Hans-Dirk Düngen

Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS‐ELD trial

Various beta‐blockers with distinct pharmacological profiles are approved in heart failure, yet they remain underused and underdosed. Although potentially of major public health importance, whether one agent is superior in terms of tolerability and optimal dosing has not been investigated. The aim of this study was therefore to compare the tolerability and clinical effects of two proven beta‐blockers in elderly patients with heart failure.

The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction

Heart failure with normal ejection fraction (HFnEF) is an important clinical entity that remains incompletely understood. The novel biomarker growth differentiation factor 15 (GDF‐15) is elevated in systolic heart failure (HFrEF) and is predictive of an adverse outcome. We investigated the clinical relevance of GDF‐15 plasma levels in HFnEF.

Galectin‐3 in patients with heart failure with preserved ejection fraction: results from the Aldo‐DHF trial

Galectin‐3 is a marker of myocardial fibrosis and mediates aldosterone‐induced cardiovascular inflammation and fibrosis. Characteristics of galectin‐3 and its response to spironolactone have not been evaluated in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to determine the association between galectin‐3 levels and patient characteristics in HFpEF; to evaluate the interaction between spironolactone and galectin‐3 levels; and to assess the association between galectin‐3 and clinical outcomes.

Serum aldosterone and its relationship to left ventricular structure and geometry in patients with preserved left ventricular ejection fraction

AIMS Cardiac remodelling might be an important mechanism for aldosterone-mediated cardiovascular (CV) morbidity and mortality. Previous studies relating aldosterone to left ventricular (LV) structure however revealed conflicting results. METHODS AND RESULTS We aimed to evaluate the relationship of serum aldosterone concentration (SAC) and aldosterone-to-renin ratio (ARR) with echocardiographic parameters of LV remodelling in CV risk patients with preserved left ventricular ejection fraction (LVEF). We studied 1575 participants (54.1% female) with CV risk factors and LVEF >50% (61.7 ± 6.1%). Of the total, 94.7% of patients had no overt heart failure. All patients underwent measurement of SAC, ARR, and comprehensive echocardiographic analysis. Overall, multivariate adjusted analysis of covariance (ANCOVA) showed a significant increase in LV mass (P= 0.001), LV mass index (P= 0.001), relative wall thickness (P= 0.011), and LV posterior wall thickness (P< 0.001) with increasing SAC. This overall association of SAC and LV remodelling was driven by a statistic significant effect exclusively in women. In multivariate logistic regression analysis higher SAC levels were independently related to concentric LV hypertrophy [odds ratio (OR; with 95% CI) by comparing SAC levels in the third gender-specific tertile with the first tertile: 1.87; 95% CI: 1.31-2.68; P= 0.001]. Higher SAC levels were positively related to concentric LVH in either sex. We observed no significant associations between the ARR and echocardiographic parameters of LV remodelling. CONCLUSION Circulating aldosterone but not ARR levels are independently related to echocardiographic parameters of LV structure, particularly in women. Higher SAC however was related to concentric LVH in either sex. Our findings in a large CV risk cohort with preserved LVEF indicate aldosterone-mediated pro-hypertrophic effects as a potential pathway for structural alterations of the left ventricular myocardium.

Normal values and clinical relevance of left atrial myocardial function analysed by speckle-tracking echocardiography: multicentre study

AIMS The aim of this multicentre study was to determine the normal range and the clinical relevance of the myocardial function of the left atrium (LA) analysed by 2D speckle-tracking echocardiography (2DSTE). METHODS AND RESULTS We analysed 329 healthy adult subjects prospectively included in 10 centres and a validation group of 377 patients with left ventricular diastolic dysfunction (LVDD). LA myocardial function was analysed by LA strain rate peak during LA contraction (LA-SRa) and LA strain peak during LA relaxation (LA-Strain). The range of values of LA myocardial function in healthy subjects was LA-SRa -2.11 ± 0.61 s(-1) and LA-Strain 45.5 ± 11.4%, and the lowest expected values of these LA analyses (calculated as -1.96 SD from the mean of healthy subjects) were LA-SRa -0.91 s(-1) and LA-Strain 23.1%. Concerning the clinical relevance of these LA myocardial analyses, LA-SRa and LA-Strain detected subtle LA dysfunction in patients with LVDD, even though LA volumetric measurements were normal. In addition, in these patients we found that the functional class (dyspnoea-NYHA classification) was inversely related to both LA-Strain and LA-SRa. CONCLUSION In the present multicentre study analysing a large cohort of healthy subjects and patients with LVDD, the normal range and the clinical relevance of the myocardial function of the LA using 2DSTE have been determined.

The burden of chronic obstructive pulmonary disease in patients hospitalized with heart failure

SummaryOBJECTIVES: Like chronic heart failure, chronic obstructive pulmonary disease (COPD) is an enormous public health problem in industrialized countries. Our aim was to determine the prevalence and clinical impact of COPD among patients hospitalized for heart failure in a community hospital serving a population of 125,000 people. METHODS: Between 2001 and 2003 a total of 638 patients (73 ± 10 years, 48% men, 74% NYHA class III) were identified with a discharge diagnosis of heart failure. Medical charts were reviewed and vital status was obtained from a Central Population Registry. RESULTS: COPD was diagnosed in 106 (17%) patients whose age was similar to those without COPD (73 ± 9 vs. 73 ± 11 years, P = 0.35). Patients with COPD were more often males (65% vs. 45%, P < 0.001). There were no differences in arterial hypertension, atrial fibrillation, diabetes mellitus and most laboratory markers except hemoglobin (141 ± 20 vs. 132 ± 20 g/l, P < 0.001) and uric acid (453 ± 136 vs. 414 ± 139 mmol/l, P = 0.013). At discharge, patients with COPD were less likely to receive beta-blockers (12% vs. 28%, odds ratio 0.35, 95% CI0.19–0.64). During follow-up, patients with COPD had higher mortality (73% vs. 60%, P = 0.016, hazard ratio 1.48, 95% CI 1.15–1.90). Kaplan–Meier (log-rank test, P = 0.002) and Cox proportional hazard analysis, adjusted for age, sex, hemoglobin, uric acid, and treatment with beta-blockers and furosemide (hazard ratio 1.38, 95% CI1.04–1.83, P = 0.024) demonstrated the prognostic importance of COPD. CONCLUSIONS: COPD is frequent among hospitalized patients with heart failure. Beta-blockers are largely underused, which is probably a major reason for the higher mortality observed in patients with concomitant chronic heart failure and COPD.

A short form of the General Self-Efficacy Scale (GSE-6): Development, psychometric properties and validity in an intercultural non-clinical sample and a sample of patients at risk for heart failure.

Objective: General self-efficacy has been found to be an influential variable related to the adaptation to stress and chronic illness, with the General Self-Efficacy (GSE) Scale by Jerusalem and Schwarzer being a reliable and valid instrument to assess this disposition. The aim of this study was to construct and test a short form of this scale to allow for a more economical assessment of the construct. Methods: The item characteristics of the original scale were assessed using an intercultural non-clinical sample (n=19,719). Six items with the highest coefficient of variation and good discrimination along the range of the trait were selected to build a short form of the instrument (GSE-6). Subsequently, the psychometric properties and the concurrent and predictive validity of the GSE-6 were tested in a longitudinal design with three measurements using a sample of patients with risk factors for heart failure (n=1,460). Results: Cronbach’s alpha for the GSE-6 was between .79 and .88. We found negative associations with symptoms of depression (–.35 and –.45), anxiety (–.35), and vital exhaustion (–.38) and positive associations with social support (.30), and mental health (.36). In addition, the GSE-6 score was positively associated with active problem-focused coping (.26) and distraction/self-encouragement (.25) and negatively associated with depressive coping (–.34). The baseline GSE-6 score predicted mental health and physical health after 28 months, even after controlling for the respective baseline score. The relative stability over twelve and 28 months was r=.50 and r=.60, respectively, while the mean self-efficacy score did not change over time. Conclusions: The six item short form of the GSE scale is a reliable and valid instrument that is useful for the economical assessment of general self-efficacy in large multivariate studies and for screening purposes.

Association of adiponectin with peripheral muscle status in elderly patients with heart failure

BACKGROUND Reduced peripheral muscle mass was demonstrated in patients with chronic heart failure (HF). Adipokines may have potent metabolic effects on skeletal muscle. The associations between adipokines, peripheral muscle mass, and muscle function have been poorly investigated in patients with HF. METHODS We measured markers of fat and bone metabolism (adiponectin, leptin, 25-hydroxy vitamin D, parathyroid hormone, osteoprotegerin, RANKL), N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in 73 non-cachectic, non-diabetic, male patients with chronic HF (age: 68 ± 7 years, New York Heart Association class II/III: 76/26%, left ventricular ejection fraction 29 ± 8%) and 20 healthy controls of similar age. Lean mass as a measure of skeletal muscle mass was measured by dual energy X-ray absorptiometry (DEXA), while muscle strength was assessed by hand grip strength measured by Jamar dynamometer. RESULTS Serum levels of adiponectin, parathyroid hormone, osteoprotegerin, RANKL, and NT-pro-BNP were elevated in patients with chronic HF compared to healthy controls (all p<0.0001), while no difference in serum levels of leptin, testosterone or SHBG was noted. Levels of 25-hydroxy vitamin D were reduced (p=0.002) in HF group. Peripheral lean mass and hand grip strength were reduced in patients with HF compared to healthy subjects (p=0.006 and p<0.0001, respectively). Using backward selection multivariable regression, serum levels of increased adiponectin remained significantly associated with reduced arm lean mass and muscle strength. CONCLUSIONS Our findings may indicate a cross-sectional metabolic association of increased serum adiponectin with reduced peripheral muscle mass and muscle strength in non-cachectic, non-diabetic, elderly HF patients.

Impaired physical quality of life in patients with diastolic dysfunction associates more strongly with neurohumoral activation than with echocardiographic parameters: Quality of life in diastolic dysfunction

BACKGROUND Quality of life (QoL) is impaired in diastolic heart failure. Little is known about QoL in diastolic dysfunction (DD) without heart failure. METHODS In the DIAST-CHF observational study, outpatients with risk factors for or a history of heart failure were included. In a cross-sectional analysis, we classified patients with preserved systolic function as having normal diastolic function (N, n = 264) or DD without (DD-, n = 957) or with (DD+, n = 321) elevated filling pressures according to echocardiography. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. RESULTS Short Form 36 physical function (SF-36-PF) was worse in DD+ (mean ± SD 67.2 ± 25.6) than in DD- (76.2 ± 22.7, P < .05) than in N (mean ± SD 81.1 ± 23.5, P < .01). Other physical dimensions and the physical component score were also lower in DD, whereas the mental component score did not differ. The SF-36-PF correlated weakly with echocardiographic indicators of diastolic function. In multivariate linear regression controlling for age, sex, body mass index, depressiveness as assessed by Patient Health Questionnaire 9, N-terminal probrain-type natriuretic peptide, and midregional proadrenomedullin (MR-proADM), individual echocardiographic parameters or grade of DD was not independently associated with SF-36-PF, whereas the presence of DD+ was. Both N-terminal probrain-type natriuretic peptide and MR-proADM were independently associated with SF-36-PF, with MR-proADM showing the stronger association. CONCLUSIONS Physical dimensions of QoL are reduced in DD. Impaired SF-36-PF is only weakly associated with DD per se but rather seems to be contingent on the presence of elevated filling pressures. Biomarkers are more strongly and independently associated with SF-36-PF and may be more adequate surrogate markers of QoL in DD than echocardiographic measurements.

Impact of the β1‐Adrenoceptor Arg389Gly Polymorphism on Heart‐Rate Responses to Bisoprolol and Carvedilol in Heart‐Failure Patients

This pharmacogenetic substudy of the prospective, double‐blind, randomized CIBIS‐ELD trial determined the impact of the β1‐adrenoceptor Arg189Gly polymorphism on heart‐rate responses to bisoprolol or carvedilol in elderly patients with heart failure (421 with sinus rhythm, 107 with atrial fibrillation). Patients were randomized 1:1 to bisoprolol or carvedilol with a fortnightly dose‐doubling scheme and guideline target doses. Patients with sinus rhythm responded essentially identically to bisoprolol and carvedilol, independent of genotype. Atrial fibrillation patients homozygous for Arg389 had a much smaller response to carvedilol than carriers of at least one Gly389 allele (mean difference 12 bpm, P < 0.00001). Carvedilol up to 2 × 12.5 mg did not reduce heart rate in Arg389Arg homozygotes at all. Interestingly, the immediate response to carvedilol did not differ between genotypes. The Arg389Gly polymorphism has a major impact on the heart‐rate response to carvedilol (but not bisoprolol) in patients with heart failure plus atrial fibrillation.