Gerhard Poelzl

Liver dysfunction in chronic heart failure: prevalence, characteristics and prognostic significance.

Eur J Clin Invest 2011

Prevalence and Prognostic Significance of Elevated γ-Glutamyltransferase in Chronic Heart Failure

Background —Serum gamma-glutamyltransferase (GGT) is associated with incident cardiovascular diseases and is a potential risk factor for disease mortality. We aimed to investigate the relevance of circulating GGT in chronic heart failure. Methods and Results —From 2000 to 2007 clinical and laboratory variables of 1033 consecutive outdoor heart failure patients were evaluated. Follow-up (mean 34.4 months) was available in 998 patients. The endpoint 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 NYHA class, LV ejection fraction, and NT-proBNP. The endpoint was recorded in 302 patients. Compared to the lowest GGT quintile, sex-stratified HR for patients in the highest quintile was 2.88 (1.99 - 4.17) in the univariate model and 1.87 (1.28 - 2.74) in the adjusted model (p<0.001). Corresponding five-year cumulative event rates were 47% and 74%, respectively. Adjusted HR for elevated GGT was 2.9 (1.64 - 5.17) for patients in NYHA I/II, and 1.2 (0.75 - 2.05) for patients in NYHA III/IV, respectively (p=0.003, for the GGT - NYHA class interaction). Conclusions —Prevalence of elevated GGT is high in chronic heart failure patients. 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—Serum &ggr;-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.

Prevalence of elevated gamma-glutamyltransferase (GGT) and prognostic significance of GGT in chronic heart failure

Background —Serum gamma-glutamyltransferase (GGT) is associated with incident cardiovascular diseases and is a potential risk factor for disease mortality. We aimed to investigate the relevance of circulating GGT in chronic heart failure. Methods and Results —From 2000 to 2007 clinical and laboratory variables of 1033 consecutive outdoor heart failure patients were evaluated. Follow-up (mean 34.4 months) was available in 998 patients. The endpoint 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 NYHA class, LV ejection fraction, and NT-proBNP. The endpoint was recorded in 302 patients. Compared to the lowest GGT quintile, sex-stratified HR for patients in the highest quintile was 2.88 (1.99 - 4.17) in the univariate model and 1.87 (1.28 - 2.74) in the adjusted model (p<0.001). Corresponding five-year cumulative event rates were 47% and 74%, respectively. Adjusted HR for elevated GGT was 2.9 (1.64 - 5.17) for patients in NYHA I/II, and 1.2 (0.75 - 2.05) for patients in NYHA III/IV, respectively (p=0.003, for the GGT - NYHA class interaction). Conclusions —Prevalence of elevated GGT is high in chronic heart failure patients. 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—Serum &ggr;-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.

Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial

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.

Safety and Effectiveness of Levosimendan in Patients with Predominant Right 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) ≤ 30%, cardiac index (CI) ≤ 2.5 l/min/m2, right atrial pressure (RAP) ≥ 10 mmHg, and pulmonary capillary wedge pressure (PCWP) ≥ 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/m2 (p < 0.001) and 14 ± 6 to 17.3 ± 8 g-m/m2/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/m2/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.ZusammenfassungHintergrund und Ziel:Levosimendan ist ein Calciumsensitizer mit positiv inotroper und vasodilatierender Wirkung, dessen Anwendung sich bei der akuten Herzinsuffizienz als sehr effektiv erwiesen hat. In der vorliegenden Untersuchung wurden speziell die Wirkung und Sicherheit dieser neuen Substanz bei Patienten mit überwiegendem Rechtsherzversagen untersucht.Patienten und Methodik:In einer Serie von 18 Patienten mit hochgradig eingeschränkter überwiegend rechtsventrikulärer Pumpfunktion, deutlich reduziertem Herzindex (CI), erhöhtem Wedge-Druck (PCWP) und klinischen Zeichen eines manifesten Rechtsherzversagens wurde Levosimendan als 24-h-Infusion mit und ohne vorausgehenden Bolus verabreicht.Ergebnisse:Dabei bestätigten sich die bereits bekannten positiven Effekte auf die Hämodynamik (Zunahme des CI von 1,7 ± 0,4 auf 2,3 ± 0,6 l/min/m2; p < 0,001; Abnahme des PCWP von 25 ± 7 auf 21 ± 5 mmHg; p < 0,01; Abnahme des systemischen Gefäßwiderstands von 1 724 ± 680 auf 1 096 ± 312 dyn * s * cm–5; p < 0,0001). Auffällig waren die Abnahme des rechtsatrialen Drucks von 15 ± 5 auf 10 ± 3 mmHg (p < 0,001) und die signifikante Steigerung des rechtsventrikulären Schlagarbeitsindex von 4,8 ± 1,8 auf 7,6 ± 3,4 g-m/m2/Schlag (p < 0,01) bei weitgehend unverändertem Lungengefäßwiderstand. Der Herzfrequenzanstieg während der Behandlung war nicht signifikant, und es traten keine Tachykardien und/oder relevanten Arrhythmien auf. Patienten mit vasopressorpflichtiger Hypotonie bereits zu Beginn oder während der Behandlung wiesen die höchste 30-Tage-Mortalität auf.Schlussfolgerung:In dieser Fallserie erwies sich die Anwendung von Levosimendan bei Patienten mit überwiegender Rechtsherzdekompensation als sicher und effektiv. Die deutliche Zunahme der rechtsventrikulären Schlagarbeit spricht eher für die Kontraktilitätssteigerung des Ventrikels und weniger für die Nachlastsenkung als dem zugrundeliegenden Wirkmechanismus von Levosimendan am rechten Ventrikel.

Renal Effects of Levosimendan: A Consensus Report

Renal dysfunction is common in clinical settings in which cardiac function is compromised such as heart failure, cardiac surgery or sepsis, and is associated with high morbidity and mortality. Levosimendan is a calcium sensitizer and potassium channel opener used in the treatment of acute heart failure. This review describes the effects of the inodilator levosimendan on renal function. A panel of 25 scientists and clinicians from 15 European countries (Austria, Finland, France, Hungary, Germany, Greece, Italy, Portugal, the Netherlands, Slovenia, Spain, Sweden, Turkey, the United Kingdom, and Ukraine) convened and reached a consensus on the current interpretation of the renal effects of levosimendan described both in non-clinical research and in clinical study reports. Most reports on the effect of levosimendan indicate an improvement of renal function in heart failure, sepsis and cardiac surgery settings. However, caution should be applied as study designs differed from randomized, controlled studies to uncontrolled ones. Importantly, in the largest HF study (REVIVE I and II) no significant changes in the renal function were detected. As it regards the mechanism of action, the opening of mitochondrial KATP channels by levosimendan is involved through a preconditioning effect. There is a strong rationale for randomized controlled trials seeking beneficial renal effects of levosimendan. As an example, a study is shortly to commence to assess the role of levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARDS).

Dose matters! Optimisation of guideline adherence is associated with lower mortality in stable patients with chronic heart failure.

AIMS Guidelines have been published for improving management of chronic heart failure (CHF). We examined the association between improved guideline adherence and risk for all-cause death in patients with stable systolic HF. METHODS Data on ambulatory patients (2006-2010) with CHF and reduced ejection fraction (HF-REF) from the Austrian Heart Failure Registry (HIR Austria) were analysed. One-year clinical data and long-term follow-up data until all-cause death or data censoring were available for 1014 patients (age 65 [55-73], male 75%, NYHA class I 14%, NYHA II 56%, NYHA III/IV 30%). A guideline adherence indicator (GAI [0-100%]) was calculated for each patient at baseline and after 12 ± 3 months that considered indications and contraindications for ACE-I/ARB, beta blockers, and MRA. Patients were considered ΔGAI-positive if GAI improved to or remained at high levels (≥ 80%). ΔGAI50+ positivity was ascribed to patients achieving a dose of ≥ 50% of suggested target dose. RESULTS Improvements in GAI and GAI50+ were associated with significant improvements in NYHA class and NT-proBNP (1728 [740-3636] to 970 [405-2348]) (p<0.001). Improvements in GAI50+, but not GAI, were independently predictive of lower mortality risk (HR 0.55 [95% CI 0.34-0.87; p=0.01]) after adjustment for a large variety of baseline parameters and hospitalisation for heart failure during follow-up. CONCLUSIONS Improvement in guideline adherence with particular emphasis on dose escalation is associated with a decrease in long-term mortality in ambulatory HF-REF subjects surviving one year after registration.

Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps.

FGF23 is associated with disease severity and prognosis in chronic heart failure

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.

Rationale and design of the multicentre randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep study)

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.