Iron deficiency occurs commonly in chronic kidney disease (CKD), but its association with heart failure and other cardiovascular outcomes, independent of anemia, is not well defined. We conducted a post-hoc analysis of the Anaemia Studies in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial. We assessed the independent associations of transferrin saturation (TSAT) and ferritin levels with cardiovascular and mortality outcomes using time-updated multivariable Cox regression models. The primary outcome was heart failure hospitalization (HFH) or cardiovascular death. Among 3,872 participants (median age 67 years, 56% women, median estimated glomerular filtration rate 18 mL/min/1.73m2), those with lower TSAT were more likely to be women, have diabetes, atrial fibrillation, and a history of cardiovascular disease. In fully adjusted models (including hemoglobin), compared to TSAT >30-≤40%, time-updated TSAT ≤20% was associated with a 2-fold higher risk of the primary outcome (HR 2.13, 95% CI 1.62-2.80), with similar associations observed for HFH (HR 1.97, 95% CI 1.40-2.79) and for cardiovascular death (HR 2.19, 95% CI 1.45-3.29), as well as all-cause mortality (HR 1.60, 95% CI 1.25-2.03). Ferritin levels ≤100 ng/mL (vs >100 to ≤300 ng/mL) were not associated with a higher risk of any cardiovascular or mortality outcomes. Iron deficiency defined by low transferrin saturation, but not low ferritin levels, is associated with increased risk of heart failure and cardiovascular death in CKD, independent of hemoglobin.

In dyssynchronous heart failure (DHF), left bundle branch block (LBBB) causes inhomogeneous left ventricular (LV) workload and systolic dysfunction. We aimed to investigate underlying metabolic remodelling in an ovine model. Eleven sheep with dual-chamber-pacemakers for LBBB-like activation (DHF) were studied at baseline and after eight weeks. Six untreated sheep served as controls (CTRL). Regional workload was evaluated using invasive hemodynamics and echocardiography. 18F-fluorodeoxyglucose-tracer positron-emission-tomography/computed tomography visualized regional glucose-uptake. Magnetic resonance imaging assessed fibrosis (late gadolinium enhancement, LGE). Septal and lateral wall tissue was analysed with histology, confocal microscopy, ultra-high-performance liquid chromatography-high resolution mass-spectrometry (UHPLC-HRMS). Dyssynchrony induced low septal and high lateral asymmetry in workload and glucose-uptake. After eight weeks, DHF animals exhibited LV dilation and LVEF decline (31.1±5.1% vs. 59.4±3.5% at baseline, p<0.05). Septal thinning and lateral hypertrophy rebalanced workload and glucose-uptake. No fibrosis was seen on LGE or histology. DHF-animals showed enrichment of mitochondria at the intercalated discs (EMID-sign) - highest in the lateral wall (DHF septal 7.0±4.8% vs. lateral 48.4±12.3%, p<0.05). Mitochondrial redox balance in DHF shifted towards a more oxidised state without evidence of oxidative stress. Metabolomics revealed no differences between septal and lateral walls but severe energy depletion of tricarboxylic acid cycle substrates and phosphocreatine in DHF (fold change DHF/CTRL 0.01, p<0.01). Experimental DHF is characterised by non-fibrotic, dilated LV without signs of oxidative stress. Workload increase in the lateral wall leads to hypertrophy and EMID, homogenizing metabolic profiles between wall segments. However, the ventricle enters energy starvation and systolic dysfunction.

Clinicians may be less inclined to consider new therapies in patients with long-standing heart failure (HF) due in part to clinical inertia. Whether the treatment effects of the non-steroidal mineralocorticoid receptor antagonist finerenone vary according to HF duration remains uncertain. In this prespecified analysis of the FINEARTS-HF trial, HF duration (defined as the time from diagnosis) was categorized into four groups: <3 months, ≥3 months to 2 years, ≥2 to 5 years, or ≥5 years. The primary outcome was a composite of cardiovascular death and total HF events. The efficacy and safety of finerenone were analyzed across the duration of HF. Among 5,977 participants with available data (age: 72±10 years; 46% female), those with longer duration HF were older and had a higher comorbidity burden, while most patients, irrespective of HF duration, had NYHA class II functional status. Compared with HF duration <3 months, longer HF duration experienced a significantly higher adjusted risk of the primary outcome. The benefit of finerenone was consistent across HF duration categories: the rate ratio (95%CI) for the primary outcome in the <3-month group was 0.84 (0.61-1.16); ≥3 months to 2 years, 0.95 (0.74-1.23); ≥2 to 5 years, 0.77 (0.61-0.98); and ≥5 years, 0.81 (0.64-1.02) (Pinteraction=0.46). Drug discontinuation due to serious adverse events was similar between finerenone and placebo, regardless of HF duration. These findings suggest that even patients with long-standing HF with only mild functional status limitation may still benefit from further therapeutic optimization with therapies such as finerenone.