Heart failure (HF) remains a major global health challenge defined by the inability of the heart to adequately meet systemic metabolic requirements. While ventricular dysfunction has traditionally been the primary focus in both conceptual and clinical frameworks of HF, emerging evidence highlights atrial myopathy—covering structural, functional, electrical, metabolic, and neurohormonal remodeling—as a central yet often overlooked contributor to disease progression across the HF spectrum. This review offers a comprehensive overview of the molecular and cellular mechanisms underlying atrial remodeling, with a focus on inflammation and innate immune activation as key pathogenic mediators. Among pattern recognition receptors, Toll-like receptors (TLRs) and NOD-like receptors (NLRs) play crucial roles in translating myocardial stress into pro-inflammatory, profibrotic, and pro-arrhythmic signals that exacerbate HF. By combining experimental and clinical evidence, we emphasize atrial myopathy as both a biomarker and an active driver of HF deterioration, advocating for the inclusion of atrial-targeted diagnostics and immunomodulatory therapies in future HF treatment approaches. Such a paradigm shift holds significant potential for improved risk stratification, arrhythmia prevention, attenuation of structural remodeling, and ultimately, better prognosis and clinical outcomes in this increasingly common syndrome.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and characterized by oxidative damage to membrane phospholipids. Increasing evidence indicates that ferroptosis contributes to myocardial ischemia-reperfusion injury (MIRI), a condition that worsens cardiac damage following restoration of blood flow to the ischemic myocardium. This study aimed to investigate the role of ferroptosis in MIRI and to determine whether pharmacological activation of the vitamin D receptor (VDR) by paricalcitol modulates ferroptosis-associated cardiac injury. Myocardial ischemia-reperfusion was induced in mice by transient ligation of the left anterior descending coronary artery followed by reperfusion. Cardiac function was evaluated by cardiac magnetic resonance imaging. Ferroptosis-related pathways were analyzed through transcriptional profiling of antioxidant and iron-regulating genes, lipidomic assessment of oxidized phospholipid species, and ultrastructural mitochondrial evaluation. Complementary in vitro experiments were performed using human AC16 cardiomyocyte-like cells under ferroptotic stress. Ischemia-reperfusion led to a sustained deterioration of cardiac structure and function and induced several alterations consistent with ferroptosis activation, including changes in ferroptosis-related gene expression, accumulation of oxidized phospholipid species, and mitochondrial structural abnormalities. Pharmacological activation of VDR by paricalcitol attenuated ferroptosis-related transcriptional alterations, reduced lipid peroxidation, and mitigated mitochondrial structural damage, collectively limiting ferroptosis-associated cardiomyocyte injury and early ventricular dilation and systolic dysfunction. These findings suggest that VDR activation limits ferroptosis-associated cardiac injury during myocardial ischemia-reperfusion and may represent a pharmacologically relevant strategy to mitigate cardiac damage linked to ferroptosis.