Distinguishing heart failure with reduced ejection fraction from heart failure with preserved ejection fraction: A phenomics approach.

AIM: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets. METHODS AND RESULTS: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age- and sex-matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi-block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross-referenced with small-molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60-71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)-8 and IL-6 were possible targets related to lower EF and worsening renal function. CONCLUSION: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF.

Differential Associations of A-/B-Type Natriuretic Peptides With Cardiac Structure, Function, and Prognosis in Heart Failure.

BACKGROUND: Natriuretic peptide (NP) elevations are prognostic in heart failure (HF), but relative atrial NP deficiency in acute HF has been suggested. OBJECTIVES: The authors compared plasma concentrations and relative strength of associations of A- and B-type NPs with cardiac structure/function and clinical outcomes in HF. METHODS: Midregional pro-atrial natriuretic peptide (MR-proANP), B-type natriuretic peptide (BNP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured in patients with compensated HF in a prospective, multicenter study. The primary outcome was a composite of HF-hospitalization or all-cause mortality. Secondary outcomes included individual primary outcome components and cardiovascular admission. RESULTS: Among 1,278 patients (age 60.1 ± 12.1 years, 82% men, left ventricular ejection fraction [LVEF] 34% ± 14%), median concentrations of MR-proANP were 990 pg/mL (Q1-Q3: 557-1,563 pg/mL), NT-proBNP 1,648 pg/mL (Q1-Q3: 652-3,960 pg/mL), and BNP 291 pg/mL (Q1-Q3: 103-777 pg/mL). No subpopulation with inappropriately low MR-proANP (relative to BNP/NT-proBNP) was observed. Clinical event rates were similar for biomarker tertiles. Increments in MR-proANP exhibited steeper associations with concurrent shifts in left ventricular size, diastolic indexes and LVEF than BNP/NT-proBNP at baseline and serially (P < 0.05), and lower odds of beneficial left ventricular reverse remodeling: OR: 0.35 (95% CI: 0.18-0.70). In single-biomarker models, MR-proANP(log10) was associated with the highest hazard (4 to 6 times) for each outcome. In multimarker models, independent associations were observed for the primary outcome (MR-proANP and NT-proBNP), HF-hospitalization and cardiovascular admission (MR-proANP only), and all-cause mortality (NT-proBNP only) (P < 0.05). The discriminative value of MR-proANP was superior to BNP/NT-proBNP (HF-hospitalization) and BNP (primary outcome) (P < 0.05). CONCLUSIONS: MR-proANP was not inappropriately low relative to concurrent BNP/NT-proBNP values. Proportional increments in MR-proANP were more pronounced than for B-peptides for given decrements in cardiac structure/function. MR-proANP offered greater independent predictive power overall.

Clinical characteristics and outcomes in Asian patients with heart failure with mildly reduced ejection fraction.

Introduction: Data on heart failure (HF) with mildly reduced ejection fraction (HFmrEF) is still emerging, especially in Asian populations. This study aims to compare the clinical characteristics and outcomes of Asian HFmrEF patients with those of HF patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Methods: Patients admitted nationally for HF between 2008 and 2014 were included in the study. They were categorised according to ejection fraction (EF). Patients with EF <40%, EF 40%-49% and EF ≥50% were categorised into the following groups: HFrEF, HFmrEF and HFpEF, respectively. All patients were followed up till December 2016. Primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death and/or HF rehospitalisations. Results: A total of 16,493 patients were included in the study - HFrEF, n = 7,341 (44.5%); HFmrEF, n = 2,272 (13.8%); and HFpEF n = 6,880 (41.7%). HFmrEF patients were more likely to be gender neutral, of mid-range age and have concomitant diabetes mellitus, hyperlipidaemia, peripheral vascular disease and coronary artery disease (P < 0.001). The two-year overall mortality rates for HFrEF, HFmrEF and HFpEF were 32.9%, 31.8% and 29.1%, respectively. HFmrEF patients had a significantly lower overall mortality rate compared to HFrEF patients (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.83-0.95; P < 0.001) and a significantly higher overall mortality rate (adjusted HR 1.25, 95% CI 1.17-1.33; P < 0.001) compared to HFpEF patients. This was similarly seen with cardiovascular mortality and HF hospitalisations, with the exception of similar HF hospitalisations between HFmrEF and HFpEF patients. Conclusion: HFmrEF patients account for a significant burden of patients with HF. HFmrEF represents a distinct HF phenotype with high atherosclerotic burden and clinical outcomes saddled in between those of HFrEF and HFpEF. Further therapeutic studies to guide management of this challenging group of patients are warranted.

Titration of medications and outcomes in multi-ethnic heart failure cohorts (with reduced ejection fraction) from Singapore and New Zealand.

AIMS: We investigated titration patterns of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) and beta-blockers, quality of life (QoL) over 6 months, and associated 1 year outcome [all-cause mortality/heart failure (HF) hospitalization] in a real-world population with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Participants with HFrEF (left ventricular ejection fraction <40%) from a prospective multi-centre study were examined for use and dose [relative to guideline-recommended maintenance dose (GRD)] of ACEis/ARBs and beta-blockers at baseline and 6 months. 'Stay low' was defined as <50% GRD at both time points, 'stay high' as ≥50% GRD, and 'up-titrate' and 'down-titrate' as dose trajectories. Among 1110 patients (mean age 63 ± 13 years, 16% women, 26% New York Heart Association Class III/IV), 714 (64%) were multi-ethnic Asians from Singapore and 396 were from New Zealand (mainly European ethnicity). Baseline use of either ACEis/ARBs or beta-blockers was high (87%). Loop diuretic was prescribed in >80% of patients, mineralocorticoid receptor antagonist in about half of patients, and statins in >90% of patients. At baseline, only 11% and 9% received 100% GRD for each drug class, respectively, with about half (47%) achieving ≥50% GRD for ACEis/ARBs or beta-blockers. At 6 months, a large majority remained in the 'stay low' category, one third remained in 'stay high', whereas 10-16% up-titrated and 4-6% down-titrated. Patients with lower (vs. higher) N-terminal pro-beta-type natriuretic peptide levels were more likely to be up-titrated or be in 'stay high' for ACEis/ARBs and beta-blockers (P = 0.002). Ischaemic aetiology, prior HF hospitalization, and enrolment in Singapore (vs. New Zealand) were independently associated with higher odds of 'staying low' (all P < 0.005) for prescribed doses of ACEis/ARBs and beta-blockers. Adjusted for inverse probability weighting, ≥100% GRD for ACEis/ARBs [hazard ratio (HR) = 0.42; 95% confidence interval (CI) 0.24-0.73] and ≥50% GRD for beta-blockers (HR = 0.58; 95% CI 0.37-0.90) (vs. Nil) were associated with lower hazards for 1 year composite outcome. Country of enrolment did not modify the associations of dose categories with 1 year composite outcome. Higher medication doses were associated with greater improvements in QoL. CONCLUSIONS: Although HF medication use at baseline was high, most patients did not have these medications up-titrated over 6 months. Multiple clinical factors were associated with changes in medication dosages. Further research is urgently needed to investigate the causes of lack of up-titration of HF therapy (and its frequency), which could inform strategies for timely up-titration of HF therapy based on clinical and biochemical parameters.

Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure.

AIMS: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF). METHODS AND RESULTS: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. CONCLUSIONS: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Epicardial adipose tissue related to left atrial and ventricular function in heart failure with preserved versus reduced and mildly reduced ejection fraction.

AIM: Different associations between epicardial adipose tissue (EAT) and cardiac function have been suggested in patients with heart failure with preserved (HFpEF) versus reduced and mildly reduced ejection fraction (HFrEF/HFmrEF). However, few studies have directly compared the association between EAT and left atrial (LA) and left ventricular (LV) function in patients with HFpEF and HFrEF/HFmrEF. METHODS AND RESULTS: We studied EAT thickness using transthoracic echocardiography in a multicentre cohort of 149 community-dwelling controls without heart failure, 99 patients with HFpEF, and 366 patients with HFrEF/HFmrEF. EAT thickness was averaged from parasternal long-axis and short-axis views, respectively, and off-line speckle tracking analysis was performed to quantify LA and LV function. Data were validated in an independent cohort of 626 controls, 243 patients with HFpEF, and 180 patients with HFrEF/HFmrEF. For LV function, LV global longitudinal strain (GLS) was measured in both derivation and validation cohorts. For LA function, LAGLS at reservoir, contractile and conduit phase were measured in the derivation cohort, and only LAGLS at reservoir phase was measured in the validation cohort. In the derivation cohort, EAT thickness was lower in HFrEF/HFmrEF (7.3 ± 2.5 mm) compared to HFpEF (8.3 ± 2.6 mm, p < 0.05) and controls (7.9 ± 1.8 mm, p < 0.05). Greater EAT thickness was associated with better LV and contractile LA function in HFrEF/HFmrEF, but not in HFpEF (p for interaction <0.05). These findings were confirmed in the validation cohort, where EAT thickness was lower in HFrEF/HFmrEF (6.7 ± 1.4 mm) compared to HFpEF (9.6 ± 2.8 mm; p < 0.05) and controls (7.7 ± 2.3 mm; p < 0.05). Greater EAT thickness was associated with better LV and reservoir LA function in patients with HFrEF/HFmrEF but worse LV and reservoir LA function in patients with HFpEF (p for interaction <0.05). Thickened EAT (EAT thickness >10 mm) was associated with LA dysfunction (LAGLS at reservoir phase <23%) in HFpEF, but not in HFrEF/HFmrEF. CONCLUSION: Epicardial adipose tissue thickness is greater in patients with HFpEF than HFrEF/HFmrEF. Increased EAT thickness is associated with worse LA and LV function in HFpEF but the opposite in HFrEF/HFmrEF.

Cardiac biomarkers retain prognostic significance in patients with heart failure and chronic obstructive pulmonary disease.

AIMS: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). We assessed the influence of COPD on circulating levels and prognostic value of three HF biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and soluble suppression of tumorigenesis-2 (sST2). METHODS: Individual data from patients with chronic HF, known COPD status, NT-proBNP and hs-TnT values (n = 8088) were analysed. A subgroup (n = 3414) had also sST2 values. RESULTS: Patients had a median age of 66 years (interquartile interval 57-74), 77% were men and 82% had HF with reduced ejection fraction. NT-proBNP, hs-TnT and sST2 were 1207 ng/l (487-2725), 17 ng/l (9-31) and 30 ng/ml (22-44), respectively. Patients with COPD (n = 1249, 15%) had higher NT-proBNP (P = 0.042) and hs-TnT (P < 0.001), but not sST2 (P = 0.165). Over a median 2.0-year follow-up (1.5-2.5), 1717 patients (21%) died, and 1298 (16%) died from cardiovascular causes; 2255 patients (28%) were hospitalized for HF over 1.8 years (0.9-2.1). NT-proBNP, hs-TnT and sST2 predicted the three end points regardless of COPD status. The best cut-offs from receiver-operating characteristics analysis were higher in patients with COPD than in those without. Patients with all three biomarkers higher than or equal to end-point- and COPD-status-specific cut-offs were also those with the worst prognosis. CONCLUSIONS: Among patients with HF, those with COPD have higher NT-proBNP and hs-TnT, but not sST2. All these biomarkers yield prognostic significance regardless of the COPD status.

Impact of change in iron status over time on clinical outcomes in heart failure according to ejection fraction phenotype.

AIMS: The importance of iron deficiency (ID) in heart failure with preserved ejection fraction (HFpEF) is unknown. In HF with reduced ejection fraction (HFrEF), ID is reported as an independent predictor of mortality in HF although not all published studies agree. Different definitions of ID have been assessed, and the natural history of untreated ID not established, which may explain the conflicting results. This study aimed to assess the relationship between ID and mortality in HFpEF, clarify which definition of ID correlates best with outcomes in HFrEF, and determine the prognostic importance of change in ID status over time. METHODS AND RESULTS: Analyses were conducted on data from 1563 patients participating in a prospective international cohort study comparing HFpEF with HFrEF. Plasma samples from baseline and 6 month visits were analysed for the presence of ID. Two ID definitions were evaluated: IDFerritin  = 'ferritin < 100 mcg/L or ferritin 100-300 mcg/L + transferrin saturation < 20%' and IDTsat  = 'transferrin saturation < 20%'. The risk of all-cause mortality and death/HF hospitalization associated with baseline ID (IDFerritin or IDTsat ) and change in ID status at 6 months (persistent, resolving, developing, or never present) was estimated in multivariable Cox proportional hazards models. Of 1563 patients, 1115 (71%) had HFrEF and 448 (29%) HFpEF. Prevalence of ID was similar in HFpEF and HFrEF (58%). Patients with ID were more likely to be female, diabetic, and have a higher co-morbid burden than patients without ID. ID by either definition did not confer independent risk for either all-cause mortality or death/HF hospitalization for patients with HFpEF [IDFerritin hazard ratio (HR) 0.65 (95% confidence interval 0.40-1.05), P = 0.08; IDTsat HR 1.16 (0.72-1.87), P = 0.55]. In the overall study cohort (HFrEF + HFpEF) and HFrEF subgroup, IDFerritin was inferior to IDTsat in prediction of all-cause mortality [overall cohort: HR 1.21 (0.95-1.53), P = 0.12 vs. HR 1.95 (1.52-2.51), P < 0.01; HFrEF: HR 1.12 (0.85-1.48), P = 0.43 vs. HR 1.57 (1.15-2.14), P < 0.01]. Persistence of IDTsat at 6 months was strongly associated with poor outcomes compared with never having IDTsat [HR 2.22 (1.42-3.46), P < 0.01] or having IDTsat at baseline self-resolve by 6 months [HR 1.40 (1.06-1.86), P = 0.02]. CONCLUSIONS: Iron deficiency is equally prevalent in HFpEF and HFrEF but is negatively prognostic only in HFrEF. The natural history of ID is important; persistent ID is strongly associated with mortality whereas resolution is not. IDTsat is the superior definition of ID and should inform future trials investigating the efficacy of intravenous iron replacement in patients with HFrEF.

NT-proBNP for Risk Prediction in Heart Failure: Identification of Optimal Cutoffs Across Body Mass Index Categories.

OBJECTIVES: The goal of this study was to assess the predictive power of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories. BACKGROUND: Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain. METHODS: Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), and mildly (BMI 30-34.9 kg/m2), moderately (BMI 35-39.9 kg/m2), or severely (BMI ≥40 kg/m2) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death. RESULTS: The study population included 12,763 patients (mean age 66 ± 12 years; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (ß = -0.174 for 1 kg/m2; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-year all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men. CONCLUSIONS: NT-proBNP maintains its independent prognostic value up to 40 kg/m2 BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients.

Financial difficulties and patient-reported outcomes among patients with advanced heart failure.

PURPOSE: Management of congestive heart failure (CHF) is associated with high health care costs and financial difficulties for patients. We aimed to comprehensively assess the association between financial difficulties and patients' quality of life (QOL) (physical, emotional, social and spiritual), perceived health care quality, and perception of being a burden to the family among patients with CHF; and to assess whether perceived control over stress moderated these associations. METHODS: This was a cross-sectional study of 250 patients using the baseline data of the Singapore Cohort of Patients with Advanced Heart Failure (SCOPAH). Patients had class 3 or 4 CHF symptoms based on the New York Heart Association and were recruited between July 2017 and August 2019. We used a 3-item questionnaire to measure financial difficulties among patients. We used multivariable linear/ordered logistic regressions to test associations between financial difficulties and each dependent variable. RESULTS: 41% of participants reported financial difficulties. A higher financial difficulties score (range: 0-6, higher score indicating greater difficulty) was associated with lower QOL (emotional, social, and spiritual) and perceived health care coordination, and a higher likelihood of patients perceiving themselves to being a burden to family (all p < 0.05) CONCLUSION: Patients with financial difficulties are vulnerable to poor outcomes. Heart failure clinics should directly assess patients' financial difficulties to help guide treatment-related discussions and to identify patients vulnerable to poor QOL.

Instability in Preference for Place of Death Among Patients With Symptoms of Advanced Heart Failure.

OBJECTIVES: Patient preference for place of death is an important component of advance care planning (ACP). If patients' preference for place of death changes over time, this questions the value of their documented preference. We aimed to assess the extent and correlates of change in preference for place of death over time among patients with symptoms of advanced heart failure. DESIGN: We conducted a secondary analysis of data from a randomized controlled trial of a formal ACP program vs usual care. SETTING AND PARTICIPANTS: We interviewed 282 patients aged 21 years old and above with heart failure and New York Heart Association Classification III and IV symptoms in Singapore. Analytic sample included 200 patients interviewed at least twice. METHODS: We assessed factors associated with patients' preference for place of death (home/institution/no preference) and change in their preference for place of death from previous time point (change toward home death/toward an institutional death/toward no preference/no change). These included patient demographics, quality of life (Kansas City Cardiomyopathy Questionnaire), and prognostic understanding. RESULTS: In our study, 66% of patients with heart failure changed their preference for place of death at least once during the study period with no consistent pattern of change. Correct prognostic understanding at the time of survey reduced the relative risk of change in preference for place of death to home (relative risk ratio 0.49, 95% confidence interval 0.32, 0.76), whereas a higher quality of life score was associated with a lower relative risk of patients changing their preferred place of death to an institution (relative risk ratio 0.99, 95% confidence interval 0.97, 1.00) relative to no change in preference. CONCLUSIONS AND IMPLICATIONS: We provide evidence of instability in patients with heart failure preference for place of death, which suggests that ACP documents should be regularly re-evaluated.

Atrial Fibrillation and the Prognostic Performance of Biomarkers in Heart Failure.

BACKGROUND: Consideration of circulating biomarkers for risk stratification in heart failure (HF) is recommended, but the influence of atrial fibrillation (AF) on prognostic performance of many markers is unclear. We investigated the influence of AF on the prognostic performance of circulating biomarkers in HF. METHODS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide, C-type natriuretic peptide (CNP), NT-proCNP, high-sensitivity troponin-T, high-sensitivity troponin-I, mid-regional-propeptide adrenomedullin, co-peptin, growth differentiation factor-15, soluble Suppressor of Tumorigenicitiy (sST2), galectin-3, and procalcitonin plasma concentrations were measured in a prospective, multicenter study of adults with HF. AF was defined as a previous history of AF, and/or presence of AF/flutter on baseline 12-lead electrocardiogram. The primary outcome was the composite of HF-hospitalization or all-cause mortality at 2 years. RESULTS: Among 1099 patients (age 62 ± 12years, 28% female), 261(24%) patients had AF. Above-median concentrations of all biomarkers were independently associated with increased risk of the primary outcome. Significant interactions with AF were detected for galectin-3 and sST2. In considering NT-proBNP for additive risk stratification, sST2 (adjusted hazard ratio [AHR]1.85, 95%confidence interval [C.I.] 1.17-2.91) and galectin-3 (AHR1.85, 95%C.I. 1.09-2.45) were independently associated with increased primary outcome only in the presence of AF. The prognostic performance of sST2 was also stronger in AF for all-cause mortality (AF: AHR2.82, 95%C.I. 1.26-6.21; non-AF: AHR1.78, 95% C.I. 1.14-2.76 without AF), while galectin-3 predicted HF-hospitalization only in AF (AHR1.64, 95%C.I. 1.03-2.62). CONCLUSIONS: AF modified the prognostic utility of selected guideline-endorsed HF-biomarkers. Application of markers for prognostic purposes in HF requires consideration of the presence or absence of AF. CLINICAL TRIAL REGISTRATION: ACTRN12610000374066.

Ethnic differences in quality of life and its association with survival in patients with heart failure.

BACKGROUND: Optimizing quality of life (QoL) is a key priority in the management of heart failure (HF). HYPOTHESIS: To investigate ethnic differences in QoL and its association with 1-year survival among patients with HF. METHODS: A prospective nationwide cohort (n = 1070, mean age: 62 years, 24.5% women) of Chinese (62.3%), Malay (26.7%) and Indian (10.9%) ethnicities from Singapore, QoL was assessed using the Minnesota Living with HF Questionnaire (MLHFQ) at baseline and 6 months. Patients were followed for all-cause mortality. RESULTS: At baseline, Chinese had a lower (better) mean MLHFQ total score (29.1 ± 21.6) vs Malays (38.5 ± 23.9) and Indians (41.7 ± 24.5); P < .001. NYHA class was the strongest independent predictor of MLHFQ scores (12.7 increment for class III/IV vs I/II; P < .001). After multivariable adjustment (including NT-proBNP levels, medications), ethnicity remained an independent predictor of QoL (P < .001). Crude 1-year mortality in the overall cohort was 16.5%. A 10-point increase of the physical component (of MLHFQ) was associated with a hazard (HR 1.22, 95% 1.03-1.43) of 1-year mortality (P = .018) in the overall cohort. An interaction between MLHFQ and ethnicity was found (P = .019), where poor MLHFQ score (per 10-point increase) predicted higher adjusted mortality only in Chinese (total score: HR 1.18 [95% CI 1.07-1.30]; physical: HR 1.44 [95% CI 1.17-1.75]; emotional score: HR 1.45 [95% CI 1.05-2.00]). CONCLUSIONS: Ethnicity is an independent determinant of QoL in HF. Despite better baseline QoL in Chinese, QoL was more strongly related to survival in Chinese vs Malays and Indians. These findings have implications for HF trials that use patient-reported outcomes as endpoints.

Instability in End-of-Life Care Preference Among Heart Failure Patients: Secondary Analysis of a Randomized Controlled Trial in Singapore.

BACKGROUND: Efforts to improve quality of end-of-life (EOL) care are increasingly focused on eliciting patients' EOL preference through advance care planning (ACP). However, if patients' EOL preference changes over time and their ACP documents are not updated, these documents may no longer be valid at the time EOL decisions are made. OBJECTIVES: To assess extent and correlates of changes in stated preference for aggressive EOL care over time. DESIGN: Secondary analysis of data from a randomized controlled trial of a formal ACP program versus usual care in Singapore. PATIENTS: Two hundred eighty-two patients with heart failure (HF) and New York Heart Association Classification III and IV symptoms were recruited and interviewed every 4 months for up to 2 years to assess their preference for EOL care. Analytic sample included 200 patients interviewed at least twice. RESULTS: Nearly two thirds (64%) of patients changed their preferred type of EOL care at least once. Proportion of patients changing their stated preference for type of EOL care increased with time and the change was not unidirectional. Patients who understood their prognosis correctly were less likely to change their preference from non-aggressive to aggressive EOL care (OR 0.66, p value 0.07) or to prefer aggressive EOL care (OR 0.53; p value 0.001). On the other hand, patient-surrogate discussion of care preference was associated with a higher likelihood of change in patient preference from aggressive to non-aggressive EOL care (OR 1.83; p value 0.03). CONCLUSION: The study provides evidence of instability in HF patients' stated EOL care preference. This undermines the value of an ACP document recorded months before EOL decisions are made unless a strategy exists for easily updating this preference. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02299180.

Circulating levels and prognostic value of soluble ST2 in heart failure are less influenced by age than N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T.

AIMS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers. METHODS AND RESULTS: Individual data from 5301 patients with chronic HF and NT-proBNP, hs-TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60-69 years (n = 1628, 31%), 70-79 years (n = 1662, 31%), and ≥ 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT-proBNP 1564 ng/L, hs-TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT-proBNP and hs-TnT, but not sST2. The best NT-proBNP and hs-TnT cut-offs for 1-year and 5-year all-cause and cardiovascular mortality and 1- to 12-month HF hospitalization increased with age, while the best sST2 cut-offs did not. When stratifying patients according to age- and outcome-specific cut-offs, this stratification yielded independent prognostic significance over NT-proBNP levels only, or the composite of NT-proBNP and hs-TnT, and improved risk prediction for most endpoints. Finally, absolute NT-proBNP, hs-TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables. CONCLUSIONS: Soluble ST2 is less influenced by age than NT-proBNP or hs-TnT; all these biomarkers predict outcome regardless of age. The use of age- and outcome-specific cut-offs of NT-proBNP, hs-TnT and sST2 allows more accurate risk stratification than NT-proBNP alone or the combination of NT-proBNP and hs-TnT.