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.

Non-invasive mid-term electrocardiogram patch monitoring is effective in detecting atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a cause of serious morbidity such as stroke. Early detection and treatment of AF is important. Current guidelines recommend screening via opportunistic pulse taking or 12­lead electrocardiogram. Mid-term ECG patch monitors increases the sensitivity of AF detection. METHODS: The Singapore Atrial Fibrillation Study is a prospective multi-centre study aiming to study the incidence of AF in patients with no prior AF and a CHA2DS2-VASc score of at least 1, with the use of a mid-term continuous ECG monitoring device (Spyder ECG). Consecutive patients from both inpatient and outpatient settings were recruited from 3 major hospitals from May 2016 to December 2019. RESULTS: Three hundred and fifty-five patients were monitored. 6 patients (1.7%) were diagnosed with AF. There were no significant differences in total duration of monitoring between the AF and non-AF group (6.39 ± 3.19 vs 5.42 ± 2.46 days, p = 0.340). Patients with newly detected AF were more likely to have palpitations (50.0% vs 11.8%, p = 0.027). Half of the patients (n = 3, 50.0%) were diagnosed on the first day of monitoring and the rest were diagnosed after 24 h. On univariate analysis, only hyperlipidemia was associated with reduced odds of being diagnosed with AF (OR HR 0.08 CI 0.01-0.74, p = 0.025). In a group of 128 patients who underwent coronary artery bypass grafting and had post-operative ECG monitoring, 9 patients (7.0%) were diagnosed with post-operative AF. CONCLUSIONS: The use of non-invasive mid-term patch-based ECG monitoring is an effective modality for AF screening.

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.

Effectiveness of telemonitoring-enhanced support over structured telephone support in reducing heart failure-related healthcare utilization in a multi-ethnic Asian setting.

AIMS: Our study aimed to compare the effectiveness of telemonitoring over structured telephone support in reducing heart failure-related healthcare utilization. METHODS: This was a non-randomised controlled study comparing 150 recently discharged heart failure patients enrolled into telemonitoring and 55 patients who only received structured telephone support after rejecting telemonitoring. Patient activation, knowledge and self-management levels were measured at baseline and the one year upon programme completion using the Patient Activation Measure, the Dutch Heart Failure Knowledge Scale and the Self-Care of Heart Failure Index respectively. Differences in heart failure-related and all-cause hospitalization rates, total bed days and mortality rates at 180 days and at one year, knowledge and self-management scores and total cost of care between groups at one year were analysed. RESULTS: Average age of telemonitoring was 57.9 years and 63.9 years for structured telephone support. Significant difference in adjusted 180-day all-cause bed days (telemonitoring: five days versus structured telephone support: 9.8 days), heart failure-related bed days (telemonitoring: 1.2 days versus structured telephone support: six days) and adjusted one-year heart failure-related bed days (telemonitoring: 2.2 days versus structured telephone support: 6.6 days) were observed. Telemonitoring was associated with reduced all-cause one-year mortality (hazard ratio 0.32, p = 0.02). Estimated mean maintenance and confidence scores were significantly higher in the telemonitoring group at one year. No differences in all-cause and HF-related readmission rates and knowledge levels were observed. The one-year total cost of care was predicted to be Singapore dollars (SG$) 2774.4 lower (p = 0.07) in telemonitoring. CONCLUSION: In conclusion, telemonitoring was associated with lower all-cause and heart failure-related total bed days at 180 days, lower heart failure-related total bed days and total cost of care at one year as compared with structured telephone support.

N-terminal pro-B-type natriuretic peptide and prognosis in Caucasian vs. Asian patients with heart failure.

AIMS: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the most frequently used biomarker in heart failure (HF), but its prognostic utility across ethnicities is unclear. METHODS AND RESULTS: This study included 546 Caucasians with HF from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure and 578 Asians with HF from the Singapore Heart Failure Outcomes and Phenotypes study. NT-proBNP was measured at discharge after HF hospitalization. The studied outcome was a composite of all-cause mortality and HF hospitalization at 18 months. Compared with Caucasian patients, Asian patients were younger (63 ± 12 vs. 71 ± 11 years); less often female (26% vs. 39%); and had lower body mass index (26 vs. 27 kg/m2 ), better renal function (61 ± 37 vs. 54 ± 20 mL/min/1.73 m2 ), lower rates of atrial fibrillation (25% vs. 46%), strikingly higher rates of diabetes (59% vs. 30%), and higher rates of hypertension (76% vs. 44%). Despite these clear inter-group differences in individual drivers of NT-proBNP, average levels were similar in Asians [2709 (1350, 6302) pg/mL] and Caucasians [2545 (1308, 5484) pg/mL] (P = 0.514). NT-proBNP was strongly associated with outcome [hazard ratio 1.28 (per doubling), 95% confidence interval 1.18-1.39, P < 0.001], regardless of ethnicity (Pinteraction  = 0.719). NT-proBNP was similarly associated with outcome in HF with reduced and preserved ejection fraction in Asian (Pinteraction  = 0.776) and Caucasian patients (Pinteraction  = 0.558). CONCLUSIONS: NT-proBNP has similar prognostic performance in Asians and Caucasians with HF despite ethnic differences in known clinical determinants of plasma NT-proBNP.

The prognostic value of highly sensitive cardiac troponin assays for adverse events in men and women with stable heart failure and a preserved vs. reduced ejection fraction.

AIMS: Circulating biomarkers are important in the diagnosis, risk stratification and management of patients with heart failure (HF). Given the current lack of biomarkers in HF with preserved ejection fraction (HFpEF), we aimed to investigate the prognostic performance of the newly developed high-sensitivity (hs) assays for cardiac troponin I (hsTnI) compared with troponin T (hsTnT) for adverse events in HFpEF vs. HF with reduced ejection fraction (HFrEF). Findings in these two HF subgroups were also compared with those in the recently defined HF with mid-range ejection fraction (HFmrEF) subgroup. METHODS AND RESULTS: Both hsTnI and hsTnT were measured in 1096 patients with HFrEF [left ventricular ejection fraction (LVEF) <50%; n = 853] or HFpEF (LVEF ≥50%; n = 243) enrolled in the Singapore Heart Failure Outcomes and Phenotypes (SHOP) study. Both troponin assays were more strongly associated with the composite endpoint (all-cause mortality or first rehospitalization for HF) in HFpEF than in HFrEF. The hsTnT assay provided the greatest additional prognostic value in HFpEF in comparison with hsTnI and NT-proBNP. TnI was more strongly associated with composite events in men with HFpEF [hazard ratio (HR) 3.33, 95% confidence interval (CI) 1.82-6.09; P < 0.001 per standard deviation (SD) increase in log-transformed hsTnI] than in women with HFpEF (HR 1.35, 95% CI 0.94-1.93; P = 0.10 per SD increase in log-transformed hsTnI). CONCLUSIONS: There is a potential role for the prognostic use of high-sensitivity troponin assays, particularly hsTnT, in men and women with HFpEF. The predictive association of hsTnI with outcome appears strongest in men with HFpEF.

Prevalence and Clinical Significance of Diabetes in Asian Versus White Patients With Heart Failure.

OBJECTIVES: The study sought to compare the prevalence, clinical correlates and prognostic impact of diabetes in Southeast Asian versus white patients with heart failure (HF) with preserved or reduced ejection fraction. BACKGROUND: Diabetes mellitus is common in HF and is associated with impaired prognosis. Asia is home to the majority of the world's diabetic population, yet data on the prevalence and clinical significance of diabetes in Asian patients with HF are sparse, and no studies have directly compared Asian and white patients. METHODS: Two contemporary population-based HF cohorts were combined: from Singapore (n = 1,002, median [25th to 75th percentile] age 62 [54 to 70] years, 76% men, 19.5% obesity) and Sweden (n = 19,537, 77 [68 to 84] years, 60% men, 24.8% obesity). The modifying effect of ethnicity on the relationship between diabetes and clinical correlates or prognosis (HF hospitalization and all-cause mortality) was examined using interaction terms. RESULTS: Diabetes was present in 569 (57%) Asian patients versus 4,680 (24%) white patients (p < 0.001). Adjusting for clinical covariates, obesity was more strongly associated with diabetes in white patients (odds ratio [OR]: 3.45; 95% confidence interval [CI]: 2.86 to 4.17) than in Asian patients (OR: 1.82; 95% CI: 1.13 to 2.96; pinteraction = 0.026). Diabetes was more strongly associated with increased HF hospitalization and all-cause mortality in Asian patients (hazard ratio: 1.50; 95% CI: 1.21 to 1.87) than in white patients (hazard ratio: 1.29; 95% CI: 1.22 to 1.36; pinteraction = 0.045). CONCLUSIONS: Diabetes was 3-fold more common in Southeast Asian compared to white patients with HF, despite younger age and less obesity, and more strongly associated with poor outcomes in Asian patients than white patients. These results underscore the importance of ethnicity-tailored aggressive strategies to prevent diabetes and its complications.

Ethnic differences in the association of QRS duration with ejection fraction and outcome in heart failure.

BACKGROUND: QRS duration (QRSd) criteria for device therapy in heart failure (HF) were derived from predominantly white populations and ethnic differences are poorly understood. METHODS: We compared the association of QRSd with ejection fraction (EF) and outcomes between 839 Singaporean Asian and 11 221 Swedish white patients with HF having preserved EF (HFPEF)and HF having reduced EF (HFREF) were followed in prospective population-based HF studies. RESULTS: Compared with whites, Asian patients with HF were younger (62 vs 74 years, p<0.001), had smaller body size (height 163 vs 171 cm, weight 70 vs 80 kg, both p<0.001) and had more severely impaired EF (EF was <30% in 47% of Asians vs 28% of whites). Overall, unadjusted QRSd was shorter in Asians than whites (101 vs 104 ms, p<0.001). Lower EF was associated with longer QRSd (p<0.001), with a steeper association among Asians than whites (pinteraction<0.001), independent of age, sex and clinical covariates (including body size). Excluding patients with left bundle branch block (LBBB) and adjusting for clinical covariates, QRSd was similar in Asians and whites with HFPEF, but longer in Asians compared with whites with HFREF (p=0.001). Longer QRSd was associated with increased risk of HF hospitalisation or death (absolute 2-year event rate for ≤120 ms was 40% and for >120 ms it was 52%; HR for 10 ms increase of QRSd was 1.04 (1.03 to 1.06), p<0.001), with no interaction by ethnicity. CONCLUSION: We found ethnic differences in the association between EF and QRSd among patients with HF. QRS prolongation was similarly associated with increased risk, but the implications for ethnicity-specific QRSd cut-offs in clinical decision-making require further study.

A tale of two tachycardias.

A patient with non-ischaemic cardiomyopathy, and pre-existing atypical atrial flutter and left bundle branch block, developed broad complex tachycardia. In this unique and uncommon case of double tachycardia, we discuss the diagnostic approach of ventricular tachycardia in patients with broad complex tachycardia, and the use of different contemporary algorithms to help diagnose ventricular tachycardia and differentiate it from supraventricular tachycardia with aberrant conduction.

Impact Of Sex On Clinical Characteristics And In-Hospital Outcomes In A Multi-Ethnic Southeast Asian Population Of Patients Hospitalized For Acute Heart Failure.

OBJECTIVES: To study sex differences in clinical characteristics and outcomes among multi-ethnic Southeast Asian patients with hospitalized heart failure (HHF). BACKGROUND: HHF is an important public health problem affecting man and women globally. Reports from Western populations suggest striking sex differences in risk factors and outcomes in HHF. However, this has not been studied in a multi-ethnic Asian population. METHODS: Using the population-based resources of the Singapore Cardiac Data Bank, we studied 5,703 consecutive cases of HHF admitted across hospitals in the Southeast Asian nation of Singapore from 1st January, 2008 through 31st December, 2009. RESULTS: Women accounted for 46% of total admissions and were characterized by older age (73 vs. 67 years; p<0.001), higher prevalence of hypertension (78.6 vs. 72.1%; p<0.001) or atrial fibrillation (22.2 vs. 18.1%; p<0.001), and lower prevalence of coronary artery disease (33.8 vs. 41.0%; p<0.001) or prior myocardial infarction (14.9 vs. 19.8%; p<0.001). Women were more likely than men to have HHF with preserved ejection fraction (42.5% versus 20.8%, p < 0.001). Women were less likely than men to receive evidencebased therapies at discharge, both in the overall group and in the sub-group with reduced ejection fraction. Women had longer lengths of stay (5.6 vs. 5.1 days; p<0.001) but similar in-hospital mortality and one-year rehospitalization rates compared to men. Independent predictors of mortality or rehospitalization in both men and women included prior myocardial infarction and reduced ejection fraction. Among women alone, additional independent predictors were renal impairment, atrial fibrillation, and diabetes. Prescription of beta-blockers and ACE-inhibitors at discharge was associated with better outcomes. CONCLUSION: Among multi-ethnic Asian patients with HHF, there are important sex differences in clinical characteristics and prognostic factors. These data may inform sex-specific strategies to improve outcomes of HHF in Southeast Asians.

The Singapore Heart Failure Outcomes and Phenotypes (SHOP) study and Prospective Evaluation of Outcome in Patients with Heart Failure with Preserved Left Ventricular Ejection Fraction (PEOPLE) study: rationale and design.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (EF) accounts for a substantial proportion of cases of HF, and to date no treatments have clearly improved outcome. There are also little data comparing HF cohorts of differing ethnicity within the Asia-Pacific region. METHODS: The Singapore Heart Failure Outcomes and Phenotypes (SHOP) study and Prospective Evaluation of Outcome in Patients with Heart Failure with Preserved Left Ventricular Ejection Fraction (PEOPLE) study are parallel prospective studies using identical protocols to enroll patients with HF across 6 centers in Singapore and 4 in New Zealand. The objectives are to determine the relative prevalence, characteristics, and outcomes of patients with HF and preserved EF (EF ≥50%) compared with those with HF and reduced EF, and to determine initial data on ethnic differences within and between New Zealand and Singapore. Case subjects (n = 2,500) are patients hospitalized with a primary diagnosis of HF or attending outpatient clinics for management of HF within 6 months of HF decompensation. Control subjects are age- and gender-matched community-based adults without HF from Singapore (n = 1,250) and New Zealand (n = 1,073). All participants undergo detailed clinical assessment, echocardiography, and blood biomarker measurements at baseline, 6 weeks, and 6 months, and are followed over 2 years for death or hospitalization. Substudies include vascular assessment, cardiopulmonary exercise testing, retinal imaging, and cardiac magnetic resonance imaging. CONCLUSIONS: The SHOP and PEOPLE studies are the first prospective multicenter studies defining the epidemiology and interethnic differences among patients with HF in the Asia-Oceanic region, and will provide unique insights into the pathophysiology and outcomes for these patients.