ESC Heart Failure最新文献

Aims

Inflammation is postulated to be a key pathogenic mechanism in heart failure with preserved ejection fraction (HFpEF). Soluble urokinase plasminogen activator receptor (suPAR), a regulator of innate immune activity, is associated with incident heart failure; however, its role in HFpEF remains unclear. We aimed to elucidate the role of suPAR in HFpEF outcomes.

Methods

In this secondary analysis of the TOPCAT trial's North American cohort, suPAR was measured at baseline and 1 year in a subset of patients with HFpEF (n = 406) treated with either spironolactone or placebo. We assessed the association between suPAR levels and adverse outcomes, whether spironolactone influenced suPAR levels and whether the association between spironolactone and outcomes is dependent on suPAR levels. The primary outcome was a composite of cardiovascular death, cardiac arrest or hospitalization for heart failure management.

Results

The mean age of participants was 69.5 years, and 46.6% were female. After a median follow-up of 2.9 years, 19.9% experienced the primary outcome event. The 5-year cumulative incidence of the primary outcome in the highest tertile of suPAR (>3.93 ng/mL) was 44%, compared with 14% in the lowest tertile (≤2.94 ng/mL) (P = 0.001). Spironolactone did not significantly change suPAR levels at 1 year, nor was its effect on outcomes modified by baseline suPAR (P for interaction = 0.6). In multivariable analysis, each doubling of baseline suPAR levels was associated with nearly twofold increased risk of the primary outcome, independent of traditional risk factors and natriuretic peptide (NP) levels (HR 1.94 [95% CI 1.33–2.83]). suPAR's risk discrimination ability was superior and additive to that of NP.

Conclusions

While suPAR levels independently predict poor outcomes in HFpEF patients, spironolactone does not modulate this inflammatory pathway. The findings suggest that suPAR represents a stable inflammatory biomarker in HFpEF, highlighting the need for further evaluation of targeted anti-inflammatory strategies in this population.

Aims

In the randomized DAPA-MI clinical trial, 10 mg of dapagliflozin once daily improved cardiometabolic outcomes versus placebo after acute myocardial infarction (MI) in patients without established diabetes or heart failure (HF). We assessed associations between baseline left ventricular ejection fraction (LVEF) and cardiometabolic outcomes in DAPA-MI.

Methods

The primary outcome, assessed using the win ratio method, was the hierarchical composite of death, hospitalization for HF, non-fatal MI, atrial fibrillation/flutter, Type 2 diabetes, New York Heart Association classification at last visit and body weight decrease of ≥5% from baseline to last visit. For the present analysis, patients were categorized using LVEF at randomization (<50% or ≥50%).

Results

Of the DAPA-MI participants with available LVEF data who received ≥1 dose of study drug (n = 3751), 2913 (77.7%) had LVEF <50% and 838 (22.3%) had LVEF ≥50%. The primary hierarchical composite outcome resulted in a win ratio favouring dapagliflozin of 1.38 (95% CI: 1.21, 1.57; P < 0.001) in patients with LVEF <50% and 1.32 (1.00, 1.73; P = 0.048) in patients with LVEF ≥ 50% (P interaction = 0.76). In a sensitivity analysis excluding patients with LVEF <30%, the primary hierarchical composite outcome resulted in a win ratio favouring dapagliflozin of 1.40 (95% CI: 1.22, 1.61; P < 0.001). There were no significant interactions between baseline LVEF and any secondary outcomes.

Conclusions

Regardless of baseline LVEF, dapagliflozin resulted in significant cardiometabolic benefits versus placebo, although there was no impact on the composite of cardiovascular death or hospitalization for HF.

Background

Galectin-3 (Gal-3) is a circulating biomarker of fibrosis, with higher levels being associated with an increased risk of progression of heart failure and kidney disease. Patients with type 2 diabetes mellitus (T2DM) are at increased risk of both.

Methods

DECLARE-TIMI 58 was a randomized, placebo-controlled trial of dapagliflozin in patients with T2DM with or at high risk for atherosclerotic cardiovascular disease and creatinine clearance ≥60 mL/min. In a nested biomarker substudy, Gal-3 was measured at baseline and in adjusted analyses associated with the prespecified kidney-specific composite endpoint [Kidney-EP; sustained ≥40% decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min, new end-stage kidney disease or adjudicated kidney-related death].

Results

Among 14 530 pts, median Gal-3 was 14.9 ng/mL [interquartile range (IQR), 11.9, 18.4]. Gal-3 was weakly associated with urine albumin creatinine ratio (r = 0.098, P < 0.0001) and eGFR (r = −0.27, P < 0.001) at baseline and independently associated with the Kidney-EP:adj hazard ratio (HR) 1.15 [95% confidence interval (CI) 1.03, 1.28] per 1-SD log (Gal-3), P = 0.013. Dapagliflozin significantly reduced the relative risk of the Kidney-EP across quartiles of baseline Gal-3 [overall HR 0.45 (95% CI 0.23, 0.85), P < 0.0001; P interaction = 0.87]. A greater risk difference was observed with dapagliflozin in patients with higher Gal-3, in whom a higher absolute risk at baseline was observed [absolute risk reduction (ARR) Q4 1.9 (95% CI 0.6, 3.2) vs. Q1 0.6% (−0.1, 1.3), ARR P trend 0.048].

Conclusions

Plasma Gal-3 is independently associated with the progression of kidney dysfunction in patients with T2DM and normal kidney function. There was a gradient of greater absolute benefit for reducing kidney disease progression in patients treated with dapagliflozin and with higher Gal-3 concentrations at baseline, in whom a higher absolute risk was observed.

Registration: clinicaltrials.gov (NCT01730534).

Background

In the EMPACT-MI trial, empagliflozin did not reduce the primary endpoint of all-cause mortality or hospitalization for heart failure (HHF) following acute myocardial infarction (AMI) but was associated with a risk reduction for HF events.

Objectives

This study aimed to evaluate whether the effect of empagliflozin on HF events is consistent in patients with and without type 2 diabetes and/or chronic kidney disease enrolled in the EMPACT-MI trial.

Methods

Post hoc analysis assessing the effect of empagliflozin on the primary endpoint and on HF events in AMI patients with and without an established recommendation for a sodium–glucose cotransporter-2 inhibitor (SGLT2i) (type 2 diabetes or chronic kidney disease).

Results

Of 6522 participants, 3489 (53%) did not have type 2 diabetes and/or chronic kidney disease. Those without these conditions were younger and with fewer comorbidities. No differences were observed for the primary endpoint. Empagliflozin reduced time to first HHF, total HHF, time to adverse event (AE) of HF (including outpatient HF events) and total AEs of HF similarly in patients with and without type 2 diabetes or chronic kidney disease. Total HHFs were 50 and 63 [adjusted event rate 1.74 and 2.31 events per 100 patient-years; rate ratio (RR) 0.75; 95% confidence interval (CI) 0.48, 1.18] in patients without and 98 and 144 (adjusted event rate 3.91 and 6.04 events per 100 patient-years; RR 0.65; 95% CI 0.45, 0.94; P for interaction = 0.61) in those with type 2 diabetes or chronic kidney disease in the empagliflozin and placebo arms, respectively. Any AEs, serious AEs and AEs leading to permanent study drug discontinuation were similar between treatment groups in both subgroups.

Conclusions

Empagliflozin improved HF outcomes similarly in patients after AMI with or without type 2 diabetes or chronic kidney disease.