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.

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.

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.

Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.

Aims: Whether prevalence and mortality of patients with heart failure with preserved or mid-range (40-49%) ejection fraction (HFpEF and HFmREF) are similar to those of heart failure with reduced ejection fraction (HFrEF), as reported in some epidemiologic studies, remains highly controversial. We determined and compared characteristics and outcomes for patients with HFpEF, HFmREF, and HFrEF in a prospective, international, multi-ethnic population. Methods and results: Prospective multi-centre longitudinal study in New Zealand (NZ) and Singapore. Patients with HF were assessed at baseline and followed over 2 years. The primary outcome was death from any cause. Secondary outcome was death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF, and HFrEF. Of 2039 patients enrolled, 28% had HFpEF, 13% HFmrEF, and 59% HFrEF. Compared with HFrEF, patients with HFpEF were older (62 vs. 72 years), more commonly female (17% vs. 48%), and more likely to have a history of hypertension (61% vs. 78%) but less likely to have coronary artery disease (55% vs. 41%). During 2 years of follow-up, 343 (17%) patients died. Adjusting for age, sex, and clinical risk factors, patients with HFpEF had a lower risk of death compared with those with HFrEF (hazard ratio 0.62, 95% confidence interval 0.46-0.85). Plasma (NT-proBNP) was similarly related to mortality in both HFpEF, HFmrEF, and HFrEF independent of the co-variates listed and of ejection fraction. Results were similar for the composite endpoint of death or HF and were consistent between Singapore and NZ. Conclusion: These prospective multinational data showed that the prevalence of HFpEF within the HF population was lower than HFrEF. Death rate was comparable in HFpEF and HFmrEF and lower than in HFrEF. Plasma levels of NT-proBNP were independently and similarly predictive of death in the three HF phenotypes. Trial Registration: Australian New Zealand Clinical Trial Registry (ACTRN12610000374066).

Racial Differences in Electrocardiographic Characteristics and Prognostic Significance in Whites Versus Asians.

BACKGROUND: Racial differences in electrocardiographic (ECG) characteristics and prognostic significance among Whites and Asians are not well described. METHODS AND RESULTS: We studied 2677 White Framingham Heart Study participants (57% women) and 2972 Asian (64% women) Singapore Longitudinal Aging Study participants (mean age 66 years in both) free of myocardial infarction or heart failure. Racial differences in ECG characteristics and effect on mortality were assessed. In linear regression models, PR interval was longer in Asians compared with Whites (multivariable-adjusted ß±SE 5.0±1.4 ms in men and 6.6±0.9 ms in women, both P<0.0006). QT interval was shorter in Asian men (ß±SE -6.2±1.2 ms, P<0.0001) and longer in Asian women (ß±SE 3.6±0.9 ms, P=0.02) compared to White men and women, respectively. Asians had greater odds of having ECG left ventricular hypertrophy (LVH) compared with Whites (odds ratio [OR] 3.56, 95% confidence interval [CI] 1.36-9.35 for men, OR 1.93, 95% CI 1.35-2.76 for women, both P<0.02). Over a mean follow-up of 11±3 years in Framingham and 8±3 years in Singapore, mortality rates were 24.5 and 13.4 per 1000 person-years among Whites and Asians, respectively. In Cox models, the presence of LVH had a greater effect on all-cause mortality in Asians compared with Whites (hazard ratio [HR] 2.66, 95% CI 1.83-3.88 vs HR 1.30, 95% CI 0.90-1.89, P for interaction=0.02). CONCLUSION: Our findings from two large community-based cohorts show prominent race differences in ECG characteristics between Whites and Asians, and also suggest a differential association with mortality. These differences may carry implications for race-specific ECG reference ranges and cardiovascular risk.

Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100.

Natriuretic peptide receptor 3 (NPR3) is the clearance receptor for the cardiac natriuretic peptides (NPs). By modulating the level of NPs, NPR3 plays an important role in cardiovascular homeostasis. Although the physiological functions of NPR3 have been explored, little is known about its regulation in health or disease. MicroRNAs play an essential role in the post-transcriptional expression of many genes. Our aim was to investigate potential microRNA-based regulation of NPR3 in multiple models. Hypoxic challenge elevated levels of NPPB and ADM mRNA, as well as NT-proBNP and MR-proADM in human left ventricle derived cardiac cells (HCMa), and in the corresponding conditioned medium, as revealed by qRT-PCR and ELISA. NPR3 was decreased while NPR1 was increased by hypoxia at mRNA and protein levels in HCMa. Down-regulation of NPR3 mRNA was also observed in infarct and peri-infarct cardiac tissue from rats undergoing myocardial infarction. From microRNA microarray analyses and microRNA target predictive databases, miR-100 was selected as a candidate regulator of NPR3 expression. Further analyses confirmed up-regulation of miR-100 in hypoxic cells and associated conditioned media. Antagomir-based silencing of miR-100 enhanced NPR3 expression in HCMa. Furthermore, miR-100 levels were markedly up-regulated in rat hearts and in peripheral blood after myocardial infarction and in the blood from heart failure patients. Results from this study point to a role for miR-100 in the regulation of NPR3 expression, and suggest a possible therapeutic target for modulation of NP bioactivity in heart disease.

Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction.

AIM: The potential diagnostic utility of circulating microRNAs in heart failure (HF) or in distinguishing HF with reduced vs. preserved left ventricular ejection fraction (HFREF and HFPEF, respectively) is unclear. We sought to identify microRNAs suitable for diagnosis of HF and for distinguishing both HFREF and HFPEF from non-HF controls and HFREF from HFPEF. METHODS AND RESULTS: MicroRNA profiling performed on whole blood and corresponding plasma samples of 28 controls, 39 HFREF and 19 HFPEF identified 344 microRNAs to be dysregulated among the three groups. Further analysis using an independent cohort of 30 controls, 30 HFREF and 30 HFPEF, presented 12 microRNAs with diagnostic potential for one or both HF phenotypes. Of these, miR-1233, -183-3p, -190a, -193b-3p, -193b-5p, -211-5p, -494, and -671-5p distinguished HF from controls. Altered levels of miR-125a-5p, -183-3p, -193b-3p, -211-5p, -494, -638, and -671-5p were found in HFREF while levels of miR-1233, -183-3p, -190a, -193b-3p, -193b-5p, and -545-5p distinguished HFPEF from controls. Four microRNAs (miR-125a-5p, -190a, -550a-5p, and -638) distinguished HFREF from HFPEF. Selective microRNA panels showed stronger discriminative power than N-terminal pro-brain natriuretic peptide (NT-proBNP). In addition, individual or multiple microRNAs used in combination with NT-proBNP increased NT-proBNP's discriminative performance, achieving perfect intergroup distinction. Pathway analysis revealed that the altered microRNAs expression was associated with several mechanisms of potential significance in HF. CONCLUSIONS: We report specific microRNAs as potential biomarkers in distinguishing HF from non-HF controls and in differentiating between HFREF and HFPEF.

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.

Growth differentiation factor 15, ST2, high-sensitivity troponin T, and N-terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction.

AIMS: Growth differentiation factor 15 (GDF15), ST2, high-sensitivity troponin T (hsTnT), and N-terminal pro brain natriuretic peptide (NT-proBNP) are biomarkers of distinct mechanisms that may contribute to the pathophysiology of heart failure (HF) [inflammation (GDF15); ventricular remodelling (ST2); myonecrosis (hsTnT); and wall stress (NT-proBNP)]. METHODS AND RESULTS: We compared circulating levels of GDF15, ST2, hsTnT, and NT-proBNP, as well as their combinations, in compensated patients with clinical HF with reduced ejection fraction (HFREF) (n = 51), HF with preserved ejection fraction (HFPEF) (n= 50), and community-based controls (n = 50). Compared with controls, patients with HFPEF and HFREF had higher median levels of GDF15 (540 pg/mL vs. 2529 and 2672 pg/mL, respectively), hsTnT (3.7 pg/mL vs. 23.7 and 35.6 pg/mL), and NT-proBNP (69 pg/mL vs. 942 and 2562 pg/mL), but not ST2 (27.6 ng/mL vs. 31.5 and 35.3 ng/mL), adjusting for clinical covariates. In receiver operating characteristic curve analyses, NT-proBNP distinguished HFREF from controls with an area under the curve (AUC) of 0.987 (P < 0.001); GDF15 distinguished HFPEF from controls with an AUC of 0.936 (P < 0.001); and the combination of NT-proBNP and GDF15 distinguished HFPEF from controls with an AUC of 0.956 (P < 0.001). NT-proBNP and hsTnT levels were higher in HFREF than in HFPEF (adjusted P < 0.04). The NT-proBNP:GDF15 ratio distinguished between HFPEF and HFREF with the largest AUC (0.709; P < 0.001). CONCLUSIONS: Our study provides comparative data on physiologically distinct circulating biomarkers in HFPEF, HFREF, and controls from the same community. These data suggest a prominent role for myocardial injury (hsTnT) with increased wall stress (NT-proBNP) in HFREF, and systemic inflammation (GDF15) in HFPEF.

COPD in Asia: where East meets West.

COPD is a global health concern, and is a major cause of chronic morbidity and mortality worldwide. According to the World Health Organization, it is currently the sixth leading cause of death in the world, and further increases in the prevalence and mortality of the disease is predicted for the coming decades. These increases are mainly linked to the epidemic of tobacco exposure and indoor and outdoor air pollution in Asian countries. The burden of COPD in Asia is currently greater than that in developed Western countries, both in terms of the total number of deaths and the burden of disease, as measured in years of life lost and years spent living with disability. The types of health-care policies and the practice of medicine vary considerably among the regions of Asia and have an impact on the burden of disease. Treatment aims in Asian countries are based on evidence-based management guidelines. Barriers to the implementation of disease management guidelines are related to issues of resource conflict and lack of organizational support rather than cultural differences in medical practice. To reduce this burden of COPD in Asian countries, there is a need for a multifaceted approach in improving awareness of prevalence and disease burden, in facilitating accurate diagnosis of COPD among chronic respiratory diseases, in championing health policies that reduce the burden of the main risk factors for COPD and in the wider use of evidence-based management for COPD.

Risk factors associated with habitual snoring and sleep-disordered breathing in a multi-ethnic Asian population: a population-based study.

INTRODUCTION: There is scant data on the risk factors of sleep-disordered breathing (SDB) in the general population in Asian countries. METHODS: Cross-sectional survey of a random population sample of 2298 adults aged 20-75 years, stratified by gender, ethnicity (Chinese, Malay and Indian) and age. An interviewer-administered questionnaire was used to elicit responses to questions on daytime somnolence and nocturnal events. Three categories of SDB were defined for analysis: habitual snoring; apnoeic snoring (SDB I); and apnoeic snoring or snoring with diurnal hypersomnia (SDB II). RESULTS: Snoring was reported by 201 persons (6.8%), SDB-I in 44 (1.9%) and SDB-II in 112 (4.9%) in the sample. The adjusted odds ratio (95% C.I.) of association with snoring were: male gender, 3.79 (2.69-5.33); older age (>60 years old), 2.15 (1.41-3.29); Indian versus Chinese, 1.54 (1.05-2.25); family history, 2.21 (1.56-3.12); obesity (BMI>30), 2.64 (1.62-4.30); neck circumference (>40 cm), 2.57 (1.59-4.11); and cigarette smoking, 2.05 (1.21-3.45). The risk factors for SDB were similar to that of snoring. CONCLUSION: Population risk factors associated with habitual snoring and SDB in Singapore are largely similar to those reported in other populations. Differential risks underscore the importance of ethnicity in determining the burden of SDB.

Validation of the English version of the Asthma Quality of Life Questionnaire in a multi-ethnic Asian population.

The purpose of study was to assess the validity, reliability and acceptability of the English version of the Asthma Quality of Life Questionnaire in a multi-ethnic Asian population. The English version of the Standardized Asthma Quality of Life Questionnaire (AQLQ-S) and the Asthma Control Questionnaire (ACQ) were self-completed by 119 English-speaking Chinese, Malay and Indian asthmatic subjects, aged 17-78. Spirometric measurements, peak expiratory flow rate, current clinical symptoms and treatment requirements were documented. Reliability and responsiveness were analyzed in a subgroup of 57 patients who were reassessed 6 weeks later. The Cronbach alpha reliability coefficient for internal consistency of the AQLQ-S was 0.97 (0.96-0.98) for the overall score. The intraclass correlation coefficient (ICC) overall score was 0.97 (95% CI: 0.94-0.99) while the responsiveness index was 1.29 with strong longitudinal validity for clinical and spirometric measures of asthma severity and asthma control score (p < 0.001). The results of this study showed that the English version of the AQLQ-S is a sensitive and valid instrument for measuring health-related quality of life in asthmatic subjects from a multi-ethnic Asian population.