[Heart failure care in a digitalized future : A discourse on resource-sparing structures and self-determined patients]. / Herzinsuffizienzversorgung in einer digitalisierten Zukunft : Ein Diskurs zu ressourcenschonenden Strukturen und selbstbestimmten Patienten.

Digital health solutions, applications of artificial intelligence (AI) and new technologies, such as cardiac magnetic resonance imaging and cardiac human genetics are currently being validated in cardiac healthcare pathways. They show promising approaches for improving existing healthcare structures in the future by strengthening the focus on predictive, preventive and personalized medicine. In addition, the accompanying use of digital health applications will become increasingly more important in the future healthcare, especially in patients with chronic diseases. In this article, the authors describe a case of chronic heart failure (HF) as an example to provide an overview of how digitalized healthcare can be efficiently designed across sectors and disciplines in the future. Moreover, the importance of a self-determined patient management for the treatment process itself is underlined. Since HF is frequently accompanied by various comorbidities during the course of the disease that are often recognized only after a delay, the necessity for a timely simultaneous and preventive treatment of multiple comorbidities in cardiovascular diseases is emphasized. Against this background the currently separately applied disease management programs (DMP) are critically questioned. The development of a holistic DMP encompassing all indications for the treatment of chronic diseases may pave the way to a more efficient medical care system.

Efficacy of telemedical interventional management in patients with heart failure (TIM-HF2): a randomised, controlled, parallel-group, unmasked trial.

BACKGROUND: Remote patient management in patients with heart failure might help to detect early signs and symptoms of cardiac decompensation, thus enabling a prompt initiation of the appropriate treatment and care before a full manifestation of a heart failure decompensation. We aimed to investigate the efficacy of our remote patient management intervention on mortality and morbidity in a well defined heart failure population. METHODS: The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial was a prospective, randomised, controlled, parallel-group, unmasked (with randomisation concealment), multicentre trial with pragmatic elements introduced for data collection. The trial was done in Germany, and patients were recruited from hospitals and cardiology practices. Eligible patients had heart failure, were in New York Heart Association class II or III, had been admitted to hospital for heart failure within 12 months before randomisation, and had a left ventricular ejection fraction (LVEF) of 45% or lower (or if higher than 45%, oral diuretics were being prescribed). Patients with major depression were excluded. Patients were randomly assigned (1:1) using a secure web-based system to either remote patient management plus usual care or to usual care only and were followed up for a maximum of 393 days. The primary outcome was percentage of days lost due to unplanned cardiovascular hospital admissions or all-cause death, analysed in the full analysis set. Key secondary outcomes were all-cause and cardiovascular mortality. This study is registered with ClinicalTrials.gov, number NCT01878630, and has now been completed. FINDINGS: Between Aug 13, 2013, and May 12, 2017, 1571 patients were randomly assigned to remote patient management (n=796) or usual care (n=775). Of these 1571 patients, 765 in the remote patient management group and 773 in the usual care group started their assigned care, and were included in the full analysis set. The percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause death was 4·88% (95% CI 4·55-5·23) in the remote patient management group and 6·64% (6·19-7·13) in the usual care group (ratio 0·80, 95% CI 0·65-1·00; p=0·0460). Patients assigned to remote patient management lost a mean of 17·8 days (95% CI 16·6-19·1) per year compared with 24·2 days (22·6-26·0) per year for patients assigned to usual care. The all-cause death rate was 7·86 (95% CI 6·14-10·10) per 100 person-years of follow-up in the remote patient management group compared with 11·34 (9·21-13·95) per 100 person-years of follow-up in the usual care group (hazard ratio [HR] 0·70, 95% CI 0·50-0·96; p=0·0280). Cardiovascular mortality was not significantly different between the two groups (HR 0·671, 95% CI 0·45-1·01; p=0·0560). INTERPRETATION: The TIM-HF2 trial suggests that a structured remote patient management intervention, when used in a well defined heart failure population, could reduce the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality. FUNDING: German Federal Ministry of Education and Research.

A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. METHODS AND RESULTS: Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. CONCLUSION: The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

The L-Arginine-asymmetric dimethylarginine ratio is an independent predictor of mortality in dilated cardiomyopathy.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is associated with increased mortality in patients with chronic heart failure but it remains unclear if the etiology of heart failure influences the prognostic value of dimethylarginines. METHODS AND RESULTS: L-Arginine, ADMA, and symmetric dimethylarginine (SDMA) were measured by liquid chromatography-tandem mass spectrometry in 341 patients with chronic heart failure due to dilated cardiomyopathy (DCM; n = 226) or ischemic cardiomyopathy (ICM; n = 115). Median (interquartile range [IQR]) ADMA and SDMA plasma levels were higher, L-arginine and the L-arginine-ADMA ratio were lower in patients with severe forms of heart failure (New York Heart Association (NYHA) functional class III or IV) compared with milder forms (NYHA functional class I or II) (ADMA 0.57 (0.14) µmol/L vs 0.54 (0.12) µmol/L [P < .001]; SDMA 0.47 (0.27) µmol/L vs 0.37 (0.13) µmol/L [P < .001]; L-arginine 81.8 (39.1) µmol/L vs 92.6 (39.3) µmol/L [P < .01]), but no significant differences were observed between the different etiologies. The L-arginine-ADMA ratio was associated with outcome only in patients with DCM. In multivariate analysis, the mortality risk of DCM patients was significantly lower for those in the highest quartile compared with the lowest quartile during a median observation time of 3.3 years (hazard ratio 0.31, 95% CI 0.11-0.88; P = .028, adjusted for other risk factors). CONCLUSIONS: DCM patients with unfavourable L-arginine-ADMA ratio are at increased risk for death.

Quantitative analysis of left ventricular dyssynchrony using cardiac computed tomography versus three-dimensional echocardiography.

OBJECTIVES: We investigated whether cardiac computed tomography (CCT) can determine intraventricular dyssynchrony in comparison to real-time three-dimensional echocardiography (RT3DE) in patients who are considered for cardiac resynchronisation therapy (CRT). METHODS: 35 patients considered for CRT were examined. Left ventricular (LV) dyssynchrony was quantified by calculating the standard deviation index (SDI) of 17 myocardial LV segments by RT3DE and ECG-gated contrast-enhanced 64-slice dual-source CCT. For both analyses the same software algorithm (4D LV-Analysis) was used. RESULTS: Close correlations were observed for end-systolic volume, end-diastolic volume and LV ejection fraction between the two techniques (r = 0.94, r = 0.92 and r = 0.95, respectively, P < 0.001 for all). For the global dyssynchrony index SDI, a high correlation was found between RT3DE and CCT (r = 0.84, P < 0.001), which further increased after exclusion of segments with poor image quality by echocardiography (r = 0.90, P < 0.001). The required time for quantitative analysis was significantly shorter (162 ± 22 s vs. 608 ± 112 s per patient, P < 0.001) and reproducibility was significantly higher for CCT compared with RT3DE (interobserver variability of 4.5 ± 3.1% vs. 7.9 ± 6.1%, P < 0.05). CONCLUSION: Quantitative assessment of LV dyssynchrony is feasible by CCT. Owing to its higher reproducibility and faster analysis time compared with RT3DE, this technique may represent a valuable alternative for dyssynchrony assessment. KEY POINTS: • Quantitative assessment of left ventricular dyssynchrony is feasible by cardiac computed tomography (CCT). • This technique has been compared with real-time three-dimensional echocardiography (RT3DE). • Reproducibility is significantly higher for CCT compared with RT3DE. • Time spent for analysis is significantly shorter for CCT. • Computed tomography may represent a valuable alternative to ultrasound for dyssynchrony assessment.

Multicentre evaluation of a second generation point-of-care assay with an extended range for the determination of N-terminal pro-brain natriuretic peptide.

BACKGROUND: In the second generation of the point-of-care (POC) assay Roche CARDIAC proBNP, the upper limit of the measuring range was extended from 3000 to 9000 ng/L. METHODS: A thirteen-site multicentre evaluation was carried out to assess the analytical performance of the POC NT-proBNP assay and to compare it with a laboratory N-terminal pro-brain natriuretic peptide (NT-proBNP) assay. RESULTS: In method comparisons of six lots of POC NT-proBNP with the lab reference method (Elecsys proBNP) mean bias ranged from -10 to +17%. In lot-to-lot comparisons all six investigated lots of POC NT-proBNP showed excellent agreement, with mean bias between -7% and +2%. The majority of all coefficients of variation obtained from ten-fold measurements using 56 native blood samples were below 8%. No interference was observed with hemolytic blood (hemoglobin concentrations up to 0.12 mmol/L), lipemic blood (triglyceride concentrations up to 14.0 mmol/L) nor icteric blood (bilirubin concentrations up to 63 micromol/L). Hematocrit values between 24% and 51% had no influence on the assay result. High NT-proBNP concentrations above the measuring range of POC NT-proBNP did not lead to false low results due to potential high-dose hook effect. Results with POC NT-proBNP were not influenced by different ambient temperatures (18 degrees C to 32 degrees C), the sample material used, nor by over- or underdosing by 15 microL compared to the regular sample volume of 150 microL. CONCLUSIONS: The POC NT-proBNP assay showed an excellent analytical performance including a good agreement with the laboratory method. The assay is therefore suitable for its intended use in point-of-care settings.

Transfemoral biopsy--a routine procedure after orthotopic heart transplantation for dilated cardiomyopathy in a patient with persistent left superior vena cava and hypoplastic right superior vena cava.

INTRODUCTION: The increasing number of end stage heart failure patients has caused a high number of transplant candidates, including patients with concomitant other cardiac abnormalities. Congenital heart failure can exhibit changes in a variety of anatomic landmarks, and performing heart transplantation in this setting can be challenging. Monitoring for possible rejection is done via intramyocardial biopsies. Here the difficulties arise from variations in anatomic structures. BACKGROUND: We present a case of a persistent left superior vena cava discovered intraoperatively during heart transplantation. The patient was a 45-year-old man who underwent transplantation for a severely reduced left ventricular function, along with a high left ventricular end-diastolic pressure and and end stage heart failure. DISCUSSION: In previous cases, the biopsy was performed by means of left-sided transjugular venous access. Bearing the well-known complications in mind, we chose the transfemoral access so we could take biopsies postoperatively. Biopsies in patients with persistent left vena cava should routinely be performed using the transfemoral access.

Immunosuppression with tacrolimus early after orthotopic heart transplantation: a comparison of prograf and advagraf.

BACKGROUND: We compared trough levels and clinical outcomes in patients who received Prograf or Advagraf (tacrolimus) de novo following heart transplantation surgery. METHODS: Eighty-two patients were included in this follow-up study. Biopsy results were controlled for the first 3 months after orthotopic heart transplantation. Trough levels were monitored for 4 weeks: daily during the first 7 days and once every week thereafter. The lengths of stay in the hospital and in intensive care were compared. The end point of the study was the 1-year mortality rate. RESULTS: We found significant differences between the groups for both biopsy results and trough levels. Trough levels differed for the first 5 days and then converged on the sixth day. The levels remained comparable throughout the monitoring period. The 1-year mortality rates for Prograf and Advagraf were 20% and 15%, respectively. CONCLUSIONS: Trough levels were comparable after an adjustment period. There were no differences between the 2 groups in their 1-year mortality rates. These results suggest that Advagraf is a safe alternative to Prograf for patients who have undergone heart transplantation.

Impact of troponin I-autoantibodies in chronic dilated and ischemic cardiomyopathy.

The aim of this study was to investigate the prognostic value of circulating troponin I (TNI)-autoantibodies in plasma of patients with chronic heart failure. Sera of 390 heart failure patients were tested for the presence of anti-TNI antibodies by enzyme-linked immunosorbent assay (ELISA), including 249 (63.8% of total) patients with dilated cardiomyopathy (DCM) and 141 (36.2% of total) patients with ischemic cardiomyopathy (ICM). A total of 72 patients (18.5% of total) were female and 318 (81.5% of total) were male. Mean patient age was 54.6 ± 11.3 years and mean follow-up time was 3.8 ± 3.2 years. TNI-autoantibodies (titer of ≥1:40) were detected in 73 out of 390 patients (18.7% of total). In TNI-autoantibody positive patients mean left ventricular ejection fraction (LVEF) was 27.6 ± 5.8%, compared to 25.8 ± 5.9% in TNI-autoantibody negative patients, P = 0.03. The combined end-point of death (n = 118, 30.3% of total) or heart transplantation (HTX) (n = 44, 11.3% of total) was reached in 162 patients (41.5% of total). Kaplan-Meier analysis demonstrated superior survival (combined end-point of death or HTX) in patients with DCM versus ICM (P = 0.0198) and TNI-autoantibody positive patients versus TNI-autoantibody negative patients (P = 0.0348). Further subgroup analysis revealed a favorable outcome in TNI-positive patients with heart failure if the patients suffered from DCM (P = 0.0334), whereas TNI-autoantibody status in patients with ICM was not associated with survival (P = 0.8486). In subsequent multivariate Weibull-analysis, a positive TNI serostatus was associated with a significantly lower all-cause mortality in DCM patients (P = 0.0492). The presence of TNI-autoantibodies in plasma is associated with an improved survival in patients with chronic DCM, but not ICM. This might possibly indicate a prophylactic effect of TNI-autoantibodies in this subgroup of patients, encouraging further studies into possible protective effects of antibodies against certain cardiac target structures.

Quantitative myocardial blush grade for the detection of cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) progressively compromises microvascular perfusion and function in heart transplantation (HTx)-recipients. The aim of our study was to investigate the ability of quantitative myocardial blush grade (MBG) to detect CAV. METHODS: In consecutive HTx-recipients (n = 72) who underwent surveillance cardiac catheterization, MBG was assessed visually and quantitatively, by analyzing the time course of contrast agent intensity rise. Hereby, the parameter G(max)/T(max) was calculated as the plateau of grey-level intensity (G(max)) divided by the time-to-peak intensity (T(max)). HTx-recipients and 18 healthy volunteers underwent cardiac magnetic resonance, to assess diastolic strain rates and myocardial perfusion reserve during pharmacologic hyperemia. RESULTS: Significant correlations were observed between G(max)/T(max) with perfusion reserve and with mean diastolic strain rates (r(2) = 0.68 and r(2) = 0.58, P < .001 for both). Visual and quantitative MBG using a cutoff value of G(max)/T(max) = 2.7/s yielded significantly higher accuracy than stenosis severity on coronary angiograms for the detection of impaired microvascular integrity as a surrogate marker for CAV (AUC = 0.78, SE = 0.06, 95% CI = 0.66-0.87 for lumen narrowing versus AUC = 0.91, SE = 0.03, 95%CI = 0.84-0.97 for G(max)/T(max); P < .01). Furthermore, quantitative MBG provided more robust prediction of survival (chi(2)= 14.0, P < .001), compared to visually estimated blush (chi(2)= 5.4, P = .02) and to coronary lumen narrowing assessment, (chi(2)= 4.8, P = .04). CONCLUSIONS: Quantification of MBG can be performed on coronary angiograms of HTx-recipients, and may help with the identification of early CAV in patients with impaired perfusion reserve but without angiographically evident atherosclerosis.

Early assessment of infarct size and prediction of functional recovery by quantitative myocardial blush grade in patients with acute coronary syndromes treated according to current guidelines.

PURPOSE: To determine whether quantification of myocardial blush grade (MBG) during cardiac catheterization can aid the determination of follow-up left ventricular (LV)-function in patients with ST-elevation and non-ST-elevation myocardial infarction (STEMI and NSTEMI). METHODS: We prospectively examined patients with first STEMI (n = 46) and NSTEMI (n = 49). ECG-gated angiographic series were used to quantify MBG by analyzing the time course of contrast agent intensity rise. Hereby, the parameter G(max)/T(max) was calculated, derived from the plateau of grey-level intensity (G(max)), divided by the time-to-peak intensity (T(max)). Cardiac magnetic resonance imaging (CMR) deemed as the standard reference for the estimation of infarct size, transmurality and of the LV-function at 6 months of follow-up. RESULTS: Cut-off values of G(max)/T(max)=5.7/sec and 3.8/sec, respectively, yielded similar accuracy as infarct transmurality for the prediction of follow-up ejection fraction >55% (AUC = 0.86 for STEMI and AUC = 0.90 for NSTEMI, by G(max)/T(max) and AUC = 0.85 for STEMI and AUC = 0.89 for NSTEMI, by infarct transmurality, respectively, P = NS). Both clearly surpassed the predictive value of visual MBG (AUC = 0.69 for STEMI and AUC = 0.68 for NSTEMI, P < 0.05). CONCLUSION: G(max)/T(max) is an easy to acquire but highly valuable surrogate parameter for infarct size, which yields equally high accuracy with infarct transmurality and favorably compares with visually assessed blush grades for the prediction of follow-up LV-function in patients with acute ischemic syndromes.

Effects of protein A immunoadsorption in patients with chronic dilated cardiomyopathy.

OBJECTIVES: The objective of this study was to investigate functional effects of immunoadsorption (IA) in patients with chronic nonfamilial dilated cardiomyopathy (DCM) regarding clinical and humoral markers of heart failure. BACKGROUND: IA has been shown to induce early hemodynamic improvement in patients with nonfamilial dilated cardiomyopathy (DCM). METHODS: We performed IA using protein A agarose columns on five consecutive days in 51 patients with chronic DCM, congestive heart failure of NYHA class ≥ II, left ventricular ejection fraction ≤50%, and mean time since initial diagnosis of 5.0 ± 5.8 years. RESULTS: Immediately after IA, immunoglobulin G (IgG) decreased by 89.4% and IgG3 by 66.7% (both P < 0.0001). Median NT-pro BNP was reduced from 1230.0 ng L(-1) at baseline to 829.0 ng L(-1) after 6 months (P < 0.0001). Also mean left ventricular ejection fraction (LVEF) was significantly improved (26.3% ± 9.4% to 28.7% ± 11.4% after 6 months, P = 0.016) and LVEF improved ≥5% (absolute) in 21 of 51 (41.2%) patients. After 6 months, bicycle spiroergometry showed a significant increase in exercise capacity from 82.0 ± 30.8 Watts to 93.1 ± 34.3 Watts (P = 0.008) while VO2max rose from 15.0 ± 4.1 to 16.4 ± 4.8 mL min(-1) kg(-1) (P = 0.01). CONCLUSIONS: In this study, on heart failure patients with nonfamilial DCM, IA therapy significantly improved clinical and humoral markers of heart failure severity. These promising results may be due to the selected study population, with a shorter disease duration and the higher amount of IgG 3 reduction. Future blinded prospective multicenter studies are necessary to identify those patients that benefit most.

[Depression, social support and compliance in patients with chronic heart failure]. / Depression, soziale Unterstützung und Compliance bei chronisch herzinsuffizienten Patienten.

Depressive patients with chronic heart failure (CHF) show less social integration and greater physical impairment as well as poorer compliance than non depressive CHF patients. Using multiple regression analyses, this study (n=84) investigated a potential mediating effect of depression on the relationship between compliance and both social support and physical functioning. Results did not support the hypothesized mediating effect of depression. However, the variables age, depression, left ventricular ejection fraction (LVEF) and social support were associated with self-reported compliance. Therefore, a lack of social support and depression should be considered as possible reasons, if patients are noncompliant during the treatment process.

Mortality and morbidity 1 year after stopping a remote patient management intervention: extended follow-up results from the telemedical interventional management in patients with heart failure II (TIM-HF2) randomised trial.

BACKGROUND: The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial showed that, compared with usual care, a structured remote patient management (RPM) intervention done over 12-months reduced the percentage of days lost due to unplanned cardiovascular hospitalisations and all-cause death. The aim of the study was to evaluate whether this clinical benefit seen for the RPM group during the initial 12 month follow-up of the TIM-HF2 trial would be sustained 1 year after stopping the RPM intervention. METHODS: TIM-HF2 was a prospective, randomised, multicentre trial done in 43 hospitals, 60 cardiology practices, and 87 general practitioners in Germany. Patients with heart failure, New York Heart Association functional class II or III, and who had been hospitalised for heart failure within 12 months before randomisation were randomly assigned to either the RPM intervention or usual care. At the final study visit (main trial), the RPM intervention was stopped and the 1 year extended follow-up period started, which lasted 1 year. The primary outcome was percentage of days lost due to unplanned cardiovascular hospitalisations and all-cause mortality. Analyses were done using the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01878630. FINDINGS: Between Aug 13, 2013, and May 12, 2017, 1538 patients were enrolled (765 to the remote patient management group and 773 to the usual care group) in the main trial. 671 of 765 patients in the remote patient management group and 673 of 773 in the usual care group completed the main trial and started the extended follow-up period up to 1 year later. In the extended follow-up period, the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality did not differ significantly between groups weighted mean 5·95% [95% CI 4·59-7·31] in the RPM group vs 6·64% [95% CI 5·19-8·08] in the usual care group [rate ratio 0·79; 95% CI 0·78-1·21]). However, when data from the main trial and the extended follow-up period were combined, the percentage of days lost due to unplanned cardiovascular hospitalisation or all-cause death was significantly less in patients allocated to the RPM group (382 [50%] of 765; weighted mean 9·28%; 95% CI 7·76-10·81) than in the UC group (398 [51%] of 773; 11·78%; 95% CI 10·08-13·49; ratio of weighted average 0·79; 95% CI 0·62-1·00; p=0·0486). INTERPRETATION: The positive effect of our RPM intervention on morbidity and mortality over the course of the main trial was no longer observed 1 year after stopping the RPM intervention. However, because the TIM-HF2 trial was not powered to show significance during the extended follow-up period, our results are exploratory and require further research. FUNDING: German Federal Ministry of Education and Research.

Reference change values and determinants of variability of NT-proANP and GDF15 in stable chronic heart failure.

Biovariability, reference change values (RCV), and index of individuality (IOI) have not been previously described for NT-proANP or GDF15. Also, the relation of changes of these markers to other clinical variables or biomarkers is unknown. In 41 patients with stable chronic systolic dysfunction, NT-proANP and GDF15 were measured alongside with clinical variables/markers comprising NT-proBNP, hsTnT, and hsCRP at four sampling intervals (2 weeks, 1-, 2-, 3-month intervals). At 2 weeks, 1-, 2-, and 3-month-follow-up, individual NT-proANP variations were 27.1, 22.5, 28.9, 15.6%, respectively, corresponding to RCVs of 53.2, 62.4, 80.2, and 43.2%, respectively. For GDF15, the respective individual variations were 6.8, 4.1, 5.5, 6.8%, corresponding to RCVs of 18.8, 11.5, 15.3 and 18.8%. Neither changes of NT-proANP or GDF15 correlated with changes in any of the clinical variables or biomarkers examined except for GDF15 with renal function. Baseline hormonal levels and clinical variables did not consistently influence the extent of change. The IOI was 0.19-0.35 according to interval for NT-proANP and 0.06-0.09 for GDF 15. In patients with CHF preselected for clinical stability changes of NT-proANP at intermediate follow-up do not correlate with changes in other variables; changes of GDF15 inversely correlate with renal function. The extent of change in both markers is not related to baseline hormonal levels or other baseline variables. RCVs are high for NT-proANP and low for GDF15, while inter-individual variation is high in GDF15 and intermediate in NT-proANP.

Variability of N-terminal probrain natriuretic peptide in stable chronic heart failure and its relation to changes in clinical variables.

BACKGROUND: We investigated the variability of N-terminal probrain natriuretic peptide (NT-proBNP) and its relation to known confounding variables in patients with stable chronic heart failure who were on a stable optimized medication regimen. METHODS: At 4 sampling intervals (14-day, 1-month, 2-month, and 3-month) the results for NT-proBNP measurements and several clinical variables were measured in samples from 41 patients with chronic systolic dysfunction who met 21 prespecified criteria for stability. RESULTS: Mean within-person NT-proBNP variabilities expressed as percentage CV were 17.6%, 18.9%, 15.5%, and 16.2% at 14-day, 1-month, 2-month, and 3-month follow-up, respectively, and the corresponding reference change values were 34.6%, 52.5%, 43.1%, and 45.0%, respectively. Within-person variability of NT-proBNP was not found to be associated with renal function, weight, or waist circumference. Likewise, age, sex, baseline NT-proBNP, New York Heart Association functional class, and ejection fraction did not influence variability of NT-proBNP. The index of individuality ranged from 0.07-0.15 depending on the time interval between test results. CONCLUSIONS: Although other reported studies have revealed variations in the range of 80%, in this prespecified stable heart-failure population variation of NT-proBNP at 14-day, 1-month, 2-month, and 3-month follow-up was lower and was not related to renal function or weight. In view of the low index of individuality we observed, within-person variation is quite low compared to between-person variation. Consideration of these facts is important for the interpretation of clinical trials and the use of NT-proBNP in monitoring patients with heart failure.

Prevalence and prognostic significance of adrenergic escape during chronic beta-blocker therapy in chronic heart failure.

AIMS: Like aldosterone escape to ACE-inhibitors, adrenergic escape (AE) to beta-blockers appears conceivable in chronic heart failure (CHF), as generalized systemic neurohumoral activation has been described as the pathophysiological basis of this syndrome. The aim of this study was to examine the prevalence and prognostic value of AE with respect to different beta-blocker agents and doses. METHODS AND RESULTS: This was a prospective, observational study of 415 patients with systolic CHF receiving chronic stable beta-blocker therapy. AE was defined by norepinephrine levels above the upper limit of normal. Irrespective of the individual beta-blocker agents used and the dose equivalent taken, the prevalence of AE was 31-39%. Norepinephrine levels neither correlated with heart rate (r=0.02; 95% CI: -0.08-0.11; P=0.74) nor were they related to underlying rhythm (P=0.09) or the individual beta-blocker agent used (P=0.87). The presence of AE was a strong and independent indicator of mortality (adjusted HR: 1.915; 95% CI: 1.387-2.645; chi2: 15.60). CONCLUSION: We verified the presence of AE in CHF patients on chronic stable beta-blocker therapy, irrespective of the individual beta-blocker agent and the dose equivalent. As AE might indicate therapeutic failure, the determination of AE could help to identify those patients with CHF that might benefit from more aggressive treatment modalities. Heart rate, however, is not a surrogate for adrenergic escape.

Validity, prognostic value and optimal cutoff of respiratory muscle strength in patients with chronic heart failure changes with beta-blocker treatment.

BACKGROUND: Training studies frequently use maximum inspiratory mouth occlusion pressure (PImax) as a therapeutic target and surrogate marker. For patients on beta-blocker (BBL), prognostic data allowing this extrapolation do not exist. Furthermore, the effects of BBL, mainstay of modern chronic heart failure therapy, on respiratory muscle function remain controversial. Finally, no proper separate cutoff according to treatment exists. DESIGN: Prospective, observational inclusion of patients with stable systolic chronic heart failure and recording of 1 year and all-time mortality for endpoint analysis. METHODS: In 686 patients, 81% men, 494 patients on BBL, PImax was measured along with clinical evaluation. The median follow-up was 50 months (interquartile range: 26-75 months). RESULTS: Patients with or without BBL did not differ significantly for PImax, percentage of predicted PImax or other marker of disease severity. PImax was a significant (hazard ratio: 0.925; 95% confidence interval: 0.879-0.975; chi(2): 8.62) marker of adverse outcome, independent of BBL-status or aetiology. Percentage of predicted PImax was not independent of PImax. The cutoff identified through receiver-operated characteristics for 1-year mortality was 4.14 kPa for patients on BBL and 7.29 kPa for patients not on BBL. When separated accordingly, 1-year mortality was 8.5 versus 21.4%, P=0.02, for patients not on BBL and 4.3 versus 16.2%, P<0.001, for patients on BBL. CONCLUSION: This study fills the gap between trials targeting respiratory muscle on a functional basis and the resultant prognostic information with regard to BBL. BBL lowered the optimal PImax cutoff values for risk stratification without changing the measured values of PImax. This should be considered at inclusion and evaluation of trials and interpretation of exercise parameters.

Exploring potential associations of suicidal ideation and ideas of self-harm in patients with congestive heart failure.

OBJECTIVE: To determine the factors, which are associated with suicidal ideation and ideas of self-harm in patients with congestive heart failure (CHF). METHODS: We examined 294 patients with documented CHF, New York Heart Association (NYHA) functional class II-IV, in a cross sectional study at three cardiac outpatient departments. Measures included self-reports of suicidal ideation and self-harm (PHQ-9), depression (SCID), health-related quality of life (SF-36), multimorbidity (CIRS-G), consumption of alcoholic beverages, as well as comprehensive clinical status. Data were analyzed using logistic regression analyses. RESULTS: 50 patients (17.1%) reported experiencing suicidal ideation and/or ideas of self-harm on at least several days over the past two weeks. The final regression model revealed significant associations with health-related quality of life, physical component (odds ratio [OR] 0.56; 95% confidence interval [CI]: 0.35-0.91), and mental component (OR 0.50; 95% CI: 0.31-0.82), consumption of alcoholic beverages (OR 1.27; 95% CI: 1.05-1.54), first-episode depression (OR 3.92; 95% CI: 1.16-13.22), and lifetime depression (OR 10.89; 95% CI: 2.49-47.72). Age was only significant in the univariable (P=.03) regression analysis. NYHA functional class, left ventricular ejection fraction (LVEF), etiology of CHF, medication, cardiovascular interventions, multimorbidity, gender, and living situation were not significantly associated with suicidal ideation or ideas of self-harm. CONCLUSIONS: Lifetime depression, in particular, increases the risk of suicidal ideation and ideas of self-harm in CHF patients. Furthermore, the findings of our study underline the necessity of differentiating between first-episode and lifetime depression in CHF-patients in future research and clinical practice.

Relation of N-terminal pro-brain natriuretic peptide levels and their prognostic power in chronic stable heart failure to obesity status.

AIMS: To investigate the relationship between body mass index (BMI) and N-terminal pro-brain natriuretic peptide (NTproBNP) level and resultant prognostic capacity in chronic heart failure (CHF) controlled for known confounders. METHODS AND RESULTS: We formed 206 triplets of patients (n = 618) with stable systolic CHF matched with respect to age, sex, renal function (MDRD, modification of diet in renal disease formula), and NYHA class, each with a BMI >30 kg/m(2) (group 3), 20-24.9 kg/m(2) (group 1), and 25-29.9 kg/m(2) (group 2). BMI conveys a 4% drop in NTproBNP per unit increase. This influence remained significant after correction for age, sex, MDRD, NYHA, heart rate, rhythm, and ejection fraction. NTproBNP remained an independent predictor of adverse outcome after correction for age, sex, BMI, NYHA, MDRD, and ejection fraction. Despite numerical differences, prognostic power was comparable between BMI groups (log-transformed NTproBNP; group 1: hazard ratio (HR) 1.435, 95% CI 1.046-1.967, chi(2) 5.02, P = 0.03; group 2: HR 1.604, 95% CI 1.203-2.138, chi(2) 10.36, P = 0.001; group 3: HR 1.735, 95% CI 1.302-2.313, chi(2) 14.12, P = 0.0002) (P = NS, all). An NTproBNP correction factor was calculated. CONCLUSION: Even matched for NYHA, age, sex, and renal function, BMI exerts a significant and independent inverse influence on NTproBNP in patients with stable CHF. NTproBNP retained equal statistical power in all three BMI groups.