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.

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.

Prognostic Value of Left Atrial Strain in Aortic Stenosis: A Competing Risk Analysis.

BACKGROUND: The role of left atrial (LA) strain as an imaging biomarker in aortic stenosis is not well established. The aim of this study was to investigate the prognostic performance of phasic LA strain in relation to clinical and echocardiographic variables and N-terminal pro-B-type natriuretic peptide in asymptomatic and minimally symptomatic patients with moderate to severe aortic stenosis and left ventricular ejection fraction > 50%. METHODS: LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured using speckle-tracking echocardiography. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, progression to New York Heart Association functional class III or IV, acute coronary syndrome, or syncope. Secondary outcomes 1 and 2 comprised the same end points but excluded acute coronary syndrome and additionally syncope, respectively. The prognostic performance of phasic LA strain cutoffs was evaluated in competing risk analyses, aortic valve replacement being the competing risk. RESULTS: Among 173 patients (mean age, 69 ± 11 years; mean peak transaortic velocity, 4.0 ± 0.8 m/sec), median LASr, LAScd, and LASct were 27% (interquartile range [IQR], 22%-32%), 12% (IQR, 8%-15%), and 16% (IQR, 13%-18%), respectively. Over a median of 2.7 years (IQR, 1.4-4.6 years), the primary outcome and secondary outcomes 1 and 2 occurred in 66 (38%), 62 (36%), and 59 (34%) patients, respectively. LASr < 20%, LAScd < 6%, and LASct < 12% were identified as optimal cutoffs of the primary outcome. In competing risk analyses, progressing from echocardiographic to echocardiographic-clinical and combined models incorporating N-terminal pro-B-type natriuretic peptide, LA strain parameters outperformed other key echocardiographic variables and significantly predicted clinical outcomes. LASr < 20% was associated with the primary outcome and secondary outcome 1, LAScd < 6% with all clinical outcomes, and LASct < 12% with secondary outcome 2. LAScd < 6% had the highest specificity (95%) and positive predictive value (82%) for the primary outcome, and competing risk models incorporating LAScd < 6% had the best discriminative value. CONCLUSIONS: In well-compensated patients with moderate to severe aortic stenosis and preserved left ventricular ejection fractions, LA strain was superior to other echocardiographic indices and incremental to N-terminal pro-B-type natriuretic peptide for risk stratification. LAScd < 6%, LASr < 20%, and LASct < 12% identified patients at higher risk for adverse outcomes.

Two-year outcome of ventricular assist device via a modified left atrium to aorta approach in cardiac amyloidosis.

Cardiac amyloidosis is a debilitating disease associated with poor long-term survival. Medical or palliative treatment is the usual course of therapy, but patients are often intolerant of conventional heart failure treatment. The current standard of care of sequential heart and bone marrow transplant is usually not feasible for ill or frail patients or in countries with limited organ donors or without transplant programmes. Left ventricular assist devices (LVAD) are not usually offered to these patients due to high peri-operative risks and risks of suction events with the LVAD in a small left ventricle. We report the 2 year outcome and discuss the challenges faced in the management of our patient with end-stage heart failure due to cardiac amyloidosis, who was successfully supported with an LVAD using a modified left atrium to aorta implantation technique.

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.

Novel predictive role for mid-regional proadrenomedullin in moderate to severe aortic stenosis.

OBJECTIVE: We investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS). METHODS: N-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses. RESULTS: Among 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker. CONCLUSION: MR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS.

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.

Echocardiographic Global Longitudinal Strain Is Associated With Myocardial Fibrosis and Predicts Outcomes in Aortic Stenosis.

Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57 ± 10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71 ± 12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74 [0.66-0.83]; P < 0.001) and calibration (Hosmer-Lemeshow χ2 = 6.37; P = 0.605) for replacement fibrosis. In the outcome cohort, 47 events occurred over 16 [3.3, 42.2] months. Patients with LV-GLS > -15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS < -21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between -21.0 and -15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e'. Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF.

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.

Case of sodium-glucose cotransporter-2 inhibitor-associated euglycaemic diabetic ketoacidosis.

Following non-elective orthopaedic surgery, a 61-year-old man with poorly controlled type 2 diabetes mellitus on empagliflozin developed high anion gap metabolic acidosis in the high-dependency unit. Metabolic acidosis persisted despite intravenous sodium bicarbonate, contributing to tachycardia and a run of non-sustained ventricular tachycardia. He was euglycaemic throughout hospital admission. Investigations revealed elevated urine and capillary ketones, and a diagnosis of sodium-glucose cotransporter-2 inhibitor-associated euglycaemic diabetic ketoacidosis was made. He was treated with an intravenous sliding scale insulin infusion and concurrent dextrose 5% with potassium chloride. Within 24 hours of treatment, his arterial pH, anion gap and serum bicarbonate levels normalised. After a further 12 hours, the intravenous insulin infusion was converted to a basal/bolus regimen of subcutaneous insulin, and he was transferred to the general ward. He was discharged well on subcutaneous insulin 6 days postoperatively.

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.

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.

Elderly Asian Patients Have Lower Revascularisation Rates and Poorer Outcomes for ST-Elevation Myocardial Infarction Compared to Younger Patients.

INTRODUCTION: There is limited information on elderly patients presenting with ST- elevation myocardial infarction (STEMI). This study aimed to study the outcomes of elderly Asian patients with STEMI compared to younger patients. MATERIALS AND METHODS: The study utilised data from 2007 to 2012 from the Singapore Myocardial Infarction Registry, a mandatory national population-based registry. Elderly patients were defined as ≥80 years of age, middle-aged to old (MAO) patients were defined as 45-80 years of age and young patients were defined as ≤45 years of age. The primary outcome of the study was 1-year mortality and secondary outcomes included in-hospital complications and mortality. RESULTS: There were 12,409 STEMI patients with 1207 (9.7%) elderly patients, 10,093 (81.3%) MAO patients and 1109 (8.9%) young patients. Elderly patients had more cardiovascular risk factors and lower rates of total percutaneous coronary intervention (26.0% vs 72.4% vs 85.5%, respectively; P <0.0001) compared to MAO and young patients. They had higher 1-year mortality (60.6% vs 18.3% vs 4.1%, respectively; P <0.0001) when compared to MAO and young patients. CONCLUSION: Elderly patients with STEMI have poorer outcomes than MAO and young patients. This is potentially attributable to a myriad of factors including age, higher burden of comorbidities and a lesser likelihood of receiving revascularisation and guideline-recommended medical therapy.

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.

CYP2C19 phenotype in South-East Asian Acute Coronary Syndrome patients and impact on major adverse cardiovascular events.

WHAT IS KNOWN AND OBJECTIVE: Several Caucasian cohort studies have associated at least one loss-of-function CYP2C19 on Clopidogrel (LoF-Clopidogrel) with major adverse cardiovascular events (MACE), and only a couple have used Clinical Pharmacogenetics Implementation Consortium (CPIC® ) phenotype grouping to study the associations. We primarily aimed to study the impact of use of platelet reactivity testing to escalate antiplatelet therapy and secondarily to study the association of CPIC phenotype with MACE outcomes in South-East Asian Acute Coronary Syndrome (ACS) subjects. METHOD: A retrospective genotype study was performed on 238 percutaneous coronary intervention subjects, originally planned for escalation of antiplatelets using platelet reactivity testing. RESULTS AND DISCUSSION: There was no difference in MACE between the switched and unswitched groups; however, 'all bleeds' and 'clinically significant bleeds' (CSB) were statistically higher in the patients who were switched to prasugrel. The subgroup of patients who remained on clopidogrel (n = 199) were analysed using phenotype categories and MACE. Eleven percent (11.4%) of CYP2C19 poor metabolizers (PM) suffered MACE, compared with 1.3% of extensive metabolizers (EM). LoF-Clopidogrel patients are significantly more likely to experience MACE compared with non-LoF subjects (8.0% vs 5.4%, P: .041). WHAT IS NEW AND CONCLUSION: In our multivariate analysis, LoF-Clopidogrel, malay ethnicity, diabetics and use of proton pump inhibitors were independent predictors of MACE. There were numerically more bleeds in LoF subjects who were on prasugrel compared with Clopidogrel (23.5% vs 11%, P = .082). Our data corroborate with current findings on platelet reactivity testing, suggesting that the assay would not be sensitive enough to pick up sufficient 'at-risk' subjects as compared to the use of CYP2C19 genotyping.

Cornell product is an ECG marker of heart failure with preserved ejection fraction.

OBJECTIVE: ECG markers of heart failure (HF) with preserved ejection fraction (HFpEF) are lacking. We hypothesised that the Cornell product (CP) is a risk marker of HFpEF and has prognostic utility in HFpEF. METHODS: CP =[(amplitude of R wave in aVL+depth of S wave in V3)×QRS] was measured on baseline 12-lead ECG in a prospective Asian population-based study of 606 healthy controls (aged 55±10 years, 45% men), 221 hypertensive controls (62±9 years, 58% men) and 242 HFpEF (68±12 years, 49% men); all with EF ≥50% and followed for 2 years for all-cause mortality and HF hospitalisations. RESULTS: CP increased across groups from healthy controls to hypertensive controls to HFpEF, and distinguished between HFpEF and hypertension with an optimal cut-off of ≥1800 mm*ms (sensitivity 40%, specificity 85%). Age, male sex, systolic blood pressure (SBP) and heart rate were independent predictors of CP ≥1800 mm*ms, and CP was associated with echocardiographic E/e' (r=0.27, p<0.01) and left ventricular mass index (r=0.46, p<0.01). Adjusting for clinical and echocardiographic variables and log N-terminal pro B-type natriuretic peptide (NT-proBNP), CP ≥1800 mm*ms was significantly associated with HFpEF (adjusted OR 2.7, 95% CI 1.0 to 7.0). At 2-year follow-up, there were 29 deaths and 61 HF hospitalisations, all within the HFpEF group. Even after adjusting for log NT-proBNP, clinical and echocardiographic variables, CP ≥1800 mm*ms remained strongly associated with a higher composite endpoint of all-cause mortality and HF hospitalisations (adjusted HR 2.1, 95% CI 1.2 to 3.5). CONCLUSION: The Cornell product is an easily applicable ECG marker of HFpEF and predicts poor prognosis by reflecting the severity of diastolic dysfunction and LV hypertrophy.

Systematic assessment of procedural parameters, influence on downstream testing and 12-month outcomes of a CT-myocardial perfusion service.

AIMS: This study describes the real-world referral pattern of patients to a CT myocardial perfusion service, the technical issues associated with providing the service, the results of the studies, and the subsequent downstream utilization of other investigations, and patient outcomes. METHODS AND RESULTS: 115 consecutive patients underwent CTA, dynamic rest and dipyridamole-stress perfusion scanning. There were 29 (25%) and 14 (12%) patients who had reversible defects and fixed defects respectively, indicating abnormal flow reserve and previous infarction respectively. In the patients with fixed defects, delayed hyperenhancement was noted in all, indicative of prior infarction, scarring and non-viability. With the existing CTA Appropriateness Criteria, the categorization of "Appropriate," "Of Uncertain Appropriateness", and "Inappropriate" would have been applied to 25%, 25% and 50% of the present studies respectively. Up to 72% could have been referred for ischemia evaluation with other modalities of functional imaging after the non-diagnostic CT angiogram. Follow up was complete in 113 subjects (98%) over a period of 14 ±â€¯8 months. In the 29 patients with abnormal flow reserve and CAD, 62% underwent invasive angiography and 94%, angioplasty within a 90-day period. In the patients who underwent angioplasty, all remained free of myocardial infarction or death and 88% remained free of myocardial infarction, death or readmission over a mean of 14 ±â€¯8 months. CONCLUSION: A CT-myocardial perfusion service provided measures of ischemia and infarct detection over that of CTA alone. The information was utilized clinically by doctors to support a strategy of referral to revascularization versus conservative medical management.