Background: Thrombosis with cardiovascular involvement is a crucial complication in COVID-19 infection. COVID-19 infects the host by the angiotensin converting enzyme-2 receptor (ACE2r), which is expressed in endothelial cells too. Thus, COVID-related thrombotic events might be due to endothelial dysfunction. IL-6 is one of the main cytokines involved in the COVID-19 inflammatory storm. Some evidence indicates that Vitamin D (VitD) has a protective role in COVID-19 patients, but the molecular mechanisms involved are still debated. Thus, we investigated the effect of VitD on Tissue Factor and adhesion molecules (CAMs) in IL-6-stimulated endothelial cells (HUVEC). Moreover, we evaluated levels of the ACE2r gene and proteins. Finally, we studied the modulation of NF-kB and STAT3 pathways. Methods: HUVEC cultivated in VitD-enriched medium were stimulated with IL-6 (0.5 ng/mL). The TF gene (RT-PCR), protein (Western blot), surface expression (FACS) and procoagulant activity (FXa generation assay) were measured. Similarly, CAMs soluble values (ELISA) and ACE2r (RT-PCR and Western blot) levels were assessed. NF-kB and STAT3 modulation (Western blot) were also investigated. Results: VitD significantly reduced TF expression at both gene and protein levels as well as TF-procoagulant activity in IL-6-treated HUVEC. Similar effects were observed for CAMs and ACE2r expression. IL-6 modulates these effects by regulating NF-κB and STAT3 pathways. Conclusions: IL-6 induces endothelial dysfunction with TF and CAMs expression via upregulation of ACE2r. VitD prevented these IL-6 deleterious effects. Thus, it might be speculated that this is one of the hypothetical mechanism(s) by which VitD exerts its beneficial effects in COVID-19 infection.

Homocysteine has long been studied as a potential cardiovascular risk factor due to its biochemical role in endothelial dysfunction, oxidative stress, inflammation, and thrombogenesis. Despite strong epidemiological and mechanistic support, the translation of homocysteine-lowering interventions into clinical benefit remains controversial. This non-systematic review aims to clarify the current understanding of homocysteine in the cardiovascular setting by distinguishing between well-established facts, clinically relevant interventions, and persistent misconceptions. We first revisit the historical emergence of homocysteine as a cardiovascular biomarker and explore its pathophysiological mechanisms, including endothelial damage, atherosclerosis progression, and prothrombotic effects—supported by in vitro and animal model studies. Subsequently, we evaluate evidence-based interventions such as B-vitamin supplementation (folate, B6, B12), lifestyle modifications, and the clinical relevance of homocysteine monitoring in specific populations (e.g., MTHFR mutations, chronic kidney disease). We then discuss common pitfalls, including the overinterpretation of genetic variants, the inappropriate use of supplementation, and the overreliance on surrogate biomarkers in clinical trials. Although elevated homocysteine remains a reproducible biomarker of cardiovascular risk, current evidence does not support routine intervention in unselected populations. A precision medicine approach—targeting high-risk subgroups and integrating homocysteine into broader cardiometabolic management—may help unlock its therapeutic relevance. Future pharmacological strategies should prioritize mechanistic insight, patient stratification, and clinically meaningful endpoints.

In recent decades, the novel role of Galectin-3 (Gal-3) in both physiological and pathological conditions has emerged. Gal-3 is a key protein involved in immunity, inflammation, cell adhesion, proliferation, differentiation, and apoptosis. Its physiological role is crucial for the regulation of these cellular functions. In pathological settings, elevated levels of Gal-3 are associated with diseases such as cancer, heart failure, and fibrotic diseases, making it an important diagnostic and prognostic biomarker in these conditions. It seems that Gal-3 acts as a bridge between different diseases. Because of its pro-inflammatory and pro-tumorigenic properties, it connects atherosclerosis and cancer, regulating inflammation, cell proliferation, immune evasion, angiogenesis and survival in both diseases. Specifically, in atherosclerosis, Gal-3 promotes plaque formation by driving inflammation, oxidative stress, lipid deposition, and vascular cell migration. In cancer, Gal-3 influences tumor growth and metastasis by modulating an immunosuppressive tumor microenvironment, increasing cell survival, and enhancing cell–matrix and cell–cell interactions. Moreover, by stimulating fibroblasts, Gal-3 favors matrix deposition and tissue fibrosis that together with the inflammatory properties contributes to adverse ventricular remodeling leading to heart failure. Finally, taking into account its role in pathogen recognition and immune cells (B and T cells) modulation, Gal-3 might be a critical factor in host defense, disease progression, and the development of autoimmune conditions. Thus, targeting Gal-3 might be a promising therapeutic strategy to pursue for management of different pathological scenarios.

Cardiovascular diseases represent one of the leading causes of morbidity and mortality worldwide despite tremendous advancements in therapeutic interventions. Prevention remains one of the most effective strategies to reduce individual risk. Apolipoprotein E (ApoE), through its genetic variants (ε2, ε3, ε4), is a well-known modulator of cardiovascular risk, traditionally studied for its role in lipid metabolism. However, recent evidence suggests that ApoE also influences endothelial function and thrombotic processes, opening new perspectives for an integrated approach to risk assessment. This narrative review explores the potential of using the APOE genotype as a key genetic biomarker, integrated with emerging endothelial markers (e.g., plasma levels of endothelin-1, nitric oxide, von Willebrand factor, endothelial adhesion molecules) to achieve a more accurate and personalized stratification of cardiovascular and thrombotic risk. The combined approach may overcome the limitations of traditional thrombophilia screening, which is often poorly informative when performed without clear clinical criteria, and may guide more targeted therapeutic decisions, particularly in borderline-risk individuals or those with unexplained thrombotic events. Finally, the review discusses the clinical implications, current challenges, and future perspectives for integrating this model into clinical practice within the framework of precision medicine. The early identification of genetically predisposed patients, together with functional endothelial assessment, could represent a breakthrough in modern cardiovascular prevention.

Vitamin D, traditionally regarded as a nutrient, is increasingly recognized as a pharmacologically active secosteroid with pleiotropic effects extending beyond calcium homeostasis and bone integrity. Together with vitamin K2, it participates in the fine-tuning of mineral metabolism and vascular health, potentially modulating cardiometabolic risk through intertwined endocrine and paracrine pathways. Despite widespread fortification and supplementation, vitamin D deficiency remains a major global health concern, driven by limited sun exposure, obesity, and metabolic dysfunction. Observational and mechanistic studies consistently link low serum 25(OH)D concentrations with hypertension, insulin resistance, heart failure, and increased cardiovascular mortality. At the molecular level, vitamin D exerts pharmacological actions—modulating the renin–angiotensin–aldosterone system, exerting anti-inflammatory and antifibrotic effects, and influencing endothelial and cardiomyocyte signaling. While experimental and epidemiological evidence suggests potential cardiovascular benefits, large randomized controlled trials (RCTs) provide conflicting results, particularly regarding hypertension and heart failure. However, these often-neutral results do not preclude a targeted action. On the contrary, clinical efficacy is strongly dependent on baseline deficiency status and the presence of metabolic cofactors. In this context, high-dose supplementation of Vitamin D, in combination with Vitamin K2 to prevent vascular calcification, elevates the supplement to a genuine pharmacological agent, with a distinct therapeutic potential for modulating cardiometabolic risk in selected patient subgroups. Emerging evidence supports the concept that vitamin D, when appropriately dosed and combined with K2, may act more as a low-potency pharmacological modulator than a simple nutritional supplement. This review synthesizes current mechanistic, observational, and interventional evidence, aiming to clarify whether vitamin D should be reclassified—from a micronutrient to a pharmacologically relevant agent—in cardiometabolic prevention and therapy, proposing a paradigm shift toward personalized and targeted dosing strategies, characteristic of precision pharmacology.

Background: Obesity has been defined as a true worldwide “pandemic” by the World Health Organization and represents one of the major public health problems. It is associated with a reduction in life expectancy of about 7–8 years due to related cardiovascular diseases such as arterial hypertension, metabolic syndrome, insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Adipose tissue is not merely a fat storage site but a true endocrine and immunologically active organ that secretes hormones and mediators (adipokines), influencing cardiovascular risk and host physiology. Objective: This review summarizes the current understanding of the role of epicardial adipose tissue (EAT) in cardiovascular disease pathophysiology and discusses its clinical diagnostic and therapeutic implications. Methods: A narrative non-systematic review was conducted focusing on recent literature concerning the biological and clinical aspects of cardiac adipose tissue, with particular emphasis on epicardial adipose tissue. The review examined its gene expression profile, secretory function, and interaction with cardiovascular structures and diseases. Findings: There are different types of adipose tissue, including cardiac adipose tissue, which comprises epicardial and pericardial (or paracardiac) fractions. Epicardial adipose tissue is unique due to its proximity to the heart and a distinct gene expression profile compared to other adipose depots such as visceral and subcutaneous fat. EAT plays a crucial role in the development and progression of cardiovascular diseases with high morbidity and mortality, acting both as a metabolic and inflammatory mediator. Conclusion: Cardiac adipose tissue, particularly EAT, is a key player in cardiometabolic disease. Understanding its pathophysiological role and incorporating imaging tools to evaluate EAT may enhance cardiovascular risk stratification and disease management.