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Aim To evaluate the clinical relevance of antiphospholipid antibodies (aPL) in patients with lower extremity peripheral artery disease (PAD). Data sources EMBASE and MEDLINE databases were searched from inception to March 2020 for clinical studies reporting on the association between of aPL [IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA)] and PAD. Methods We determined the pooled prevalence (PP) of patients positive for aPL in PAD or the PP of PAD in patients positive for aPL; we employed Peto's odds ratio with random effect for the meta-analysis. Results Twenty-one studies comprising 6,057 patients were evaluated: in patients with PAD, the PP of IgG aCL was 12% vs 4.1% in those without, IgM aCL was 13.2% vs 2.1%, and LA 13.3% vs 3.3%, respectively. The PP of patients with LA was greater in critical limb ischemia than in the control group (19.3% vs 4.2%). Also, the PP of patients with LA was greater in the failed than in the successful revascularisation group (35.8% vs 15.8%). The PP of post-procedural revascularisation failures was similar in the groups given or not given oral anticoagulation (59.2% vs 61.9%). Conclusion All the aPL related to PAD regardless of diagnostic definition used, whereas LA related also to critical limb ischaemia and failed revascularisation. Data expressed as percentage of participants positive for aPL limit the interpretation of these relationships.

Background The prevalence of heart failure with preserved ejection fraction (HFpEF) in patients with antiphospholipid syndrome (APS) is unknown. Methods Prospective multicenter cohort study including 125 patients: 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 (Figure). 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, p=0.035), anti β-2-glycoprotein-I IgG >40 GPL (OR 5.28, 1.53–18.27, p=0.009), lupus anticoagulants DRVVT >1.25 (OR 5.20, 95% CI 1.10–24.68, p=0.038), (OR 3.56, 95% CI 1.11–11.47, p=0.033) and triple positivity (OR 3.56, 95% CI 1.11–11.47, p=0.033) were associated with HFpEF after adjustment for age and sex. Discussion HFpEF has a clinically relevant prevalence in patients with APS. The role of antiphospholipid antibodies in the pathogenesis and prognosis of HFpEF needs to be investigated. Funding Acknowledgement Type of funding sources: None.

Objectives: COVID-19 may show no peculiar signs and symptoms that may differentiate it from other infective or non-infective etiologies, thus, early recognition and prompt management are crucial to improve survival. The aim of this study was to describe clinical, laboratory, and radiological characteristics and outcomes of hospitalized COVID-19 patients compared to those with other infective or non-infective etiologies. Methods: We performed a prospective study from March 2020 to February 2021. All patients hospitalized for suspected or confirmed COVID-19 were prospectively recruited. All patients were evaluated according to a predefined protocol for diagnosis of suspected SARS-CoV-2 infection. The primary endpoint was evaluation of clinical, laboratory, and radiological characteristics associated or not with COVID-19 etiology at time of hospitalization in an emergency department. Results: A total of 1036 patients were included in the study: 717 (69%) patients with confirmed COVID-19 and 319 (31%) without COVID-19, hospitalized for other causes. The main causes of hospitalization among non-COVID-19 patients were acute heart failure (44%) and bacterial pneumonia (45.8%). Overall, 30-day mortality was 9% among the COVID-19 group and 35% in the non-COVID-19 group. Multivariate analysis showed variables (fever &gt, 3 days, dry cough, acute dyspnea, lymphocytes &lt, 1000 × 103/µL, and ferritin &gt, 250 ng/mL) independently associated with COVID-19 etiology. A decision tree was elaborated to early detect COVID-19 patients in the emergency department. Finally, Kaplan–Meier curves on 30-day survival in COVID-19 patients during the first wave (March–May 2020, n = 289 patients) and the second wave (October–February 2021, n = 428 patients) showed differences between the two study periods (p = 0.021). Conclusions: Patients with confirmed diagnosis of COVID-19 may show peculiar characteristics at time of hospitalization that could help physicians to distinguish from other infective or non-infective etiologies. Finally, a different 30-day mortality rate was observed during different periods of the pandemic.

Mastocytosis is a rare disease characterized by clonal proliferation of mast cells (MCs) in different organs. Clinical manifestations of mastocytosis are mostly due to release of mediators from MCs and, in many cases, such as urticaria, flushing, angioedema, and anaphylaxis, are an expression of the biological effects of mediators on endothelial cells. Chronic secretion of mediators in patients with mastocytosis can lead to alteration of endothelial function.We sought to investigate endothelial function in patients with mastocytosis using a noninvasive technique of flow-mediated dilation (FMD).Twenty-five adult patients with indolent and advanced forms of mastocytosis and 20 healthy control subjects were enrolled in the study. Ultrasound assessment of FMD was performed by measuring changes in the diameter of the brachial artery after 5 minutes of arterial occlusion. Changes in FMD were correlated with clinical parameters and serum tryptase levels.Patients with mastocytosis had lower FMD compared with healthy control subjects (P .001). Advanced and smoldering forms showed a lower FMD compared with indolent forms (P .001). FMD inversely correlated with age and serum tryptase levels and directly with median arterial pressure and recurrent flushing episodes. No correlation was found between FMD and osteoporosis, recurrent anaphylaxis, presence of skin lesions, and long-term antihistamine treatment.Endothelial dysfunction, as demonstrated by FMD reduction, is detectable in patients with mastocytosis and is more severe in patients with high tryptase levels and advanced disease. Endothelial function appears to be negatively influenced by MC proliferation rather than by the severity of mediator-related symptoms.

Background Patients with non valvular atrial fibrillation (AF) and cancer represent a high-risk subgroup of patients in whom the management of oral anticoagulation may be challenging. The relationship between cancer type and the risk of cardiovascular events (CVEs) in patients with AF is unclear. Purpose To investigate the incidence of CVEs in patients with AF and cancer according to cancer type. Methods Prospective cohort study including 2,092 consecutive AF patients on vitamin K antagonists. Principal endpoint was the occurrence of CVEs including fatal/non-fatal myocardial infarction and ischemic stroke and cardiovascular death. We also performed a subgroup analysis of cardiac and thromboembolic events separately. Patients with cancer were divided in subgroups based on cancer site as follows: group 1 gastrointestinal tract; group 2 respiratory tract; group 3 genitourinary tract; group 4 other sites. Results Mean age was 73.7±9.1 years and 42.1% were woman; 367 (17.5%) had cancer, of these 21% gastro-intestinal, 10% respiratory, 28% genito-urinary and 41% had other localization. Patients with cancer were older than those without but with similar clinical characteristics. During a mean follow up of 35.9±28.0 months (6264.5 patient-years), 203 CVEs occurred (3.24%/year, 95% CI 2.81–3.72) of whom 86 were cardiac ischemia (1.37%/year, 95% CI 1.10–1.69), 70 thromboembolic events (1.12%/year, 95% CI 0.87–1.41) and 47 cardiovascular deaths (0.75%/year, 95% CI 0.55–0.99). The incidence of CVEs for AF patients with and without cancer was respectively (n=45, 3.78%, 95% CI 2.76–5.06) and (n=158, 3.11%/year, 95% CI 2.65–3.64). In particular, compared to patients without cancer, a higher incidence rate of CVEs was found in patients with gastrointestinal tract cancer (5.61%/year, 95% CI 2.90–9.79, p=0.046), and in patients with respiratory tract cancer (6.15%/year, 95% CI 2.66–12.1, p=0.055), while no difference was found in patients with genito-urinary tract cancer (2.24%/year, 95% CI 0.97–4.41, p=0.362) and other site cancer (3.11%/year, 95% CI 2.65–3.64, p=0.512). Cox regression multivariate analysis showed that factors associated with cardiac events were COPD, dyslipidemia, TTR Conclusions Our findings suggest an association between cancer type and specific ischemic complications in AF patients. In particular, we found a higher risk of cardiac complications in patients with gastrointestinal cancer and of thromboembolic events in patients with respiratory cancer. These associations need to be confirmed in larger studies. Funding Acknowledgement Type of funding source: None

Background: To investigate the association between family history of atrial fibrillation (AF) with cardiovascular events (CVEs), major adverse cardiac events (MACE), and cardiovascular mortality. Methods: Multicenter prospective observational cohort study including 1722 nonvalvular AF patients from February 2008 to August 2019 in Italy. Family history of AF was defined as the presence of AF in a first-degree relative: mother, father, sibling, or children. Primary outcome was a composite of CVEs including fatal/nonfatal ischemic stroke and myocardial infarction, and cardiovascular death. Second, we analyzed the association with major adverse cardiac event. Results: Mean age was 74.6±9.4 years; 44% of women. Family history of AF was detected in 368 (21.4%) patients, and 3.5% had ≥2 relatives affected by AF. Age of AF onset progressively decreased from patients without family history of AF, compared with those with single and multiple first-degree affected relatives ( P P =0.039), major adverse cardiac event (hazard ratio, 1.917 [95% CI, 1.207–3.045], P =0.006), and cardiovascular mortality (hazard ratio, 2.008 [95% CI, 1.047–3.851], P =0.036). Subgroup analysis showed that this association was modified by age, sex, and prior ischemic heart disease. Conclusions: In a cohort of elderly patients with a high atherosclerotic burden, family history of AF is evident in >20% of patients and was associated with an increased risk for CVEs and mortality. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01882114.

INTRODUCTION The relationship between autoimmune hemolytic anemia and antiphospholipid antibodies (aPL) and/or antiphospholipid syndrome has never been systematically addressed. METHODS Systematic review of EMBASE and PubMed databases performed according to PRISMA guidelines from inception to March 2020; meta-analysis performed by Peto's odds ratio for rare events. FINDINGS Forty-five studies with different outcomes met the inclusion/exclusion criteria. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) positivity was greater in end-stage renal disease (ESRD) than controls (20.2% vs. 2.6%, P = 0.001, I2 >80%; I2 = heterogeneity), particularly in hemodialysis patients (18.3% vs. 8%, I2 = 0%). The PP of lupus anticoagulant was greater in ESRD than controls (8.7% vs. 0.2%, P

Severe anaphylaxis is a generalized reaction in which cardiovascular and respiratory involvement lead to a fatal or near-fatal outcome. Triggers of severe anaphylaxis differ from one age group to another and are mostly represented by drugs and hymenoptera stings in adults and food in children. Several risk factors and cofactors can increase the odds of severe anaphylaxis by different and still undefined mechanisms. Major risk factors for severe anaphylaxis include old age, male sex, and preexisting medical conditions such as mast cell disorders, cardiovascular diseases, and uncontrolled asthma. Antihypertensive drugs appear to increase the severity of anaphylaxis probably by impairing compensatory mechanism to support blood pressure during the reaction. Severe reactions are also associated with transient cofactors such as exercise following specific allergen exposure, treatment with nonsteroidal anti-inflammatory drugs, and alcohol consumption. Identification of risk factors and potential concurrent cofactors for each individual patient is mandatory to prevent severe anaphylaxis. Risk stratification is crucial to develop personalized prevention strategies and action plans to avoid potentially life-threatening reactions.

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 &gt, 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 &gt, 40 GPL (odds ratio (OR) 3.43, 95% confidence interval (CI) 1.09–10.77, p = 0.035), anti β-2-glycoprotein-I IgG &gt, 40 GPL (OR 5.28, 1.53–18.27, p = 0.009), lupus anticoagulants DRVVT &gt, 1.25 (OR 5.20, 95% CI 1.10–24.68, p = 0.038), and triple positivity (OR 3.56, 95% CI 1.11–11.47, p = 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, p = 0.008), age (OR 1.07, 95% CI 1.00–1.14, p = 0.044), and aβ2GPI IgG &gt, 40 GPL (OR 8.62, 95% CI 1.23–60.44, p = 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.

Community-acquired pneumonia (CAP) is complicated by cardiovascular events as myocardial infarction and stroke but the underlying mechanism is still unclear. We hypothesized that endothelial dysfunction may be implicated and that endotoxemia may have a role.Fifty patients with CAP and 50 controls were enrolled. At admission and at discharge, flow-mediated dilation (FMD), serum levels of endotoxins and oxidative stress, as assessed by serum levels of nitrite/nitrate (NOx) and isoprostanes, were studied.At admission, a significant difference between patients with CAP and controls was observed for FMD (2.1±0.3 vs 4.0±0.3%, p0.001), serum endotoxins (157.8±7.6 vs 33.1±4.8pg/ml), serum isoprostanes (341±14 vs 286±10 pM, p=0.009) and NOx (24.3±1.1 vs 29.7±2.2μM). Simple linear correlation analysis showed that serum endotoxins significantly correlated with Pneumonia Severity Index score (Rs=0.386, p=0.006). Compared to baseline, at discharge CAP patients showed a significant increase of FMD and NOx (from 2.1±0.3 to 4.6±0.4%, p0.001 and from 24.3±1.1 to 31.1±1.5μM, p0.001, respectively) and a significant decrease of serum endotoxins and isoprostanes (from 157.8±7.6 to 55.5±2.3pg/ml, p0.001, and from 341±14 to 312±14 pM, p0.001, respectively). Conversely, no changes for FMD, NOx, serum endotoxins and isoprostanes were observed in controls between baseline and discharge. Changes of FMD significantly correlated with changes of serum endotoxins (Rs=-0.315; p=0.001).The study provides the first evidence that CAP is characterized by impaired FMD with a mechanism potentially involving endotoxin production and oxidative stress.

Antiphospholipid antibodies (aPL) are well-known risk factors for venous and arterial thrombosis, but their association with cognitive dysfunction has not been widely investigated in the general population and in patients with primary and secondary antiphospholipid syndrome (APS). We performed a systematic review searching MEDLINE via PubMed and Cochrane (CENTRAL) databases for observational studies reporting on the association between aPL and dementia in the general population, in subjects carrying aPL, in patients with cognitive disorder/dementia, and in primary and secondary APS. Prevalence of anticardiolipin (aCL) IgG ranged from 5.9% to 31.1% in the general population, with aCL titers being more elevated in subjects with functional decline of cognitive functions or with neurological alterations as detected by imaging. The prevalence of aPL ranged from 6.0 to 56.6% in patients with vascular dementia. Regarding patients with primary and secondary APS, a severe cognitive deficit has been described in up to 60% of patients, 33.3% of systemic lupus erythematosus (SLE)-APS and 22.2% of SLE patients without aPL. Five studies included patients with primary APS with divergent results, while 18 studies investigated the association between aPL and cognitive impairment in patients with SLE. Of these, 14 reported a positive association between aPL, mostly aCL and LAC, and cognitive impairment while little evidence on anti β2-Glycoprotein I exists. Mechanisms leading to cognitive dysfunction are not well characterized and may include vascular aPL-induced micro and macro-thrombosis and immune-mediated neuronal toxicity pathways in the cerebral district.

Anticardiolipin antibodies of the immunoglobulin G isotype (IgG aCL) have been suggested as risk factor for arterial and venous thrombosis. No conclusive data in patients with coronary artery disease (CAD) do exist. We investigate the risk of recurrent CAD according to the presence of IgG aCL.We performed a systematic review and meta-analysis to evaluate the risk of recurrent major adverse cardiac events (MACE) associated with the presence of IgG aCL in patients with CAD. MEDLINE and Cochrane databases were searched. We conducted a meta-analysis of the relative risk (RR) both at 12 and 24 months.We included 11 eligible studies with a total of 2425 patients, 283 IgG aCL+ and 2142 IgG aCL-. The prevalence of IgG aCL+ ranged from 6.1% to 43.3%. A total of 341 cardiac events were reported: 71 (25.1%) in IgG aCL+ and 270 (12.6%) in IgG aCL- patients. We found an increased risk of recurrent MACE in patients with high IgG aCL both at 12 (RR 2.17, 2.5-97.5%CI, 1.54-3.00) and 24 months (RR 2.11, 2.5-97.5%CI, 1.62-2.66). This association was even stronger in patients with juvenile CAD (i.e.50 years) at both 12 (RR 3.21, 2.5-97.5%CI, 1.74-5.41) and 24 months (RR 3.24, 2.5-97.5%CI, 1.84-5.21).Patients with CAD and elevated IgG aCL have a doubled risk of recurrent MACE at 12 and 24 months. The presence of aCL should be suspected in patients with recurrent CAD events or in patients with juvenile CAD.

The relationship between antiphospholipid antibodies (aPL) and autoimmune haemolytic anaemia (AIHA) has never been systematically addressed. The aim of this study is to assess the link between aPL and AIHA in adult systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). This study performed an EMBASE/PubMed search from inception to June 2019 and meta-analysis using Peto’s odds ratios. The pooled prevalence (PP) of IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA) was greater in AIHA +ve than AIHA –ve patients (34.7% vs. 27.6%, p = 0.03; 33.3% vs. 21.8%, p < 0.0001; 20.9% vs. 8.3%, p = 0.01). The PP of AIHA was greater in: (1) IgG and IgM aCL +ve than -ve patients (21.8% vs. 11.1%, p = 0.001 and 18.7% vs. 6.3%, p < 0.0001), (2) in SLE related APS than in primary APS patients (22.8% vs. 3.9% p < 0.0001), (3) in APS +ve than APS -ve SLE patients (23.2% vs. 8.4%, p = 0.01), and (4) in thrombotic APS than non-thrombotic APS/SLE patients (26.8% vs. 10%, p = 0.03). The PP of IgG/IgM aCL and LA was greater in DAT +ve than DAT -ve patients (42.4% vs. 12.8%, p < 0.0001; 26.2% vs. 12.8%, p = 0.03 and 29.2% vs. 15.7%, p = 0.004 respectively). It was found that AIHA prevalence is maximal in SLE with aPL/APS, low-moderate in SLE without aPL and minimal in PAPS. Moreover, AIHA is rightly included among the classification criteria for SLE but not for APS/aPL. The significance of an isolated DAT positivity remains unclear in this setting

To evaluate the effect of antiphospholipid antibodies (aPL) on renal allograft outcome after kidney transplantation.A systematic search of EMBASE and PubMed databases from inception to July 2018 was run according to PRISMA guidelines; Peto's odds ratio (OR) for rare events was used for the meta-analysis.Our inclusion/exclusion criteria were met by 22 cohort studies having different outcomes: allograft thrombosis (n = 9) and thromboprophylaxis (n = 3), allograft loss from any cause (n = 9), allograft malfunction (n = 3), duration (n = 2), glomerular filtration rate at 1 year (n = 3) and allograft rejection (n = 5). The pooled prevalence of allograft thrombosis and of thrombotic microangiopathy was greater in aPL+ve than negative recipients (10.4% vs 1.7%, p 0.0001 and 10.2% vs 0%, p = 0.005, respectively). The pooled prevalence of allograft thrombosis was 75% in patients not taking anticoagulation whereas none of the anticoagulated recipients developed thrombosis (p 0.0001). The pooled prevalence of allograft loss was greater in aPL+ve recipients (28% vs 18% respectively, p 0.0001); the pooled prevalence of aPL was greater in allograft loss recipients compared to those who did not lose it (51% vs 33%, p 0.0001). The pooled prevalence of allograft malfunction and rejection was similar in aPL-ve and aPL+ve recipients (32.2% vs 40.3% and 14.9% vs 14.4%, respectively) but graft duration was shorter in aPL+ve than aPL-ve recipients (p = 0.001) and glomerular filtration rate at 1 year was lower in aPL + ve than aPL-ve recipients (p 0.0001).APL relate strongly to allograft thrombosis, loss and duration but not to allograft malfunction and rejection. Oral antivitamin K anticoagulants effectively prevent allograft thrombosis in aPL recipients. The debate on the role of aPL in renal transplant is limited by the expression of data as percentage of recipients positive for aPL rather than aPL titres in many studies.

To further the knowledge of oxidative stress in systemic sclerosis (SSc), we performed a systematic review and meta-analysis on studies measuring isoprostane, a vasoactive agent deriving from arachidonic acid and implicated in the vasculopathy of SSc.Systematic search following the PRISMA guidelines in PubMed and EMBASE between January-1990/December-2017 using the terms: oxidative stress, isoprostane, systemic sclerosis and scleroderma.After the screening process, 8 studies including 240 SSc patients and 192 controls were included in the systematic review and meta-analysis, 6 investigating urinary and 2 serum isoprostane: random effect meta-analysis revealed isoprostane overgeneration in SSc (p .001) with wide heterogeneity (IThere is some evidence for isoprostane overgeneration in SSc that confirms the occurrence of oxidative stress in this setting: further prospective studies with specified outcomes are needed to evaluate the prognostic value of this functional biomarker.

Background NAFLD is associated to Insulin Resistance (IR). IR is responsible for Endothelial Dysfunction (ED) through the impairment of eNOS function. Although eNOS derangement has been demonstrated in experimental models, no studies have directly shown that eNOS dysfunction is associated with NAFLD in humans. The aim of this study is to investigate eNOS function in NAFLD patients. Methods Fifty-four NAFLD patients were consecutively enrolled. All patients underwent clinical and laboratory evaluation and liver biopsy. Patients were divided into two groups by the presence of NAFL or NASH. We measured vascular reactivity induced by patients’ platelets on isolated mice aorta rings. Immunoblot assays for platelet-derived phosphorylated-eNOS (p-eNOS) and immunohistochemistry for hepatic p-eNOS have been performed to evaluate eNOS function in platelets and liver specimens. Flow-mediated-dilation (FMD) was also performed. Data were compared with healthy controls. Results Twenty-one (38, 8%) patients had NAFL and 33 (61, 7%) NASH. No differences were found between groups and controls except for HOMA and insulin (p

Platelet activation plays a major role in cardiovascular events (CVEs). Mediterranean diet (Med-Diet) reduces the incidence of stroke and myocardial infarction but it is still unclear if it affects platelet activation. Aim of the study was to evaluate the effect of Med-Diet on the urinary excretion of 11-dehydro-thromboxane (Tx) B2, a marker of in vivo platelet activation, in patients with atrial fibrillation (AF).Prospective observational cohort study including 801 non-valvular AF patients on chronic treatment with warfarin/acenocumarol referring to I Medical Clinic - Atherothrombosis Center of Sapienza University of Rome, Italy, from February 2008 to December 2013. Adherence to Med-Diet was evaluated by a short nine-items dietary questionnaire. Urinary excretion of 11-dehydro-TxB2 was measured in all patients.Mean follow-up was 33.9 (±19.8) months, yielding 2223 patient/year of observation. Mean age of patients was 73.3 (±8.9) years, 43.7% were female. Median value of urinary TxB2 was 105.5 [60.0-190.0] ng/mg creatinine. We found a significant inverse correlation between total Med-Diet score and 11-dehydro-TxB2 values (Rs: -0.356, p0.001). In a multivariable stepwise linear regression analysis, history of stroke/TIA (β = 0.146, p = 0.003), olive oil (β = -0.130, p = 0.007), wine (β = -0.102, p = 0.036) and antiplatelet drugs (β = -0.098, p = 0.045) were independently associated to 11-dehydro-TxB2. We found no differences in the rate of ischemic or bleeding events across tertiles of Med-Diet score during follow-up.Med-Diet adherence is inversely associated to urinary excretion of 11-dehydro-TxB2, suggesting that Med-Diet may favorably affect platelet function in AF patients. Clinical Trial Registration: ClinicalTrials.gov NCT01882114.

BACKGROUND Recent findings suggest that patients with atrial fibrillation (AF), in addition being at thromboembolic risk, are at risk of myocardial infarction (MI). Our aim was to investigate predictors of MI and cardiovascular death in a cohort of patients with AF who were taking anticoagulants. METHODS We prospectively followed up 1,019 patients with AF for a median of 33.7 months (3,223 person-years). All patients were treated with oral vitamin K antagonists. Primary outcome was a composite end point of cardiovascular events (CVEs) including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death. RESULTS The mean age of the patients was 73.2 years, and 43.8' were women. At follow-up, 111 CVEs (3.43'/y) had occurred: 47 fatal-nonfatal MI/revascularization and 64 cardiovascular deaths. In addition, 31 stroke/transient ischemic attacks (0.96'/y) were recorded. Patients experiencing CVEs were older ( P P = .005), heart failure ( P = .001), and prior cardiac ( P P P P = .011), history of cerebrovascular (HR, 1.704; 95' CI, 1.119-2.597; P = .013) and cardiac (HR, 1.658; 95' CI, 1.105-2.489; P = .015) events, MetS (HR, 1.663; 95' CI, 1.107-2.499; P = .014), heart failure (HR, 1.584; 95' CI, 1.021-2.456; P = .040), and male sex (HR, 1.499; 95' CI, 1.010-2.223; P = .044) predicted CVEs. CONCLUSIONS Patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF. TRIAL REGISTRY ClinicalTrials.gov ; No.: NCT01882114; URL: www.clinicaltrials.gov

Some evidences suggest that the use of digoxin may be harmful inatrial fibrillation (AF) patients. The aim of the study was to investigate in a "real world" of AF patients receiving vitamin K antagonists (VKAs), the relationship between digoxin use and mortality.Prospective single-center observational study including 815 consecutive non-valvular AF patients treated with VKAs. Total mortality was the primary outcome of the study. We also performed a sub-analysis considering only cardiovascular (CV) deaths. Time in therapeutic range (TTR) was used for anticoagulation quality.Median follow-up was 33.2months (2460 person-years); 171 (21.0%) patients were taking digoxin. Compared to those without, patients on digoxin were older (p=0.007), with a clinical history of HF (p0.001) and at higher risk of thromboembolic events (p0.001). No difference in TTR between the two groups was registered (p=0.598). During the follow-up, 85 deaths occurred: 47 CV and 38 non-CV deaths; 35 deaths occurred in digoxin users (20.6%). A significant increased rate of total mortality was observed in digoxin-treated patients (p0.001). Multivariable analysis showed that digoxin was associated with total mortality (hazard ratio [HR]: 2.224, p0.001) and CV death (HR: 4.686, p0.001). A propensity score-matched analysis confirmed that digoxin was associated with total mortality (HR: 2.073, p=0.0263) and CV death (HR: 4.043, p=0.004).In AF patients on good anticoagulation control with VKAs, digoxin use was associated with a higher rate of total and CV mortality.

Background and aims Blood lysosomal acid lipase (LAL) is reduced in non-alcoholic steatohepatitis, which is the major cause of cryptogenic cirrhosis (CC); few data on LAL activity in CC do exist. We investigated LAL activity in a cohort of patients with liver cirrhosis. Methods This is a multicentre cohort study including 274 patients with liver cirrhosis of different aetiology from 19 centres of Internal Medicine, Gastroenterology and Hepatology distributed throughout Italy. Blood LAL activity (nmol/spot/h) was measured with dried blood spot extracts using Lalistat 2. Results Overall, 133 patients had CC, and 141 patients had cirrhosis by other causes (61 viral, 53 alcoholic, 20 alcoholic + viral, 7 autoimmune). Mean age was 64.2 ± 13.4 years, and 28.5% were women. Patients with CC were older compared to other aetiology-cirrhosis, with a lower Child-Turcotte-Pugh (CTP, p=0.003) and MELD (p=0.009) score, and a higher prevalence of cardio-metabolic risk factors and previous ischemic events. In the whole cohort, median LAL activity value was 0.58 nmol/spot/h, 0.49 and 0.65 in the groups of CC and known-aetiology cirrhosis, respectively (p=0.002). The difference remained significant after adjustment for white blood cells count (p=0.001). Multivariable linear regression analysis showed that CC (vs. known aetiology, Beta = −0.144, p=0.018), platelet count (Beta = 0.398, p < 0.001) and CTP score (Beta = −0.133, p=0.022) were associated with log-LAL activity. Similar results were found using MELD as covariate. Conclusions We found a marked reduction of LAL activity in patients with cryptogenic cirrhosis compared to the other known aetiologies. A prospective study will clarify the role of LAL in chronic liver diseases.

Background: NAFLD is associated to Insulin Resistance (IR). IR is responsible for Endothelial Dysfunction (ED) through the impairment of eNOS function. Although eNOS derangement has been demonstrated in experimental models, no studies have directly shown that eNOS dysfunction is associated with NAFLD in humans. The aim of this study is to investigate eNOS function in NAFLD patients.Methods: Fifty-four NAFLD patients were consecutively enrolled. All patients underwent clinical and laboratory evaluation and liver biopsy. Patients were divided into two groups by the presence of NAFL or NASH. We measured vascular reactivity induced by patients' platelets on isolated mice aorta rings. Immunoblot assays for platelet-derived phosphorylated-eNOS (p-eNOS) and immunohistochemistry for hepatic p-eNOS have been performed to evaluate eNOS function in platelets and liver specimens. Flow-mediated-dilation (FMD) was also performed. Data were compared with healthy controls.Results: Twenty-one (38, 8%) patients had NAFL and 33 (61, 7%) NASH. No differences were found between groups and controls except for HOMA and insulin (p < 0.0001). Vascular reactivity demonstrated a reduced function induced from NAFLD platelets as compared with controls (p < 0.001), associated with an impaired p-eNOS in both platelets and liver (p < 0.001). NAFL showed a higher impairment of eNOS phosphorylation in comparison to NASH (p < 0.01). In contrast with what observed in vitro, the vascular response by FMD was worse in NASH as compared with NAFL.Conclusions: Our data showed, for the first time in humans, that NAFLD patients show a marked eNOS dysfunction, which may contribute to a higher CV risk. eNOS dysfunction observed in platelets and liver tissue didn't match with FMD.

Abrikossoffov tumor rijetka je dobroćudna neoplazma mekih tkiva i može se pojaviti na bilo kojem dijelu tijela, uključujući i orofacijalno područje. Obično je benigan, ali postoje podatci da je lokalno bio agresivan i maligan s udaljenim metastazama. Etiologija je nepoznata jer je u nekoliko istraživanja dokazano da zahvaća različite stanice. U prikazanom slučaju riječ je o Dominikanki u dobi od 36 godina koja je upućena na Odjel oralne i maksilofacijalne kirurgije poliklinike Federico Drugi u Napulju zbog ograničene i na opip čvoraste lezije od 17 milimetara na dorzumu jezika. Terapija se sastojala od ekscizijske biopsije na temelju dijagnostičke hipoteze o Abrikossoffovu tumoru, što je potvrđeno histopatološkom analizom te histokemijskom i imunokemijskom procjenom. Abrikossoffov tumor rijetka je neoplazma koja se mora oprezno dijagnosticirati nakon što se uzmu u obzir svi histološki i klinički parametri radi pravilnoga odabira terapije., Abrikossoff’s tumour is a rare benign soft tissue neoplasm that can occur in any part of the body, including the orofacial region. The tumour is usually benign, but there are reports of cases in which the tumour shows a locally aggressive behaviour, malignancy, and distant metastases. The aetiology is unknown, since several studies have shown that different cells are involved. In the present case, a 36-year-old Dominican woman was referred to the Department of Oral and Maxillofacial Surgery in Policlinico Federico II, Naples with a circumscribed lesion and sessile nodule on the dorsum of the tongue measuring about 17 mm in diameter. The treatment consisted of an excisional biopsy performed on the basis of the diagnostic hypothesis of Abrikossoff’s tumour, which was confirmed by histopathological analysis and histochemistry and immunohistochemistry evaluation. Abrikossoff’s tumour is an uncommon neoplasm which must be carefully diagnosed considering all the histological and clinical aspects in order to be treated correctly.

Community-acquired pneumonia (CAP) is complicated by cardiac events in the early phase of the disease. Aim of this study was to assess if these intrahospital cardiac complications may account for overall mortality and cardiovascular events occurring during a long-term follow-up. Three hundred one consecutive patients admitted to the University-Hospital, Policlinico Umberto I, with community-acquired pneumonia were prospectively recruited and followed up for a median of 17.4 months. Primary end point was the occurrence of death for any cause, and secondary end point was the occurrence of cardiovascular events (cardiovascular death, nonfatal myocardial infarction [MI], and stroke). During the intrahospital stay, 55 patients (18%) experienced a cardiac complication. Of these, 32 had an MI (29 non-ST-elevation MI and 3 ST-elevation MI) and 30 had a new episode of atrial fibrillation (7 nonmutually exclusive events). During the follow-up, 89 patients died (51% of patients with an intrahospital cardiac complication and 26% of patients without, p0.001) and 73 experienced a cardiovascular event (47% of patients with and 19% of patients without an intrahospital cardiac complication, p0.001). A Cox regression analysis showed that intrahospital cardiac complications, age, and Pneumonia Severity Index were significantly associated with overall mortality, whereas intrahospital cardiac complications, age, hypertension, and diabetes were significantly associated with cardiovascular events during the follow-up. In conclusion, this prospective study shows that intrahospital cardiac complications in the early phase of pneumonia are associated with an enhanced risk of death and cardiovascular events during long-term follow-up.

Aims It is unclear if atrial fibrillation (AF) patients treated with oral vitamin K antagonists (VKAs) must follow a specific diet to avoid interference with anticoagulation. The aim of this study was to assess if Mediterranean diet (Med-Diet) may affect quality of anticoagulation, as expressed by the time in therapeutic range (TTR). Methods and results A prospective observational study including 553 non-valvular AF patients. Time in therapeutic range was calculated for all patients treated with VKAs, and adherence to Med-Diet was evaluated with a validated nine-item dietary questionnaire. Cardiovascular events (CVEs), such as cardiovascular death and fatal/non-fatal stroke or myocardial infarction, and bleedings were recorded. The median follow-up was 31.6 months. The median number of international normalized ratios for each patient was 63.0 (35.0–98.0) and 38 730 blood samples were analysed. In the whole cohort, the mean TTR was 65.5 ± 17.8%. The mean Med-Diet score was 5.19 ± 1.6, with frequent use of olive oil (90.1%), fruits (88.4%), and vegetables (69.3%) and low meat intake (71.2%). There were no differences among tertiles of Med-Diet score regarding TTR. A multivariable linear regression analysis showed that diabetes ( β : −0.105, P = 0.015) and the use of angiotensin converting enzyme inhibitor/angiotensin receptor blockers ( β : 0.153, P < 0.001) were associated with TTR. Compared with those without, AF patients with a CVE had significantly lower TTR (65.9 ± 17.9 vs. 59.6 ± 15.9, P = 0.029) and Med-Diet score (5.2 ± 1.5 vs. 4.4 ± 1.9, P = 0.004). A reduction of CVE was observed for each point of the Med-Diet score (hazard ratio 0.790, P = 0.017). Conclusion In our cohort of AF patients, Med-Diet is not associated with changes in TTR, and thus can be recommended for AF patients who are taking VKAs.

Recent studies report a prevalence of non-alcoholic fatty liver disease (NAFLD) of between 70% and 80% in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Nevertheless, it is not possible to differentiate between simple steatosis and non-alcoholic steatohepatitis (NASH) with non-invasive tests. The aim of this study was to differentiate between simple steatosis and NASH by liver biopsy in patients with hypertransaminasemia and MS or T2DM. Two hundred and fifteen patients with increased ALT levels and MS, and 136 patients at their first diagnosis of T2DM regardless of ALT values were consecutively admitted to a tertiary hepatology center between January 2004 and November 2014. Exclusion criteria were other causes of liver disease/ALT increase. Each patient underwent a clinical, laboratory and ultrasound evaluation, and a liver biopsy. Gender distribution, age, and body mass index were similar in the two groups of patients, whereas cholesterol levels, glycemia and blood pressure were significantly different between the two groups. The prevalence of NAFLD was 94.82% in MS patients and 100% in T2DM patients. NASH was present in 58.52% of MS patients and 96.82% of T2DM. Consequently, this study reveals that, by using liver biopsy, almost all patients with T2DM or MS have NAFLD, which in patients with T2DM means NASH. Importantly, it suggests that NASH may be one of the early complications of T2DM due to its pathophysiological correlation with insulin resistance.

Patients with nonvalvular atrial fibrillation (AF) show high residual cardiovascular (CV) risk despite oral anticoagulants. Urinary 11-dehydro-thromboxane B2 (TxB2) is associated with an increased risk of CV events (CVEs), but its predictive value in patients with anticoagulated AF is unknown.A prospective single-center cohort study, including 837 patients with AF, was conducted. Mean time of follow-up was 30.0 months, yielding 2,062 person-years of observation. Urinary 11-dehydro-TxB2 was measured at baseline. The primary end point was the occurrence of a CVE including fatal/nonfatal myocardial infarction and ischemic stroke, transient ischemic attack, cardiac revascularization, and CV death.Mean age of patients was 73.1 years, and 43.6% were women. Median 11-dehydro-TxB2 levels were 100 (interquartile range 50-187) ng/mg of urinary creatinine. Overall, the anticoagulation control was adequate (63.9% of mean time in therapeutic range). A CVE occurred in 99 (11.8%) patients, and 55 were CV deaths. At baseline, 11-dehydro-TxB2 levels were higher in patients with a CVE compared with those without (186 [107-400] vs 98 [52-170], P.001). An increased rate of CVEs (log-rank test, P.001) and CV deaths (P.001) was observed across tertiles of 11-dehydro-TxB2. Cardiovascular events were associated with age (hazard ratios [HR] 1.72 per 1 SD, 95% CI 1.33-2.21, P.001), diabetes mellitus (HR 1.89, 95% CI 1.20-2.96, P = .005), heart failure (HR 1.60, 95% CI 1.01-2.54, P = .044), history of stroke/transient ischemic attack (HR 1.96, 95% CI 1.25-3.06, P = .003), and 11-dehydro-TxB2 (HR 1.64 per 1 SD, 95% CI 1.42-1.89, P.001).Urinary 11-dehydro-TxB2 levels are associated with a residual risk of CVEs and CV mortality in patients with AF despite anticoagulant treatment.

Peripheral arterial disease (PAD) is a hallmark of generalized atherosclerosis. Depending on the specific diagnostic criteria that are being used, the prevalence of PAD may be as high as 30 % in the population of people 70 or more years old. Unfortunately, although PAD is prevalent and has many important consequences for patients, it is often under-detected and under-treated by primary care physicians. The aim of this review is to provide an overview of the available literature on epidemiology and antiplatelets management of PAD patients. In particular, we focus on the "hidden" side of PAD burden, the asymptomatic patients, who are at high risk of negative cardiovascular outcomes. Identification of such PAD patients is therefore an important clinical goal to reduce mortality and morbidity and reduce the social cost of atherosclerotic disease. Early screening of PAD and an evidence-based antithrombotic approach are also discussed as potential strategies to counteract the negative impact of such condition in general population, as well as, in patients with other cardiovascular diseases.Die periphere arterielle Verschlusskrankheit (PAVK) ist eine Markererkrankung der systemischen Arteriosklerose. In Abhängigkeit von den verwendeten diagnostischen Kriterien kann die Prävalenz der PAVK ungefähr 30 % der Bevölkerung im Alter von 70 Jahren und älter betragen. Obwohl die PAVK weit verbreitet ist, wird sie oft nicht erkannt und ist generell unterversorgt. Das Ziel dieses Artikels ist es, einen Überblick über die vorhandene Literatur zur Epidemiologie und Behandlung mit Thrombozytenfunktionshemmern zu geben. Insbesondere konzentrieren wir uns auf die „versteckten“ Seiten der PAVK bei asymptomatischen Patienten, die ein hohes Risiko für eine kardiovaskuläre Mortalität aufweisen. Die Identifizierung solcher PAVK-Patienten ist daher ein wichtiges klinisches Ziel, um Mortalität und Morbidität zu verringern und die Kosten der arteriosklerotischen Erkrankungen zu reduzieren. Ein rechtzeitiges Screening der PAVK und ein evidenzbasierter antithrombotischer Ansatz werden als mögliche Strategien diskutiert.

In the present study, we tested the hypothesis that oxidative stress could be implicated in myocardial damage during the acute phase of pneumonia. NOX2 activation, the catalytic subunit of NADPH oxidase, and high-sensitivity cardiac troponin T (hs-cTnT) elevation have been analyzed in two hundred forty-eight consecutive patients hospitalized for community-acquired pneumonia. Serum NOX2-derived peptide (sNOX2-dp), a marker of NOX2 activation, and 8-isoprostaglandin F2α (8-iso-PGF2α), a marker of oxidative stress, were measured upon admission; serum hs-cTnT and ECG were measured every 12 and 24 h, respectively. One hundred thirty-five patients (54%) showed elevated serum levels of hs-cTnT (>0.014 μg/L). A logistic regression analysis showed sNOX2-dp (p

ReplyWe thank Dr Yildiz and Dr Soydinc for their interest and commentsonourrecentworkregardingtheassociationbetweentheuseofdigox-in and increased mortality in patients affected by atrial fibrillation (AF)[1].IntheirLettertotheEditor[2],Authorsraisemanyinterestingques-tions, suggesting that other factors, in addition to those reported in ourobservational study, may influence the incidence of cardiovascularoutcome in AF digoxin-treated patients.A crucialpointraisedby theAuthorsconcernsthe dosageof digoxinand blood concentrations, as these two factors contribute to the in-creasedriskofmortality[3].Digoxinserumlevelsabovethetherapeuticrangecanbefoundinapercentageofpatientsrangingfrom4to10%[4],and are known to be associated with cardiac toxicity and increasedmortality [5]. However, in a large cohort of 5100 patients in whichblood concentration of digoxin was measured, clinical toxicity attribut-ed to thepro-arrhythmic effectof digoxin havebeensuspected for only0.25% of total patients treated with digitalis [3].Renal dysfunction is another critical issue, which requires digoxintailoring to avoid toxicity; thus, 50%–70% of digitalis is excreted un-changed by the kidney [6].Noteworthy, in the large RIKS-HIA trial [7] including 1493 patientswith and 5540 without digoxin, the relative risk for death betweenpatients discharged with and without digoxin, after adjustment forpropensity score, was independent from baseline serum creatinine.Recent findings from the TREAT-AF study [8] confirmed that, in avery large cohort of 122,465 AF patients (353,168 person-years), theincreased mortality by digoxin was apparently independent from theestimated glomerular filtration rate (eGFR), the effect persisting alsoin the propensity-matched cohort.Inourpopulation,wefoundnodifferencesinrenalfunctionbetweenAF patients treated (n = 90, eGFR calculated by MDRD formula, 69.5[56.4–88.9] ml/min) or not (n = 426, eGFR 73.6 [59.5–87.3] ml/min,p = 0.601) with digoxin.Body mass composition did not apparently influence results fromour study, as at baseline no differences of body mass index (27.4 ±5.0 vs. 27.4 ± 4.7 kg/m

Objectives: Reduced vitamin E levels have been reported in patients with non-alcoholic steatohepatitis (NASH), but no conclusive data on patients with simple steatosis (SS) are available. Aim of this study was to investigate the association between serum vitamin E levels and SS. Methods: A cohort of 312 patients with cardio-metabolic risk factors was screened for liver steatosis by ultrasonography (US). We reasonably classified as SS patients with US-fatty liver, normal liver function tests (LFTs) and with Cytokeratin 18 6 months). Serum cholesterol-adjusted vitamin E (Vit E/chol) levels were measured. Results: Mean age was 53.9±12.5 years and 38.4% were women. Non-alcoholic fatty liver disease (NAFLD) was detected at US in 244 patients; of those 39 had biopsy-proven NASH and 2 borderline NASH. Vit E/chol was reduced in both SS (3.4±2.0, P

BackgroundTroponins may be elevated in patients with pneumonia, but associations with myocardial infarction (MI) and with platelet activation are still undefined.ObjectivesThe aim of this study was to investigate the relationship between troponin elevation and in vivo markers of platelet activation in the early phase of hospitalization of patients affected by community-acquired pneumonia.MethodsA total of 278 consecutive patients hospitalized for community-acquired pneumonia, who were followed up until discharge, were included. At admission, platelet activation markers such as plasma soluble P-selectin, soluble CD40 ligand, and serum thromboxane B2 (TxB2) were measured. Serum high-sensitivity cardiac troponin T levels and electrocardiograms were obtained every 12 and 24 h, respectively.ResultsAmong 144 patients with elevated high-sensitivity cardiac troponin T, 31 had signs of MI and 113 did not. Baseline plasma levels of soluble P-selectin and soluble CD40 ligand and serum TxB2 were significantly higher in patients who developed signs of MI. Logistic regression analysis showed plasma soluble CD40 ligand (p < 0.001) and soluble P-selectin (p < 0.001), serum TxB2 (p = 0.030), mean platelet volume (p = 0.037), Pneumonia Severity Index score (p = 0.030), and ejection fraction (p = 0.001) to be independent predictors of MI. There were no significant differences in MI rate between the 123 patients (45%) taking aspirin (100 mg/day) and those who were not aspirin treated (12% vs. 10%; p = 0.649). Aspirin-treated patients with MIs had higher serum TxB2 compared with those without MIs (p = 0.005).ConclusionsMI is an early complication of pneumonia and is associated with in vivo platelet activation and serum TxB2 overproduction; aspirin 100 mg/day seems insufficient to inhibit thromboxane biosynthesis. (MACCE in Hospitalized Patients With Community-acquired Pneumonia; NCT01773863)