Microplastics and Nanoplastics in Atheromas and Cardiovascular Events.

BACKGROUND: Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking. METHODS: We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis-gas chromatography-mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs. RESULTS: A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 µg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 µg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001). CONCLUSIONS: In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947.).

Role of Dickkopf-3 in Blood Pressure Regulation in Mice and Hypertensive Rats.

BACKGROUND: Dkk3 (Dickkopf-3) is a secreted glycoprotein known for its proapoptotic and angiogenic activity. The role of Dkk3 in cardiovascular homeostasis is largely unknown. Remarkably, the Dkk3 gene maps within a chromosome segment linked to the hypertensive phenotype in spontaneously hypertensive rats (SHR). METHODS: We used Dkk3-/- mice or stroke-resistant (sr) and stroke-prone (sp) SHR to examine the role of Dkk3 in the central and peripheral regulation of blood pressure (BP). We used lentiviral expression vector to rescue Dkk3 in knockout mice or to induce Dkk3 overexpression or silencing in SHR. RESULTS: Genetic deletion of Dkk3 in mice enhanced BP and impaired endothelium-dependent acetylcholine-induced relaxation of resistance arteries. These alterations were rescued by restoring Dkk3 expression either in the periphery or in the central nervous system (CNS). Dkk3 was required for the constitutive expression of VEGF (vascular endothelium growth factor), and the action of Dkk3 on BP and endothelium-dependent vasorelaxation was mediated by VEGF-stimulated phosphatidylinositol-3-kinase pathway, leading to eNOS (endothelial NO synthase) activation both in resistance arteries and the CNS. The regulatory function of Dkk3 on BP was confirmed in SHR stroke-resistant and SHR stroke-prone in which was blunted in both resistance arteries and brainstem. In SHR stroke-resistant, lentiviral expression vector-induced Dkk3 expression in the CNS largely reduced BP, whereas Dkk3 knock-down further enhanced BP. In SHR stroke-prone challenged with a hypersodic diet, lentiviral expression vector-induced Dkk3 expression in the CNS displayed a substantial antihypertensive effect and delayed the occurrence of stroke. CONCLUSIONS: These findings demonstrate that Dkk3 acts as peripheral and central regulator of BP by promoting VEGF expression and activating a VEGF/Akt (protein kinase B)/eNOS hypotensive axis.

Intravenous antiplatelet therapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention : A report from the INVEST-STEMI group.

The use of intravenous antiplatelet therapy during primary percutaneous coronary intervention (PPCI) is not fully standardized. The aim is to evaluate the effectiveness and safety of periprocedural intravenous administration of cangrelor or tirofiban in a contemporary ST-segment elevation myocardial infarction (STEMI) population undergoing PPCI. This was a multicenter prospective cohort study including consecutive STEMI patients who received cangrelor or tirofiban during PPCI at seven Italian centers. The primary effectiveness measure was the angiographic evidence of thrombolysis in myocardial infarction (TIMI) flow < 3 after PPCI. The primary safety outcome was the in-hospital occurrence of BARC (Bleeding Academic Research Consortium) 2-5 bleedings. The study included 627 patients (median age 63 years, 79% males): 312 received cangrelor, 315 tirofiban. The percentage of history of bleeding, pulmonary edema and cardiogenic shock at admission was comparable between groups. Patients receiving cangrelor had lower ischemia time compared to tirofiban. TIMI flow before PPCI and TIMI thrombus grade were comparable between groups. At propensity score-weighted regression analysis, the risk of TIMI flow < 3 was significantly lower in patients treated with cangrelor compared to tirofiban (adjusted OR: 0.40; 95% CI: 0.30-0.53). The risk of BARC 2-5 bleeding was comparable between groups (adjusted OR:1.35; 95% CI: 0.92-1.98). These results were consistent across multiple prespecified subgroups, including subjects stratified for different total ischemia time, with no statistical interaction. In this real-world multicenter STEMI population, the use of cangrelor was associated with improved myocardial perfusion assessed by coronary angiography after PPCI without increasing clinically-relevant bleedings compared to tirofiban.

Cardiovascular Implications of microRNAs in Coronavirus Disease 2019.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to be a global challenge due to resulting morbidity and mortality. Cardiovascular (CV) involvement is a crucial complication in coronavirus disease 2019 (COVID-19), and no strategies are available to prevent or specifically address CV events in COVID-19 patients. The identification of molecular partners contributing to CV manifestations in COVID-19 patients is crucial for providing early biomarkers, prognostic predictors, and new therapeutic targets. The current report will focus on the role of microRNAs (miRNAs) in CV complications associated with COVID-19. Indeed, miRNAs have been proposed as valuable biomarkers and predictors of both cardiac and vascular damage occurring in SARS-CoV-2 infection. SIGNIFICANCE STATEMENT: It is essential to identify the molecular mediators of coronavirus disease 2019 (COVID-19) cardiovascular (CV) complications. This report focused on the role of microRNAs in CV complications associated with COVID-19, discussing their potential use as biomarkers, prognostic predictors, and therapeutic targets.

Prognostic significance of the SYNTAX score and SYNTAX score II in patients with myocardial infarction treated with percutaneous coronary intervention.

OBJECTIVES: We aimed to evaluate the prognostic significance of the SYNTAX score (SS) and SYNTAX score II (SS-II) in a contemporary real-world cohort of myocardial infarction (MI) patients treated with percutaneous coronary intervention (PCI). BACKGROUND: The role of SS and SS-II in the prognostic stratification of patients presenting with MI and undergoing PCI has been poorly investigated. METHODS: This study included MI patients treated with PCI from January 2015 to April 2020 at the University Hospital of Salerno. Patients were divided into tertiles according to the baseline SS and SS-II values. The primary outcome measure was all-cause mortality at long-term follow-up; secondary outcome measures were cardiovascular (CV) death and MI. RESULTS: Overall, 915 patients were included in this study. Mean SS and SS-II were 16.1 ± 10.0 and 31.6 ± 11.5, respectively. At propensity weighting adjusted Cox regression analysis, both SS (hazard ratio [HR]: 1.02; 95% confidence interval [CI]: 1.02-1.06; p = 0.017) and SS-II (HR: 1.08; 95% CI: 1.07-1.10; p < 0.001) were significantly associated with the risk of all-cause mortality at long-term follow-up; both SS (HR 1.04; CI 1.01-1.06; p < 0.001) and SS-II (HR 1.08; CI 1.06-1.10; p < 0.001) were significantly associated with the risk of CV death, but only SS-II showed a significant association with the risk of recurrent MI (HR 1.03; CI 1.01-1.05; p < 0.001). At 5 years, SS-II showed a significantly higher discriminative ability for all-cause mortality than SS (area under the curve: 0.82 vs. 0.64; p < 0.001). SS-II was able to reclassify the risk of long-term mortality beyond the SS (net reclassification index 0.88; 95% CI: 0.38-1.54; p = 0.033). CONCLUSIONS: In a real-world cohort of MI patients treated with PCI, SS-II was a stronger prognostic predictor of long-term mortality than SS.

SIRT1 pharmacological activation rescues vascular dysfunction and prevents thrombosis in MTHFR deficiency.

Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/-) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/- mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.

Clinical outcome of patients with ST-elevation myocardial infarction and angiographic evidence of coronary artery ectasia.

OBJECTIVES: The aim of this study was to describe the prevalence of coronary artery ectasia (CAE) in patients with ST-elevation myocardial infarction (STEMI) and to compare the long-term outcome of subjects with and without CAE undergoing emergent coronary angiography. BACKGROUND: The prognostic impact of CAE in STEMI patients has been poorly investigated. METHODS: This retrospective, single-center, study included consecutive patients with STEMI undergoing emergent coronary angiography from January 2012 to December 2017. The primary endpoint was the assessment of recurrent myocardial infarction (MI) in patients with versus those without CAE at the longest available follow-up. The propensity score weighting technique was employed to account for potential selection bias between groups. RESULTS: From 1,674 patients with STEMI, 154 (9.2%) had an angiographic evidence of CAE; 380 patients were included in the no CAE group. CAE patients were more often males and smokers, and showed a lower prevalence of diabetes than no CAE patients. After percutaneous coronary intervention, the corrected thrombolysis in MI frame count (p < .001) and the myocardial blush grade (p < .001) were significantly lower in CAE than in no CAE patients. The mean follow-up was 1,218.3 ± 574.8 days. The adjusted risk for the primary outcome resulted significantly higher in patients with CAE compared to those without (adjusted HR: 1.84; p = .017). No differences in terms of all-cause and cardiac death were found between groups. CONCLUSIONS: In this study, STEMI patients with CAE had a distinct clinical and angiographic profile, and showed a significantly higher risk of recurrent MI than those without CAE.

Lipoprotein(a) levels and risk of adverse events after myocardial infarction in patients with and without diabetes.

INTRODUCTION: The aim of this study was to evaluate the association of lipoprotein(a) [Lp(a)] levels with long-term outcome in patients with recent history of myocardial infarction (MI), and to investigate if diabetes may influence this association. METHODS: Consecutive MI patients who underwent urgent/emergent coronary angiography from February 2013 to June 2019 were prospectively collected. The primary outcome was the composite of MI recurrence and all-cause death. The propensity score weighting technique was used to account for covariates potentially influencing the relationship between Lp(a) levels and the study outcomes. RESULTS: The study population consisted of 1018 post-MI patients (median age 63 years). Diabetes was reported in 280 patients (27.5%), who showed lower Lp(a) levels than patients without diabetes (p = 0.026). At a median follow-up of 1121 days, the primary outcome was reported in 182 patients (17.9%). At univariable Cox regression analysis, Lp(a) was associated with the risk of the primary outcome in the overall population and in non-diabetic patients, but not in diabetics. The adjusted Cox regression analysis confirmed the independent association between Lp(a) values and the primary outcome in non-diabetic patients, but not in diabetics.Lp(a) levels > 70 mg/dL were independently associated with the risk of the primary outcome in non-diabetic patients (adjusted HR: 2.839; 95% CI, 1.382-5.832), but not in diabetics. CONCLUSIONS: In this real-world post-MI population, increasing Lp(a) levels were significantly associated with the risk of recurrent MI and all-cause death, and very high Lp(a) serum concentration independently predicted long-term outcome in non-diabetic patients, but not in diabetics.

High TARC plasma levels confer protection to long living individuals by inducing M2 profile.

A way to delay aging and the related low-grade chronic inflammatory state is to study the model of positive physiology such as the Long-Living Individuals (LLIs). Our recent studies have shown higher levels of the host defense BPI Fold-Containing Family B Member 4 (BPIFB4) protein in the LLIs' blood. Notably, BPIFB4 has been shown to influence monocytes typesetting and M2 anti-inflammatory phenotype (CD206+CD163++) macrophages skewing. According to the role of a complex cytokine milieu in guiding the macrophage polarization, here we found that circulating concentrations of thymus and activation regulated chemokine (TARC)/CCL17 and small-inducible cytokine B10 (IP-10)/CXCL10) cytokines, were additionally associated with the LLIs' state. In a differentiation process in vitro, the addition of LLIs' plasma to the cell culture medium, enhanced the ability of monocytes, either from LLIs or controls, to acquire a M2 phenotype. Interestingly, a neutralizing antibody against TARC blunted the M2 skewing effect of the LLIs' plasma. Collectively, these data indicate that exceptional longevity may associate with a peculiar anti-inflammatory myeloid profile responsible for improved reparative processes and reduced inflammatory status mediated in part by TARC and M2 generation.

Clinical conditions and echocardiographic parameters associated with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a recently recognized viral infective disease which can be complicated by acute respiratory stress syndrome (ARDS) and cardiovascular complications including severe arrhythmias, acute coronary syndromes, myocarditis and pulmonary embolism. The aim of the present study was to identify the clinical conditions and echocardiographic parameters associated with in-hospital mortality in COVID-19. METHODS: This is a multicentre retrospective observational study including seven Italian centres. Patients hospitalized with COVID-19 from 1 March to 22 April 2020 were included into study population. The association between baseline variables and risk of in-hospital mortality was assessed through multivariable logistic regression and competing risk analyses. RESULTS: Out of 1401 patients admitted at the participating centres with confirmed diagnosis of COVID-19, 226 (16.1%) underwent transthoracic echocardiography (TTE) and were included in the present analysis. In-hospital death occurred in 68 patients (30.1%). At multivariable analysis, left ventricular ejection fraction (LVEF, P < .001), tricuspid annular plane systolic excursion (TAPSE, P < .001) and ARDS (P < .001) were independently associated with in-hospital mortality. At competing risk analysis, we found a significantly higher risk of mortality in patients with ARDS vs those without ARDS (HR: 7.66; CI: 3.95-14.8), in patients with TAPSE ≤17 mm vs those with TAPSE >17 mm (HR: 5.08; CI: 3.15-8.19) and in patients with LVEF ≤50% vs those with LVEF >50% (HR: 4.06; CI: 2.50-6.59). CONCLUSIONS: TTE might be a useful tool in risk stratification of patients with COVID-19. In particular, reduced LVEF and reduced TAPSE may help to identify patients at higher risk of death during hospitalization.

Trehalose, a natural disaccharide, reduces stroke occurrence in the stroke-prone spontaneously hypertensive rat.

Cerebrovascular disease, a frequent complication of hypertension, is a major public health issue for which novel therapeutic and preventive approaches are needed. Autophagy activation is emerging as a potential therapeutic and preventive strategy toward stroke. Among usual activators of autophagy, the natural disaccharide trehalose (TRE) has been reported to be beneficial in preclinical models of neurodegenerative diseases, atherosclerosis and myocardial infarction. In this study, we tested for the first time the effects of TRE in the stroke-prone spontaneously hypertensive rat (SHRSP) fed with a high-salt stroke permissive diet (JD). We found that TRE reduced stroke occurrence and renal damage in high salt-fed SHRSP. TRE was also able to decrease systolic blood pressure. Through ex-vivo studies, we assessed the beneficial effect of TRE on the vascular function of high salt-fed SHRSP. At the molecular level, TRE restored brain autophagy and reduced mitochondrial mass, along with the improvement of mitochondrial function. The beneficial effects of TRE were associated with increased nuclear translocation of TFEB, a transcriptional activator of autophagy. Our results suggest that TRE may be considered as a natural compound efficacious for the prevention of hypertension-related target organ damage, with particular regard to stroke and renal damage.

Cardiovascular risk factors and mortality in hospitalized patients with COVID-19: systematic review and meta-analysis of 45 studies and 18,300 patients.

BACKGROUND: A high prevalence of cardiovascular risk factors including age, male sex, hypertension, diabetes, and tobacco use, has been reported in patients with Coronavirus disease 2019 (COVID-19) who experienced adverse outcome. The aim of this study was to investigate the relationship between cardiovascular risk factors and in-hospital mortality in patients with COVID-19. METHODS: MEDLINE, Cochrane, Web of Sciences, and SCOPUS were searched for retrospective or prospective observational studies reporting data on cardiovascular risk factors and in-hospital mortality in patients with COVID-19. Univariable and multivariable age-adjusted analyses were conducted to evaluate the association between cardiovascular risk factors and the occurrence of in-hospital death. RESULTS: The analysis included 45 studies enrolling 18,300 patients. The pooled estimate of in-hospital mortality was 12% (95% CI 9-15%). The univariable meta-regression analysis showed a significant association between age (coefficient: 1.06; 95% CI 1.04-1.09; p < 0.001), diabetes (coefficient: 1.04; 95% CI 1.02-1.07; p < 0.001) and hypertension (coefficient: 1.01; 95% CI 1.01-1.03; p = 0.013) with in-hospital death. Male sex and smoking did not significantly affect mortality. At multivariable age-adjusted meta-regression analysis, diabetes was significantly associated with in-hospital mortality (coefficient: 1.02; 95% CI 1.01-1.05; p = 0.043); conversely, hypertension was no longer significant after adjustment for age (coefficient: 1.00; 95% CI 0.99-1.01; p = 0.820). A significant association between age and in-hospital mortality was confirmed in all multivariable models. CONCLUSIONS: This meta-analysis suggests that older age and diabetes are associated with higher risk of in-hospital mortality in patients infected by SARS-CoV-2. Conversely, male sex, hypertension, and smoking did not independently correlate with fatal outcome.

Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism.

AIMS: Here, we aimed to determine the therapeutic effect of longevity-associated variant (LAV)-BPIFB4 gene therapy on atherosclerosis. METHODS AND RESULTS: ApoE knockout mice (ApoE-/-) fed a high-fat diet were randomly allocated to receive LAV-BPIFB4, wild-type (WT)-BPIFB4, or empty vector via adeno-associated viral vector injection. The primary endpoints of the study were to assess (i) vascular reactivity and (ii) atherosclerotic disease severity, by Echo-Doppler imaging, histology and ultrastructural analysis. Moreover, we assessed the capacity of the LAV-BPIFB4 protein to shift monocyte-derived macrophages of atherosclerotic mice and patients towards an anti-inflammatory phenotype. LAV-BPIFB4 gene therapy rescued endothelial function of mesenteric and femoral arteries from ApoE-/- mice; this effect was blunted by AMD3100, a CXC chemokine receptor type 4 (CXCR4) inhibitor. LAV-BPIFB4-treated mice showed a CXCR4-mediated shift in the balance between Ly6Chigh/Ly6Clow monocytes and M2/M1 macrophages, along with decreased T cell proliferation and elevated circulating levels of interleukins IL-23 and IL-27. In vitro conditioning with LAV-BPIFB4 protein of macrophages from atherosclerotic patients resulted in a CXCR4-dependent M2 polarization phenotype. Furthermore, LAV-BPIFB4 treatment of arteries explanted from atherosclerotic patients increased the release of atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1ß, inducing endothelial nitric oxide synthase phosphorylation and restoring endothelial function. Finally, significantly lower plasma BPIFB4 was detected in patients with pathological carotid stenosis (>25%) and intima media thickness >2 mm. CONCLUSION: Transfer of the LAV of BPIFB4 reduces the atherogenic process and skews macrophages towards an M2-resolving phenotype through modulation of CXCR4, thus opening up novel therapeutic possibilities in cardiovascular disease.

Multi-Systemic Alterations by Chronic Exposure to a Low Dose of Bisphenol A in Drinking Water: Effects on Inflammation and NAD+-Dependent Deacetylase Sirtuin1 in Lactating and Weaned Rats.

Bisphenol A (BPA) is largely used as a monomer in some types of plastics. It accumulates in tissues and fluids and is able to bypass the placental barrier, affecting various organs and systems. Due to huge developmental processes, children, foetuses, and neonates could be more sensitive to BPA-induced toxicity. To investigate the multi-systemic effects of chronic exposure to a low BPA dose (100 µg/L), pregnant Wistar rats were exposed to BPA in drinking water during gestation and lactation. At weaning, newborn rats received the same treatments as dams until sex maturation. Free and conjugated BPA levels were measured in plasma and adipose tissue; the size of cerebral ventricles was analysed in the brain; morpho-functional and molecular analyses were carried out in the liver with a focus on the expression of inflammatory cytokines and Sirtuin 1 (Sirt1). Higher BPA levels were found in plasma and adipose tissue from BPA treated pups (17 PND) but not in weaned animals. Lateral cerebral ventricles were significantly enlarged in lactating and weaned BPA-exposed animals. In addition, apart from microvesicular steatosis, liver morphology did not exhibit any statistically significant difference for morphological signs of inflammation, hypertrophy, or macrovesicular steatosis, but the expression of inflammatory cytokines, Sirt1, its natural antisense long non-coding RNA (Sirt1-AS LncRNA) and histone deacetylase 1 (Hdac1) were affected in exposed animals. In conclusion, chronic exposure to a low BPA dose could increase the risk for disease in adult life as a consequence of higher BPA circulating levels and accumulation in adipose tissue during the neonatal period.

Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19.

BACKGROUND: Understanding how HLA polymorphisms may affect both susceptibility, course and severity of Covid-19 infection could help both at the clinical level to identify individuals at higher risk from the disease and at the epidemiological one to explain the differences in the epidemic trend among countries or even within a specific country. Covid-19 disease in Italy showed a peculiar geographical distribution from the northern most affected regions to the southern ones only slightly touched. METHODS: In this study we analysed the regional frequencies for the most common Italian haplotypes from the Italian Bone Marrow Donor Registry (HLA-A, -B, -C and -DRB1 at four-digit level). Then we performed Pearson correlation analyses among regional haplotypes estimated frequency in the population and Covid-19 incidence and mortality. RESULTS: In this study we found that the two most frequent HLA haplotypes in the Italian population, HLA-A*:01:01g-B*08:01 g-C*07:01g-DRB1*03:01g and HLA-A*02.01g-B*18.01g-C*07.01g-DRB1*11.04g, had a regional distribution overlapping that of Covid-19 and showed respectively a positive (suggestive of susceptibility) and negative (suggestive of protection) significant correlation with both Covid-19 incidence and mortality. CONCLUSIONS: Based on these results, in order to define such HLA haplotypes as a factor effectively associated to the disease susceptibility, the creation of national networks that can collect patients' samples from all regions for HLA typing should be highly encouraged.

3-Hydroxytyrosol Promotes Angiogenesis In Vitro by Stimulating Endothelial Cell Migration.

Cardiovascular diseases, followed by strokes, represent the leading cause of mortality worldwide. Despite its success in preventing cardiovascular diseases, the therapeutic potential of 3-Hydroxytyrosol (HT) for treating ischemic diseases is yet to be investigated in detail, especially with regard to ischemic heart disease, which is a major challenge for humans. We assessed that low concentrations (1-5 µM) of HT, generally achieved after the ingestion of olive oil, stimulate endothelial cells migration and angiogenesis in an in vitro model. At early time points (1-6 h), HT induces the expression of different proteins such as proto-oncogene tyrosine-protein kinase Src (Src), rho-associated protein kinase (ROCK) and matrix metalloproteinase-2 (MMP-2) protein influencing cell adhesion, cytoskeletal dynamics and cell migration. We observed that at the same time, HT induces prominent vascular formation in the tube formation assay, accompanied by an increase in the expression of the vascular endothelial growth factor receptor (VEGF-R2) and PI3K-Akt-eNOS protein pathways, which are recognized for their central role in angiogenesis. Therefore, in addition to the proven capability of HT to regulate reactive oxygen species (ROS) levels, through both direct scavenging properties and indirect antioxidant efficacy, our results revealed that HT promotes angiogenesis, arguing in favor of great pharma-nutritional potential in ischemic injuries.

A Novel Promising Frontier for Human Health: The Beneficial Effects of Nutraceuticals in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) such as hypertension, atherosclerosis, myocardial infarction, and diabetes are a significant public health problem worldwide. Although several novel pharmacological treatments to reduce the progression of CVDs have been discovered during the last 20 years, the better way to contain the onset of CVDs remains prevention. In this regard, nutraceuticals seem to own a great potential in maintaining human health, exerting important protective cardiovascular effects. In the last years, there has been increased focus on identifying natural compounds with cardiovascular health-promoting effects and also to characterize the molecular mechanisms involved. Although many review articles have focused on the individual natural compound impact on cardiovascular diseases, the aim of this manuscript was to examine the role of the most studied nutraceuticals, such as resveratrol, cocoa, quercetin, curcumin, brassica, berberine and Spirulina platensis, on different CVDs.

PTX3: an inflammatory protein modulating ultrastructure and bioenergetics of human endothelial cells.

BACKGROUND: Pentraxin 3 (PTX3), an acute-phase inflammation protein produced by several cell types, has long been described as a possible biomarker for age-related cardiovascular and cerebrovascular diseases. Although several mechanisms of action have been identified to date in the vascular and immune systems, the direct effects of PTX3 on isolated endothelial cells at morphological and metabolic levels remain unknown. FINDINGS: PTX3 induced cytoplasmic vacuolization and dilution of mitochondrial matrix in isolated, human endothelial cells. Moreover, metabolic assays revealed that PTX3 increases respiratory capacity in support of mitochondrial function, and partially sustains the glycolytic pathway. CONCLUSIONS: PTX3 has, per se, a direct action on ultrastructural and bioenergetic parameters of isolated endothelial cells. This finding can be associated with our previous demonstration of a deleterious effect of PTX3 on the endothelial layer. More studies are needed to clearly demonstrate any direct correlation between these ultrastructural and bioenergetic changes with endothelial dysfunction, especially with regard to age-related cerebro- and cardio-vascular diseases.

The Main Determinants of Diabetes Mellitus Vascular Complications: Endothelial Dysfunction and Platelet Hyperaggregation.

Diabetes mellitus is a common disease that affects 3⁻5% of the general population in Italy. In some countries of northern Europe or in North America, it can even affect 6⁻8% of the population. Of great concern is that the number of cases of diabetes is constantly increasing, probably due to the increase in obesity and the sedentary nature of the population. According to the World Health Organization, in the year 2030 there will be 360 million people with diabetes, compared to 170 million in 2000. This has important repercussions on the lives of patients and their families, and on health systems that offer assistance to patients. In this review, we try to describe in an organized way the pathophysiological continuity between diabetes mellitus, endothelial dysfunction, and platelet hyperaggregation, highlighting the main molecular mechanisms involved and the interconnections.