Why the study?
AF and HF frequently coexist, but therapeutic progress is hindered by limited understanding of the atrial substrate sustaining AF in HF, with high recurrence despite current therapies.
Answers are grounded in this paper and cite their sources.
Targeting the atrial substrate through emerging molecular pathways represents a promising strategy to reduce atrial fibrillation burden in patients with heart failure.
Atrial fibrillation (AF) and heart failure (HF) frequently coexist, yet therapeutic progress is hindered by limited understanding of the atrial substrate that sustains AF in HF. This review summarizes key mechanisms through which HF promotes a pro-arrhythmic atrial environment. Hemodynamic stress, neurohormonal activation, fibrosis, proteostasis derailment, mitochondrial dysfunction, calcium-handling defects, DNA damage, and inflammation collectively drive atrial structural and electrical remodeling. Although guideline-directed HF therapies and catheter ablation improve outcomes, AF recurrence remains high, underscoring the need to target upstream molecular pathways. Emerging studies identify several druggable mechanisms, including heat shock protein induction, HDAC6-dependent cytoskeletal remodeling, NAD⁺/mitochondrial preservation, PARP1/DNA damage signaling, CaMKII and stress-kinase regulation, NLRP3 inflammasome inhibition, and modulation of mechanosensitive channels such as TRPC6 and Piezo1. Targeting the atrial substrate represents a promising strategy to reduce AF burden in HF. Biomarker-guided mechanistic trials and rational combination therapies will be essential to translate these insights into effective treatments.
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Sultan et al. (2026) conducted a review in Patients with atrial fibrillation (AF) and heart failure (HF) including preserved and reduced ejection fraction. Catheter ablation and guideline-directed HF therapies (including ACE inhibitors, ARBs, ARNIs, beta-blockers, MRAs, diuretics, SGLT2 inhibitors) vs. Rate control or placebo/usual care was evaluated on Composite of cardiovascular death or worsening heart failure or survival and hospitalization (Catheter ablation reduces mortality and heart failure hospitalizations; ACE inhibitors/ARBs reduce relative risk of incident AF by 44%, with up to 78% reduction in severe LV dysfunction; early rhythm control reduces composite primary endpoint by 22% (EAST-AFNET 4)).
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