Systemic iron deficiency (SID), even in the absence of anemia, worsens the prognosis and increases mortality in heart failure (HF). Recent clinical-epidemiological studies, however, have shown that a myocardial iron deficiency (MID) is frequently present in cases of severe HF even in the absence of SID and without anemia. In addition, experimental studies have shown a poor correlation between the state of systemic and myocardial iron. MID in animal models may lead to severe mitochondrial dysfunction, alterations of mitophagy and mitochondrial biogenesis, with profound alterations in cardiac mechanics and the occurrence of a fatal cardiomyopathy, all effects prevented by intravenous administration of iron. This shifts the focus to the myocardial state of iron, in the absence of anemia, as an important factor in prognostic worsening and mortality in HF. There is now epidemiological evidence that SID worsens prognosis and mortality also in patients with acute and chronic coronary heart disease, and experimental evidence that MID aggravates acute myocardial ischemia as well as post-ischemic remodeling. Intravenous administration of ferric carboxymaltose or ferric dextrane improves post-ischemic adverse remodeling. We here review such evidence, propose that MID worsens ischemia/reperfusion injury, and discuss possible molecular mechanisms, such as chronic hyperactivation of HIF1-α; exacerbation of cytosolic and mitochondrial calcium overload, amplified increase of mitochondrial [NADH]/[NAD⁺] ratio, and depletion of energy status and NAD⁺ content with inhibition of sirtuin 1-3 activity. Such evidence now portrays iron metabolism as a core factor not only in heart failure, but also in myocardial ischemia.

BACKGROUND: Various measures of abnormal left atrial (LA) structure or function (LA myopathy) are associated with a higher risk of ischemic stroke and dementia, independent of atrial fibrillation. However, limited data exist on their prognostic usefulness. Therefore, we aimed to assess the ability of markers of LA myopathy to improve the prediction of ischemic stroke and dementia. METHODS: The ARIC study (Atherosclerosis Risk in Communities) is a prospective community-based cohort study. For this analysis, we included participants who attended visit 5 (2011–2013) without a history of stroke or atrial fibrillation and had a 12-lead ECG and a transthoracic echocardiogram. Markers of LA myopathy included P wave abnormalities from 12-lead ECG, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and LA volume and strain parameters from the echocardiogram. The primary composite outcome comprised ischemic stroke and dementia, which were ascertained through hospital surveillance, cohort follow-up, and death registries. To determine improvement in risk prediction of the composite outcome, each marker was individually added to a model that included CHA ₂ DS ₂ -VASc variables, and Akaike information criterion, C statistic, and its change were computed. Cox proportional hazards models were used to assess the independent association of LA myopathy markers with the outcome. RESULTS: Among 4712 participants (59% female; mean age, 74 years), 193 ischemic strokes and 769 dementia cases were ascertained over a median follow-up of 8.3 years. Of LA myopathy markers, only LA reservoir strain and NT-proBNP significantly improved C statistic when added to the CHA ₂ DS ₂ -VASc model (base C statistic, 0.677) for the prediction of the composite outcome. Adding the LA reservoir yielded the highest increase in C statistic (0.010 [95% CI, 0.003–0.017]), and the model including the LA reservoir showed the lowest Akaike information criterion. In multivariable regression models, LA volume index, NT-proBNP, and LA strain parameters were significantly associated with the composite outcome. CONCLUSIONS: Of various LA myopathy markers, LA reservoir yields the greatest improvement in the prediction of ischemic stroke and dementia, supporting its use to identify people at high risk of cerebrovascular events and dementia.

Aims: To evaluate prevalence, clinical predictors, brain lesions and cognitive test scores of high-risk carotid plaque features—namely intraplaque haemorrhage (IPH), lipid-rich necrotic core (LRNC), and plaque ulceration—in patients with asymptomatic, intermediate-degree carotid artery stenosis. Methods and results: The Carotid Artery Multi-modality imaging Prognostic (CAMP) study is a prospective, observational cohort study enrolling patients with 40–60% asymptomatic carotid artery stenosis assessed by Doppler ultrasound. The present study is a cross-sectional analysis of baseline data. High-risk plaque characteristics were evaluated with multimodal vascular imaging, including computed tomography and magnetic resonance angiography, while brain magnetic resonance imaging and neurocognitive testing assessed covert brain infarcts, cerebral small vessel disease, and cognitive functions. Among 155 patients (mean age: 72 years, 27% female, 29% with chronic coronary syndromes), at least one high-risk plaque feature (LRNC, IPH, or ulcer) was present in 51% of cases. IPH and LRNC were present in 23% for both, and ulceration in 38%. Patients with high-risk plaque features had higher high-sensitivity cardiac troponin T and 3-vessel coronary artery disease. Non-lacunar brain infarcts [cortical and large (>15 mm) subcortical brain infarcts] and markers of small vessel disease (lacunar infarcts or white matter hyperintensities) were observed in 11% and 71% of patients, respectively. In univariate analysis, homolateral IPH, LRNC, and ≥50% carotid stenosis were associated with non-lacunar brain infarcts. In multivariable models adjusted for cardiovascular risk factors and carotid stenosis, both IPH and LRNC remained significantly associated with non-lacunar brain infarcts. When high-risk plaque features (LRNC and/or IPH) and ≥50% stenosis were included in the same model, only high-risk plaque features remained significantly associated with non-lacunar brain infarcts. Low visuospatial and nonverbal memory test scores were common, with a tendency towards poorer performance in patients with high-risk features, although the differences were not statistically significant. Conclusion: High-risk plaque features are frequent in patients with asymptomatic intermediate carotid disease and are associated with non-lacunar covert brain infarcts. Cognitive impairment was common in the cohort, although not associated with high-risk carotid plaque. These findings support the use of a comprehensive plaque characterization beyond stenosis grading for cerebrovascular risk assessment in such patients.

Carotid atherosclerosis remains one of the primary etiological factors underlying ischemic stroke, contributing to adult neurological disability and mortality. In recent years, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, actively modulating molecular pathways involved in atherogenesis. This systematic review, the first to be exclusively focused on carotid atherosclerosis, aimed at synthesizing current findings on the differential expression of ncRNAs throughout the natural history of the disease, thus providing the first comprehensive attempt to delineate a stage-specific ncRNA expression profile in carotid disease. A comprehensive literature search was conducted in PubMed and Scopus databases in January 2025, following PRISMA guidelines. Original studies involving human subjects with carotid atherosclerosis, evaluating the expression of intracellular or circulating ncRNAs, were included and then categorized according to their association with cardiovascular risk factors, carotid intima-media thickness (cIMT), presence of atherosclerotic plaques, plaque vulnerability, clinical symptoms, and ischemic stroke. Out of 148 articles initially identified, 49 met the inclusion criteria and were analyzed in depth. Among the different classes of ncRNAs, microRNAs (miRNAs) were the most frequently reported as dysregulated, followed by circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Notably, the majority of identified ncRNAs were implicated in key pathogenic mechanisms such as inflammatory signaling, vascular smooth muscle cell (VSMC) phenotypic modulation, and ABCA1-mediated cholesterol efflux. Collectively, the evidence underscores the association and possible involvement of ncRNAs in the initiation and progression of carotid atherosclerosis and its cerebrovascular complications. Their relative stability in biological fluids and cell-specific expression profiles highlight their strong potential as minimally invasive biomarkers and—possibly—novel therapeutic targets.

Background and aims. Carotid atherosclerosis remains one of the primary etiological factors underlying ischemic stroke, contributing to adult neurological disability and mortality. In recent years, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, actively modulating molecular pathways involved in atherogenesis. This systematic review, the first to be exclusively focused on carotid atherosclerosis, aimed at synthesizing current findings on the differential expression of ncRNAs throughout the natural history of the disease, thus providing the first comprehensive attempt to delineate a stage-specific ncRNA expression profile in carotid disease. Methods. A comprehensive literature search was conducted in PubMed and Scopus databases in January 2025, following PRISMA guidelines. Original studies involving human subjects with carotid atherosclerosis, evaluating the expression of intracellular or circulating ncRNAs were included and then categorized according to their association with cardiovascular risk factors, carotid intima-media thickness (cIMT), presence of atherosclerotic plaques, plaque vulnerability, clinical symptoms, and ischemic stroke. Results. Out of 148 articles initially identified, 49 met the inclusion criteria and were analyzed in depth. Among the different classes of ncRNAs, microRNAs (miRNAs) were the most frequently reported as dysregulated, followed by circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Notably, the majority of identified ncRNAs were implicated in key pathogenic mechanisms such as inflammatory signaling, vascular smooth muscle cell (VSMC) phenotypic modulation, and ABCA1-mediated cholesterol efflux. Conclusions. Collectively, the evidence underscores the association and possible involvement of ncRNAs in the initiation and progression of carotid atherosclerosis and its cerebrovascular complications. Their relative stability in biological fluids and cell-specific expression profiles highlight their strong potential as minimally invasive biomarkers and – possibly – novel therapeutic targets.