METHODS: BMP10 levels were quantified in 2085 chronic HF patients from the European BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort and in 1487 patients from the Scottish validation cohort. Multivariable linear regression identified independent associates of BMP10. Proteomic analysis of 6369 proteins with subsequent gene set enrichment analysis was used to explore biological pathways associated with elevated BMP10. Cox proportional hazards models adjusting for established risk factors were used to associate BMP10 levels with clinical outcomes, including all-cause mortality and HF hospitalisation.

RESULTS: In a multivariable model including clinical and echocardiographic parameters, log-transformed and standardised BMP10 levels were significantly associated with a history of atrial fibrillation (Sβ=0.419; p<0.001), and with echocardiographic features reflecting atrial stress, such as increased left atrial diameter (Sβ=0.075; p=0.048). By contrast, these were not among the strongest associates of NT-proBNP levels. Gene set enrichment analysis showed significant overrepresentation in pathways of muscle contraction and extracellular matrix organisation. Higher log-transformed and standardised BMP10 levels predicted a combined outcome of 2-year all-cause mortality and HF rehospitalisation (HR=1.10, 95% CI=1.02-1.19), with the validation cohort yielding comparable results.

METHODS AND FINDINGS: Utilising the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry (11 Asian regions including Taiwan, Hong Kong, China, India, Malaysia, Thailand, Singapore, Indonesia, Philippines, Japan, and Korea; 46 centres with enrolment between 1 October 2012 and 6 October 2016), we prospectively examined 5,964 patients with symptomatic HF (mean age 61.3 ± 13.3 years, 26% women, mean BMI 25.3 ± 5.3 kg/m2, 16% with HF with preserved ejection fraction [HFpEF; ejection fraction ≥ 50%]), among whom 2,051 also had waist-to-height ratio (WHtR) measurements (mean age 60.8 ± 12.9 years, 24% women, mean BMI 25.0 ± 5.2 kg/m2, 7% HFpEF). Patients were categorised by BMI quartiles or WHtR quartiles or 4 combined groups of BMI (low, <24.5 kg/m2 [lean], or high, ≥24.5 kg/m2 [obese]) and WHtR (low, <0.55 [thin], or high, ≥0.55 [fat]). Cox proportional hazards models were used to examine a 1-year composite outcome (HF hospitalisation or mortality). Across BMI quartiles, higher BMI was associated with lower risk of the composite outcome (ptrend < 0.001). Contrastingly, higher WHtR was associated with higher risk of the composite outcome. Individuals in the lean-fat group, with low BMI and high WHtR (13.9%), were more likely to be women (35.4%) and to be from low-income countries (47.7%) (predominantly in South/Southeast Asia), and had higher prevalence of diabetes (46%), worse quality of life scores (63.3 ± 24.2), and a higher rate of the composite outcome (51/232; 22%), compared to the other groups (p < 0.05 for all). Following multivariable adjustment, the lean-fat group had higher adjusted risk of the composite outcome (hazard ratio 1.93, 95% CI 1.17-3.18, p = 0.01), compared to the obese-thin group, with high BMI and low WHtR. Results were consistent across both HF subtypes (HFpEF and HF with reduced ejection fraction [HFrEF]; pinteraction = 0.355). Selection bias and residual confounding are potential limitations of such multinational observational registries.

CONCLUSIONS: In this cohort of Asian patients with HF, the 'obesity paradox' is observed only when defined using BMI, with WHtR showing the opposite association with the composite outcome. Lean-fat patients, with high WHtR and low BMI, have the worst outcomes. A direct correlation between high WHtR and the composite outcome is apparent in both HFpEF and HFrEF.

METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials.

METHODS: In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed.

RESULTS: Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia.