Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA. We evaluated the effects of sodium zirconium cyclosilicate (SZC) in optimizing use of spironolactone among participants with HFrEF and hyperkalemia. REALIZE-K (NCT04676646) was a prospective, double-blind, randomized- withdrawal trial in participants with HFrEF (NYHA II-IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA- induced hyperkalemia. During open-label run-in, participants underwent spironolactone titration (target: 50 mg/daily); those with hyperkalemia started SZC. Participants with normokalemia (potassium 3.5-5.0 mEq/L) on SZC and spironolactone ≥25 mg/daily were randomized to continued SZC or placebo for 6 months. The primary endpoint was optimal treatment response (normokalemia on spironolactone ≥25 mg/daily without rescue therapy for hyperkalemia [months 1-6]). The five key secondary endpoints were tested hierarchically. Exploratory endpoints included a composite of adjudicated cardiovascular death or worsening HF events (hospitalizations and urgent visits). Overall, 203 participants were randomized (SZC 102, placebo 101). Higher percentage of SZC- versus placebo-treated participants had optimal response (71% vs 36%; OR 4.45 [95% CI 2.89-6.86]; p<0.001). SZC (versus placebo) improved the first four key secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR 4.58 [2.78-7.55]; p<0.001), receiving spironolactone ≥25 mg/daily (81% vs 50%; OR 4.33 [2.50-7.52]; p<0.001), time to hyperkalemia (HR 0.51 [0.37-0.71]; p<0.001), time to decrease/discontinuation of spironolactone due to hyperkalemia (HR 0.37 [0.17-0.73]; p=0.006). There was no between-group difference in KCCQ-CSS at 6 months (-1.01 points [-6.64-4.63]; p=0.72). Adverse events (64% vs 63%) and serious adverse events (23% vs 22%) were balanced between SZC and placebo, respectively. Composite of CV death or worsening HF occurred in 11 (11%) participants in the SZC group (1 with CV death, 10 with HF events) and 3 (3%) participants in the placebo group (1 with CV death, 2 with HF events; log-rank nominal p=0.034). In participants with HFrEF and hyperkalemia, SZC led to large improvements in the percentage of participants with normokalemia while on optimal spironolactone dose, and reduced risk of hyperkalaemia and down-titration/discontinuation of spironolactone. Although underpowered for clinical outcomes, more participants had HF events with SZC than placebo, which should be factored into the clinical decision making.

Worsening kidney function (WKF) is common in patients with acute heart failure (AHF) syndromes. Although WKF has traditionally been associated with worse outcomes on a population level, serum creatinine concentrations vary greatly during episodes of worsening heart failure, with substantial individual heterogeneity in terms of their clinical meaning. Consequently, interpreting such changes within the appropriate clinical context is essential to unravel the pathophysiology of kidney function changes and appropriately interpret their clinical meaning. This article aims to provide a critical overview of WKF in AHF, aiming to provide physicians with some tips and tricks to appropriately interpret kidney function changes in the context of AHF.

The impact of sex in patients with CAD has been widely reported, but little is known about the influence of sex on the risk of new-onset HF in patients with known or suspected CAD. We aimed to examine sex-related differences and new-onset heart failure (HF) risk in patients with known or suspected coronary artery disease (CAD) undergoing vasodilator stress cardiac magnetic resonance (CMR). We prospectively evaluated 5899 consecutive HF-free patients submitted to stress CMR for known or suspected CAD. Ischaemic burden (number of segments with stress-induced perfusion deficit) and left ventricular ejection fraction (LVEF) were assessed by CMR. The association between sex and new-onset HF (including outpatient diagnosis or acute HF hospitalization) was evaluated using a Cox proportional hazards regression model adjusted for competing events [death, myocardial infarction (MI), and revascularization]. A total of 2289 (38.8%) patients were women. During a median follow-up of 4.5 years, 610 (10.3%) patients died, 191 (3.2%) suffered an MI, 905 (15.3%) underwent revascularization, and 314 (5.3%) developed new-onset HF. Unadjusted new-onset HF rates were higher in women than in men (1.25 vs. 0.83 per 100 person-years, P = 0.001). After comprehensive multivariate adjustment, women showed an increased risk of new-onset HF (hazard ratio 1.58, 95% confidence interval 1.18–2.10; P = 0.002). We found a sex-differential effect along the continuum of LVEF (P-value for interaction = 0.007). At lower LVEF, there was an increased risk in both sexes. However, compared with men, the risk of new-onset HF was higher in women with LVEF >55%. Women with known or suspected CAD are at a higher risk of new-onset HF. Further studies are needed to unravel the mechanisms behind these sex-related differences.

Heart failure with preserved ejection fraction (HFpEF) often coexists with chronic kidney disease (CKD). Exercise intolerance is a major determinant of quality of life and morbidity in both scenarios. We aimed to evaluate the associations between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and carbohydrate antigen 125 (CA125) with maximal aerobic capacity (peak VO₂) in ambulatory HFpEF and whether these associations were influenced by kidney function. This single-centre study prospectively enrolled 133 patients with HFpEF who performed maximal cardiopulmonary exercise testing. Patients were stratified across estimated glomerular filtration rate (eGFR) categories (<60 ml/min/1.73 m² versus ≥60 ml/min/1.73 m²). The mean age of the sample was 73.2 ± 10.5 years and 56.4% were female. The median of peak VO₂ was 11.0 ml/kg/min (interquartile range 9.0–13.0). A total of 67 (50.4%) patients had an eGFR <60 ml/min/1.73 m². Those patients had higher levels of NT-proBNP and lower peak VO₂, without differences in CA125. In the whole sample, NT-proBNP and CA125 were inversely correlated with peak VO₂ (r = −0.43, P < .001 and r = −0.22, P = .010, respectively). After multivariate analysis, we found a differential association between NT-proBNP and peak VO₂ across eGFR strata (P for interaction = .045). In patients with an eGFR ≥60 ml/min/1.73 m², higher NT-proBNP identified patients with poorer maximal functional capacity. In individuals with eGFR <60 ml/min/1.73 m², NT-proBNP was not significantly associated with peak VO₂ [β = 0.02 (95% confidence interval −0.19–0.23), P = .834]. Higher CA125 was linear and significantly associated with worse functional capacity without evidence of heterogeneity across eGFR strata (P for interaction = .620). In patients with stable HFpEF, NT-proBNP was not associated with maximal functional capacity when CKD was present. CA125 emerged as a useful biomarker for estimating effort intolerance in HFpEF irrespective of the presence of CKD.

Purpose: Vasodilator stress cardiac magnetic resonance (VS-CMR) has become crucial in the workup of patients with known or suspected chronic coronary syndrome (CCS). Whether traditional exercise ECG testing (ExECG) contributes prognostic information beyond VS-CMR is unclear. Methods: We retrospectively included 288 patients with known or suspected CCS who had undergone ExECG and subsequent VS-CMR in our institution. Clinical, ExECG, and VS-CMR variables were recorded. We defined the serious adverse events (SAE) as a combined endpoint of acute coronary syndrome, admission for heart failure, or all-cause death. Results: During a mean follow-up of 4.2 ± 2.15 yr, we registered 27 SAE (15 admissions for acute coronary syndrome, eight admissions for heart failure, and four all-cause deaths). Once adjusted for clinical, ExECG, and VS-CMR parameters associated with SAE, the only independent predictors were HR_max in ExECG (HR = 0.98: 95% CI, 0.96-0.99; P = .01) and more extensive stress-induced perfusion defects (PDs, number of segments) in VS-CMR (HR = 1.19: 95% CI, 1.07-1.34; P < .01). Adding HR_max significantly improved the predictive power of the multivariable model for SAE, including PDs (continuous reclassification improvement index: 0.47: 95% CI, 0.10-0.81; P < .05). The annualized SAE rate was 1% (if PD < 2 segments and HR_max > 130 bpm), 2% (if PD < 2 segments and HR_max ≤ 130 bpm), 3.2% (if PD ≥ 2 segments and HR_max > 130 bpm), and 6.3% (if PD ≥ 2 segments and HR_max ≤ 130 bpm), P < .01, for the trend. In patients on β-blocker therapy, however, only PDs in VS-CMR, but not HR_max, predicted SAE. Conclusions: We conclude that ExECG contributes significantly to prognostic information beyond VS-CMR in patients with known or suspected CCS.