Background: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with the risk of several chronic and acute diseases. However, updated data on vitamin D status in Mediterranean countries, including Italy, remain limited, hindering effective public health strategies. Objective: To assess serum 25(OH)D levels and their seasonal variation in healthy blood donors aged 18–65 years living in Northern Italy and not taking vitamin D supplements. Given the latitude and high levels of environmental pollution, cutaneous vitamin D synthesis may be impaired in this population. Recent Italian guidelines on supplementation highlight the need for updated data on hypovitaminosis D prevalence and seasonal synthesis capacity. Methods: In this exploratory cross-sectional study, 534 blood donors (268 men and 266 women) attending the Transfusion Medicine Unit of Verona University Hospital were enrolled between April 2016 and May 2018. Serum 25(OH)D concentrations were analysed according to season. Clinical, lifestyle, pharmacological and dietary characteristics were also collected. Results: Among healthy, normal-weight individuals, the prevalence of vitamin D insufficiency (25(OH)D<50 nmol/L) was low and limited to one-two months per year. Overweight and obesity significantly reduced the likelihood of achieving adequate 25(OH)D levels through cutaneous synthesis for several months. Mean 25(OH)D concentrations were higher than those previously reported in the same area, while seasonal variation remained preserved. Conclusions: Despite persistent environmental pollution, seasonal vitamin D synthesis is not impaired in this Northern Italy population. Updated data show higher 25(OH)D levels compared to past studies, supporting current recommendations against routine supplementation in healthy normal-weight individuals under 70 years

In the original publication [...].

Background: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with the risk of several chronic and acute diseases. However, updated data on vitamin D status in Mediterranean countries, including Italy, remain limited, hindering effective public health strategies. Objective: To assess serum 25(OH)D levels and their seasonal variation in healthy blood donors aged 18-65 years living in Northern Italy and not taking vitamin D supplements. Given the latitude and the high levels of environmental pollution, cutaneous vitamin D synthesis may be impaired in this population. Recent Italian guidelines on supplementation emphasize the need for updated data on the prevalence of hypovitaminosis D and seasonal variation in endogenous vitamin D synthesis. Methods: In this exploratory retrospective cross-sectional study, 534 blood donors (268 men and 266 women) attending the Transfusion Medicine Unit of the Verona University Hospital were enrolled between April 2016 and May 2018. Serum 25(OH)D concentrations were analyzed by season. Clinical, lifestyle, pharmacological and dietary characteristics were also collected. Results: Among healthy, normal-weight individuals, the prevalence of vitamin D insufficiency (25(OH)D < 50 nmol/L) was low and limited to one-two months per year. Overweight and obesity significantly reduced the likelihood of achieving adequate 25(OH)D levels through cutaneous synthesis for several months. Mean 25(OH)D concentrations were higher than those previously reported in the same area, while seasonal variation remained preserved. Conclusions: In a relatively small non-supplemented population of blood donors living in a high polluted urban area of Northern Italy, seasonal vitamin D synthesis seems to be preserved. These updated data show higher 25(OH)D levels compared to past findings. Although these data certainly warrant further validation through a national survey involving other regions of Italy and in not selected population, they appear to be in line with the SIOMMMS recommendations against indiscriminate serum 25(OH)D testing and against routine supplementation for healthy normal-weight individuals under 70 years.

BACKGROUND:Hypertension is a major global health issue. Aldosterone synthase inhibitors (ASIs) have emerged as a promising therapeutic strategy for blood pressure control. METHODS:A thorough search of the MEDLINE and Embase databases up to March 30, 2024, identified randomized trials comparing ASIs with a placebo for hypertension treatment. Data extraction was done independently by 2 authors. Both random-effects (Restricted maximum likelihood) and fixed-effects meta-analyses were conducted to account for diversity and study size, respectively. Risk ratios for binary outcomes and mean differences for continuous outcomes were calculated. RESULTS:Seven randomized controlled trials involving 1440 patients (mean age, 60 years; 39% women) were included. The analysis showed that ASIs reduced office systolic blood pressure by 6.3 mm Hg ([95% CI, -8.8 to -3.8]; P<0.0001) and diastolic blood pressure by 2.2 mm Hg ([95% CI, -4.2 to -0.2]; P=0.03). The risk ratio for adverse events was 1.1 ([95% CI, 0.9-1.2]; P=0.3), with a similar trend for serious adverse events (risk ratio, 1.0 [95% CI, 0.5-2.3]; P=0.95). No treatment-related deaths occurred. However, the risk of hyperkalemia was higher with ASIs (risk ratio, 2.5 [95% CI, [1.2-5.4]; P<0.02). CONCLUSIONS:ASIs effectively reduce systolic and diastolic blood pressure in hypertensive patients and have a tolerable safety profile. The increased risk of hyperkalemia requires careful monitoring. These findings suggest ASIs are a potential treatment option for hypertension, pending further research in larger studies.

Primary aldosteronism (PA), the most common cause of secondary hypertension, is increasingly recognized as an independent driver of adverse cardiac remodeling, mediated through mechanisms beyond elevated blood pressure alone. Chronic aldosterone excess leads to myocardial fibrosis, left ventricular hypertrophy, and diastolic dysfunction via mineralocorticoid receptor activation, oxidative stress, inflammation, and extracellular matrix dysregulation. These changes culminate in a distinct cardiomyopathy phenotype, often underrecognized in early stages. Multimodality cardiac imaging, led primarily by conventional and speckle-tracking echocardiography, and complemented by exploratory cardiac magnetic resonance (CMR) techniques such as T1 mapping and late gadolinium enhancement, enables non-invasive assessment of structural, functional, and tissue-level changes in aldosterone-mediated myocardial damage. While numerous studies have established the diagnostic and prognostic relevance of imaging in PA, several gaps remain. Specifically, the relative sensitivity of different modalities in detecting subclinical myocardial changes, the long-term prognostic significance of imaging biomarkers, and the differential impact of adrenalectomy versus medical therapy on cardiac reverse remodeling require further clarification. Moreover, the lack of standardized imaging-based criteria for defining and monitoring PA-related cardiomyopathy hinders widespread clinical implementation. This narrative review aims to synthesize current knowledge on the pathophysiological mechanisms of aldosterone-induced cardiac remodeling, delineate the strengths and limitations of existing imaging modalities, and critically evaluate the comparative effects of surgical and pharmacologic interventions. Emphasis is placed on early detection strategies, identification of imaging biomarkers with prognostic utility, and integration of multimodal imaging into clinical decision-making pathways. By outlining current evidence and highlighting key unmet needs, this review provides a framework for future research aimed at advancing personalized care and improving cardiovascular outcomes in patients with PA.

BACKGROUND:Activated factor VII-antithrombin complex (FVIIa-AT) is an indirect plasma biomarker of the interaction between tissue factor (TF) and FVIIa. High FVIIa-AT levels have been associated with an increased risk of mortality. METHODS:We investigated the genetic determinants of FVIIa-AT plasma levels by a candidate gene approach in a cohort of 610 subjects with (n = 478) or without (n = 132) angiographically-demonstrated coronary artery disease (CAD). RESULTS:Plasma concentration of FVIIa-AT did not differ between CAD and CAD-free subjects, but predicted the mortality risk in CAD during a median follow-up of 64-months. Among 7 polymorphisms in 4 candidate genes, codifying for FVII, TF, Endothelial Protein C Receptor (EPCR), and Low-density lipoprotein receptor-Related Protein 1 (LRP1), none was associated with CAD. Three of them were independently associated with FVIIa-AT plasma concentration. F3 -603 A > G polymorphism predicted mortality in CAD consistent with the influence on FVIIa-AT levels, with the G allele-carriers having both higher FVIIa-AT concentration (86.4 with 95 %CI 82.4-90.5 versus 76.7 with 95 %CI 71.0-82.8 pM) and higher mortality risk (HR 1.92 with 95 %CI 1.08-3.41) as compared with AA homozygotes. Conversely, the F7 -323 A1/A2, the strongest genetic predictor of FVIIa-AT variability, and EPCR Ser219Gly polymorphisms were associated with FVIIa-AT levels but were not predictive of mortality. CONCLUSIONS:Our results indicate that FVIIa-AT plasma levels are influenced by distinct genetic determinants linked to either TF or FVII expression. The heterogeneous association of FVIIa-AT-related polymorphisms with mortality risk in CAD suggests a predominant role of TF expression rather than FVII levels in the setting of secondary cardiovascular prevention.

Background/Objectives: Fatty acids (FAs) play crucial roles in human physiology, and their levels have been associated with hypertension, although with inconsistent findings. Primary Aldosteronism (PA), a common, often underdiagnosed form of secondary hypertension, carries a higher risk of organ damage compared to essential hypertension (EH). This study aimed to compare plasma FA profiles of patients with unilateral PA and EH and explore the impact of therapies. Methods: Participants were recruited at the Hypertension Unit of Verona University Hospital. PA diagnosis/subtype was confirmed according to guidelines. Blood samples were collected at enrollment and at follow-up (after treatment with a mineralocorticoid receptor antagonist (MRA) and adrenalectomy). Plasma long- and very-long-chain FAs were extracted and analyzed using gas chromatography. Results: Each sample was assessed for a panel of 19 selected FA species. Compared to EH (n = 60), PA patients (n = 22) exhibited lower plasma levels of behenic acid (p = 0.03), total monounsaturated fatty acids (p = 0.02), specifically palmitoleic (p = 0.005) and erucic acids (p = 0.02), and higher levels of ω6 polyunsaturated fatty acids (PUFAs, p = 0.02). Longitudinal analysis in PA patients showed that MRAs decreased total saturated FAs (pADJ = 0.01) and increased total PUFAs (pADJ = 0.006), and these changes were largely maintained even after adrenalectomy. Conclusions: This pilot study reveals significant alterations in the plasma FA profiles of PA patients compared to EH, suggesting a more prominent inflammatory state in PA. Both pharmacological and surgical interventions induced a positive shift in the FA profile of PA patients. These findings highlight the potential of FAs as biomarkers for PA risk stratification and may offer novel therapeutic opportunities.

BACKGROUND: Primary aldosteronism (PA) is a common curable cause of secondary hypertension that significantly increases left ventricular mass (LVM) and predisposes patients to adverse cardiovascular outcomes. Although adrenalectomy and medical therapy with mineralocorticoid receptor antagonists (MRAs) are both used to treat PA, their long-term comparative efficacy in reversing cardiac structural changes remains debated. METHODS: We systematically searched MEDLINE and Embase for prospective and retrospective clinical trials published up to November 22, 2024, with a minimum follow-up of 6 months that reported changes in LVM in patients with PA treated with adrenalectomy or MRAs. Data were independently extracted by 2 reviewers, and risk-of-bias assessments were conducted using standardized tools. The primary outcome was the percentage reduction in indexed LVM; secondary outcomes included changes in cardiac remodeling, and systolic and diastolic function parameters. RESULTS: Seventeen studies comprising 1696 patients (49% adrenalectomy, 51% MRA therapy) were analyzed. Adrenalectomy yielded a significantly greater indexed LVM reduction (mean difference, -3.5% [95% CI, -4.9% to -2.2%]; P<0.0001) and a 32% reduction in left ventricular hypertrophy risk ratio, compared with a 19% reduction with MRAs. Meta-regression revealed that shorter hypertension duration predicted greater LVM regression following adrenalectomy, whereas high dietary sodium attenuated MRA effects. In addition, left ventricular ejection fraction improved modestly after adrenalectomy. CONCLUSIONS: Adrenalectomy provides superior long-term regression of LVM and left ventricular hypertrophy compared with MRAs in PA, supporting its use as the first-line treatment for unilateral PA. Future research should compare emerging nonsteroidal MRAs and aldosterone synthase inhibitors to further optimize cardiac remodeling outcomes.

Background: Tissue factor (TF), the main initiator of the coagulation cascade, plays a role in cancer progression and prognosis. Activated factor VII-antithrombin complex (FVIIa-AT) is considered an indirect marker of TF exposure by reflecting TF-FVIIa interaction. Objectives: To assess the link between FVIIa-AT plasma levels, TF messenger RNA (mRNA) expression, and survival in cancer. Methods: TF pathway-related coagulation biomarkers were assessed in 136 patients with cancer (52 with hepatocellular carcinoma, 41 with cholangiocarcinoma, and 43 with colon cancer) undergoing surgical intervention with curative intent. TF mRNA expression analysis in neoplastic vs nonneoplastic liver tissues was evaluated in a subgroup of 91 patients with primary liver cancer. Results: FVIIa-AT levels were higher in patients with cancer than in 136 sex- and agematched cancer -free controls. In patients with cancer, high levels of FVIIa-AT and total TF pathway inhibitor were associated with an increased mortality risk after adjustment for confounders, but only FVIIa-AT remained a predictor of mortality by including both FVIIa-AT and total TF pathway inhibitor in Cox regression (hazard ratio, 2.80; 95% CI, 1.23-6.39; the highest vs the lowest quartile). This association remained significant even after adjustment for extracellular vesicle-associated TF-dependent procoagulant activity. In the subgroup of patients with primary liver cancer, patients with high TF mRNA levels had an increased mortality risk compared with that for those with low TF mRNA levels (hazard ratio, 1.92; 95% CI, 1.03-3.57), and there was a consistent correlation among high FVIIa-AT levels, high TF mRNA levels, and increased risk of mortality. Conclusion: High FVIIa-AT levels may allow the identification of patients with cancer involving high TF expression and predict a higher mortality risk in liver cancer.

Introduction: Hypertension is a widespread health concern globally, often associated with excessive aldosterone production. Aldosterone synthase inhibitors (ASIs) have been proposed as potential therapeutic agents. Yet, their effectiveness and safety in managing blood pressure in hypertensive adults are not definitively established. This study aims to elucidate this matter through a comprehensive systematic review and meta-analysis of Randomized Controlled Trials (RCTs). Hypothesis: We hypothesize that ASIs could be a safe and effective strategy for managing blood pressure in adults diagnosed with hypertension. Methods: A systematic review and meta-analysis of seven RCTs were conducted to assess the impact of ASIs versus placebo in hypertensive patients. The studies were systematically sourced from MEDLINE and EMBASE until March 30 th , 2024. Continuous outcomes were pooled using the mean difference (MD), and dichotomous outcomes were pooled using the risk ratio (RR), both with their respective confidence intervals (CI). Results: Our meta-analysis incorporated data from seven randomized studies, averaging 7.7 ± 2.4 weeks in duration, and involving a total of 1440 patients. Compared to placebo, ASIs showed effectiveness in controlling systolic blood pressure (MD: -6.12 mm Hg; 95% CI [−4.32, −7.92]; p < 0.0001; I 2 = 0%) and diastolic blood pressure (MD: −2.71; 95% CI [−1.07, −4.36]; p = 0.001; I 2 = 0%). Notably, the incidence of adverse events did not significantly differ from that observed with placebo (RR: 1.11; 95% CI 0.95 to 1.29; p = 0.18; I 2 = 0%). Conclusions: Our findings suggest that ASIs could be a safe and effective approach for managing blood pressure in hypertensive adults, with no significant difference in the incidence of adverse events compared to placebo. These results advocate for further investigation of ASIs in larger, long-term trials to confirm their safety and efficacy, and to explore any additional therapeutic benefits over mineralocorticoid receptor antagonists. Future research should also thoroughly examine the potential benefits of these inhibitors in diverse patient populations, including those with obesity-associated hypertension and suppressed plasma renin activity.

Antiphospholipid syndrome (APS) is an acquired thrombophilic disorder related to the presence of antiphospholipid antibodies (LAC, anticardiolipin, anti Beta2-glycoprotein) known to cause venous and arterial thrombosis and recurrent pregnancy loss. Skin disorder is a frequent finding usually due to vascular thrombosis involving the dermal layer and can be either localized or widespread causing necrosis and ulceration of the skin, without histological evidence of vasculitis. We present a case of a woman with APS with both arterial and venous thrombotic involvement associated with an atypical dermatological manifestation histologically consistent with a pauci-inflammatory intermediate-deep dermal arteriolar platelet-mediated thrombosis that appeared despite anticoagulation with warfarin and responding to the addition of antiplatelet therapy.

The sodium chloride cotransporter (NCC) is essential for electrolyte balance, blood pressure regulation, and pathophysiology of hypertension as it mediates the reabsorption of ultrafiltered sodium in the renal distal convoluted tubule. Given its pivotal role in the maintenance of extracellular fluid volume, the NCC is regulated by a complex network of cellular pathways, which eventually results in either its phosphorylation, enhancing sodium and chloride ion absorption from urines, or dephosphorylation and ubiquitination, which conversely decrease NCC activity. Several factors could influence NCC function, including genetic alterations, hormonal stimuli, and pharmacological treatments. The NCC’s central role is also highlighted by several abnormalities resulting from genetic mutations in its gene and consequently in its structure, leading to dysregulation of blood pressure control. In the last decade, among other improvements, the acquisition of knowledge on the NCC and other renal ion channels has been favored by studies on extracellular vesicles (EVs). Dietary sodium and potassium intake are also implicated in the tuning of NCC activity. In this narrative review, we present the main cornerstones and recent evidence related to NCC control, focusing on the context of blood pressure pathophysiology, and promising new therapeutical approaches.

Tissue factor (TF) is a transmembrane glycoprotein that represents the fundamental physiological initiator of the coagulation cascade through its interaction with factor VII. TF belongs to the cytokine receptor protein superfamily and contributes to the transduction of cellular signaling. Therefore, TF-related pathways are involved in multiple pathophysiological processes, not only in coagulation/thrombosis but in a wider mechanisms’ panorama, ranging from infective to neoplastic diseases. Consistently, the measurement of TF activity could have a diagnostic and/or prognostic meaning in different clinical conditions. However, the transmembrane localization, the expression on different cellular types and circulating extracellular vesicles, and the different conformations (encrypted and decrypted) and variants (such as the soluble alternatively spliced TF) hamper TF assessment in clinical practice. The activated factor VII-antithrombin (FVIIa–AT) complex is proposed as an indirect biomarker of the TF–FVIIa interaction and, consequently, of the functionally active TF expression. In this narrative review, we evaluate the clinical studies investigating the role of plasma concentration of FVIIa–AT in health and disease. Although without conclusive data, high FVIIa–AT concentrations predict the worst clinical outcomes in different pathologic conditions, such as cardiovascular disease and cancer, thereby suggesting that overactivation of TF-related pathways may play an unfavorable role in various clinical settings.

Objective: Fatty acids (FAs) represent a wide class of lipids performing a variety of functions in living organisms. FA plasma concentration is greatly related to dietary intake. FA levels have been proven to be useful biomarkers for the prediction of cardiovascular disease (CVD) development and progression, due to their capability to mediate endothelial disfunction. As one of the major CVD risk factors, hypertension can also be affected by FA concentration. In particular, hypertensive patients with primary aldosteronism (PA) are characterized by a higher incidence of cardiovascular complications and endothelial dysfunction than patients with essential hypertension (EH). Aims of the study were: 1) analyze FA plasma levels in hypertensive subjects, focusing on the comparison between patients affected by PA and EH; 2) evaluate possible correlations between FA and other biochemical parameter in order to better characterize the pathophysiological mechanisms involved in the disease. Design and method: PA and EH patients were enrolled, and biochemical parameters were collected. Plasma FAs were extracted through a direct transesterification reaction and separated using gas chromatography. Peak identification and quantification were performed with commercially available reference FAs, using heptadecanoic acid (17:0) as the internal standard. FA levels were presented as percentages of total FAs. Results: Significant differences in the FA plasma levels were detected between PA patients and EH patients, for palmitoleic acid (POA) and for non-esterified fatty acids (NEFAs). Lower POA and higher NEFAs percentage were found in APA (n=22) compared to EH subjects (n=101) (POA 1.67 [95%CI, 1.37, 2.49] vs 2.62 [95%CI, 1.88, 3.11] respectively, P<0.01, and NEFAs 92.89 ± 1.65 vs 91.77 ± 1.44 respectively, P<0.01). Conclusions: This study provides insights into the possible role of fatty acids in the physiopathology of primary aldosteronism. Hypertensive patients with APA compared to EH were characterized by higher concentrations of NEFAs (a category of fatty acids previously associated with a detrimental effect by promoting endothelial dysfunction, oxidative stress, and vascular cell growth) and lower POA. Further analyses are required to better characterize the precise cellular mechanisms in which these fatty acids are involved.

Background: Urinary extracellular vesicles (uEVs) can be released by different cell types facing the urogenital tract and are involved in cellular trafficking, differentiation and survival. UEVs can be easily detected in urine and provide pathophysiological information "in vivo" without the need of a biopsy. Based on these premises, we hypothesized that uEVs proteomic profile may serve as a valuable tool in the differential characterization between Essential Hypertension (EH) and primary aldosteronism (PA). Methods: Patients with essential hypertension (EH) and PA were enrolled in the study (EH= 12, PA=24: 11 Bilateral Primary Aldosteronism subtype (BPA) and 13 Aldosterone Producing Adenoma (APA)). Clinical and biochemical parameters were available for all the subjects. UEVs were isolated from urine by ultracentrifugation and analysed by Transmission Electron Microscopy (TEM) and nanotrack particle analysis (NTA). UEVs protein content was investigated through an untargeted MS-based approach. Statistical and network analysis was performed to identify potential candidates for the identification and classification of PA. Results: MS analysis provided more than 300 protein identifications. Exosomal markers CD9 and CD63 were detected in all samples. Several molecules characterizing EH vs PA patients as well as BPA and APA subtypes were identified after statistical elaboration and filtering of the results. In particular, some key proteins involved in water reabsorption mechanisms, such as AQP1 and AQP2, were among the best candidates for discriminating EH vs PA, as well as A1AG1 (AGP1). Conclusion: Through this proteomic approach, we identified uEVs molecular indicators that can improve PA characterization and help in the gain of insights of the pathophysiological features of this disease. In particular, PA was characterized by a reduction of AQP1 and AQP2 expression as compared with EH.