Depression, anxiety, and quality of life as predictors of rehospitalization in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is a severe condition, often co-occurring with depression and anxiety, that strongly affects the quality of life (QoL) in some patients. Conversely, depressive and anxiety symptoms are associated with a 2-3 fold increase in mortality risk and were shown to act independently of typical risk factors in CHF progression. The aim of this study was to examine the impact of depression, anxiety, and QoL on the occurrence of rehospitalization within one year after discharge in CHF patients. METHODS: 148 CHF patients were enrolled in a 10-center, prospective, observational study. All patients completed two questionnaires, the Hospital Anxiety and Depression Scale (HADS) and the Questionnaire Short Form Health Survey 36 (SF-36) at discharge timepoint. RESULTS: It was found that demographic and clinical characteristics are not associated with rehospitalization. Still, the levels of depression correlated with gender (p ≤ 0.027) and marital status (p ≤ 0.001), while the anxiety values ​​were dependent on the occurrence of chronic obstructive pulmonary disease (COPD). However, levels of depression (HADS-Depression) and anxiety (HADS-Anxiety) did not correlate with the risk of rehospitalization. Univariate logistic regression analysis results showed that rehospitalized patients had significantly lower levels of Bodily pain (BP, p = 0.014), Vitality (VT, p = 0.005), Social Functioning (SF, p = 0.007), and General Health (GH, p = 0.002). In the multivariate model, poor GH (OR 0.966, p = 0.005) remained a significant risk factor for rehospitalization, and poor General Health is singled out as the most reliable prognostic parameter for rehospitalization (AUC = 0.665, P = 0.002). CONCLUSION: Taken together, our results suggest that QoL assessment complements clinical prognostic markers to identify CHF patients at high risk for adverse events. CLINICAL TRIAL REGISTRATION: The study is registered under http://clinicaltrials.gov (NCT01501981, first posted on 30/12/2011), sponsored by Charité - Universitätsmedizin Berlin.

Performance of a cardiac lipid panel compared to four prognostic scores in chronic heart failure.

The cardiac lipid panel (CLP) is a novel panel of metabolomic biomarkers that has previously shown to improve the diagnostic and prognostic value for CHF patients. Several prognostic scores have been developed for cardiovascular disease risk, but their use is limited to specific populations and precision is still inadequate. We compared a risk score using the CLP plus NT-proBNP to four commonly used risk scores: The Seattle Heart Failure Model (SHFM), Framingham risk score (FRS), Barcelona bio-HF (BCN Bio-HF) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score. We included 280 elderly CHF patients from the Cardiac Insufficiency Bisoprolol Study in Elderly trial. Cox Regression and hierarchical cluster analysis was performed. Integrated area under the curves (IAUC) was used as criterium for comparison. The mean (SD) follow-up period was 81 (33) months, and 95 (34%) subjects met the primary endpoint. The IAUC for FRS was 0.53, SHFM 0.61, BCN Bio-HF 0.72, MAGGIC 0.68, and CLP 0.78. Subjects were partitioned into three risk clusters: low, moderate, high with the CLP score showing the best ability to group patients into their respective risk cluster. A risk score composed of a novel panel of metabolite biomarkers plus NT-proBNP outperformed other common prognostic scores in predicting 10-year cardiovascular death in elderly ambulatory CHF patients. This approach could improve the clinical risk assessment of CHF patients.

Myocardial deformation assessed among heart failure entities by cardiovascular magnetic resonance imaging.

AIMS: Although heart failure (HF) is a leading cause for hospitalization and mortality, normalized and comparable non-invasive assessment of haemodynamics and myocardial action remains limited. Moreover, myocardial deformation has not been compared between the guideline-defined HF entities. The distribution of affected and impaired segments within the contracting left ventricular (LV) myocardium have also not been compared. Therefore, we assessed myocardial function impairment by strain in patients with HF and control subjects by magnetic resonance imaging after clinically phenotyping these patients. METHODS AND RESULTS: This prospective study conducted at two centres in Germany between 2017 and 2018 enrolled stable outpatient subjects with HF [n = 56, including HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF)] and a control cohort (n = 12). Parameters assessed included measures for external myocardial function, for example, cardiac index and myocardial deformation measurements by cardiovascular magnetic resonance imaging, left ventricular global longitudinal strain (GLS), the global circumferential strain (GCS) and the regional distribution of segment deformation within the LV myocardium, as well as basic phenotypical characteristics. Comparison of the cardiac indices at rest showed no differences neither between the HF groups nor between the control group and HF patients (one-way ANOVA P = 0.70). The analysis of the strain data revealed differences between all groups in both LV GLS (One-way ANOVA: P < 0.01. Controls vs. HFpEF: -20.48 ± 1.62 vs. -19.27 ± 1.25. HFpEF vs. HFmrEF: -19.27 ± 1.25 vs. -15.72 ± 2.76. HFmrEF vs. HFrEF: -15.72 ± 2.76 vs. -11.51 ± 3.97.) and LV GCS (One-way ANOVA: P < 0.01. Controls vs. HFpEF: -19.74 ± 2.18 vs. -17.47 ± 2.10. HFpEF vs. HFmrEF: -17.47 ± 2.10 vs. -12.78 ± 3.47. HFrEF: -11.41 ± 3.27). Comparing the segment deformation distribution patterns highlighted the discriminating effect between the groups was much more prominent between the groups (one-way ANOVA P < 0.01) when compared by a score combining regional effects and a global view on the LV. Further analyses of the patterns among the segments affected showed that while the LVEF is preserved in HFpEF, the segments impaired in their contractility are located in the ventricular septum. The worse the LVEF is, the more segments are affected, but the septum remains an outstanding location with the most severe contractility impairment throughout the HF entities. CONCLUSIONS: While cardiac index at rest did not differ significantly between controls and stable HF patients suffering from HFrEF, HFmrEF, or HFpEF, the groups did differ significantly in LV GLS and LV GCS values. Regional strain analysis revealed that the LV septum is the location affected most, with reduced values already visible in HFpEF and further reductions in HFmrEF and HFrEF.

Cardio-microcurrent device for chronic heart failure: first-in-human clinical study.

AIMS: Most devices for treating ambulatory Class II and III heart failure are linked to electrical pulses. However, a steady electric potential gradient is also necessary for appropriate myocardial performance and may be disturbed by structural heart diseases. We investigated whether chronic application of electrical microcurrent to the heart is feasible and safe and improves cardiac performance. The results of this study should provide guidance for the design of a two-arm, randomized, controlled Phase II trial. METHODS AND RESULTS: This single-arm, non-randomized pilot study involved 10 patients (9 men; mean age, 62 ± 12 years) at two sites with 6 month follow-up. All patients had New York Heart Association (NYHA) Class III heart failure and non-ischaemic dilated cardiomyopathy, with left ventricular ejection fraction (LVEF) <35%. A device was surgically placed to deliver a constant microcurrent to the heart. The following tests were performed at baseline, at hospital discharge, and at six time points during follow-up: determination of LVEF and left ventricular end-diastolic/end-systolic diameter by echocardiography; the 6 min walk test; and assessment of NYHA classification and quality of life (36-Item Short-Form Health Survey questionnaire). Microcurrent application was feasible and safe; no device-related or treatment-related adverse events occurred. During follow-up, rapid and significant signal of efficacy (P < 0.005) was present with improvements in LVEF, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and distance walked. For eight patients, NYHA classification improved from Class III to Class I (for seven, as early as 14 days post-operatively); for one, to Class II; and for one, to Class II/III. 36-Item Short-Form Health Survey questionnaire scores also improved highly significantly. CONCLUSIONS: Chronic application of microcurrent to the heart is feasible and safe and leads to a rapid and lasting improvement in heart function and a near normalization of heart size within days. The NYHA classification and quality of life improve just as rapidly.

Incremental prognostic value of a novel metabolite-based biomarker score in congestive heart failure patients.

AIMS: The Cardiac Lipid Panel (CLP) is a newly discovered panel of metabolite-based biomarkers that has shown to improve the diagnostic value of N terminal pro B type natriuretic peptide (NT-proBNP). However, little is known about its usefulness in predicting outcomes. In this study, we developed a risk score for 4-year cardiovascular death in elderly chronic heart failure (CHF) patients using the CLP. METHODS AND RESULTS: From the Cardiac Insufficiency Bisoprolol Study in Elderly trial, we included 280 patients with CHF aged >65 years. A targeted metabolomic analysis of the CLP biomarkers was performed on baseline serum samples. Cox regression was used to determine the association of the biomarkers with the outcome after accounting for established risk factors. A risk score ranging from 0 to 4 was calculated by counting the number of biomarkers above the cut-offs, using Youden index. During the mean (standard deviation) follow-up period of 50 (8) months, 35 (18%) subjects met the primary endpoint of cardiovascular death. The area under the receiver operating curve for the model based on clinical variables was 0.84, the second model with NT-proBNP was 0.86, and the final model with the CLP was 0.90. The categorical net reclassification index was 0.25 using three risk categories: 0-60% (low), 60-85% (intermediate), and >85% (high). The continuous net reclassification index was 0.772, and the integrated discrimination index was 0.104. CONCLUSIONS: In patients with CHF, incorporating a panel of three metabolite-based biomarkers into a risk score improved the prognostic utility of NT-proBNP by predicting long-term cardiovascular death more precisely. This novel approach holds promise to improve clinical risk assessment in CHF patients.

Variability of Myocardial Strain During Isometric Exercise in Subjects With and Without Heart Failure.

Background: Fast strain-encoded cardiac magnetic resonance imaging (cMRI, fast-SENC) is a novel technology potentially improving characterization of heart failure (HF) patients by quantifying cardiac strain. We sought to describe the impact of isometric handgrip exercise (HG) on cardiac strain assessed by fast-SENC in HF patients and controls. Methods: Patients with stable HF and controls were examined using cMRI at rest and during HG. Left ventricular (LV) global longitudinal strain (GLS) and global circumferential (GCS) were derived from image analysis software using fast-SENC. Strain change < -0.5 and > +0.5 was classified as increase and decrease, respectively. Results: The study population comprised 72 subjects, including HF with reduced, mid-range and preserved ejection fraction and controls (HFrEF n = 18 HFmrEF n = 18, HFpEF n = 17, controls: n = 19). In controls, LV GLS remained stable in 36.8%, increased in 36.8% and decreased in 26.3% of subjects during HG. In HF subgroups, similar patterns of LV GLS response were observed (HFpEF: stable 41.2%, increase 35.3%, decrease: 23.5%; HFmrEF: stable 50.0%, increase 16.7%, decrease: 33.3%; HFrEF: stable 33.3%, increase 22.2%, decrease: 44.4%, p = 0.668). Mean change between LV GLS at rest and during HG ranged close to zero with broad standard deviation in all subgroups and was not significantly different between subgroups (+1.2 ± 5.4%, -0.6 ± 8.3%, -1.7 ± 10.7%, and -3.1 ± 19.4%, p = 0.746 in controls, HFpEF, HFmrEF and HFrEF, respectively). However, the absolute value of LV GLS change-irrespective of increase or decrease-was significantly different between subgroups with 4.4 ± 3.2% in controls, 5.9 ± 5.7% in HFpEF, 6.8 ± 8.3% in HFmrEF and 14.1 ± 13.3% in HFrEF (p = 0.005). The absolute value of LV GLS change significantly correlated with resting LVEF, NTproBNP and Minnesota Living with Heart Failure questionnaire scores. Conclusion: The response to isometric exercise in LV GLS is heterogeneous in all HF subgroups and in controls. The absolute value of LV GLS change during HG exercise is elevated in HF patients and associated with measures of HF severity. The diagnostic utility of fast-SENC strain assessment in conjunction with HG appears to be limited. Trial Registration: URL: https://www.drks.de; Unique Identifier: DRKS00015615.

Multilayer myocardial strain improves the diagnosis of heart failure with preserved ejection fraction.

AIMS: The diagnostic and treatment of patients with heart failure with preserved ejection fraction (HFpEF) are both hampered by an incomplete understanding of the pathophysiology of the disease. Novel imaging tools to adequately identify these patients from individuals with a normal cardiac function and respectively patients with HF with reduced EF are warranted. Computing multilayer myocardial strain with feature tracking is a fast and accurate method to assess cardiac deformation. Our purpose was to assess the HFpEF diagnostic ability of multilayer strain parameters and compare their sensitivity and specificity with other established parameters. METHODS AND RESULTS: We included 20 patients with a diagnosis of HFpEF and, respectively, 20 matched controls. We assessed using feature-tracking cardiac magnetic resonance longitudinal and circumferential myocardial strain at three distinct layers of the myocardium: subendocardial (Endo-), mid-myocardial (Myo-), and subepicardial (Epi-). Comparatively, we additionally assessed various others clinical, imaging, and biochemical parameters with a putative role in HFpEF diagnostic: left ventricular end-diastolic volume (LVEDV), left ventricular mass (LVM), interventricular septum (IVS) wall thickness and free wall thickness, left atrial volume and strain, septal and lateral mitral annular early diastolic velocity (e`), E/e´ ratio, and plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Global longitudinal strain (GLS) is significantly impaired at Endo (-20.8 ± 4.0 vs. -23.2 ± 3.4, P = 0.046), Myo- (-18.0 ± 3.0 vs. -21.0 ± 2.5, P = 0.002), and Epi- (-12.2 ± 2.0 vs. -16.2 ± 2.5, P < 0.001) levels. Compared with any other imaging parameter, an Epi-GLS lower than 13% shows the highest ability to detect patients with HFpEF [area under the curve (AUC) = 0.90 (0.81-1), P < 0.001] and in tandem with NT-proBNP can diagnose with maximal sensibility (93%) and specificity (100%), patients with HFpEF from normal, composed variable [AUC = 0.98 (0.95-1), P < 0.001]. In a logistic regression model, a composite predictive variable taking into account both GLS Epi and NT-proBNP values in each individual subject reached a sensitivity of 89% and a specificity of 100% with an AUC of 0.98 (0.95-1), P < 0.001, to detect HFpEF. CONCLUSIONS: Epi-GLS is a promising new imaging parameter to be considered in the clinical assessment of HFpEF patients. Given its excellent specificity, in tandem with a highly sensitive parameter such as NT-proBNP, Epi-GLS holds the potential to greatly improve the current diagnostic algorithms.

Soluble (pro)renin receptor in elderly chronic heart failure patients.

Overactivation of renin-angiotensin system (RAS) is one of the main pathophysiological features in the evolution of chronic heart failure (CHF). The (pro)renin receptor ((P)RR) represents an important player in a tissue renin-angiotensin system (tissue RAS), which mediates tissue injury through fibrosis and hypertrophy of the affected organs in CHF patients. In our study we used plasma samples from 556 elderly subjects with CHF and 198 healthy participants in order to evaluate prognostic and diagnostic potential of s(P)RR in setting of CHF. The patients with CHF showed significantly higher plasma levels of s(P)RR than the healthy volunteers (p=0.0005). We observed association between higher s(P)RR plasma concentrations and lower left ventricular ejection fraction and higher degree of left ventricular dilatation on baseline echocardiography examination of the CHF patients. Elderly CHF patients with higher baseline s(P)RR plasma concentration were at same risk for death, stroke and hospitalization due to heart failure worsening at mean follow-up from forty-eight months in comparison to low s(P)RR counterparts.

Syncopes and clinical outcome in heart failure: results from prospective clinical study data in Germany.

AIMS: Whereas syncopal episodes are a frequent complication of cardiovascular disorders, including heart failure (HF), little is known whether syncopes impact the prognosis of patients with HF. We aimed to assess the impact of a history of syncope (HoS) on overall and hospitalization-free survival of these patients. METHODS AND RESULTS: We pooled the data of prospective, nationwide, multicentre studies conducted within the framework of the German Competence Network for Heart Failure including 11 335 subjects. Excluding studies with follow-up periods <10 years, we assessed 5318 subjects. We excluded a study focusing on cardiac changes in patients with an HIV infection because of possible confounding factors and 849 patients due to either missing key parameters or missing follow-up data, resulting in 3594 eligible subjects, including 2130 patients with HF [1564 patients with heart failure with reduced ejection fraction (HFrEF), 314 patients with heart failure with mid-range ejection fraction, and 252 patients with heart failure with preserved ejection fraction (HFpEF)] and 1464 subjects without HF considered as controls. HoS was more frequent in the overall cohort of patients with HF compared with controls (P < 0.001)-mainly driven by the HFpEF subgroup (HFpEF vs. controls: 25.0% vs. 12.8%, P < 0.001). Of all the subjects, 14.6% reported a HoS. Patients with HFrEF in our pooled cohort showed more often syncopes than subjects without HF (15.0% vs. 12.8%, P = 0.082). Subjects with HoS showed worse overall survival [42.4% vs. 37.9%, hazard ratio (HR) = 1.21, 99% confidence interval (0.99, 1.46), P = 0.04] and less days alive out of hospital [HR = 1.39, 99% confidence interval (1.18, 1.64), P < 0.001] compared with all subjects without HoS. Patients with HFrEF with HoS died earlier [30.3% vs. 41.6%, HR = 1.40, 99% confidence interval (1.12, 1.74), P < 0.001] and lived fewer days out of hospital than those without HoS. We could not find these changes in mortality and hospital-free survival in the heart failure with mid-range ejection fraction and HFpEF cohorts. HoS represented a clinically high-risk profile within the HFrEF group-combining different risk factors. Further analyses showed that among patients with HFrEF with HoS, known cardiovascular risk factors (e.g. age, male sex, diabetes mellitus, and anaemia) were more prevalent. These constellations of the risk factors explained the effect of HoS in a multivariable Cox regression models. CONCLUSIONS: In a large cohort of patients with HF, HoS was found to be a clinically and easily accessible predictor of both overall and hospitalization-free survival in patients with HFrEF and should thus routinely be assessed.

CMR Tissue Characterization in Patients with HFmrEF.

The characteristics and optimal management of heart failure with a moderately reduced ejection fraction (HFmrEF, LV-EF 40-50%) are still unclear. Advanced cardiac MRI offers information about function, fibrosis and inflammation of the myocardium, and might help to characterize HFmrEF in terms of adverse cardiac remodeling. We, therefore, examined 17 patients with HFpEF, 18 with HFmrEF, 17 with HFrEF and 17 healthy, age-matched controls with cardiac MRI (Phillips 1.5 T). T1 and T2 relaxation time mapping was performed and the extracellular volume (ECV) was calculated. Global circumferential (GCS) and longitudinal strain (GLS) were derived from cine images. GLS (-15.7 ± 2.1) and GCS (-19.9 ± 4.1) were moderately reduced in HFmrEF, resembling systolic dysfunction. Native T1 relaxation times were elevated in HFmrEF (1027 ± 40 ms) and HFrEF (1033 ± 54 ms) compared to healthy controls (972 ± 31 ms) and HFpEF (985 ± 32 ms). T2 relaxation times were elevated in HFmrEF (55.4 ± 3.4 ms) and HFrEF (56.0 ± 6.0 ms) compared to healthy controls (50.6 ± 2.1 ms). Differences in ECV did not reach statistical significance. HFmrEF differs from healthy controls and shares similarities with HFrEF in cardiac MRI parameters of fibrosis and inflammation.

Early NT-proBNP and MR-proANP associated with QoL 1 year after acutely decompensated heart failure: secondary analysis from the MOLITOR trial.

Aim: Heart failure negatively impacts quality of life (QoL), which in turn contributes to an adverse long-term prognosis. We aimed at identifying biomarker trajectories after an episode of acutely decompensated heart failure (ADHF) that differ between patients showing average versus impaired QoL 1 year later, thus allowing to predict impaired QoL. Methods: Biomarkers were repeatedly measured throughout the year in 104 ADHF patients. QoL was assessed at discharge and 1 year after ADHF. Logistic regression and receiver operating characteristic analyses were used to identify predictors of impaired QoL while controlling psychosocial confounders. Results: MR-proANP predicted impaired physical and mental QoL. NT-proBNP measurements were important predictors for poor physical QoL. Conclusion: MR-proANP and NT-proBNP predict poor QoL after an epidode of ADHF. The trial is registered at http://clinicaltrials.gov as MOLITOR (IMpact of therapy optimisation On the Level of biomarkers in paTients with Acute and Decompensated ChrOnic HeaRt Failure) with unique identifier: NCT01501981.

Biatrial Remodeling in Patients with Cystic Fibrosis Running Title: Atrial Function in Cystic Fibrosis.

BACKGROUND: Previous studies have focused on left and right ventricular remodeling in cystic fibrosis (CF), whereas atrial function has not been assessed in detail so far. We sought to investigate left and right atrial (LA and RA) function in patients with CF. METHODS: This retrospective investigation included 82 CF patients (64 survivors and 18 non-survivors) who were referred to CF department over the period of four years, as well as 32 control subjects matched by age and gender. All participants underwent an echocardiographic examination including a strain analysis, which was performed offline and blinded for groups. RESULTS: LA and RA volume indexes were significantly higher in CF patients than in controls and were particularly high in CF non-survivors. LA conduit and reservoir functions were significantly worse in CF survivors and non-survivors, compared with control subjects. RA phasic function was not different between controls, CF survivors and non-survivors. The parameters of lung function (forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1)) and the LA and RA volume indexes were predictors of mortality in CF patients. However, in a multivariate analysis, only FVC was an independent predictor of mortality in CF patients. CONCLUSIONS: Our results suggest that both atria are enlarged, but only LA function is impaired in CF patients. LA reservoir and conduit function is particularly deteriorated in CF patients. Though statistical significance was not reached due to our limited sample size, there was a trend of deterioration of LA and RA function from controls across CF survivors to CF non-survivors. LA and RA enlargement represented predictors of mortality in CF patients.

Anti-ß1-Adrenoreceptor auto-Antibodies in elderly heart failure patients.

An autoimmune reaction directed against the cardiac b1-adrenergic receptor (beta1-ADR) leading to the generation of autoantibodies (AA) against this G-coupled receptor has been described in patients with heart failure (HF). Agonist-like beta1-ADR-AA are associated with morbidity in HF patients and even predict mortality. Standardised and valid diagnostic tools to detect beta 1-ADR-AA in clinical routine are lacking. We used a novel ELISA approach to investigate beta 1-ADR-AA in a cohort of 574 HF patients of the CIBIS-ELD trial with follow up. The CIBIS-ELD trial compared the titration of bisoprolol and carvedilol to recommended target doses in regard to BB tolerability in patients aged 65 years and older. Patient with left ventricular (LV) ejection fraction (EF) less than 50% or LV diameter end diastolic (DED) more than 55 cm showed significantly higher levels of beta1-ADR-AA. Although not yet fully validated, this ELISA allowed for a negative correlation of beta1-ADR-AA with the EF at baseline and at the follow up, beta1-ADR-AA further correlated positively with basal heart rate at follow up 12 weeks later. beta1-ADR-AA levels thus determined  significantly increased under titration with beta-blockers (pless  than 0.01). Changes in beta1-ADR-AA between F-Up and baseline were significantly higher in patients who used beta blockers (p=0.016) before study inclusion. The type of beta-blocker titrated in this study did not affect log beta1-ADR-AA levels at baseline (p=0.132), follow-up (p=0.058), nor the change (p=0.426). beta1-ADR-AA levels were estimated using a novel, commercially available ELISA. Although not yet fully validated, this ELISA allowed for pathophysiological insights: beta1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (pless  than 0.01), irrespective of type of BB. Higher levels of beta1-ADR-AA at baseline are associated with higher heart rates, lower ejection fraction and enlarged left ventricles. The relevance of the beta1-ADR-AA biomarker should be further evaluated.

The ß-blocker uptitration in elderly with heart failure regarding biomarker levels: CIBIS-ELD substudy.

AIM: We investigated if the baseline value of mid-regional pro-atrial natriuretic peptide (NP), N-terminal pro-B-type NP and copeptin may be helpful in optimizing ß-blocker uptitration in elderly patients with heart failure. PATIENTS & METHODS: According to the biomarkers' levels, 457 patients were divided into three subgroups and compared with each other at baseline and 3 months after. RESULTS: All mid-regional pro-atrial NP and N-terminal pro-B-type NP subgroups had significant amelioration of left ventricle ejection fraction and New York Heart Association (NYHA) class after 3 months of ß-blocker uptitration (p < 0.001). More prominent improvement of left ventricle ejection fraction and New York Heart Association class was observed in subgroups with lower versus higher NPs levels. CONCLUSION: NPs levels, unlike copeptin levels, might be useful tool for objective selection of elderly heart failure patients who could have the greatest benefit of forced uptitration.

Prognostic performance of serial in-hospital measurements of copeptin and multiple novel biomarkers among patients with worsening heart failure: results from the MOLITOR study.

AIMS: In heart failure, various biomarkers are established for diagnosis and risk stratification; however, little is known about the relevance of serial measurements during an episode worsening heart failure (WHF). This study sought to investigate the trajectory of natriuretic peptides and multiple novel biomarkers during hospitalization for WHF and to determine the best time point to predict outcome. METHODS AND RESULTS: MOLITOR (Impact of Therapy Optimisation on the Level of Biomarkers in Patients with Acute and Decompensated Chronic Heart Failure) was an eight-centre prospective study of 164 patients hospitalized with a primary diagnosis of WHF. C-terminal fragment of pre-pro-vasopressin (copeptin), N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), and C-terminal pro-endothelin-1 (CT-proET1) were measured on admission, after 24, 48, and 72 h, and every 72 h thereafter, at discharge and follow-up visits. Their performance to predict all-cause mortality and rehospitalization at 90 days was compared. All biomarkers decreased during recompensation (P < 0.05) except MR-proADM. Copeptin at admission was the best predictor of 90 day mortality or rehospitalization (χ2  = 16.63, C-index = 0.724, P < 0.001), followed by NT-proBNP (χ2  = 10.53, C-index = 0.646, P = 0.001), MR-proADM (χ2  = 9.29, C-index = 0.686, P = 0.002), MR-proANP (χ2  = 8.75, C-index = 0.631, P = 0.003), and CT-proET1 (χ2  = 6.60, C-index = 0.64, P = 0.010). Re-measurement of copeptin at 72 h and of NT-proBNP at 48 h increased prognostic value (χ2  = 23.48, C-index = 0.718, P = 0.00001; χ2  = 14.23, C-index = 0.650, P = 0.00081, respectively). CONCLUSIONS: This largest sample of serial measurements of multiple biomarkers in WHF found copeptin at admission with re-measurement at 72 h to be the best predictor of 90 day mortality and rehospitalization.

Systemic inflammation and functional capacity in elderly heart failure patients.

BACKGROUND: Elevated C-reactive protein (CRP) is associated with adverse outcomes in heart failure (HF) patients. Beta-blocker therapy may lower CRP levels. METHODS AND RESULTS: To assess if the changes of high-sensitivity (hs) CRP levels in HF patients over 12-week titration with beta-blockers correlate with functional capacity, plasma hs-CRP levels were measured in 488 HF patients [72.1 ± 5.31 years, LVEF 40% (33/50)]. Hs-CRP, NT-proBNP and 6-min-walk-test (6MWT) were assessed at baseline and at week 12. Patients were divided based on hs-CRP changes (cut-off > 0.3 mg/dl) into low-low (N = 225), high-high (N = 132), low-high (N = 54), high-low (N = 77) groups. At baseline, median hs-CRP concentration was 0.25 (0.12/0.53) mg/dl, NT-proBNP 551 (235/1455) pg/ml and average 6MWT distance 334 ± 105 m. NT-proBNP changes were significantly different between the four hs-CRP groups (P = 0.011). NT-proBNP increased in the low-high group by 30 (- 14/88) pg/ml and decreased in the high-low group by - 8 (- 42/32) pg/ml. 6MWT changes significantly differed between groups [P = 0.002; decrease in the low-high group (- 18 ± 90 m) and improvement in the low-low group (24 ± 62 m)]. CONCLUSION: After beta-blocker treatment, hs-CRP levels are associated with functional capacity in HF patients. Whether this represents a potential target for intervention needs further study.

Heart failure awareness survey in Germany: general knowledge on heart failure remains poor.

AIMS: Previous studies demonstrated poor public awareness of heart failure (HF) compared with myocardial infarction and stroke. With respect to several activities to improve HF awareness in recent years, we present data on the development of HF awareness and information sources in Germany over 8 years. METHODS AND RESULTS: In 2007, 2012, and 2015, respectively, 2531, 359, and 171 respondents answered questions about causes, presentation, prognosis, and treatment of HF from a survey developed by the German Competence Network HF. Relationships between respondents' sociodemographic data and their HF knowledge were explored and changes in knowledge and use of information sources analysed. Sixty-eight per cent of respondents knew HF as 'weakness of the heart'. Seventy-nine per cent knew shortness of breath, 74% reduced exercise tolerance, and 52% knew leg edema as symptoms. Only 40% knew all three symptoms. Although up to 34% of the respondents were directly or indirectly affected by HF, they demonstrated poor knowledge about severity and prognosis. Between 2007 and 2015, overall HF awareness has not changed; awareness about treatment has dropped significantly. Younger respondents used all media, especially internet, for information about health; older respondents preferred printed/verbal media and their physician. CONCLUSIONS: We found rather insufficient public knowledge on HF etiology and symptoms but especially about management, severity, and prognosis, which is essential for good self-care and adherence of patients. Heart failure awareness has not improved even though awareness campaigns were held over the years. It seems that especially older patients should be much more approached by their family physicians.

Reliability of peripheral arterial tonometry in patients with heart failure, diabetic nephropathy and arterial hypertension.

Endothelial dysfunction plays a major role in cardiovascular diseases and pulse amplitude tonometry (PAT) offers a non-invasive way to assess endothelial dysfunction. However, data about the reliability of PAT in cardiovascular patient populations are scarce. Thus, we evaluated the test-retest reliability of PAT using the natural logarithmic transformed reactive hyperaemia index (LnRHI). Our cohort consisted of 91 patients (mean age: 65±9.7 years, 32% female), who were divided into four groups: those with heart failure with preserved ejection fraction (HFpEF) ( n=25), heart failure with reduced ejection fraction (HFrEF) ( n=22), diabetic nephropathy ( n=21), and arterial hypertension ( n=23). All subjects underwent two separate PAT measurements at a median interval of 7 days (range 4-14 days). LnRHI derived by PAT showed good reliability in subjects with diabetic nephropathy (intra-class correlation (ICC) = 0.863) and satisfactory reliability in patients with both HFpEF (ICC = 0.557) and HFrEF (ICC = 0.576). However, in subjects with arterial hypertension, reliability was poor (ICC = 0.125). We demonstrated that PAT is a reliable technique to assess endothelial dysfunction in adults with diabetic nephropathy, HFpEF or HFrEF. However, in subjects with arterial hypertension, we did not find sufficient reliability, which can possibly be attributed to variations in heart rate and the respective time of the assessments. Clinical Trial Registration Identifier: NCT02299960.

Regional differences in health-related quality of life in elderly heart failure patients: results from the CIBIS-ELD trial.

AIM: Patient-reported outcomes such as health-related quality of life (HRQoL) are main treatment goals for heart failure (HF) and therefore endpoints in multinational therapy trials. However, little is known about country-specific differences in HRQoL and in treatment-associated HRQoL improvement. The present work sought to examine those questions. METHODS AND RESULTS: We analysed data from the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS-ELD) trial, in which patients from central and south-eastern Europe completed the HRQoL questionnaire SF-36 at baseline and the end of a 12-week beta-blocker up-titration (follow-up). 416 patients from Serbia (mean age 72.21 years, 69% NYHA-class I-II, 27.4% women) and 114 from Germany (mean age 73.64 years, 78.9% NYHA-class I-II, 47.4% women) were included. Controlling for clinical variables, the change in mental HRQoL from baseline to follow-up was modulated by Country: Serbian patients, M baseline = 37.85 vs. M follow-up = 40.99, t(526) = 5.34, p < .001, reported a stronger increase than Germans, M baseline = 37.66 vs. M follow-up = 38.23, t(526) = 0.68, ns. For physical HRQoL, we observed a main effect of Country, M Serbia = 39.28 vs. M Germany = 35.29, t(526) = 4.24, p < .001. CONCLUSION: We observed significant differences in HF patients from Germany and Serbia and country-specific differences between Serbian and German patients in mean physical HRQoL. Changes in mental HRQoL were modulated by country. Those results may reflect psychological, sociocultural, aetiological differences or regional differences in phenotype prevalence. More importantly, they suggest that future multinational trials should consider such aspects when designing a trial in order to avoid uncertainties aligned to data interpretation and to improve subsequent treatment optimisation.

A Novel Lipid Biomarker Panel for the Detection of Heart Failure with Reduced Ejection Fraction.

OBJECTIVES: In this study we aimed to identify novel metabolomic biomarkers suitable for improved diagnosis of heart failure with reduced ejection fraction (HFrEF). METHODS: We prospectively recruited 887 individuals consisting of HFrEF patients with either ischemic (ICMP, n = 257) or nonischemic cardiomyopathy (NICMP, n = 269), healthy controls (n = 327), and patients with pulmonary diseases (n = 34). A single-center identification (n = 238) was followed by a multicenter confirmation study (n = 649). Plasma samples from the single-center study were subjected to metabolite profiling analysis to identify metabolomic features with potential as HFrEF biomarkers. A dedicated analytical protocol was developed for the routine analysis of selected metabolic features in the multicenter cohort. RESULTS: In the single-center study, 92 of 181 metabolomic features with known chemical identity (51%) were significantly changed in HFrEF patients compared to healthy controls (P <0.05). Three specific metabolomic features belonging to the lipid classes of sphingomyelins, triglycerides, and phosphatidylcholines were selected as the cardiac lipid panel (CLP) and analyzed in the multicenter study using the dedicated analytical protocol. The combination of the CLP with N-terminal pro-B-type natriuretic peptide (NT-proBNP) distinguished HFrEF patients from healthy controls with an area under the curve (AUC) of 0.97 (sensitivity 80.2%, specificity 97.6%) and was significantly superior compared to NT-proBNP alone (AUC = 0.93, sensitivity 81.7%, specificity 88.1%, P <0.001), even in the subgroups with mildly reduced left ventricular EF (0.94 vs 0.87; P <0.001) and asymptomatic patients (0.95 vs 0.91; P <0.05). CONCLUSIONS: The new metabolomic biomarker panel has the potential to improve HFrEF detection, even in mild and asymptomatic stages. The observed changes further indicate lipid alterations in the setting of HFrEF.