Effect of adaptive servo ventilation on central sleep apnea and sleep structure in systolic heart failure patients: polysomnography data from the SERVE-HF major sub study.

This SERVE-HF (Treatment of Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure) sub study analysis evaluated polysomnography (PSG) data in patients with heart failure with reduced ejection fraction (HFrEF) and predominant central sleep apnea (CSA) randomised to guideline-based medical therapy, with or without adaptive servo ventilation (ASV). Patients underwent full overnight PSG at baseline and at 12 months. All PSG recordings were analysed by a core laboratory. Only data for patients with baseline and 3- or 12-month values were included. The sub study included 312 patients; the number with available PSG data differed for each variable (94-103 in the control group, 77-99 in the ASV group). After 12 months, baseline-adjusted respiratory measures were significantly better in the ASV group versus control. Although some between-group differences in sleep measures were seen at 12 months (e.g., better sleep efficiency in the ASV group), these were unlikely to be clinically significant. The number of periodic leg movements during sleep (PLMS) increased in the ASV group (p = 0.039). At 12 months, the respiratory arousal index was significantly lower in the ASV versus control group (p < 0.001), whilst the PLMS-related arousal index was significantly higher in the ASV group (p = 0.04 versus control). ASV attenuated the respiratory variables characterising sleep apnea in patients with HFrEF and predominant CSA in SERVE-HF. Sleep quality improvements during ASV therapy were small and unlikely to be clinically significant. The increase in PLMS and PLMS-related arousals during ASV warrants further investigation, particularly relating to their potential association with increased cardiovascular risk.

Association of serious adverse events with Cheyne-Stokes respiration characteristics in patients with systolic heart failure and central sleep apnoea: A SERVE-Heart Failure substudy analysis.

BACKGROUND AND OBJECTIVE: Increases in Cheyne-Stokes respiration (CSR) cycle length (CL), lung-to-periphery circulation time (LPCT) and time to peak flow (TTPF) may reflect impaired cardiac function. This retrospective analysis used an automatic algorithm to evaluate baseline CSR-related features and then determined whether these could be used to identify patients with systolic heart failure (HF) who experienced serious adverse events in the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF) substudy. METHODS: A total of 280 patients had overnight diagnostic polysomnography data available; an automated algorithm was applied to quantify CSR-related features. RESULTS: Median baseline CL, LPCT and TTPF were similar in the control (n = 152) and adaptive servo-ventilation (ASV, n = 156) groups. In both groups, CSR-related features were significantly longer in patients who did (n = 129) versus did not (n = 140) experience a primary endpoint event (all-cause death, life-saving cardiovascular intervention or unplanned hospitalization for worsening HF): CL, 61.1 versus 55.1 s (P = 0.002); LPCT, 36.5 versus 31.5 s (P < 0.001); TTPF, 15.20 versus 13.35 s (P < 0.001), respectively. This finding was independent of treatment allocation. CONCLUSION: Patients with systolic HF and central sleep apnoea who experienced serious adverse events had longer CSR CL, LPCT and TTPF. Future studies should examine an independent role for CSR-related features to enable risk stratification in systolic HF.

Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure.

BACKGROUND: Central sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea. METHODS: We randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure. RESULTS: In the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006). CONCLUSIONS: Adaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).

Adaptive servo ventilation for central sleep apnoea in heart failure: SERVE-HF on-treatment analysis.

This on-treatment analysis was conducted to facilitate understanding of mechanisms underlying the increased risk of all-cause and cardiovascular mortality in heart failure patients with reduced ejection fraction and predominant central sleep apnoea randomised to adaptive servo ventilation versus the control group in the SERVE-HF trial.Time-dependent on-treatment analyses were conducted (unadjusted and adjusted for predictive covariates). A comprehensive, time-dependent model was developed to correct for asymmetric selection effects (to minimise bias).The comprehensive model showed increased cardiovascular death hazard ratios during adaptive servo ventilation usage periods, slightly lower than those in the SERVE-HF intention-to-treat analysis. Self-selection bias was evident. Patients randomised to adaptive servo ventilation who crossed over to the control group were at higher risk of cardiovascular death than controls, while control patients with crossover to adaptive servo ventilation showed a trend towards lower risk of cardiovascular death than patients randomised to adaptive servo ventilation. Cardiovascular risk did not increase as nightly adaptive servo ventilation usage increased.On-treatment analysis showed similar results to the SERVE-HF intention-to-treat analysis, with an increased risk of cardiovascular death in heart failure with reduced ejection fraction patients with predominant central sleep apnoea treated with adaptive servo ventilation. Bias is inevitable and needs to be taken into account in any kind of on-treatment analysis in positive airway pressure studies.

Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes.

BACKGROUND: Insulin-resistant states, including type 2 diabetes (T2D) and prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. Therefore, it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin ≥5.7% to <6.5%) with previous CV complications. STUDY DESIGN: ALEPREVENT was a phase III, multicenter, randomized, double-blind, trial comparing aleglitazar 150 µg or placebo daily in patients with T2D or prediabetes with established, stable CV disease. The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events. However, the trial was halted prematurely after 1,999 patients had been randomized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar. RESULTS: At study termination after 58 ± 38 days of treatment, data had been collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. However, compared with placebo, aleglitazar increased the incidence of hypoglycemia (86 vs 166; P < .0001), and muscular events (3 vs12; P = .012). CONCLUSIONS: Even within a short duration of exposure, aleglitazar was associated with excess adverse events, corroborating the findings of a larger and longer trial in T2D. Coupled with the previous failure of several other peroxisome proliferator-activated receptor α/γ activators, this class now holds little promise for CV therapeutics.

Determining the prevalence and predictors of sleep disordered breathing in patients with chronic heart failure: rationale and design of the SCHLA-HF registry.

BACKGROUND: The objective of the SCHLA-HF registry is to investigate the prevalence of sleep-disordered breathing (SDB) in patients with chronic heart failure with reduced left ventricular systolic function (HF-REF) and to determine predictors of SDB in such patients. METHODS: Cardiologists in private practices and in hospitals in Germany are asked to document patients with HF-REF into the prospective SCHLA-HF registry if they meet predefined inclusion and exclusion criteria. Screening was started in October 2007 and enrolment was completed at the end of May 2013. After enrolment in the registry, patients are screened for SDB. SDB screening is mainly undertaken using the validated 2-channel ApneaLink™ device (nasal flow and pulse oximetry; ResMed Ltd., Sydney, Australia). Patients with a significant number of apneas and hypopneas per hour recording time (AHI ≥15/h) and/or clinical symptoms suspicious of SDB will be referred to a cooperating sleep clinic for an attended in-lab polysomnography with certified scoring where the definite diagnosis and, if applicable, the differentiation between obstructive and central sleep apnea will be made. Suggested treatment will be documented. DISCUSSION: Registries play an important role in facilitating advances in the understanding and management of cardiovascular disease. The SCHLA-HF registry will provide consistent data on a large group of patients with HF-REF that will help to answer questions on the prevalence, risk factors, gender differences and stability of SDB in these patients by cross-sectional analyses. Further insight into the development of SDB will be gained by extension of the registry to include longitudinal data.

Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure.

AIMS: Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator. This study evaluated the haemodynamic effect and safety of cinaciguat added to standard therapy in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS: In this placebo-controlled, phase IIb study (NCT00559650), 139 patients admitted with ADHF, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, left ventricular ejection fraction <40%, and a pre-existing need for invasive haemodynamic monitoring were randomized 2:1 to cinaciguat:placebo (continuous i.v. infusion). The dose was titrated for 8 h and maintained for 16-40 h (starting dose: 100 µg/h). At 8 h, mean PCWP changed from 25.7 ± 5.0 mmHg by -7.7 mmHg with cinaciguat and from 25.0 ± 5.3 mmHg by -3.7 mmHg with placebo (P < 0.0001). The mean right atrial pressure changed from 12.4 ± 5.3 mmHg by -2.7 mmHg with cinaciguat and from 11.8 ± 4.9 mmHg by -0.6 mmHg with placebo (P= 0.0019). Cinaciguat also decreased the pulmonary and systemic vascular resistance and the mean arterial pressure, and increased the cardiac index (all P < 0.0001 vs. placebo). Systolic blood pressure changed by -21.6 ± 17.0 mmHg with cinaciguat and -5.0 ± 14.5 mmHg with placebo. Adverse events were experienced by 71 and 45% of patients receiving cinaciguat and placebo, respectively. No adverse effects on the 30-day mortality were seen; however, the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h. CONCLUSION: Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.

Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial).

BACKGROUND: Contrast medium-induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium-induced acute kidney injury. METHODS AND RESULTS: Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL · min(-1) · 1.73 m(-2)) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium-induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium-induced kidney injury, defined as an increase in serum creatinine ≥25% or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium-induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07-0.57; P=0.002). No major adverse events were related to remote ischemic preconditioning. CONCLUSIONS: Remote ischemic preconditioning before contrast medium use prevents contrast medium-induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.germanctr.de. Unique identifier: U1111-1118-8098.

ECG as a risk stratification tool in patients with wearable cardioverter-defibrillator.

BACKGROUND: The wearable cardioverter defibrillator (WCD) is increasingly used in patients at elevated risk for ventricular arrhythmias but not fulfilling the indications for an implantable cardioverter defibrillator (ICD). Currently, there is an insufficient risk prediction of fatal arrhythmias in patients at risk. In this study, we assessed the prognostic role of baseline electrocardiogram (ECG) in WCD patients. METHODS: WCD patients from diverse clinical institutions in Germany (n = 227) were retrospectively enrolled and investigated for the incidences of death or ventricular arrhythmias during WCD wearing. In addition, the widely accepted ECG predictors of adverse outcome were analyzed in patients with arrhythmic events. RESULTS: Life-threatening arrhythmias occurred in 22 (9.7 %) patients, mostly in subjects with ischemic heart disease (15 of 22). There was no difference in baseline left ventricular ejection fraction (LVEF) in subjects with and without arrhythmic events (31.3 ±â€¯7.9 % vs. 32.6 ±â€¯8.3 %; p = 0,24). Patients with arrhythmia exhibited significantly longer QRS duration (109.5 ±â€¯23.1 ms vs. 100.6 ±â€¯22.3 ms, p = 0,04), Tpeak-Tend (Tp-e) (103.1 ±â€¯15.6 ms vs. 93.2 ±â€¯19.2 ms, p = 0,01) and QTc (475.0 ±â€¯60.0 ms vs. 429.6 ±â€¯59.4 ms, p < 0,001) intervals. In contrast, no significant differences were found for incidences of fragmented QRS (27.3 % vs. 24 %, p = 0.79) and inverted/biphasic T-waves (16.6 % vs. 22.7 %, p = 0,55). In multivariate regression analysis both Tp-e (HR 1.03; 95 % CI 1.001-1.057; p = 0.02) and QTc (HR 1.02; 95 % CI 1.006-1.026; p < 0.001) were identified as independent predictors of ventricular arrhythmias. After WCD use, the prophylactic ICD was indicated in 76 patients (33 %) with uneventful clinical course but persistent LVEF ≤35 %. The ECG analysis in these subjects did not reveal any relevant changes in arrhythmogenesis markers. CONCLUSIONS: ECG repolarization markers Tp-e and QTc are associated with malignant arrhythmias in WCD patients and may be used - in addition to other established risk markers - to identify appropriate patients for ICD implantation.

Prevalence and predictors of sleep-disordered breathing in chronic heart failure: the SchlaHF-XT registry.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing prevalence. Sleep-disordered breathing (SDB) is an important co-morbidity in HFpEF. The SchlaHF-XT registry evaluated the sex-specific prevalence and predictors of SDB, including obstructive (OSA) and central sleep apnoea, in patients with HFpEF compared with heart failure with mildly reduced (HFmrEF) or reduced (HFrEF) ejection fraction. METHODS AND RESULTS: Consecutive adults with chronic heart failure treated according to current guidelines were enrolled. The presence of moderate-to-severe SDB (apnoea-hypopnoea index ≥15/h) was determined using Type 3 polygraphic devices. Of 3289 patients included, 2032 had HFpEF, 559 had HFmrEF, and 698 had HFrEF, of whom 34, 21, 23, and 42%, respectively, were female. Prevalence of SDB in HFpEF was high, but significantly lower than in HFmrEF or HFrEF (36% vs. 41 and 48%, respectively). Rates of SDB in males and females were 41 and 28% in HFpEF, 44 and 30% in HFmrEF, and 50 and 40% in HFrEF. The proportion of males and females with SDB who had OSA was significantly greater in those with HFpEF vs. HFrEF. Male sex, older age, higher body mass index, and New York Heart Association functional Class III/IV were significant predictors of moderate-to-severe SDB in HFpEF patients. CONCLUSIONS: Prevalence of SDB in HFpEF was high, but lower than in patients with HFmrEF or HFrEF. Moderate-to-severe SDB occurred more frequently in males than in females across the whole spectrum of heart failure. In both sexes, the proportion of OSA in SDB patients with HFpEF was higher than in those with HFrEF.

Lipid lowering in patients with chronic kidney disease: a SHARP turn in the wrong direction?

The question whether lipid-lowering treatment is associated with a decrease in cardiovascular morbidity and mortality in patients with chronic kidney disease has been disputed for a while, with recent trials in patients on haemodialysis failing to show benefit. Recently, the long-awaited results of the SHARP (Study of Heart And Renal Protection) trial were published. This randomized trial compared the effects of either simvastatin 20 mg plus ezetimibe 10 mg daily or placebo on the occurrence of a first major vascular event in 9720 patients with chronic kidney disease. There was a 17% relative risk reduction but no benefit on survival. We address our concerns regarding the conclusions drawn from this trial. The trial has a major design flaw by comparing the effects of two different lipid-lowering drugs with placebo. Although the SHARP trial showed that lipid lowering may be beneficial for patients with chronic kidney disease, the clinically as well as economically important question remains unanswered as to whether it was statin therapy and/or ezetimibe that mediated this effect. A great opportunity to investigate superiority, equipoise, or potential inferiority of ezetimibe compared to statins was missed.

Evaluation of the functional status questionnaire in heart failure: a sub-study of the second cardiac insufficiency bisoprolol survival study (CIBIS-II).

AIMS: We evaluated a generic quality of life (QoL) Functional Status Questionnaire (FSQ), in patients with chronic heart failure (CHF). The FSQ assesses the 3 main dimensions of QoL: physical functioning, mental health and social role. It also includes 6 single item questions about: work status, frequency of social interactions, satisfaction with sexual relationships, days in bed, days with restricted activity and overall satisfaction with health status. The FSQ was compared to the Minnesota Living with Heart Failure questionnaire (MLwHF). METHODS AND RESULTS: The FSQ was evaluated in a substudy (n = 340) of the second Cardiac Insufficiency Bisoprolol Survival study (CIBIS-II), a placebo-controlled mortality trial. 265 patients (75%) patients completed both questionnaires at 6 months of follow-up. Both questionnaires indicated substantially impaired QoL. The FSQ demonstrated high internal consistency (Cronbach's α > 0.7 for all items except "social activity" = 0.66) and construct and concurrent validity. After 6 months, the only item on either questionnaire to show a difference between the placebo- and bisoprolol-treatment groups was the single item FSQ question about "days in bed" (p = 0.018 in favour of bisoprolol). CONCLUSIONS: The FSQ performed well in this study, provided additional information to the MLwHF questionnaire and allowed interesting comparisons with other chronic medical conditions. The FSQ may be a useful general QoL instrument for studies in CHF.

Local thrombolysis for successful treatment of acute stroke in an adolescent with cardiac myxoma.

Intracardiac myxomas are the most common benign cardiac tumors in adults. They are a rare source of cardiogenic embolisms and sudden death, especially in young patients. This report describes the case of a male adolescent who presented with right-sided paresis and aphasia. Magnetic resonance imaging of the brain revealed an ischemic stroke without evidence of acute bleeding. Intra-arterial local thrombolysis was immediately started. An echocardiographic screening after successful thrombolysis with a remarkable recovery of symptoms detected a thrombotic-like mass in the left atrium. The mass was excised surgically, confirmed as a benign atrial myxoma, and the patient was discharged with restitution ad integrum. Thus, contrary to some critical reports, thrombolytic therapy for acute ischemic strokes due to atrial myxomas may be safe and highly effective.

Diabetes-related defects in sarcoplasmic Ca2+ release are prevented by inactivation of G(alpha)11 and G(alpha)q in murine cardiomyocytes.

Neurohumoral stimulation of Gq-coupled receptors has been proposed as a central mechanism in the pathogenesis of diabetic heart disease. The resulting contractile dysfunction is closely related to abnormal intracellular Ca(2+) handling with functional defects of the sarcoplasmic reticulum (SR). The present study was therefore designed to determine the role of G(q)-protein signaling via G(alpha)(11) and G(alpha)(q) in diabetes for the induction of functional and structural changes in the Ca(2+) release complex of the SR. An experimental type 1-diabetes was induced in wild type, G(alpha)(11) knockout, and G(alpha)(11/q)-knockout mice by injection of streptozotocin. Cardiac morphology and function was assessed in vivo by echocardiography. SR Ca(2+) leak was tested in vitro based on a (45)Ca(2+) assay and protein densities as well as gene expression of ryanodine receptor (RyR2), FKBP12.6, sorcin, and annexin A7 were analyzed by immunoblot and RT-PCR. In wild type animals 8 weeks of diabetes resulted in cardiac hypertrophy and SR Ca(2+) leak was increased. In addition, diabetic wild type animals showed reduced protein levels of FKBP12.6 and annexin A7. In G(alpha)(11)- and G(alpha)(11/q)-knockout animals, however, SR Ca(2+) release and cardiac phenotype remained unchanged upon induction of diabetes. Densities of the proteins that we presently analyzed were also unaltered in G(alpha)(11)-knockout mice. G(alpha)(11/q)-knockout animals even showed increased expression of sorcin and annexin A7. Thus, based on the present study we suggest a signaling pathway via the G(q)-proteins, G(alpha)(11) and G(alpha)(q), that could link increased neurohumoral stimulation in diabetes with defective RyR2 channel function by regulating protein expression of FKBP12.6, annexin A7, and sorcin.

[Diabetes and heart failure]. / Diabetes und Herzinsuffizienz.

Heart failure is a common complication of type 2 diabetes and bears a poor prognosis. For patients with diabetes and heart failure the commonly accepted standards for diagnosis and treatment of heart failure are to be applied, although prospective diabetes- specific trials are lacking. The optimum HbA(1c) target value as well as the optimum blood glucoselowering treatment are not known. Due to an absence of prospective randomized trials the treatment should follow general therapeutic principles (low incidence of side effects, combination therapy, patient-friendly dosage, costs).

Rare cause for sudden right heart failure.

Right heart failure occurs daily in clinical settings, but an underlying cardiac malignant tumor is very uncommon. We report a case of a 48-year-old man presenting only with palpitations and decompensated heart failure. Echocardiographic imaging revealed a large tumor of the right ventricle. Shortly after a putatively successful surgical approach, the patient was admitted again with heart failure symptoms. On reassessment, a complete relapse with multiple metastases could be seen. Generally, cardiac malignant tumors are diagnosed at a time-point when therapeutic options are very limited or even postmortem. Broad echocardiographic screening in patients with unspecific symptoms might be helpful to detect cardiac malignant tumors at early stages.

Safety and tolerability of beta-blockers: prejudices & reality.

Beta-blockers (BB) substantially improve survival in chronic heart failure and after myocardial infarction. However, concern about side-effects may deter clinicians from prescribing these life-saving drugs. In reality, absolute contraindications are rare. Only 3-5% of patients are intolerant because of hypotension or bradycardia. Data from randomized controlled trials and retrospective studies show that most patients eligible to receive BB tolerate them well. BB are not contraindicated in chronic obstructive pulmonary disease (COPD); in fact, these patients also benefit because of their high cardiovascular risk. In patients with COPD, as in the elderly, BB should be started at a low dose and uptitrated slowly. Monitoring of lung function during initiation is important, as undiagnosed coexistent asthma could be revealed. When patients are unaware of the drug in use, erectile dysfunction (ED) is reported no more often with BB than with any other drug prescribed for heart failure or hypertension. However, when patients are aware of the potential side-effects of BB, the resultant anxiety may cause ED. Patients should be reassured that BB prolong life and in the great majority are not the cause of ED, which may rather be related to the underlying disease (diabetes, hypertension, and atherosclerosis).

Heart rate at discharge in patients with acute decompensated heart failure is a predictor of mortality.

AIMS: Heart failure is a syndrome with increasing prevalence in concordance with the aging population and better survival rates from myocardial infarction. Morbidity and mortality are high in chronic heart failure patients, particularly in those with hospital admission for acute decompensation. Several risk stratification tools and score systems have been established to predict mortality in chronic heart failure patients. However, identification of patients at risk with easy obtainable clinical factors that can predict mortality in acute decompensated heart failure (ADHF) are needed to optimize the care-path. METHODS AND RESULTS: We retrospectively analyzed electronic medical records of 78 patients with HFrEF and HFmrEF who were hospitalized with ADHF in the Heart Center of the University Hospital Cologne in the year 2011 and discharged from the ward after successful treatment. 37.6 ± 16.4 months after index hospitalization 30 (38.5%) patients had died. This mortality rate correlated well with the calculated predicted survival with the Seattle Heart Failure Model (SHFM) for each individual patient. In our cohort, we identified elevated heart rate at discharge as an independent predictor for mortality (p = 0.016). The mean heart rate at discharge was lower in survived patients compared to patients who died (72.5 ± 11.9 vs. 79.1 ± 11.2 bpm. Heart rate of 77 bpm or higher was associated with an almost doubled mortality risk (p = 0.015). Heart rate elevation of 5 bpm was associated with an increase of mortality of 25% (p = 0.022). CONCLUSIONS: Patients hospitalized for ADHF seem to have a better prognosis, when heart rate at discharge is < 77 bpm. Heart rate at discharge is an easily obtainable biomarker for risk prediction of mortality in HFrEF and HFmrEF patients treated for acute cardiac decompensation. Taking into account this parameter could be useful for guiding treatment strategies in these high-risk patients. Prospective data for validation of this biomarker and specific intervention are needed.

Biomarkers in patients with heart failure and central sleep apnoea: findings from the SERVE-HF trial.

AIMS: The Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure trial investigated the effects of adaptive servo-ventilation (ASV) (vs. control) on outcomes of 1325 patients with heart failure and reduced ejection fraction (HFrEF) and central sleep apnoea (CSA). The primary outcome (a composite of all-cause death or unplanned HF hospitalization) did not differ between the two groups. However, all-cause and cardiovascular (CV) mortality were higher in the ASV group. Circulating biomarkers may help in better ascertain patients' risk, and this is the first study applying a large set of circulating biomarkers in patients with both HFrEF and CSA. METHODS AND RESULTS: Circulating protein-biomarkers (n = 276) ontologically involved in CV pathways, were studied in 749 (57% of the trial population) patients (biomarker substudy), to investigate their association with the study outcomes (primary outcome, CV death and all-cause death). The mean age was 69 ± 10 years, and > 90% were male. The groups (ASV vs. control and biomarker substudy vs. no biomarker) were well balanced. The "best" clinical prognostic model included male sex, systolic blood pressure < 120 mmHg, diabetes, loop diuretic, cardiac device, 6-min walking test distance, and N-terminal pro BNP as the strongest prognosticators. On top of the "best" clinical prognostic model, the biomarkers that significantly improved both the discrimination (c-index) and the net reclassification index (NRI) of the model were soluble suppression of tumorigenicity 2 for the primary outcome; neurogenic locus notch homolog protein 3 (Notch-3) for CV-death and all-cause death; and growth differentiation factor 15 (GDF-15) for all-cause death only. CONCLUSIONS: We studied 276 circulating biomarkers in patients with HFrEF and central sleep apnoea; of these biomarkers, three added significant prognostic information on top of the best clinical model: soluble suppression of tumorigenicity 2 (primary outcome), Notch-3 (CV and all-cause death), and GDF-15 (all-cause death).

Bioprofiles and mechanistic pathways associated with Cheyne-Stokes respiration: insights from the SERVE-HF trial.

INTRODUCTION: The SERVE-HF trial included patients with heart failure and reduced ejection fraction (HFrEF) with sleep-disordered breathing, randomly assigned to treatment with Adaptive-Servo Ventilation (ASV) or control. The primary outcome was the first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening heart failure. A subgroup analysis of the SERVE-HF trial suggested that patients with Cheyne-Stokes respiration (CSR) < 20% (low CSR) experienced a beneficial effect from ASV, whereas in patients with CSR ≥ 20% ASV might have been harmful. Identifying the proteomic signatures and the underlying mechanistic pathways expressed in patients with CSR could help generating hypothesis for future research. METHODS: Using a large set of circulating protein-biomarkers (n = 276, available in 749 patients; 57% of the SERVE-HF population) we sought to investigate the proteins associated with CSR and to study the underlying mechanisms that these circulating proteins might represent. RESULTS: The mean age was 69 ± 10 years and > 90% were male. Patients with CSR < 20% (n = 139) had less apnoea-hypopnea index (AHI) events per hour and less oxygen desaturation. Patients with CSR < 20% might have experienced a beneficial effect of ASV treatment (primary outcome HR [95% CI] = 0.55 [0.34-0.88]; p = 0.012), whereas those with CSR ≥ 20% might have experienced a detrimental effect of ASV treatment (primary outcome HR [95% CI] = 1.39 [1.09-1.76]; p = 0.008); p for interaction = 0.001. Of the 276 studied biomarkers, 8 were associated with CSR (after adjustment and with a FDR1%-corrected p value). For example, higher PAR-1 and ITGB2 levels were associated with higher odds of having CSR < 20%, whereas higher LOX-1 levels were associated with higher odds of CSR ≥ 20%. Signalling, metabolic, haemostatic and immunologic pathways underlie the expression of these biomarkers. CONCLUSION: We identified proteomic signatures that may represent underlying mechanistic pathways associated with patterns of CSR in HFrEF. These hypothesis-generating findings require further investigation towards better understanding of CSR in HFrEF. SUMMARY OF THE FINDINGS: PAR-1 proteinase-activated receptor 1, ADM adrenomedullin, HSP-27 heat shock protein-27, ITGB2 integrin beta 2, GLO1 glyoxalase 1, ENRAGE/S100A12 S100 calcium-binding protein A12, LOX-1 lectin-like LDL receptor 1, ADAM-TS13 disintegrin and metalloproteinase with a thrombospondin type 1 motif, member13 also known as von Willebrand factor-cleaving protease.