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.

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.

Cardiac and renal biomarkers in recreational runners following a 21 km treadmill run.

BACKGROUND: Highly trained athletes running 42 km or more demonstrate elevated cardiac biomarkers, ventricular dysfunction, and decreased glomerular filtration rate (GFR). Whether similar changes occur in the much larger population of recreational runners following half-marathon distance running is unclear. HYPOTHESIS: Recreational runners exhibit changes in myocardial and renal biomarkers, including ventricular strain, after a half-marathon treadmill run. METHODS: 10 recreational subjects (mean age 36.5 ± 6.5 years) ran 21 km on a treadmill (mean completion time 121.6 ± 16.1 minutes). Serum high-sensitivity troponin T (hsTnT), amino-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) were measured prior to, 1 hour post-, and 24 hours post-exercise. Pre- and post-exercise echocardiograms were performed. RESULTS: All biomarkers increased 1 hour post-exercise: hsTnT by 8.5 ± 8.5 pg/ml (P < .05), NT-ProBNP by 26.2 ± 22.8 pg/ml (P < .05) and NGAL by 29.5 ± 37.7 ng/ml (P=NS). By 24 hours post-run, these biomarkers declined toward baseline levels. Right ventricle (RV) free wall and left ventricle global longitudinal strain decreased by 5.5% and 1.8%, respectively (P < .001). Changes in NGAL correlated well with changes in serum creatinine (R = 0.79, P < .01) and GFR (R = -0.73, P < .05). Faster 21 km completion times, and a larger reduction in post-exercise RV strain, were associated with higher NGAL levels: (R = -0.75, P = .01) and (R = 0.66, P < .05), respectively. CONCLUSION: A 21 km run in recreational runners is associated with transient ventricular stunning and reversible changes in myocardial and renal biomarkers. Whether repeated bouts of similar activity contributes to chronic cardiac or kidney dysfunction deserves further evaluation.

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.

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.

Combining Circulating MicroRNA and NT-proBNP to Detect and Categorize Heart Failure Subtypes.

BACKGROUND: Clinicians need improved tools to better identify nonacute heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to derive and validate circulating microRNA signatures for nonacute heart failure (HF). METHODS: Discovery and validation cohorts (N = 1,710), comprised 903 HF and 807 non-HF patients from Singapore and New Zealand (NZ). MicroRNA biomarker panel discovery in a Singapore cohort (n = 546) was independently validated in a second Singapore cohort (Validation 1; n = 448) and a NZ cohort (Validation 2; n = 716). RESULTS: In discovery, an 8-microRNA panel identified HF with an area under the curve (AUC) 0.96, specificity 0.88, and accuracy 0.89. Corresponding metrics were 0.88, 0.66, and 0.77 in Validation 1, and 0.87, 0.58, and 0.74 in Validation 2. Combining microRNA panels with N-terminal pro-B-type natriuretic peptide (NT-proBNP) clearly improved specificity and accuracy from AUC 0.96, specificity 0.91, and accuracy 0.90 for NT-proBNP alone to corresponding metrics of 0.99, 0.99, and 0.93 in the discovery and 0.97, 0.96, and 0.93 in Validation 1. The 8-microRNA discovery panel distinguished HFpEF from HF with reduced ejection fraction with AUC 0.81, specificity 0.66, and accuracy 0.72. Corresponding metrics were 0.65, 0.41, and 0.56 in Validation 1 and 0.65, 0.41, and 0.62 in Validation 2. For phenotype categorization, combined markers achieved AUC 0.87, specificity 0.75, and accuracy 0.77 in the discovery with corresponding metrics of 0.74, 0.59, and 0.67 in Validation 1 and 0.72, 0.52, and 0.68 in Validation 2, as compared with NT-proBNP alone of AUC 0.71, specificity 0.46, and accuracy 0.62 in the discovery; with corresponding metrics of 0.72, 0.44, and 0.57 in Validation 1 and 0.69, 0.48, and 0.66 in Validation 2. Accordingly, false negative (FN) (81% Singapore and all NZ FN cases were HFpEF) as classified by a guideline-endorsed NT-proBNP ruleout threshold, were correctly reclassified by the 8-microRNA panel in the majority (72% and 88% of FN in Singapore and NZ, respectively) of cases. CONCLUSIONS: Multi-microRNA panels in combination with NT-proBNP are highly discriminatory and improved specificity and accuracy in identifying nonacute HF. These findings suggest potential utility in the identification of nonacute HF, where clinical assessment, imaging, and NT-proBNP may not be definitive, especially in HFpEF.

Left atrial appendage mass.

Left atrial (LA) masses are known to be associated with peripheral embolization. Accurate identification of etiology is crucial because treatment strategies may differ. We present the case of a young woman, who was initially diagnosed with a LA thrombus and anticoagulated. The diagnosis was revised to a primary cardiac tumor after review of the echocardiographic findings. Surgical excision revealed an atrial myxoma in an unusual location.

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).

Disparity Between Indications for and Utilization of Implantable Cardioverter Defibrillators in Asian Patients With Heart Failure.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) are lifesaving devices for patients with heart failure (HF) and reduced ejection fraction. However, utilization and determinants of ICD insertion in Asia are poorly defined. We determined the utilization, associations of ICD uptake, patient-perceived barriers to device therapy and, impact of ICDs on mortality in Asian patients with HF. METHODS AND RESULTS: Using the prospective ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry, 5276 patients with symptomatic HF and reduced ejection fraction (HFrEF) from 11 Asian regions and across 3 income regions (high: Hong Kong, Japan, Korea, Singapore, and Taiwan; middle: China, Malaysia, and Thailand; and low: India, Indonesia, and Philippines) were studied. ICD utilization, clinical characteristics, as well as device perception and knowledge, were assessed at baseline among ICD-eligible patients (EF ≤35% and New York Heart Association Class II-III). Patients were followed for the primary outcome of all-cause mortality. Among 3240 ICD-eligible patients (mean age 58.9±12.9 years, 79.1% men), 389 (12%) were ICD recipients. Utilization varied across Asia (from 1.5% in Indonesia to 52.5% in Japan) with a trend toward greater uptake in regions with government reimbursement for ICDs and lower out-of-pocket healthcare expenditure. ICD (versus non-ICD) recipients were more likely to be older (63±11 versus 58±13 year; P<0.001), have tertiary (versus ≤primary) education (34.9% versus 18.1%; P<0.001) and be residing in a high (versus low) income region (64.5% versus 36.5%; P<0.001). Among 2000 ICD nonrecipients surveyed, 55% were either unaware of the benefits of, or needed more information on, device therapy. ICD implantation reduced risks of all-cause mortality (hazard ratio, 0.71; 95% confidence interval, 0.52-0.97) and sudden cardiac deaths (hazard ratio, 0.33; 95% confidence interval, 0.14-0.79) over a median follow-up of 417 days. CONCLUSIONS: ICDs reduce mortality risk, yet utilization in Asia is low; with disparity across geographic regions and socioeconomic status. Better patient education and targeted healthcare reforms in extending ICD reimbursement may improve access. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT01633398. Unique identifier: NCT01633398.

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.

Effects of Aortic Valve Replacement on Severe Aortic Stenosis and Preserved Systolic Function: Systematic Review and Network Meta-analysis.

The survival benefits of aortic valve replacement (AVR) in the different flow-gradient states of severe aortic stenosis (AS) is not known. A comprehensive search in PubMed/MEDLINE, Embase, Cochrane Library, CNKI and OpenGrey were conducted to identify studies that investigated the prognosis of severe AS (effective orifice area ≤1.0 cm2) and left ventricular ejection fraction ≥50%. Severe AS was stratified by mean pressure gradient [threshold of 40 mmHg; high-gradient (HG) and low-gradient (LG)] and stroke volume index [threshold of 35 ml/m2; normal-flow (NL) and low-flow (LF)]. Network meta-analysis was conducted to assess all-cause mortality among each AS sub-type with rate ratio (RR) reported. The effects of AVR on prognosis were examined using network meta-regression. In the pooled analysis (15 studies and 9,737 patients), LF states (both HG and LG) were associated with increased mortality rate (LFLG: RR 1.88; 95% CI: 1.43-2.46; LFHG: RR: 1.77; 95% CI: 1.16-2.70) compared to moderate AS; and NF states in both HG and LG had similar prognosis as moderate AS (NFLG: RR 1.11; 95% CI: 0.81-1.53; NFHG: RR 1.16; 95% CI: 0.82-1.64). AVR conferred different survival benefits: it was most effective in NFHG (RR with AVR /RR without AVR : 0.43; 95% CI: 0.22-0.82) and least in LFLG (RR with AVR /RR without AVR : 1.19; 95% CI: 0.74-1.94).

Right ventricular dysfunction in left-sided heart failure with preserved versus reduced ejection fraction.

BACKGROUND: Right ventricular (RV) dysfunction is recognized as a major prognostic factor in left-sided heart failure (HF). However, the relative contribution of RV dysfunction in HF with preserved (HFpEF) vs. reduced ejection fraction (HFrEF) is unclear. METHODS AND RESULTS: Right ventricular longitudinal strain (RVLS), tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were determined by echocardiography in 657 age- and gender-matched groups of patients with HFpEF [left ventricular ejection fraction (LVEF) ≥50%; n=219] and HFrEF (LVEF <50%; n=219) and in controls without HF (n=219) from an Asian population-based cohort study. Across control to HFpEF and HFrEF groups, RV function deteriorated as measured by RVLS (-26.7 ± 5%, -22.7±6.6% and -18.2 ± 6.7%, respectively) and TAPSE (21.0 ± 3.9, 17.5 ± 5.1 and 14.7 ± 4.7 mm, respectively), whereas PASP increased (26.8 ± 7.1, 34.5 ± 11.9 and 39.3 ± 16.2 mmHg, respectively) (all P<0.001). Controlling for PASP in control, HFpEF and HFrEF subjects, the magnitude of RVLS/PASP (-1.06 ± 0.32, -0.75 ± 0.32 and -0.56 ± 0.36, respectively) and TAPSE/PASP ratios (0.83 ± 0.23, 0.54 ± 0.24 and 0.55 ± 0.29, respectively) similarly decreased across groups. Right ventricular dysfunction (by both TAPSE and RVLS) was independently associated with left ventricular systolic dysfunction and atrial fibrillation, but not with PASP. Among patients with HF, both TAPSE/PASP and RVLS/PASP ratios were related to the composite endpoint of all-cause death and HF hospitalization, even after multivariable adjustment [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.74 and HR 3.09; 95% CI 1.52-6.26, respectively], with no difference between HFrEF and HFpEF. CONCLUSIONS: Right ventricular dysfunction is present in HFpEF and is even more pronounced in HFrEF for any given degree of pulmonary hypertension. It is independently predicted by left ventricular dysfunction but not by PASP. Right ventricular-arterial coupling is prognostically important in HF regardless of LVEF.

Dynamic Responses in Retinal Vessel Caliber With Flicker Light Stimulation and Risk of Diabetic Retinopathy and Its Progression.

Purpose: This study investigated the associations between the responses of retinal vessels to flickering light and the incidence and progression of diabetic retinopathy (DR). Methods: A prospective cohort study of adult subjects with diabetes mellitus. The dynamic vessel analyser (DVA) was used to measure retinal vascular dilatation in response to diffuse illuminance flicker. Diabetic retinopathy was graded from retinal photography at baseline and at 1 year. Incident DR and two-step change in DR were analyzed. Results: There were 276 subjects in total, with a mean age of 59.8 ± 8.9 years. The majority were male (73%) and the mean glycated hemoglobin A1c (HbA1c) level and mean duration of diabetes were 7.7 ± 1.4% and 14.0 ± 10.5 years, respectively. After adjustments for age, sex, smoking, duration of diabetes, HbA1c, hypertension, and hyperlipidemia, the responses of retinal arterioles to flicker stimulation were lower in subjects with incident DR (P = 0.048). Subjects with greater arteriolar dilatory responses were less likely to have DR progression (odds ratio [OR] 1.85, [95% confidence interval [CI] 1.33-2.56], P = 0.012, per SD decrease). Subjects with greater venular dilatory responses were also less likely to have DR progression (OR 1.89, [95% CI 1.35-2.63], P = 0.003, per SD decrease). There were no significant associations between arteriolar or venular dilation response and incident proliferative DR (PDR) and DR regression. Conclusions: Reduced retinal arteriolar and venular dilatory responses to flickering light are associated with risk of DR progression at 1 year in adult patients with diabetes.

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.

Regional and ethnic differences among patients with heart failure in Asia: the Asian sudden cardiac death in heart failure registry.

AIMS: To characterize regional and ethnic differences in heart failure (HF) across Asia. METHODS AND RESULTS: We prospectively studied 5276 patients with stable HF and reduced ejection fraction (≤40%) from 11 Asian regions (China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Taiwan, and Thailand). Mean age was 59.6 ± 13.1 years, 78.2% were men, and mean body mass index was 24.9 ± 5.1 kg/m2. Majority (64%) of patients had two or more comorbid conditions such as hypertension (51.9%), coronary artery disease (CAD, 50.2%), or diabetes (40.4%). The prevalence of CAD was highest in Southeast Asians (58.8 vs. 38.2% in Northeast Asians). Compared with Chinese ethnicity, Malays (adjusted odds ratio [OR] 1.97, 95% CI 1.63-2.38) and Indians (OR 1.44, 95% CI 1.24-1.68) had higher odds of CAD, whereas Koreans (OR 0.38, 95% CI 0.29-0.50) and Japanese (OR 0.44, 95% CI 0.36-0.55) had lower odds. The prevalence of hypertension and diabetes was highest in Southeast Asians (64.2 and 49.3%, respectively) and high-income regions (59.7 and 46.2%, respectively). There was significant interaction between ethnicity and region, where the adjusted odds were 3.95 (95% CI 2.51-6.21) for hypertension and 4.91 (95% CI 3.07-7.87) for diabetes among Indians from high- vs. low-income regions; and 2.60 (95% CI 1.66-4.06) for hypertension and 2.62 (95% CI 1.73-3.97) for diabetes among Malays from high- vs. low-income regions. CONCLUSIONS: These first prospective multi-national data from Asia highlight the significant heterogeneity among Asian patients with stable HF, and the important influence of both ethnicity and regional income level on patient characteristics. CLINICALTRIALSGOV IDENTIFIER: NCT01633398.

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.

Joint Effect of Early Microvascular Damage in the Eye &Kidney on Risk of Cardiovascular Events.

Microalbuminuria is associated with an increased risk of cardiovascular disease (CVD), but not all individuals require treatment. Retinal microvascular abnormalities and microalbuminuria reflect early systemic microvascular changes. We examined the joint effect of retinal abnormalities and microalbuminuria on CVD risk in an Asian cohort. We conducted a prospective, population-based study. Retinal abnormalities were defined as presence of retinopathy and/or retinal venular widening. Microalbuminuria was defined as urinary albumin: creatinine ratio between 30-300 mg/g. Incident CVD was defined as newly diagnosed clinical stroke, acute myocardial infarction or CVD death. Cox regression models were performed to determine the associations between retinal abnormalities and microalbuminuria with risk of CVD, while controlling for established risk factors. 3,496 participants (aged ≥ 40) were free of prevalent CVD. During the follow-up (5.8 years), 126 (3.60%) participants developed CVD. Persons presenting with both retinal abnormalities and microalbuminuria were 6.71 times (95% CI, 2.68, 16.79) as likely to have incident CVD compared with those without either abnormalities. There was a significant interaction effect between retinal abnormalities and microalbuminuria on incident CVD. Assessment of retinal abnormalities in patients with microalbuminuria may provide additional value in identifying persons at risk of developing CVD.