Circulating miR-133a-3p defines a low-risk subphenotype in patients with heart failure and central sleep apnea: a decision tree machine learning approach.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and central sleep apnea (CSA) are at a very high risk of fatal outcomes. OBJECTIVE: To test whether the circulating miRNome provides additional information for risk stratification on top of clinical predictors in patients with HFrEF and CSA. METHODS: The study included patients with HFrEF and CSA from the SERVE-HF trial. A three-step protocol was applied: microRNA (miRNA) screening (n = 20), technical validation (n = 60), and biological validation (n = 587). The primary outcome was either death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening of heart failure, whatever occurred first. MiRNA quantification was performed in plasma samples using miRNA sequencing and RT-qPCR. RESULTS: Circulating miR-133a-3p levels were inversely associated with the primary study outcome. Nonetheless, miR-133a-3p did not improve a previously established clinical prognostic model in terms of discrimination or reclassification. A customized regression tree model constructed using the Classification and Regression Tree (CART) algorithm identified eight patient subphenotypes with specific risk patterns based on clinical and molecular characteristics. MiR-133a-3p entered the regression tree defining the group at the lowest risk; patients with log(NT-proBNP) ≤ 6 pg/mL (miR-133a-3p levels above 1.5 arbitrary units). The overall predictive capacity of suffering the event was highly stable over the follow-up (from 0.735 to 0.767). CONCLUSIONS: The combination of clinical information, circulating miRNAs, and decision tree learning allows the identification of specific risk subphenotypes in patients with HFrEF and CSA.

Post-discharge prognosis of patients admitted to hospital for heart failure by world region, and national level of income and income disparity (REPORT-HF): a cohort study.

BACKGROUND: Heart failure is a global public health problem, affecting a large number of individuals from low-income and middle-income countries. REPORT-HF is, to our knowledge, the first prospective global registry collecting information on patient characteristics, management, and prognosis of acute heart failure using a single protocol. The aim of this study was to investigate differences in 1-year post-discharge mortality according to region, country income, and income inequality. METHODS: Patients were enrolled during hospitalisation for acute heart failure from 358 centres in 44 countries on six continents. We stratified countries according to a modified WHO regional classification (Latin America, North America, western Europe, eastern Europe, eastern Mediterranean and Africa, southeast Asia, and western Pacific), country income (low, middle, high) and income inequality (according to tertiles of Gini index). Risk factors were identified on the basis of expert opinion and knowledge of the literature. FINDINGS: Of 18 102 patients discharged, 3461 (20%) died within 1 year. Important predictors of 1-year mortality were old age, anaemia, chronic kidney disease, presence of valvular heart disease, left ventricular ejection fraction phenotype (heart failure with reduced ejection fraction [HFrEF] vs preserved ejection fraction [HFpEF]), and being on guideline-directed medical treatment (GDMT) at discharge (p<0·0001 for all). Patients from eastern Europe had the lowest 1-year mortality (16%) and patients from eastern Mediterranean and Africa (22%) and Latin America (22%) the highest. Patients from lower-income countries (ie, ≤US$3955 per capita; hazard ratio 1·58, 95% CI 1·41-1·78), or with greater income inequality (ie, from the highest Gini tertile; 1·25, 1·13-1·38) had a higher 1-year mortality compared with patients from regions with higher income (ie, >$12 235 per capita) or lower income inequality (ie, from the lowest Gini tertile). Compared with patients with HFrEF, patients with HFpEF had a lower 1-year mortality with little variation by income level (pinteraction for HFrEF vs HFpEF <0·0001). INTERPRETATION: Acute heart failure is associated with a high post-discharge mortality, particularly in patients with HFrEF from low-income regions with high income inequality. Regional differences exist in the proportion of eligible patients discharged on GDMT, which was strongly associated with mortality and might reflect lack of access to post-discharge care and prescribing of GDMT. FUNDING: Novartis Pharma.

Point-of-care B-type natriuretic peptide and portable echocardiography for assessment of patients with suspected heart failure in primary care: rationale and design of the three-part Handheld-BNP program and results of the training study.

BACKGROUND: Patients with suspected heart failure (HF) often present first to general practitioners (GPs). Timely and accurate HF diagnosis and reliable prognostic information have remained unmet goals in primary care, where patient evaluation often relies on clinical assessment only. The Handheld-BNP program investigates whether additional use of portable echocardiography (ECHO) and point-of-care determination of B-type natriuretic peptide (BNP) improves the accuracy of HF diagnosis and aids risk prediction in primary care. METHODS AND RESULTS: A research network was established between 2 academic centers, 2 × 6 cardiologists, and 2 × 24 GPs inexperienced with ECHO and BNP. The Training Study investigates the feasibility of implementing GP use and interpretation of ECHO and BNP. After training, competence is assessed using multiple-choice testing (pass mark: > 80% correct diagnoses). In the cluster-randomized four-arm Screening Study, each GP passes in random order through four study arms: clinical assessment (CA), CA + BNP, CA + ECHO, and CA + ECHO + BNP. Cardiologists' diagnoses serve as reference. Primary endpoint is the rate of correct GP diagnoses per study arm. In the Prognostic Follow-Up Study, patients are followed up centrally for 72 months. Forty-four GPs were successfully trained. With 225 ± 34 (75 ± 3) and 233 ± 28 (81 ± 7) min, respectively, total ECHO (BNP) training times were similar between centers I and II. Furthermore, training results did not differ between centers. CONCLUSIONS: Standardized training of limited duration enabled GPs to use ECHO and BNP for HF diagnosis. The Handheld-BNP program will provide robust evaluation of the diagnostic effectiveness and prognostic value of these tools in primary care. TRIAL REGISTRATION: http://www.controlled-trials.com (ISRCTN23325295).

Comparative potential of the 2-item versus the 9-item patient health questionnaire to predict death or rehospitalization in heart failure.

BACKGROUND: Depression is common in heart failure and associated with adverse clinical outcomes. We investigated the potential of the 2-item patient health questionnaire (PHQ-2) versus that of the 9-item version (PHQ-9) to predict death or rehospitalization. METHODS AND RESULTS: Participants of the Interdisciplinary Network for Heart Failure program were eligible, if they completed the PHQ-9 during baseline assessment. All participants were hospitalized for cardiac decompensation and had a left ventricular ejection fraction ≤40% before discharge. PHQ-2 scores were extracted from the answers to the first 2 PHQ-9 questions. To analyze associations of PHQ-2 and PHQ-9 with both, death and rehospitalization, univariable Cox regression models were used. To compare screening efficacy of both tools, c-statistics were computed. The sample consisted of 852 patients, (67.6±12.1 years; 27.7% women; 42.3% New York Heart Association class III/IV). Follow-up was 18 months (100% complete). During follow-up, 152 patients died and 482 were rehospitalized. Both, PHQ-2 and PHQ-9, predicted death in univariable analysis (hazard ratio, 1.18; 95% confidence interval, 1.09-1.29; P<0.001 and hazard ratio, 1.07; 95% confidence interval, 1.04-1.09; P<0.001, respectively), as well as rehospitalization (hazard ratio, 1.07; confidence interval, 1.01-1.21; P=0.02 and hazard ratio, 1.03; confidence interval, 1.01-1.04; P=0.001, respectively). These results were confirmed by c-statistics. CONCLUSIONS: In univariable models and confirmed by c-statistics the potential of both PHQ-2 and PHQ-9 to predict death and hospitalization was similar. In clinical practice, PHQ-2 screening seems thus sufficiently reliable and more feasible than the time-consuming PHQ-9 to identify patients at an increased risk of adverse outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN 23325295.

Effects of structured heart failure disease management on mortality and morbidity depend on patients' mood: results from the Interdisciplinary Network for Heart Failure Study.

AIMS: Depression is common in heart failure (HF) and associated with adverse outcomes. Randomized comparisons of the effectiveness of HF care strategies by patients' mood are scarce. We therefore investigated in a randomized trial a structured collaborative disease management programme (HeartNetCare-HF™; HNC) recording mortality, morbidity, and symptoms in patients enrolled after hospitalization for decompensated systolic HF according to their responses to the 9-item Patient Health Questionnaire (PHQ-9) during an observation period of 180 days. METHODS AND RESULTS: Subjects scoring <12/≥12 were categorized as non-depressed/depressed, and those ignoring the questionnaire as PHQ-deniers. Amongst 715 participants (69 ± 12 years, 29% female), 141 (20%) were depressed, 466 (65%) non-depressed, and 108 (15%) PHQ-deniers. The composite endpoint of mortality and re-hospitalization was neutral overall and in all subgroups. However, HNC reduced mortality risk in both depressed and non-depressed patients [adjusted hazard ratios (HRs) 0.12, 95% confidence interval (CI) 0.03-0.56, P = 0.006, and 0.49, 95% CI 0.25-0.93, P = 0.03, respectively], but not in PHQ-deniers (HR 1.74, 95% CI 0.77-3.96, P = 0.19; P = 0.006 for homogeneity of HRs). Average frequencies of patient contacts in the HNC arm were 12.8 ± 7.9 in non-depressed patients, 12.4 ± 7.1 in depressed patients, and 5.5 ± 7.2 in PHQ-deniers (P < 0.001). CONCLUSIONS: Early after decompensation, HNC reduced mortality risk in non-depressed and even more in depressed subjects, but not in PHQ-deniers. This suggests that differential acceptability and chance of success of care strategies such as HNC might be predicted by appropriate assessment of patients' baseline characteristics including psychological disposition. These post-hoc results should be reassessed by prospective evaluation of HNC in larger HF populations.

Mode of action and effects of standardized collaborative disease management on mortality and morbidity in patients with systolic heart failure: the Interdisciplinary Network for Heart Failure (INH) study.

BACKGROUND: Trials investigating efficacy of disease management programs (DMP) in heart failure reported contradictory results. Features rendering specific interventions successful are often ill defined. We evaluated the mode of action and effects of a nurse-coordinated DMP (HeartNetCare-HF, HNC). METHODS AND RESULTS: Patients hospitalized for systolic heart failure were randomly assigned to HNC or usual care (UC). Besides telephone-based monitoring and education, HNC addressed individual problems raised by patients, pursued networking of health care providers and provided training for caregivers. End points were time to death or rehospitalization (combined primary), heart failure symptoms, and quality of life (SF-36). Of 1007 consecutive patients, 715 were randomly assigned (HNC: n=352; UC: n=363; age, 69±12 years; 29% female; 40% New York Heart Association class III-IV). Within 180 days, 130 HNC and 137 UC patients reached the primary end point (hazard ratio, 1.02; 95% confidence interval, 0.81-1.30; P=0.89), since more HNC patients were readmitted. Overall, 32 HNC and 52 UC patients died (1 UC patient and 4 HNC patients after dropout); thus, uncensored hazard ratio was 0.62 (0.40-0.96; P=0.03). HNC patients improved more regarding New York Heart Association class (P=0.05), physical functioning (P=0.03), and physical health component (P=0.03). Except for HNC, health care utilization was comparable between groups. However, HNC patients requested counseling for noncardiac problems even more frequently than for cardiovascular or heart-failure-related issues. CONCLUSIONS: The primary end point of this study was neutral. However, mortality risk and surrogates of well-being improved significantly. Quantitative assessment of patient requirements suggested that besides (tele)monitoring individualized care considering also noncardiac problems should be integrated in efforts to achieve more sustainable improvement in heart failure outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.

Impact of depression on quality of life assessment in heart failure.

BACKGROUND: Depression is highly prevalent in patients with chronic heart failure (CHF) and may bias patients' reports of their health-related quality of life (HRQoL). Depressed patients may rate their limitations of HRQoL worse even when their condition is rather good. We aimed to examine whether co-morbid depression alters the relationship between disease severity and HRQoL, thus compromising the validity of a CHF-specific HRQoL measure. METHODS: A sample of 233 outpatients with CHF (mean age 64.5 years, 70% male) was evaluated. Depression was measured with the Patient Health Questionnaire and CHF-specific HRQoL with the Kansas City Cardiomyopathy Questionnaire (KCCQ). CHF severity was assessed with physician ratings of the New York Heart Association (NYHA) functional class. RESULTS: Both NYHA functional class and depression independently impacted the various subscales of the KCCQ. Regarding the symptom- and function-related subscales, a dose-response relationship between disease severity and HRQoL was observed also in depressed patients. In contrast, in the quality of life subscale covering life satisfaction an interaction effect of disease severity and depression was found. In this subscale, a dose-response relationship between increasing disease severity and worsening HRQoL was no longer present among the depressed. CONCLUSIONS: Both disease severity and depression impacted each heart failure-specific HRQoL dimension while the presence of depression seemed to distort the relationship between disease severity and HRQoL in the quality of life subscale. As quality of life may depend more on the presence of depression than on the severity of CHF, assessing depression may help interpreting HRQoL scores.

Assessment of the contractile reserve in patients with intermediate coronary lesions: a strain rate imaging study validated by invasive myocardial fractional flow reserve.

AIMS: The present study aims to compare the change of left ventricular deformation during dobutamine stress echocardiography (DSE) with the reference standard of invasive myocardial fractional flow reserve (FFR) to assess the haemodynamic significance of intermediate coronary lesions. METHODS AND RESULTS: In 30 patients with an intermediate coronary artery stenosis in one epicardial coronary artery, FFR measurements were performed during coronary catheterization. In case of an FFR < 0.75 after intracoronary adenosine administration, the stenosis was considered significant, indicating ischaemia. In addition, during DSE, peak systolic strain rate and systolic strain of the region of interest (supplied by the stenotic vessel) and of a non-ischaemic remote region were assessed at baseline and at peak stress. Thirteen patients had an FFR >or= 0.75, indicating normal flow reserve (non-ischaemic group). The remaining 17 patients with an FFR < 0.75 comprised the ischaemic group. At baseline DSE, mean values of strain rate (-1.2 +/- 0.3 s(-1)) and strain (-17 +/- 8%) were not significantly different between both groups. In the ischaemic group, in the target region, strain at peak stress decreased to - 10 +/- 8%, whereas strain rate remained unchanged. In contrast, in the non-ischaemic group, strain at peak stress remained unchanged (-18 +/- 7%), whereas strain rate increased to - 2.5 +/- 1.1 s(-1). The receiver operating characteristic curve analysis revealed the change in strain rate as the best parameter to detect ischaemia, with a sensitivity of 89% and a specificity of 86%. In the remote region, in both groups, strain rate (-1.4 +/- 0.4 s(-1)) and strain values (-20 +/- 7%) were not significantly different at baseline, and strain rate doubled and strain remained unchanged at DSE peak stress. CONCLUSION: Non-invasive evaluation of regional deformation, using strain rate imaging during DSE, predicted the relevance of intermediate coronary stenosis. In this context, strain rate is superior to strain measurements for the quantification of the contractile reserve.

Assessment of cardiac allograft vasculopathy late after heart transplantation: when is coronary angiography necessary?

BACKGROUND: Cardiac allograft vasculopathy (CAV) represents a major prognostic factor in long-term survivors of heart transplantation (HTx). Reliable diagnosis of CAV late after HTx is important but remains the domain of invasive techniques such as coronary angiography. METHODS: To test alternative approaches, 54 consecutive HTx recipients (mean time since HTx: 52 months) were studied with intravascular ultrasound (IVUS), angiography, dobutamine stress echocardiography and immunofluorescence staining against anti-thrombin III (AT-III) in endomyocardial biopsies. Univariate and multivariate predictors as well as receiver-operating-characteristic (ROC) curves of different sets of predictors were calculated. RESULTS: Using IVUS as reference standard, CAV was present in 80% of subjects. Coronary angiography identified CAV correctly in only 44% of cases. If AT-III staining alone was used as a diagnostic criterion, CAV was correctly identified in 77% of subjects. In a multivariate analysis, only AT-III, donor age and echocardiography at rest emerged as independent predictors of CAV (p < 0.05 for all), yielding an excellent discriminative power. CONCLUSIONS: With almost equal reliability when compared with IVUS, CAV can be identified using information on donor age, wall motion score at rest and AT-III staining late after HTx. Coronary angiography may be limited to patients with a high probability score and should not be used routinely for surveillance of CAV.