Publications by authors named "Vittoria Cammisotto"

46 Publications

Antiphospholipid Antibodies and Heart Failure with Preserved Ejection Fraction. The Multicenter ATHERO-APS Study.

J Clin Med 2021 Jul 19;10(14). Epub 2021 Jul 19.

Department of General Surgery and Surgical Specialties "Paride Stefanini", Sapienza University of Rome, 00155 Rome, Italy.

Background: The prevalence of heart failure with preserved ejection fraction (HFpEF) in patients with antiphospholipid syndrome (APS) is unknown.

Methods: A prospective multicenter cohort study including 125 patients was conducted: 91 primary APS (PAPS), 18 APS-SLE, and 16 carriers. HFpEF was diagnosed according to the 2019 European Society of Cardiology criteria: patients with ≥5 points among major and minor functional and morphological criteria including NT-ProBNP > 220 pg/mL, left atrial (LA) enlargement, increased left ventricular filling pressure.

Results: Overall, 18 (14.4%) patients were diagnosed with HFpEF; this prevalence increased from 6.3% in carriers to 13.2% in PAPS and 27.8% in APS-SLE. Patients with HFpEF were older and with a higher prevalence of hypertension and previous arterial events. At logistic regression analysis, age, arterial hypertension, anticardiolipin antibodies IgG > 40 GPL (odds ratio (OR) 3.43, 95% confidence interval (CI) 1.09-10.77, = 0.035), anti β-2-glycoprotein-I IgG > 40 GPL (OR 5.28, 1.53-18.27, = 0.009), lupus anticoagulants DRVVT > 1.25 (OR 5.20, 95% CI 1.10-24.68, = 0.038), and triple positivity (OR 3.56, 95% CI 1.11-11.47, = 0.033) were associated with HFpEF after adjustment for age and sex. By multivariate analysis, hypertension (OR 19.49, 95% CI 2.21-171.94, = 0.008), age (OR 1.07, 95% CI 1.00-1.14, = 0.044), and aβ2GPI IgG > 40 GPL (OR 8.62, 95% CI 1.23-60.44, = 0.030) were associated with HFpEF.

Conclusion: HFpEF is detectable in a relevant proportion of APS patients. The role of aPL in the pathogenesis and prognosis of HFpEF needs further investigation.
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http://dx.doi.org/10.3390/jcm10143180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306431PMC
July 2021

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways.

Int J Mol Sci 2021 Jul 3;22(13). Epub 2021 Jul 3.

I Clinica Medica, Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy.

Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. In a multicenter before-after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 ( < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.
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http://dx.doi.org/10.3390/ijms22137193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267646PMC
July 2021

Impaired Clinical Efficacy of Aspirin in Hypoalbuminemic Patients With Diabetes Mellitus.

Front Pharmacol 2021 22;12:695961. Epub 2021 Jun 22.

Department of Clinical, Internal, Anaesthesiological, and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

To investigate the impact of albumin levels on the aspirin efficacy, since aspirin inhibits platelet aggregation (PA) by cyclooxygenase one irreversible acetylation that is less effective in patients with type 2 diabetes mellitus (T2DM). A total of 612 aspirin (100 mg/day)-treated T2DM patients were followed-up for 54.4 ± 7.3 months. The primary endpoint, a composite of cardiovascular events (CVEs) including CV death, myocardial infarction, ischemic stroke and coronary revascularization, was analysed according to baseline values of serum albumin (≥ or < 3.5 g/dL). Serum thromboxane (Tx)B was also measured. 250 (40.8%) patients had serum albumin < 3.5 g/dL; these patients were overweight and had higher values of fibrinogen ( = 0.009), high sensitivity C-reactive protein ( = 0.001) and fasting plasma glucose ( < 0.0001) compared to those with albumin ≥ 3.5 g/dL. During follow-up, 86 CVEs were recorded, 49 and 37 in patients with serum albumin < or ≥3.5 g/dL, respectively ( = 0.001). At multivariable Cox regression analysis, serum albumin < 3.5 g/dL (hazard ratio [HR] 1.887, 95% confidence interval [CI] 1.136-3.135, = 0.014), age (HR 1.552 for every 10 years, 95%CI 1.157-2.081, = 0.003), fasting plasma glucose (HR 1.063, 95%CI 1.022-1.105, = 0.002) and beta-blocker use (HR 0.440, 95%CI 0.270-0.717, = 0.001) were associated to CVEs. Serum TxB levels ( = 377) were 0.32 ± 0.12 and 0.24 ± 0.12 ng/ml in patients with albumin < or ≥ 3.5 g/dL, respectively ( < 0.001). In T2DM patients, the efficacy of aspirin varies according to albumin levels. Hypoalbuminemia associated with impaired TxB inhibition and an increased risk of long-term CVEs.
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http://dx.doi.org/10.3389/fphar.2021.695961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258313PMC
June 2021

Impact of chronic use of heat-not-burn cigarettes on oxidative stress, endothelial dysfunction and platelet activation: the SUR-VAPES Chronic Study.

Thorax 2021 06 19;76(6):618-620. Epub 2021 Apr 19.

IRCCS NeuroMed, Pozzilli, Italy.

Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215900DOI Listing
June 2021

Thrombosis in Covid-19 and non-Covid-19 pneumonia: role of platelets.

Platelets 2021 Jun 7:1-9. Epub 2021 Jun 7.

I Clinica Medica, Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Platelets may be a target of bacteria and viruses, which can directly or indirectly activate them so promoting thrombosis. In accordance with this, community-acquired pneumonia (CAP) is complicated by ischemia-related vascular disease (myocardial infarction and stroke) in roughly 10% of patients while the incidence of venous thrombosis is uncertain. In CAP platelet biosynthesis of TxA2 is augmented and associated with myocardial infarction; however, a cause-effect relationship is still unclear as unclear is if platelet activation promotes thrombosis or functional changes of coronary tree such vasospasm. Retrospective studies suggested a potential role of aspirin in reducing mortality but the impact on vascular disease is still unknown. Coronavirus disease 2019 (Covid-19) is complicated by thrombosis in roughly 20% of patients with an almost equivalent localization in arterial and venous circulation. Platelet activation seems to have a pivot role in the thrombotic process in Covid-19 as consistently evidenced by its involvement in promoting Tissue Factor up-regulation via leucocyte interaction. Until now, antiplatelet treatment has been scarcely considered for the treatment of Covid-19; interventional trials, however, are in progress to explore this issue. The aim of this review is 1) to compare the type of vascular diseases complicating CAP and Covid-19 2) to assess the different role of platelets in both diseases and 3) to discuss if antiplatelet treatment is potentially useful to improve clinical outcomes.
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http://dx.doi.org/10.1080/09537104.2021.1936478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204311PMC
June 2021

Low-Grade Endotoxemia and Thrombosis in COVID-19.

Clin Transl Gastroenterol 2021 06 4;12(6):e00348. Epub 2021 Jun 4.

Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Introduction: Patients with community-acquired pneumonia display enhanced levels of lipopolysaccharides (LPS) compared with controls, suggesting that low-grade endotoxemia may be implicated in vascular disturbances. It is unknown whether this occurs in patients with coronavirus 2019 (COVID-19) and its impact on thrombotic complications.

Methods: We measured serum levels of zonulin, a marker of gut permeability, LPS, and D-dimer in 81 patients with COVID-19 and 81 healthy subjects; the occurrence of thrombotic events in COVID-19 during the intrahospital stay was registered.

Results: Serum LPS and zonulin were higher in patients with COVID-19 than in control subjects and, in COVID-19, significantly correlated (R = 0.513; P < 0.001). Among the 81 patients with COVID-19, 11 (14%) experienced thrombotic events in the arterial (n = 5) and venous circulation (n = 6) during a median follow-up of 18 days (interquartile range 11-27 days). A logistic regression analysis showed that LPS (P = 0.024) and D-dimer (P = 0.041) independently predicted thrombotic events.

Discussion: The study reports that low-grade endotoxemia is detectable in patients with COVID-19 and is associated with thrombotic events. The coexistence of low-grade endotoxemia with enhanced levels of zonulin may suggest enhanced gut permeability as an underlying mechanism.
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http://dx.doi.org/10.14309/ctg.0000000000000348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183715PMC
June 2021

Corticosteroid use, myocardial injury and in-hospital cardiovascular events in patients with community-acquired pneumonia.

Br J Clin Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

Mediterranea Cardiocentro, Naples, Italy.

Background And Purpose: Corticosteroids are often prescribed to community-acquired pneumonia (CAP) patients, but the relationship with major cardiovascular events (MACEs) is unclear.

Experimental Approach: 541 CAP patients were recruited (334 males, mean age 71.9 ± 16.2 years). High-sensitivity troponin T (hs-cTnT) was measured at admission, during the hospital stay and at discharge. MACE occurrence was registered during a long-term follow-up.

Key Results: Overall, 318 patients (59%) showed hs-cTnT elevation >99th percentile (>0.014 μg/L). Age, heart failure and the increasing quintiles of hs-cTnT (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.82-2.58, P < .001) predicted MACEs. Among patients with hs-cTnT >0.014 μg/L at admission, 102 patients (31%) were on corticosteroids and showed lower hs-cTnT increase (P = .021), (NADPH) oxidase-2 (Nox2) activation (P = .005) and incidence of MACEs than untreated ones (HR 0.64, 95% CI 0.41-0.97, P = .038); no effect of corticosteroids on MACEs was observed in CAP patients with normal troponin. In vitro study showed that glucocorticoids have an antioxidant effect via downregulation of Nox2 activity.

Conclusion And Implications: The study provides evidence that corticosteroid use is associated with lower increase of hs-cTnT and incidence of MACEs in CAP patients.
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http://dx.doi.org/10.1111/bcp.14936DOI Listing
June 2021

Chocolate enriched by extra virgin olive oil improves endothelial function and oxidative stress in patients with diabetes.

Nutrition 2021 Apr 7;90:111270. Epub 2021 Apr 7.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; Mediterranea Cardiocentro, Napoli, Italy. Electronic address:

Objective: Endothelial dysfunction and oxidative stress are among the most relevant mechanisms underlying the atherosclerotic process in patients with type 2 diabetes mellitus (T2 DM). Extra virgin olive oil (EVOO) reduces postprandial glycemia with a mechanism counteracting oxidative stress-mediated incretin down-regulation in healthy subjects and in patients with impaired fasting glucose. The aim of this study was to evaluate if the intake of chocolate enriched by EVOO had positive effects on endothelial function and oxidative stress in patients with T2 DM.

Methods: In this study we enrolled and randomly assigned 25 consecutive patients with T2 DM to receive 40 g of EVOO-enriched chocolate or 40 g of control chocolate spread. Participants were assessed at baseline and 2 h after chocolate intake. Endothelial function was assessed by arterial brachial flow-mediated dilation (FMD); oxidative stress was evaluated by the measurement of serum nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (Nox2) levels, nitric oxide availability, and serum hydrogen peroxide breakdown activity (HBA).

Results: We observed a significant increase of FMD, nitric oxide (NO) availability, and HBA in the EVOO-enriched chocolate group (P < 0.001). Conversely, soluble Nox2-derived peptide (sNox2-dp) levels significantly decreased (P < 0.001). No significant change was observed in the control chocolate group. To assess the relation of EVOO-enriched chocolate to endothelial function and oxidative stress, a general linear model (GLM) analysis was performed; a significant difference for treatments was found with respect to FMD, NO availability, HBA, and sNox-dp.

Conclusions: Administration of 40 g of EVOO-enriched chocolate is associated with increased endothelial function and reduction of oxidative stress in patients with T2 DM. Future studies are needed to analyze the effect of chronic assumption of EVOO-enriched chocolate on vascular function, oxidative stress, and cardiovascular complications in patients with T2 DM.
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http://dx.doi.org/10.1016/j.nut.2021.111270DOI Listing
April 2021

Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study.

Molecules 2021 Mar 6;26(5). Epub 2021 Mar 6.

I Clinica Medica, Atherothrombosis Centre, Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy.

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones ( < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin.
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http://dx.doi.org/10.3390/molecules26051425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961992PMC
March 2021

Nox2 up-regulation and hypoalbuminemia in patients with type 2 diabetes mellitus.

Free Radic Biol Med 2021 05 26;168:1-5. Epub 2021 Mar 26.

Mediterranea Cardiocentro, Napoli, Italy; Department of Clinical, Internal, Anaesthesiologic, and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy. Electronic address:

Type 2 diabetes mellitus (T2DM) is associated with oxidative stress but the underlying mechanisms promoting oxidative stress as well as its relationship with cardiovascular events is still unclear. In 375 T2DM patients who were followed-up for approximately 5 years we measured the serum levels of soluble NOX2-derived peptide (sNOX2-dp), a marker of Nox2 activation, and albumin, a powerful antioxidant protein. In the entire cohort soluble Nox2 and serum albumin were significantly correlated (r = -0.348, P < 0.0001). During the follow-up 49 cardiovascular events (CVE) were registered, of which 45 were non-fatal myocardial infarction (MI); patients with non-fatal MI had significantly higher soluble NOX2/albumin ratio compared to cardiovascular events-free patients. Cox regression analysis showed a significant association between sNox2-dp/serum albumin ratio and the incidental risk of non-fatal MI (HR 1.106, CI95% 1.020-1.198, P = 0.014). The study suggests that redox status imbalance negatively influences vascular outcomes in T2DM.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.03.026DOI Listing
May 2021

Beneficial effects of a combination of natural product activators of autophagy on endothelial cells and platelets.

Br J Pharmacol 2021 05 24;178(10):2146-2159. Epub 2021 Apr 24.

Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy.

Background And Purpose: Oxidative stress and insufficient autophagy activity are associated with inflammatory processes and are common features of many cardiovascular diseases (CVDs). We investigated if a combination of natural activators of autophagy could modulate oxidative stress, platelet aggregation and endothelial cell survival and function in response to stress.

Experimental Approach: Ex vivo platelet aggregation and activation, H O production and autophagy were measured in platelets of subjects at high cardiovascular risk, including smokers, patients with metabolic syndrome (MetS) and patients with atrial fibrillation (AF). In vitro, the effects of a mixture of natural pro-autophagy molecules and antioxidants on platelets and human umbilical vein endothelial cells (HUVECs) were evaluated.

Key Result: Autophagy appeared to be inhibited, whereas aggregation was increased in platelets from AF and MetS patients and in smokers, as compared with healthy subjects. Treatment of platelets isolated from these patients with a mixture composed of trehalose, spermidine, catechin and epicatechin (Mix1) or with a mixture composed of trehalose, spermidine and nicotinamide (Mix2), significantly reduced platelet activation and oxidative stress, and increased autophagy, compared with the effect of each compound alone. Similarly, treatment of HUVECs with a combination of these compounds exhibited beneficial effects and increased endothelial cell survival, nitric oxide bioavailability and angiogenesis in response to stress in a potentiated manner.

Conclusion And Implications: A combination of natural activators of autophagy could inhibit platelet activity and oxidative stress and improve endothelial cell survival and function in a potentiated manner representing a useful strategy to reduce the effect of risk factors on CVD occurrence.

Linked Articles: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.
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http://dx.doi.org/10.1111/bph.15399DOI Listing
May 2021

The Role of Antioxidants Supplementation in Clinical Practice: Focus on Cardiovascular Risk Factors.

Antioxidants (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

Faculty of Medicine and Surgery, Sapienza University of Rome, 04100 Latina, Italy.

Oxidative stress may be defined as an imbalance between reactive oxygen species (ROS) and the antioxidant system to counteract or detoxify these potentially damaging molecules. This phenomenon is a common feature of many human disorders, such as cardiovascular disease. Many of the risk factors, including smoking, hypertension, hypercholesterolemia, diabetes, and obesity, are associated with an increased risk of developing cardiovascular disease, involving an elevated oxidative stress burden (either due to enhanced ROS production or decreased antioxidant protection). There are many therapeutic options to treat oxidative stress-associated cardiovascular diseases. Numerous studies have focused on the utility of antioxidant supplementation. However, whether antioxidant supplementation has any preventive and/or therapeutic value in cardiovascular pathology is still a matter of debate. In this review, we provide a detailed description of oxidative stress biomarkers in several cardiovascular risk factors. We also discuss the clinical implications of the supplementation with several classes of antioxidants, and their potential role for protecting against cardiovascular risk factors.
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http://dx.doi.org/10.3390/antiox10020146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909411PMC
January 2021

Lipopolysaccharide induces platelet activation in HIV patients: the role of different viral load patterns.

HIV Med 2021 Jul 10;22(6):434-444. Epub 2021 Jan 10.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

Objectives: This study aimed to assess whether gut-derived lipopolysaccharide (LPS) could affect platelet function in HIV-1 patients with residual viral load.

Methods: In 23 HIV-1 patients on effective antiretroviral treatment, 10 treatment-naïve HIV-1 subjects and 20 healthy subjects (HS), LPS, zonulin, markers of platelet activation and oxidative stress were evaluated. In vitro, platelets from HS were exposed to plasma from HIV-1-infected treated and untreated patients.

Results: Compared with HS, LPS was higher in treated and treatment-naïve subjects with HIV-1 (7.7 ± 2.9, 80.9 ± 13.7 and 75.3 ± 22.6 pg/mL, P < 0.001 vs. HS) as well as serum zonulin (1.3 ± 0.5, 6.1 ± 1.5 and 5.3 ± 1.7 ng/mL, P < 0.001 vs. HS). LPS and zonulin were correlated in HIV patients (Spearman correlation coefficient (rS) = 0.73, P < 0.0001). Levels of soluble CD40 ligand (sCD40L), soluble P-selectin (sP-selectin) and thromboxane B (TxB ) were higher in HIV-1-treated and treatment-naïve subjects compared with HS as well as NADPH oxidase 2 (NOX2) activation and hydrogen peroxide (H O ) production. In vitro, sCD40L, sP-selectin and TxB production, NOX2 activation and p47 phosphorylation were higher in platelets exposed to plasma from HIV-1 patients with different viral load compared with the exposure to plasma from HS. This effect was blunted in platelets pre-treated with TLR4 or TLR7 inhibitors.

Conclusions: Low-grade endotoxaemia and persistent viraemia increase platelet function with a mechanism mediated by NOX2 in patients with HIV-1 infection.
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http://dx.doi.org/10.1111/hiv.13059DOI Listing
July 2021

Nox2 activation in Covid-19.

Redox Biol 2020 09 25;36:101655. Epub 2020 Jul 25.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.

Nox2 is responsible for artery dysfunction via production of reactive oxidant species. RNA viruses may activate Nox2, but it is unknown if this occurs in coronavirus 2019(Covid-19). Nox2 activation by soluble Nox2-derived peptide(sNox2-dp) was measured in patients hospitalized for Covid-19 (n = 182) and controls (n = 91). sNox2-dp values were higher in Covid-19 patients versus controls and in severe versus non severe Covid-19. Patients with thrombotic events(n = 35,19%) had higher sNox2-dp than thrombotic event-free ones. A logistic regression analysis showed that sNox2 and coronary heart disease predicted thrombotic events. Oxidative stress by Nox2 activation is associated severe disease and thrombotic events in Covid-19 patients.
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http://dx.doi.org/10.1016/j.redox.2020.101655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381406PMC
September 2020

Poor Adherence to Mediterranean Diet and Serum Lipopolysaccharide are Associated with Oxidative Stress in Patients with Non-Alcoholic Fatty Liver Disease.

Nutrients 2020 Jun 10;12(6). Epub 2020 Jun 10.

I Clinica Medica, Department of Clinical Internal, Anestesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome 00185, Italy.

Oxidative stress plays a pivotal role in non-alcoholic fatty liver disease (NAFLD). Factors inducing oxidative stress in NAFLD may be several; however, a relationship with the adherence to Mediterranean Diet (Med-diet) and with serum lipopolysaccharide (LPS) has been poorly investigated in this setting. The aim was to investigate factors associated with impaired oxidative stress in NAFLD, focusing on the potential role of LPS and Med-diet. We enrolled 238 consecutive outpatients from the PLINIO study, in whom we measured the soluble Nox2-derived peptide (sNox2-dp), a marker of systemic oxidative stress, and serum LPS. Adherence to Med-diet was investigated by a nine-item validated dietary questionnaire. Serum sNox2-dp and LPS were higher in patients with NAFLD compared to those without (25.0 vs. 9.0 pg/mL, < 0.001 and 62.0 vs. 44.9 pg/mL, < 0.001, respectively). In patients with NAFLD, the highest sNox2-dp tertile was associated with the top serum LPS tertile (Odds Ratio (OR): 4.71; p < 0.001), APRI > 0.7 (OR: 6.96; p = 0.005) and Med-diet-score > 6 (OR: 0.14; p = 0.026). Analyzing individual foods, the daily consumption of wine (OR: 0.29, = 0.046) and the adequate weekly consumption of fish (OR: 0.32, = 0.030) inversely correlated with the top sNox2-dp tertile. In conclusion, patients with NAFLD showed impaired oxidative stress. Levels of sNox2 correlated with serum LPS and with low adherence to Med-Diet.
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http://dx.doi.org/10.3390/nu12061732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352324PMC
June 2020

Letter by Violi et al Regarding Article, "Rivaroxaban Reduces Arterial Thrombosis by Inhibition of Fxa-Driven Platelet Activation via Protease Activated Receptor-1".

Circ Res 2020 05 7;126(10):e114-e115. Epub 2020 May 7.

Department of General Surgery and Surgical Speciality Paride Stefanini (V.C.), Sapienza University of Rome, Italy.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.316895DOI Listing
May 2020

Is There an Association Between Atherosclerotic Burden, Oxidative Stress, and Gut-Derived Lipopolysaccharides?

Antioxid Redox Signal 2020 May 18. Epub 2020 May 18.

Division I Medical Clinic, Department of Clinical, Internistic, Anaesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Recent studies hypothesized a role of gut microbiota favoring atherosclerosis an increased oxidative stress, but data in peripheral artery disease (PAD) have not been provided yet. The aim of this study was to assess serum lipopolysaccharide (LPS) as well as oxidative stress in PAD patients and controls (CT). Furthermore, we wanted to analyze the relationship between LPS and the severity of atherosclerosis in the lower limb arteries. Eighty consecutive subjects, including 40 PAD patients and 40 CT were recruited. A cross-sectional study was performed to compare serum LPS, soluble Nox2-derived peptide (sNox2-dp), hydrogen peroxide (HO), HO breakdown activity (HBA) and ankle brachial index (ABI) in these two groups. Serum zonulin was used to assess gut permeability. Compared with CT, PAD patients had significant higher values of LPS, zonulin, sNox2-dp, and HO; conversely ABI and HBA were significantly lower in PAD patients. LPS serum levels were associated with atherosclerotic burden as depicted by the inverse correlation with ABI. LPS was also associated with oxidative stress as shown by its direct correlation with markers of oxidative stress such as sNox2-dp, serum HO, and HBA. Finally, we found a significant correlation between LPS and zonulin. A multiple linear regression analysis showed that LPS was significantly associated only with ABI. These findings suggest that LPS is elevated in PAD patients with a close association with the atherosclerotic burden and oxidative stress. The correlation between LPS and zonulin suggests that changes in gut permeability could be a potential trigger of LPS translocation in the peripheral circulation.
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http://dx.doi.org/10.1089/ars.2020.8109DOI Listing
May 2020

A novel role of MMP2 in regulating platelet NOX2 activation.

Free Radic Biol Med 2020 05 5;152:355-362. Epub 2020 Apr 5.

Mediterranea, Cardiocentro, 80122, Napoli, Italy; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100, Latina, Italy. Electronic address:

NOX2 has a key role for cellular production of reactive oxidant species (ROS) and although the mechanism of its activation is well known, little is known about its regulation. Metallo-proteinases (MMPs) regulate numerous protein activities both in physiological and pathological conditions but their interplay with NOX2 and ROS formation is still unclear. We performed experimental studies in human platelets and polymorphonuclear leukocytes (PMNs) to investigate the interplay of MMP2 with NOX2 activity. In collagen-stimulated platelets and in PMA-stimulated PMNs from healthy subjects, an immediate burst of ROS was detected at 10 min to then decline at 20 min. Coincidentally, sNOX2-dp, a split-off product of NOX2, increased and peaked at 10 min. ROS production was persistent whereas sNOX2dp is not released in cells treated with MMP2 inhibitor compared to other MMPs inhibitors. Western blot analysis showed the highest MMP2 expression on the cell membrane 10 min after stimulation. Moreover, the co-immunoprecipitation assay confirms the interaction between MMP2 and NOX2 that formed an active immuno-complex. Treating cells with NOX2ds-tat, an inhibitor of NADPH oxidase, significantly reduced ROS formation, sNOX2-dp, MMP2 expression and MMP2-NOX2-complex, which were all restored if cells were added with HO. The study provides the first evidence that MMP2 has a key role in blunting platelet NOX2 activity and eventually ROS formation.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.03.033DOI Listing
May 2020

PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation.

Antioxidants (Basel) 2020 Apr 2;9(4). Epub 2020 Apr 2.

Mediterranea Cardiocentro, 80122 Naples, Italy.

Background: High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) is predictive of cardiovascular events (CVEs) in atrial fibrillation (AF). We hypothesized that PCSK9 may directly induce platelet activation (PA).

Methods: We measured platelet aggregation, recruitment, Thromboxane B2 (TxB2) formation and soluble P-selectin levels as markers of PA and soluble Nox2-derived peptide (sNox2-dp), HO, isoprostanes and oxidized Low-Density-Lipoprotein (oxLDL) to analyze oxidative stress (OS) in 88 patients having PCSK9 values < ( = 44) or > ( = 44) 1.2 ng/mL, balanced for age, sex and cardiovascular risk factors. Furthermore, we investigated if normal ( = 5) platelets incubated with PCSK9 (1.0-2.0 ng/mL) alone or with LDL (50 µg/mL) displayed changes of PA, OS and down-stream signaling.

Results: PA and OS markers were significantly higher in patients with PCSK9 levels > 1.2 ng/mL compared to those with values < 1.2 ng/mL ( < 0.001). Levels of PCSK9 significantly correlated with markers of PA and OS. Platelets incubation with PCSK9 increased PA, OS and p38, p47 and Phospholipase A2 (PLA2) phosphorylation. These changes were amplified by adding LDL and blunted by CD36 or Nox2 inhibitors. Co-immunoprecipitation analysis revealed an immune complex of PCSK9 with CD36.

Conclusions: We provide the first evidence that PCSK9, at concentration found in the circulation of AF patients, directly interacts with platelets via CD36 receptor and activating Nox2: this effect is amplified in presence of LDL.
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http://dx.doi.org/10.3390/antiox9040296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222182PMC
April 2020

Profiling the Acute Effects of Modified Risk Products: Evidence from the SUR-VAPES (Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking) Cluster Study.

Curr Atheroscler Rep 2020 02 7;22(2). Epub 2020 Feb 7.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 74, 04100, Latina, Italy.

Purpose Of Review: Modified risk products (MRP) are promoted as a safer alternative to traditional combustion cigarettes (TCC) in chronic smokers. Evidence for their lower hazardous profile is building, despite several controversies. Yet, it is unclear whether individual responses to MRP differ among consumers. We hypothesized that different clusters of subjects exist in terms of acute effects of MRP.

Recent Findings: Pooling data from a total of 60 individuals, cluster analysis identified at least three clusters (labelled 1 to 3) of subjects with different electronic vaping cigarettes (EVC) effects and at least two clusters (labelled 4 to 5) of subjects with different heat-not-burn cigarettes (HNBC) effects. Specifically, oxidative stress, platelet aggregation, and endothelial dysfunction after EVC were significantly different cluster-wise (all p < 0.05), and oxidative stress and platelet aggregation after HNBC were significantly different (all p < 0.05). In particular, subjects belonging to Cluster 1 appeared to have less detrimental responses to EVC usage than subjects in Cluster 2 and 3, as shown by non-significant changes in flow-mediated dilation (FMD) and less marked increase in Nox2-derived peptide (NOX). Conversely, those assigned to Cluster 3 had the worst reaction in terms of changes in FMD, NOX, and P-selectin. Furthermore, individuals belonging to Cluster 4 responded unfavorably to both HNBC and EVC, whereas those in Cluster 5 interestingly showed less adverse results after using HNBC than EVC. Results for main analyses were consistent employing different clusters, tests, and bootstrap. Individual responses to MRP differ and smokers aiming at using EVC or HNBC as a risk reduction strategy should consider trying different MRP aiming at finding the one which is less detrimental, with subjects resembling those in Cluster 1 preferably using EVC and those resembling Cluster 5 preferably using HNBC.
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http://dx.doi.org/10.1007/s11883-020-0824-4DOI Listing
February 2020

Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD.

Hepatology 2020 08 22;72(2):470-485. Epub 2020 May 22.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

Background And Aims: Lipopolysaccharides (LPS) is increased in nonalcoholic fatty liver disease (NAFLD), but its relationship with liver inflammation is not defined.

Approach And Results: We studied Escherichia coli LPS in patients with biopsy-proven NAFLD, 25 simple steatosis (nonalcoholic fatty liver) and 25 nonalcoholic steatohepatitis (NASH), and in mice with diet-induced NASH. NASH patients had higher serum LPS and hepatocytes LPS localization than controls, which was correlated with serum zonulin and phosphorylated nuclear factor-κB expression. Toll-like receptor 4 positive (TLR4 ) macrophages were higher in NASH than simple steatosis or controls and correlated with serum LPS. NASH biopsies showed a higher CD61 platelets, and most of them were TLR4 . TLR4 platelets correlated with serum LPS values. In mice with NASH, LPS serum levels and LPS hepatocyte localization were increased compared with control mice and associated with nuclear factor-κB activation. Mice on aspirin developed lower fibrosis and extent compared with untreated ones. Treatment with TLR4 inhibitor resulted in lower liver inflammation in mice with NASH.

Conclusions: In NAFLD, Escherichia coli LPS may increase liver damage by inducing macrophage and platelet activation through the TLR4 pathway.
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http://dx.doi.org/10.1002/hep.31056DOI Listing
August 2020

Oleuropein-enriched chocolate by extra virgin olive oil blunts hyperglycaemia in diabetic patients: Results from a one-time 2-hour post-prandial cross over study.

Clin Nutr 2020 07 21;39(7):2187-2191. Epub 2019 Sep 21.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Mediterranea, Cardiocentro-Napoli, Italy. Electronic address:

Background & Aims: Oleuropein, a component of extra virgin olive oil (EVOO), reduces post-prandial glycemia with a mechanism counteracting oxidative stress-mediated incretin down-regulation. In this study we evaluated if the intake of an oleuropein-enriched chocolate could have positive effects on glycaemia and insulin levels in patients with type 2 diabetes mellitus (T2DM) and healthy subjects (HS).

Methods: Twenty-five consecutive T2DM patients and 20 HS were recruited. Participants were randomized to receive 40 g oleuropein-enriched chocolate by EVOO or 40 g control chocolate spread in a cross-over design. Serum glucose, insulin, glucagon-like peptide-1 (GLP1), and dipeptidyl-peptidase-4 (DPP4) were measured before and 2 h after chocolate intake.

Results: In T2DM, the pairwise comparisons showed that intake of oleuropein-enriched chocolate was associated with a significantly less increase of blood glucose compared to control; GLM analysis showed a significant difference for treatments with respect to glucose (p = 0.04), GLP1 (p < 0.001) and DPP-4 activity (p = 0.01). In HS, the pairwise comparisons showed that, after oleuropein-enriched chocolate intake, blood glucose concentration and DPP4 activity did not change; conversely a significant increase was observed for insulin and GLP1. After control chocolate intake, a significant increase for blood glucose, insulin levels and DPP4 activity were observed while GLP1 did not change.

Conclusion: The study shows that using EVOO as source of oleuropein administration of 40 g oleuropein-enriched chocolate is associated with a modest increase or no change of glycemia in T2DM and HS respectively, via an incretin-mediated mechanism.
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http://dx.doi.org/10.1016/j.clnu.2019.09.006DOI Listing
July 2020

Glutathione infusion before primary percutaneous coronary intervention: a randomised controlled pilot study.

BMJ Open 2019 08 8;9(8):e025884. Epub 2019 Aug 8.

Department of Heart and Great Vessels, Sapienza University of Rome, Rome, Italy.

Objective: In the setting of reperfused ST-elevation myocardial infarction (STEMI), increased production of reactive oxygen species (ROS) contributes to reperfusion injury. Among ROS, hydrogen peroxide (HO) showed toxic effects on human cardiomyocytes and may induce microcirculatory impairment. Glutathione (GSH) is a water-soluble tripeptide with a potent oxidant scavenging activity. We hypothesised that the infusion of GSH before acute reoxygenation might counteract the deleterious effects of increased HO generation on myocardium.

Methods: Fifty consecutive patients with STEMI, scheduled to undergo primary angioplasty, were randomly assigned, before intervention, to receive an infusion of GSH (2500 mg/25 mL over 10 min), followed by drug administration at the same doses at 24, 48 and 72 hours elapsing time or placebo. Peripheral blood samples were obtained before and at the end of the procedure, as well as after 5 days. HO production, 8-iso-prostaglandin F2α (PGF2α) formation, HO breakdown activity (HBA) and nitric oxide (NO) bioavailability were determined. Serum cardiactroponin T (cTpT) was measured at admission and up to 5 days.

Results: Following acute reperfusion, a significant reduction of HO production (p=0.0015) and 8-iso-PGF2α levels (p=0.0003), as well as a significant increase in HBA (p<0.0001)and NO bioavailability (p=0.035), was found in the GSH group as compared with placebo. In treated patients, attenuated production of HO persisted up to 5 days from the index procedure (p=0.009) and these changes was linked to those of the cTpT levels (r=0.41, p=0.023).

Conclusion: The prophylactic and prolonged infusion of GSH seems to determine a rapid onset and persistent blunting of HO generation improving myocardial cell survival. Nevertheless, a larger trial, adequately powered for evaluation of clinical endpoints, is ongoing to confirm the current finding.

Trial Registration Number: EUDRACT 2014-00448625; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-025884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701599PMC
August 2019

Interaction between serum endotoxemia and proprotein convertase subtilisin/kexin 9 (PCSK9) in patients with atrial fibrillation: A post-hoc analysis from the ATHERO-AF cohort.

Atherosclerosis 2019 10 4;289:195-200. Epub 2019 Jul 4.

I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy; Mediterranea Cardiocentro, Napoli, 80122, Italy. Electronic address:

Background And Aims: Lipopolysaccharides (LPS) is emerging as a novel risk factor for cardiovascular events (CVEs). Furthermore, in vitro evidence suggested that LPS may elicit proprotein convertase subtilisin/kexin 9 (PCSK9) expression, but their relationship in vivo has not been investigated.

Methods: We conducted a post-hoc analysis of a prospective, single centre cohort study of 907 patients with non-valvular atrial fibrillation (AF). At baseline, PCSK9, LPS and NADPH oxidase (sNox2-dp) were measured. PCSK9 and LPS were correlated with the incidence of CVEs.

Results: Median PCSK9 and LPS were 1200 [900-1970] and 49.9 [15.0-108.2] pg/ml, respectively. LPS and PCSK9 were significantly correlated (rS 0.378, p < 0.001). Logistic regression analysis showed that LPS was associated with PCSK9 above the median (odds ratio [OR] 1.727 95% confidence interval [CI] 1.147-2.600 p = 0.009). Other factors associated with PCSK9 above the median were sNox2-dp (OR 1.759 C.I. 95% 1.167-2.650, p = 0.007), use of antiplatelet drugs (OR 0.437 95%CI 0.219-0.871 p = 0.017) and high adherence to Mediterranean diet (OR 0.737 95%CI 0.643-0.845 p = 0.001). Olive oil (OR 0.376 95%CI 0.185-0.763, p = 0.001) and wine (OR 0.460 95%CI 0.289-0.733 p = 0.007) were negatively associated with PCSK9. Patients with concomitant high PCSK9 and LPS (LPS ≥88 pg/ml and PCSK9 ≥1570 pg/ml) had an increased risk of CVEs compared to those with low levels (LPS <24.3 pg/ml and PCSK9 <1000 pg/ml, Log-Rank test, p = 0.022).

Conclusions: This study demonstrated, for the first time in vivo, that circulating levels of PCSK9 and LPS are associated with a mechanism possibly involving NADPH oxidase activation. Patients with concomitant increase of PCSK9 and LPS showed a higher risk of CVEs.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.07.002DOI Listing
October 2019

Impairment between Oxidant and Antioxidant Systems: Short- and Long-term Implications for Athletes' Health.

Nutrients 2019 06 15;11(6). Epub 2019 Jun 15.

Faculty of Medicine and Surgery, Course E, Sapienza University of Rome, 04100 Latina (LT), Italy.

The role of oxidative stress, an imbalance between reactive oxygen species production (ROS) and antioxidants, has been described in several patho-physiological conditions, including cardiovascular, neurological diseases and cancer, thus impacting on individuals' lifelong health. Diet, environmental pollution, and physical activity can play a significant role in the oxidative balance of an organism. Even if physical training has proved to be able to counteract the negative effects caused by free radicals and to provide many health benefits, it is also known that intensive physical activity induces oxidative stress, inflammation, and free radical-mediated muscle damage. Indeed, variations in type, intensity, and duration of exercise training can activate different patterns of oxidant-antioxidant balance leading to different responses in terms of molecular and cellular damage. The aim of the present review is to discuss (1) the role of oxidative status in athletes in relation to exercise training practice, (2) the implications for muscle damage, (3) the long-term effect for neurodegenerative disease manifestations, (4) the role of antioxidant supplementations in preventing oxidative damages.
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http://dx.doi.org/10.3390/nu11061353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627820PMC
June 2019

Enhanced NOX-2 derived oxidative stress in offspring of patients with early myocardial infarction.

Int J Cardiol 2019 10 7;293:56-59. Epub 2019 May 7.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy; Cardiocentro Mediterranea, Napoli, Italy.

Background: Offspring of patients with early myocardial infarction have a higher risk to develop cardiovascular events; the underlying physiopathology is still unclear. Several lines of evidence support a role for oxidative stress in atherogenesis and NADPH oxidase-2 (NOX-2) is considered a major source of O2 in human. Furthermore, oxidative stress regulates arachidonic acid metabolism via activation of platelet phospholipase-A2. The aim of this study was to address NOX-2 activity as well as serum thromboxane B2 (TXB2) and 8-isoPGF2-alpha in offspring of patients with premature myocardial infarction.

Methods: Ninety-two consecutive subjects, including 46 offspring of patients with premature myocardial infarction and 46 healthy subjects (HS) matched for age and gender, were recruited. A cross sectional study was performed to compare serum activity of soluble NOX-2-dp (sNOX-2-dp), blood levels of isoprostanes and serum TXB2 in these two groups.

Results: Compared with HS, offspring of patients with early myocardial infarction had higher values of serum TxB2, isoprostanes and sNOX-2-dp. Bivariate analysis in the overall population showed that serum sNOX-2-dp levels were significantly associated with serum isoprostanes and TXB2. A multiple linear regression analysis was performed to define the independent predictors of sNOX-2-dp. Serum isoprostanes (SE: 0.07; standardized coefficient β: 0.579; P < 0.001) and TXB2 levels (SE: 0.06; standardized coefficient β: 0.211; P < 0.001) were significantly associated to sNOX-2-dp (R2: 0.42).

Conclusion: This study shows that Nox-2 activation is a key determinant of oxidative stress and platelet activation in offspring of patients with premature myocardial infarction.
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http://dx.doi.org/10.1016/j.ijcard.2019.05.014DOI Listing
October 2019

Prasugrel and Ticagrelor: the Romulus and Remus of Antiplatelet Therapy?

Am J Cardiovasc Drugs 2019 08;19(4):377-379

Unità Operativa di Interventistica Cardiovascolare, Presidio Ospedaliero Pineta Grande, Castel Volturno, Italy.

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http://dx.doi.org/10.1007/s40256-019-00340-wDOI Listing
August 2019

Acute Effects of Heat-Not-Burn, Electronic Vaping, and Traditional Tobacco Combustion Cigarettes: The Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking ( SUR - VAPES ) 2 Randomized Trial.

J Am Heart Assoc 2019 03;8(6):e010455

2 IRCCS NEUROMED Pozzilli Italy.

Background Little clinical research on new-generation heat-not-burn cigarettes ( HNBC ) in comparison with electronic vaping cigarettes ( EVC ) and traditional tobacco combustion cigarettes ( TC ) has been reported. We aimed to appraise the acute effects of single use of HNBC , EVC, and TC in healthy smokers. Methods and Results This was an independent, cross-over, randomized trial in 20 TC smokers, with allocation to different cycles of HNBC , EVC , and TC . All participants used all types of products, with an intercycle washout of 1 week. End points were oxidative stress, antioxidant reserve, platelet activation, flow-mediated dilation, blood pressure, and satisfaction scores. Single use of any product led to an adverse impact on oxidative stress, antioxidant reserve, platelet function, flow-mediated dilation, and blood pressure. HNBC had less impact than EVC and TC on soluble Nox2-derived peptide (respectively, P=0.004 and 0.001), 8-iso-prostaglandin F2α- III ( P=0.004 and <0.001), and vitamin E ( P=0.018 and 0.044). HNBC and EVC were equally less impactful than TCs on flow-mediated dilation ( P=0.872 for HNBC versus EVC ), HO ( P=0.522), HO breakdown activity ( P=0.091), soluble CD 40 ligand ( P=0.849), and soluble P-selectin ( P=0.821). The effect of HNBC and, to a lesser extent EVC , on blood pressure was less evident than that of TC , whereas HNBC appeared more satisfying than EVC (all P<0.05). Conclusions Acute effects of HNBC , EVC, and TC are different on several oxidative stress, antioxidant reserve, platelet function, cardiovascular, and satisfaction dimensions, with TCs showing the most detrimental changes in clinically relevant features. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 03301129.
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http://dx.doi.org/10.1161/JAHA.118.010455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475061PMC
March 2019

Nox2-mediated platelet activation by glycoprotein (GP) VI: Effect of rivaroxaban alone and in combination with aspirin.

Biochem Pharmacol 2019 05 13;163:111-118. Epub 2019 Feb 13.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Mediterranea, Cardiocentro-Napoli, Italy. Electronic address:

Factor Xa (FXa) has been reported to activate platelet via interaction with glycoprotein (GP) VI but the underlying mechanism has not been fully elucidated. We investigated if Nox2-derived oxidative stress is implicated in FXa-induced platelet aggregation (PA), and the effect of a FXa inhibitor, namely rivaroxaban, with or without aspirin (ASA), on PA. We performed an in vitro study measuring convulxin-induced PA, thromboxane (Tx) B and isoprostanes biosynthesis, soluble Nox2-dp (sNox2-dp), a marker of Nox2 activation, soluble GPVI (sGPVI) and PLA activation in platelets from healthy subjects (n = 5) added with and without a Nox2 inhibitor. The same variables were also examined in platelets treated with rivaroxaban (15-60 ng/ml), combined or less with ASA (25 µM). Convulxin-stimulated platelets increased sGPVI, sNox2-dp, HO, eicosanoid biosynthesis and PLA phosphorylation, which were all inhibited by a Nox2 inhibitor. Rivaroxaban alone significantly reduced PA, sGPVI, TxB and isoprostanes biosynthesis, concomitantly with Syk, sNox2-dp and PLA activation in a dose-dependent fashion; a significant effect was achieved with 30 ng/ml rivaroxaban. Docking simulation analysis showed that rivaroxaban interacts with GPVI. In platelets co-incubated with ASA, rivaroxaban amplified the ASA antiplatelet effect, which was achieved with 30 ng/ml and prevalently attributable to Nox2 inhibition and impaired isoprostane biosynthesis. Here we show that rivaroxaban, at concentrations achievable in human circulation, inhibits PA via GPVI interaction and eventually Nox2-mediated isoprostanes biosynthesis and amplifies the ASA antiplatelet effect.
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http://dx.doi.org/10.1016/j.bcp.2019.02.016DOI Listing
May 2019

Digoxin and Platelet Activation in Patients With Atrial Fibrillation: In Vivo and In Vitro Study.

J Am Heart Assoc 2018 11;7(22):e009509

1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy.

Background Digoxin use was shown to be associated with an increased risk of cardiovascular events in atrial fibrillation ( AF ). We hypothesized that digoxin may affect cardiovascular risk by increasing platelet activation. Methods and Results Post hoc analysis of a prospective study of anticoagulated patients with AF . Patients were divided into 2 groups balanced for age, sex, and cardiovascular risk factors: digoxin users (n=132) and nonusers (n=388). Urinary excretion of 11-dehydro-thromboxane B (TxB), a marker of platelet activation, and serum digoxin concentration ( SDC ) were measured. In vitro experiments were performed on platelets from healthy subjects and AF patients, which were incubated with scalar doses of digoxin (0.6-2.4 ng/mL) with or without prestimulation with a sub-threshold of collagen. Median 11-dehydro-TxB was 105.0 ( interquartile range, 60.0-190.0) ng/mg creatinine, and median SDC was 0.65 ( interquartile range, 0.40-1.00) ng/mL. Urinary 11-dehydro-TxB and SDC were correlated ( r=0.350, P<0.001). Patients in the upper tertile of SDC showed higher 11-dehydro-TxB compared with non-digoxin users ( P=0.019). In vitro study showed an increased basal platelet activation in patients with AF compared with healthy subjects . Digoxin (2.4 ng/mL) induced calcium mobilization, PAC -1 (procaspase-activating compound 1) and platelet aggregation in AF patients but not in healthy subjects . After pretreatment with a sub-threshold of collagen, digoxin dose-dependent induced calcium mobilization, arachidonic acid release, TxB biosynthesis, PAC -1 and soluble platelet selectin expression, and platelet aggregation, which were inhibited by antibody against digoxin. Conclusions We found a significant in vivo correlation between SDC and platelet activation. Supratherapeutic SDC increased in vitro platelet aggregation via calcium-related phospholipase A phosphorylation. Our findings may have clinical implications for AF patients treated with digoxin.
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http://dx.doi.org/10.1161/JAHA.118.009509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404445PMC
November 2018
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