failure undergoing mechanical circulatory support., Methods: A consecutive 164 patients with heart failure with New York Heart Association class IV undergoing mechanical circulatory support were investigated for acute liver failure using the King's College criteria. Clinical characteristics of heart failure together with hemodynamic and laboratory values were analyzed by logistic regression., Results: A total of 45 patients (27.4%) with heart failure developed subsequent acute liver failure with a hospital mortality of 88.9%. Duration of heart failure, cause, cardiopulmonary resuscitation, use of vasopressors, central venous pressure, pulmonary capillary wedge pressure, pulmonary pulsatility index, cardiac index, and transaminases were not significantly associated with acute liver failure. Repeated decompensation, atrial fibrillation (P < .001) and the use of inotropes (P = .007), mean arterial (P = .005) and pulmonary pressures (P = .042), cholinesterase, international normalized ratio, bilirubin, lactate, and pH (P < .001) were predictive of acute liver failure in univariate analysis only. In multivariable analysis, decreased antithrombin III was the strongest single measurement indicating acute liver failure (relative risk per %, 0.84; 95% confidence interval, 0.77-0.93; P = .001) and remained an independent predictor when adjustment for the Model for End-Stage Liver Disease score was performed (relative risk per %, 0.89; 95% confidence interval, 0.80-0.99; P = .031). Antithrombin III less than 59.5% was identified as a cutoff value to predict acute liver failure with a corresponding sensitivity of 81% and specificity of 87%., Conclusions: In addition to the Model for End-Stage Liver Disease score, decreased antithrombin III activity tends to be superior in predicting acute liver failure compared with traditionally thought predictors. Antithrombin III measurement may help to identify patients more precisely who are developing acute liver failure during mechanical circulatory support., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Elevated levels of fibroblast growth factor 23 (FGF23) are associated with incident heart failure in individuals with or without chronic kidney disease. We aimed to investigate the association between serum FGF23 concentrations and disease severity and long-term outcome in patients with stable heart failure., Materials and Methods: Serum levels of C-term FGF23 (Ct-FGF23) concentrations, inorganic phosphate (Pi ), parathormone (PTH) and 25-hydroxyvitamin D (25(OH)D) were measured in 208 patients with nonischaemic heart failure (age 48 ± 15 years; 70% male; NYHA Class I 27·8%, NYHA Class II 43·4%, NYHA Class III/IV 28·8%; LV-EF 34 ± 15%; eGFR ≥60 mL/min/1·73 m(2) in 86%)., Results: Median Ct-FGF23 levels were 18·2 RU/mL (7·5-40·8RU/mL). A dose-response relationship was found between median Ct-FGF23 levels and increasing NYHA class (I: 11·9 RU/mL, II: 15·8 RU/mL, III/IV: 38·8 RU/mL; P < 0·001). Ct-FGF23 correlated with NTproBNP (r = 0·307, P < 0·001), central venous pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure and inversely correlated with cardiac output after adjustment for renal function (eGFR) and Pi . LnCt-FGF23 was related with the combined endpoint of death or heart transplantation (hazard ratio 1·452 [1·029-2·048]; P = 0·034) independent of Pi , PTH, 25(OH)D, age and sex., Conclusion: The phosphatonin FGF23 is strongly associated with disease severity and long-term outcome in patients with nonischaemic heart failure and preserved renal function. Further studies are needed to evaluate the pathophysiologic role of FGF23 and its potential as a biomarker in heart failure., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)

Aims: The aim of this study was to determine whether intermittent ambulatory treatment with levosimendan would improve functional capacity, quality of life, and event-free survival in patients with advanced heart failure., Methods and Results: This was a prospective, randomized, double-blind, placebo-controlled, multicentre, parallel-group trial of pulsed infusions of levosimendan in 120 outpatients with advanced heart failure (EF ≤35%, NYHA class III or IV). The study was conducted at 11 centres in Austria, Greece, and Germany. Levosimendan (0.2 µg/kg/min) or placebo was administered for 6 h at 2-week intervals over 6 weeks, in addition to standard care therapy. The primary outcome was the proportion of patients with a ≥20% improvement in the 6 min walk test and a ≥15% score increase on the Kansas City Cardiomyopathy Questionnaire at the end of the 24-week study period. Secondary outcomes included event-free survival after 24 weeks. Analyses were performed on an intention-to-treat basis. The primary endpoint was reached in 19% of patients receiving levosimendan and 15.8% of patients receiving placebo (odds ratio 1.25; 95% confidence interval 0.44-3.59; P = 0.810). Cardiac death (four vs. one), heart transplants (two vs. one), and acute heart failure (14 vs. nine) were more frequent with placebo as compared with levosimendan. The incidence of side effects was comparable between groups., Conclusion: Intermittent ambulatory treatment with levosimendan in patients with advanced heart failure did not improve significantly functional capacity or quality of life as compared with placebo. An adequately powered, event-driven trial is warranted to enlarge on our findings., Trial Registration: NCT01065194., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Background: The cardio-renal syndrome is common and eGFR is an established biomarker in chronic heart failure (CHF). Recent findings also indicate a predictive role of liver function abnormalities such as GGT in CHF. We aimed to jointly investigate the characteristics and importance of renal and hepatic failure in CHF., Methods: Clinical and laboratory parameters of 1290 ambulatory patients (NYHA class I 25%, II 47%, III/IV 27%; median LV-EF 29%) were evaluated. Hemodynamics was available in 253 patients. The endpoint was defined as death from any cause or heart transplantation., Results: eGFR <60mL/min and GGT elevations were highly prevalent (25% and 44%, respectively; 12.8% for both). Renal and hepatic dysfunctions were correlated with disease severity and independently associated with adverse outcome in univariate (p<0.001) and multivariate analyses (p=0.012 and p<0.001, respectively). Signs of congestion and elevated CVP but not CI were independent predictors of changes in eGFR and GGT. In patients with concurrent impairment of both organs estimated five-year event rate was 46% as compared to 25% in patients with eGFR and GGT in the normal ranges (HR 3.12, 95% CI 2.33-4.18; p<0.001)., Conclusions: Impairment of renal and hepatic function is related to functional status and a poor prognosis in patients with mild to moderate heart failure. Concurrent involvement of both organs indicates disease progression and further elevates the hazard for adverse outcomes. Moreover, our data suggest that venous congestion rather than forward failure accounts for the development of renal and hepatic dysfunctions in these patients., (Copyright © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Elevated serum phosphate levels are associated with excess risk for cardiovascular mortality in patients with and without chronic kidney disease and with increased risk for incident heart failure. We determined the association of serum phosphate concentrations with disease severity and long-term outcome in patients with overt heart failure., Methods and Results: Clinical and laboratory parameters of 974 ambulatory heart failure patients were evaluated. Prevalence of elevated phosphate levels (>4.5 mg/dL) was 5.8% in men and 6.0% in women. Phosphate was significantly correlated with disease severity as assessed by New York Heart Association class, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide (P < .01, respectively). Multivariate sex-stratified Cox regression analysis adjusted for various clinically relevant covariates revealed baseline phosphate to be independently associated with death from any cause or heart transplantation (HR 1.26 [95% CI 1.04-1.52]; P < .001). This relation was maintained in patients with and without chronic kidney disease. After categorization based on quartiles of phosphate levels, a graded, independent relation between phosphate and outcome was observed (P for trend <.001)., Conclusions: We found a graded, independent relation between serum phosphate and adverse outcome in patients with stable heart failure. Also, serum phosphate was related to disease severity. These findings further highlight the clinical importance of serum phosphate in cardiovascular disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Although abnormal liver morphology and function have long been recognized, characterization and importance of liver dysfunction in heart failure are poorly defined. This study sought to investigate the relevance of circulating liver function tests (LFTs) in an unselected chronic heart failure (CHF) cohort., Materials and Methods: A total of 1032 consecutive ambulatory patients with CHF were enrolled from 2000 to 2008. Clinical and laboratory variables including LFTs were collected at study entry. Follow-up (median 36 months) was available in 1002 (97·1%) patients. The endpoint was defined as death from any cause or heart transplantation. Hazard ratios (HR) for transplant-free survival were estimated per log unit using Cox proportional hazard regression models for sex-stratified data., Results: Sex-specific prevalence of cholestatic enzyme elevation was 19·2% as opposed to elevated transaminases in 8·3%. Cholestatic enzymes, but not transaminases, were significantly associated with severity of heart failure syndrome and backward failure. The endpoint was recorded in 339 patients (33·8%). T-Bil, γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) were associated with adverse outcome in bivariate models. Of these, GGT [HR 1·22 (1·06, 1·41); P = 0·006] and ALP [HR 1·52 (1·09, 2·12); P = 0·014] were independently associated with the endpoint after adjustment for a wide array of clinical and laboratory predictors., Conclusions: Liver dysfunction is frequent in CHF and characterized by a predominantly cholestatic enzyme profile that is associated with disease severity and prognosis. Thus, we propose a cardio-hepatic syndrome in CHF. Future studies are needed to clarify the exact mechanisms of organ interaction., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Gamma-glutamyltransferase (GGT) and total bilirubin (T-Bil) are elevated and of prognostic significance in chronic heart failure (CHF). This study sought to compare these novel cardiovascular risk markers in CHF., Methods and Results: We evaluated 1,087 ambulatory patients from our heart failure program. Long-term follow-up was available in 1,056 patients. The combined end point was defined as death of any cause or heart transplantation. Prevalence of elevated GGT was 43% in men and 48% in women, that of T-Bil 17% and 8%, respectively. Both variables were significantly correlated with severity of heart failure. GGT and T-Bil were associated with transplant-free survival in bivariate analysis (P values <.001 and .006, respectively). However, GGT (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.13-1.44; P < .001), but not T-Bil, remained an independent predictor of prognosis in the multivariate model. Also, categorized GGT levels beyond the gender-specific normal ranges were predictive of the combined end point (HR 1.55, 95% CI 1.23-1.95). Elevation of both GGT and T-Bil further increased the risk of reaching the end point (HR 2.57, 95% CI 1.74-3.18)., Conclusions: GGT and T-Bil are associated with disease severity in CHF. However, only GGT is independently associated with adverse outcome. Our findings further highlight the clinical importance of GGT in cardiovascular disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Elevated heart rate (70 beats per minute-bpm or more) is a predictor of impaired prognosis in patients with ischemic heart failure. The Austrian Working Group on Heart Failure has established a registry in May 2006 for all patients referred to dedicated heart failure clinics with a planned follow-up after 12 ± 3 months. Here we report an analysis of the prognostic impact of elevated heart rate at referral in a well-defined cohort of heart failure patients., Methods: Between May 2006 and October 2009 1904 patients have been documented in the Austrian Heart Failure Registry. One thousand threehundred and sixty three patients (72%) had sinus rhythm at referral. Kaplan-Meier and Cox proportional hazards regression analyses were used to compare overall and cardiovascular mortality between high (70 bpm or more) and low heart-rate groups. Patients who were lost-to-follow-up (n = 166) were censored at the time of last contact., Results: At baseline in 793 patients (58%) heart rate has been elevated (70 bpm or more) while in 562 patients it has been below 70 bpm, in 8 patients no baseline heart rate has been recorded. Groups were equally balanced regarding age, gender and cardiovascular risk factors with the exception of smokers (more active smokers in the high heart-rate group: 23 vs 14%; p = 0.001) and valvular cause of heart failure (more frequent in the high heart-rate group: 3% vs 1%; p = 0.012). Patients in the high heart-rate group had significantly higher median NT-pro-BNP (1470 pg/ml, IQR 499-4188 pg/ml) compared to patients in the low heart-rate group (784 pg/ml, IQR 314-2162 pg/ml; p < 0.001). NYHA functional classes III and IV have been more frequent in the high heart-rate group than in the low heart-rate group (32% and 22%, respectively; p < 0.001) while reduced left ventricular ejection fraction (39% or less) has been more frequent in the high heart-rate group than in the low heart-rate group (71% and 61%, respectively; p < 0.001). In the high heart-rate group treatment with beta-blockers has been less frequent than in the low heart rate group (76% and 86%, respectively; p < 0.01) while dosage of beta-blocker therapy has been comparable in both groups. Of the 75 patients who died within 3.5 years 38 deaths had a cardiovascular cause. Cox proportional hazards analysis revealed that high NYHA functional class (III and IV) and elevated heart rate (70 bpm or more) were the best predictors of overall mortality while cardiovascular mortality could best be predicted by NYHA functional classes III and IV., Conclusion: Higher NYHA-functional classes and elevated heart rate are predictors of adverse outcome in chronic heart failure patients.

Aims: Advanced chronic heart failure (CHF) is a clinical syndrome with high morbidity and mortality that often requires inotropic support for the alleviation of symptoms and congestion. There are no definite evidence-based data on the safety and efficacy of intermittent infusions of inotropic agents in this severe clinical condition. The purpose of the LevoRep study is to clarify whether pulsed infusions of the new inotropic agent levosimendan administered in an outpatient setting can safely improve exercise capacity, quality-of-life (QoL), and outcome in advanced CHF patients., Methods: The LevoRep study is a prospective, randomized, double-blind, placebo-controlled, two-armed, parallel-group, multicentre trial. The study is designed to investigate the effects of pulsed infusions of levosimendan (6 h administration at 0.2 microg/kg/min every 2 weeks) on the composite endpoint (primary endpoint) comprising changes in functional capacity and QoL (20% or greater improvement in the 6 min walk test and 15% or higher score on the Kansas City Cardiomyopathy Questionnaire) at the end of the 24 week study period. In addition, short-term (8 weeks from randomization) and long-term (24 weeks from randomization) event-free survival (secondary endpoint) will be assessed. The LevoRep study aims to include 120 outpatients with advanced CHF., Conclusion: LevoRep is the first prospective randomized trial to assess the effects of pulsed infusions of an inotrope on hard endpoints as well as on the safety in patients with advanced CHF on an outpatient basis. The results are expected to promote the development of evidence-based recommendations for the ambulatory management of patients with end-stage heart failure.

Background: Serum gamma-glutamyltransferase (GGT) is associated with incident cardiovascular diseases and is a potential risk factor for disease mortality. We investigated the relevance of circulating GGT in chronic heart failure., Methods and Results: From 2000 to 2007 clinical and laboratory variables of 1033 consecutive outdoor patients with heart failure were evaluated. Follow-up (mean, 34.4 months) was available in 998 patients. The end point was defined as death from any cause or heart transplantation. A forward stepwise Cox proportional hazards regression model for sex-stratified data was used. Prevalence of elevated GGT was 42.9% in men (GGT >65 U/L) and 50.2% in women (GGT >38 U/L), which was higher than for sex- and age-matched healthy subjects (18.6% in men, 19.2% in women) derived from a large historical control group. GGT was associated with severity of heart failure as assessed by New York Heart Association class, left-ventricular ejection fraction, and amino-terminal pro-B-type natriuretic peptide. The end point was recorded in 302 patients. Compared with the lowest GGT quintile, sex-stratified hazard ratios for patients in the highest quintile were 2.88 (1.99 to 4.17) in the univariate model and 1.87 (1.28 to 2.74) in the adjusted model (P<0.001). Corresponding 5-year cumulative event rates were 47% and 74%, respectively. Adjusted hazard ratios for elevated GGT was 2.9 (1.64 to 5.17) for patients in New York Heart Association I/II, and 1.2 (0.75 to 2.05) for patients in New York Heart Association III/IV, respectively (P=0.003, for the GGT-New York Heart Association class interaction)., Conclusions: Prevalence of elevated GGT is high in patients with chronic heart failure. The GGT levels are associated with disease severity. Increased GGT is an independent predictor of death or heart transplantation. GGT may provide additional prognostic information, especially in patients with mild heart failure.

Background and Purpose: Levosimendan is a new calcium sensitizer that enhances the contractile force of the myocardium and exhibits additional vasodilating properties. The present study describes the hemodynamic effects of levosimendan in patients with acute predominant right heart failure in need of inotropic therapy., Patients and Methods: 18 patients (15 male, age 60 +/- 17 years) with acute heart failure, predominant right ventricular dysfunction, left ventricular ejection fraction (LVEF) < or = 30%, cardiac index (CI) < or = 2.5 l/min/m(2), right atrial pressure (RAP) > or = 10 mmHg, and pulmonary capillary wedge pressure (PCWP) > or = 15 mmHg were investigated. Following a loading dose, levosimendan was administered intravenously for 24 h., Results: After 24 h, CI and left ventricular stroke work index increased from 1.7 +/- 0.4 to 2.3 +/- 0.6 l/min/m(2) (p < 0.001) and 14 +/- 6 to 17.3 +/- 8 g-m/m(2)/beat (p < 0.05), respectively. PCWP and systemic vascular resistance decreased from 25 +/- 7 to 21 +/- 5 mmHg (p < 0.01) and 1,724 +/- 680 to 1,096 +/- 312 dyne * s * cm(-5) (p < 0.0001), respectively. RAP was reduced from 15 +/- 5 to 10 +/- 3 mmHg (p < 0.001), whereas decreases in mean pulmonary artery pressure and pulmonary vascular resistance were not significant. Right ventricular stroke work index (RVSWI) increased from 4.8 +/- 1.8 to 7.6 +/- 3.4 g-m/m(2)/beat (p < 0.01)., Conclusion: Levosimendan therapy is feasible and improves hemodynamics in patients with acute predominant right heart failure. Augmentation in RVSWI indicates an increase in right ventricular contractility rather than reduction in afterload as a possible pathophysiological mechanism.

B-type natriuretic peptide (BNP; Abbott Diagnostics) and N-terminal proBNP (NT-proBNP, Roche Diagnostics) were compared in consecutive samples of 458 patients (mean age 60 years+/-16 years; 159 female, 299 male) sent for NT-proBNP measurement to investigate influences on both markers. BNP and NT-proBNP showed a close correlation with each other (r=0.89, p<0.0001). Using age- and gender-adjusted upper reference values the inter-rater agreement of both parameters was satisfactory (83%, Cohen's kappa coefficient=0.7). The combination of normal BNP and elevated NT-proBNP was significantly more frequent than vice versa (61 vs. 16 patients), and a calculated glomerular filtration rate<60 ml/min/1.73 m(2) was found in 39% of these patients. Multiple linear regression analysis revealed a significant influence of a reduced ejection fraction (<50%), renal dysfunction (calculated glomerular filtration rate<60 ml/min/1.73 m(2)), anemia, hypertension, age, and gender on both BNP and NT-proBNP. In conclusion, despite a close correlation and a satisfactory agreement between both markers in classification, frequent discrepancies in individual patients demonstrate that both markers are clinically not completely equivalent.

Background: Chronic heart failure is associated with high mortality and morbidity. In spite of a number of trials showing significant improvement in survival and reduction in hospitalization for patients who received ACE inhibitors/AT1 receptor antagonists (ACEI/ARB), beta-blockers and spironolactone, and notwithstanding the recommendations of national and international guidelines for the management of heart failure, substantial proportions of patients are not receiving this treatment. The aim of our study was to analyse 1. the efficiency of a specialized heart failure clinic in translating guidelines into clinical practice, and 2. the effect of optimized neurohormonal therapy on patient outcome., Methods and Results: The data of patients with systolic heart failure and an ejection fraction < or = 35% referred to the Innsbruck Heart Failure and Transplantation Program between February 2000 and October 2001 were analysed. The number of patients treated with ACEI/ARB, beta-blocker and spironolactone increased significantly in the investigation period (p < 0.05). Equivalent dose for captopril and bisoprolol per patient developed from 66.4 +/- 42.8 to 96.5 +/- 41.9 mg (p < 0.001) and from 2.0 +/- 2.9 to 6.3 +/- 4.0 mg (p < 0.001), respectively. Optimization of neurohormonal therapy was associated with a significant improvement in NYHA class (2.5 +/- 0.8 vs. 1.9 +/- 0.8; p < 0.001). No relevant changes were noticed for blood pressure, serum creatinine, serum sodium, and serum potassium, whereas heart rate dropped significantly. Kaplan-Meier curves examining the time to first event of the combined end point of mortality and hospitalisation for worsening heart failure revealed a clear benefit for patients on combined neurohormonal therapy (ACEI/ARB and beta-blocker, n = 86) when compared with patients on neurohormonal monotherapy (ACEI/ARB or beta-blocker, n = 35), (p < or = 0.001). Differences remained significant (p = 0.022) after adjusting for NYHA class at referral, age, gender, etiology of the underlying cardiomyopathy, ejection fraction, and atrial fibrillation in Cox regression analysis., Conclusion: Guidelines for the management of chronic heart failure patients can be translated efficiently into clinical practice by a specialized heart failure clinic. Optimization of therapy is associated with an improvement in functional status and a decrease in mortality or hospitalization for worsening heart failure. Therefore the nationwide installation of specialized heart failure clinics is required.

Aims: Amyloid cardiomyopathy is an underappreciated cause of morbidity and mortality. Recent evidence suggests that ATTR wild‐type cardiomyopathy (ATTRwt‐CM) is probably much more common than widely appreciated. So far, no data are available on comparison of mortality from ATTRwt‐CM and other heart failure aetiologies. Methods and results: This was a retrospective, observational, cohort study of 2251 patients and their data collected prospectively from May 2000 to June 2018. Long‐term mortality was the main outcome measure. Underlying cardiomyopathies were classified as amyloid CM (6.1%) [ATTRwt 3.0%; light‐chain amyloidosis (AL) 3.1%], dilated CM (dCMP) (46.4%), ischaemic heart disease (IHD) (24.4%), hypertensive heart disease (HHD) (14.6%), hypertrophic CM (HCM) (5.1%), and valvular heart disease (VHD) (3.4%). Median duration of follow‐up was 7.1 years (interquartile range 3.4–11.3). Five‐year overall survival in the whole cohort was 80.1%. In multivariate analysis, individuals with amyloid CM were 3.74 times [95% confidence interval (CI) 2.72–5.14; P < 0.001] more likely to die of any reason than were individuals with dCMP. Mortality was higher in AL‐CM compared with ATTRwt‐CM [hazard ratio (HR) 2.88; 95% CI 1.48–5.58; P = 0.002]. Mortality rates in patients with ATTRwt‐CM were higher than in patients with dCMP (HR 1.96; 95% CI 1.24–3.22; P = 0.007), HCM (HR 2.94; 95% CI 1.28–6.67; P = 0.011), HHD (HR 2.08; 95% CI 1.27–3.45; P = 0.004), VHD (HR 2.38; 95% CI 1.30–4.35; P = 0.005), or left ventricular ejection fraction ≥ 40% (HR 1.99; 95% CI 1.12–3.52; P = 0.018). Conclusions: Our study demonstrates that amyloid CM is independently associated with poor survival among patients with various causes of heart failure. ATTRwt‐CM had a better long‐term prognosis than did AL‐CM, but was associated with higher mortality than were dCMP, HCM, HHD, VHD, and heart failure with preserved or mid‐range ejection fraction. [ABSTRACT FROM AUTHOR]

I Background: i Current guidelines recommend specific dosages of -blockers and renin-angiotensin system inhibitors for patients with heart failure with reduced ejection fraction, because patients who receive this treatment have fewer hospitalizations and live longer ([1]). Distribution among categories of response differs significantly for all medication groups - patients who received the drug with a higher numerical dosage were less likely to reach the recommended dosage. I Discussion: i We have shown that for a large number of representative patients with chronic systolic heart failure, the uptitration of drugs stopped when the dosage was further away from the recommended dosage for drugs with higher versus those with lower recommended dosages. [Extracted from the article]

Abstract: Background: Gamma-glutamyltransferase (GGT) and total bilirubin (T-Bil) are elevated and of prognostic significance in chronic heart failure (CHF). This study sought to compare these novel cardiovascular risk markers in CHF. Methods and Results: We evaluated 1,087 ambulatory patients from our heart failure program. Long-term follow-up was available in 1,056 patients. The combined end point was defined as death of any cause or heart transplantation. Prevalence of elevated GGT was 43% in men and 48% in women, that of T-Bil 17% and 8%, respectively. Both variables were significantly correlated with severity of heart failure. GGT and T-Bil were associated with transplant-free survival in bivariate analysis (P values <.001 and .006, respectively). However, GGT (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.13–1.44; P < .001), but not T-Bil, remained an independent predictor of prognosis in the multivariate model. Also, categorized GGT levels beyond the gender-specific normal ranges were predictive of the combined end point (HR 1.55, 95% CI 1.23–1.95). Elevation of both GGT and T-Bil further increased the risk of reaching the end point (HR 2.57, 95% CI 1.74–3.18). Conclusions: GGT and T-Bil are associated with disease severity in CHF. However, only GGT is independently associated with adverse outcome. Our findings further highlight the clinical importance of GGT in cardiovascular disease. [Copyright &y& Elsevier]

The article offers a study which examines the relevance of circulating serum γ-glutamyl transferase (GGT) in chronic heart failure. It notes the findings of the study that prevalence of elevated GGT is high in patients having chronic heart failure and GGT levels are related to disease severity. It cites that advanced GGT is an independent predictor of death or heart transplantation.

Abstract: Background: The role of serum uric acid (SUA) as a risk factor for cardiovascular disease (CVD) remains controversial. Little is known about its predictive value for mortality from congestive heart failure (CHF) and stroke, particularly in elderly, post-menopausal women. Methods: The relation of SUA to risk of death from total CVD, CHF, stroke and coronary heart disease (CHD) was examined prospectively in a large cohort of 28613 elderly Austrian women (mean age 62.3 years), followed-up for a median of 15.2 years. Adjusted Cox proportional hazards models were calculated to evaluate SUA as an independent predictor for fatal CVD events. Results: SUA in the highest quartile (≥5.41 mg/dL) was significantly associated with mortality from total CVD (p <0.0001), showing a clear dose–response relationship; the adjusted hazard ratio (95%CI) in comparison to the lowest SUA quartile was 1.35 (1.20–1.52). In subgroup analyses SUA was independently predictive for deaths from acute and subacute (p <0.0001) and chronic forms (p =0.035) of CHD, yielding adjusted hazard ratios for the highest versus lowest SUA quartile of 1.58 (1.19–2.10) and 1.25 (1.01–1.56), respectively. SUA was further significantly related to fatal CHF (p <0.0001) and stroke (p =0.018); the adjusted hazard ratios for the highest versus lowest SUA quartile were 1.50 (1.04–2.17) and 1.37 (1.09–1.74), respectively. Conclusions: These findings, for the first time, demonstrate that SUA is an independent predictor for all major forms of death from CVD including acute, subacute and chronic forms of CHD, CHF and stroke in elderly, post-menopausal women. [Copyright &y& Elsevier]