Is there an interplay between adherence to mediterranean diet, antioxidant status, and vascular disease in atrial fibrillation patients?

Mediterranean Diet (Med-Diet) is associated with reduced incidence of vascular events (VEs) in atrial fibrillation (AF), but the mechanism accounting for its beneficial effect is only partially known. We hypothesized that Med-Diet may reduce VEs by improving antioxidant status, as assessed by glutathione peroxidase 3 (GPx3) and superoxide dismutase (SOD). We performed a prospective cohort study investigating the relationship between adherence to Med-Diet, serum baseline GPx3 and SOD activities, and the occurrence of VEs in 690 AF patients. GPx3 activity was directly associated with Med-Diet score (B = 0.192, p < 0.001) and inversely with age (B = −0.124, p = 0.001), after adjustment for potential confounders; Med-Diet weakly affected SOD levels. During a mean follow-up of 46.1 ± 28.2 months, 89 VEs were recorded; patients with VEs had lower GPx3 levels compared with those without VEs (p = 0.002); and no differences regarding SOD activity were found. Multivariable Cox regression analysis showed that age (Hazard ratio [HR]:1.065, p < 0.001), logGPx3 (above median, HR: 0.629, p < 0.05), and Med-Diet score (HR: 0.547, p < 0.05) predicted VEs. Med-Diet favorably modulates antioxidant activity of GPx3 in AF, resulting in reduced VEs rate. We hypothesize that the modulation of GPx3 levels by Med-Diet could represent an additional nutritional strategy to prevent VEs in AF patients

Is there an interplay between adherence to mediterranean diet, antioxidant status, and vascular disease in atrial fibrillation patients?

Mediterranean Diet (Med-Diet) is associated with reduced incidence of vascular events (VEs) in atrial fibrillation (AF), but the mechanism accounting for its beneficial effect is only partially known. We hypothesized that Med-Diet may reduce VEs by improving antioxidant status, as assessed by glutathione peroxidase 3 (GPx3) and superoxide dismutase (SOD). We performed a prospective cohort study investigating the relationship between adherence to Med-Diet, serum baseline GPx3 and SOD activities, and the occurrence of VEs in 690 AF patients. GPx3 activity was directly associated with Med-Diet score (B = 0.192, p < 0.001) and inversely with age (B = −0.124, p = 0.001), after adjustment for potential confounders; Med-Diet weakly affected SOD levels. During a mean follow-up of 46.1 ± 28.2 months, 89 VEs were recorded; patients with VEs had lower GPx3 levels compared with those without VEs (p = 0.002); and no differences regarding SOD activity were found. Multivariable Cox regression analysis showed that age (Hazard ratio [HR]:1.065, p < 0.001), logGPx3 (above median, HR: 0.629, p < 0.05), and Med-Diet score (HR: 0.547, p < 0.05) predicted VEs. Med-Diet favorably modulates antioxidant activity of GPx3 in AF, resulting in reduced VEs rate. We hypothesize that the modulation of GPx3 levels by Med-Diet could represent an additional nutritional strategy to prevent VEs in AF patients

Lipopolysaccharide as trigger of platelet aggregation via eicosanoid over-production

The effect of lipopolysaccharide (LPS) on platelet aggregation is still controversial. We performed in vitro and ex vivo studies in controls and in patients with community-acquired pneumonia (CAP) to assess the effect of LPS on platelet activation (PA). LPS (15-100 pg/ml) significantly increased PA only if combined with sub-threshold concentrations (STC) of collagen or ADP; this effect was associated with increased platelet H2O2 production, Nox2 activation, PLA2 phosphorylation, thromboxane (Tx)A2 and 8-iso-PGF2α-III, and was inhibited by aspirin, TxA2 receptor antagonist or by Toll-like receptor 4 blocking peptide (TLR4bp). Analysis of up-stream signalling potentially responsible for Nox2 and PLA2 activation demonstrated that LPS-mediated PA was associated with phosphorylation of AKT, p38 and p47phox translocation. In 10 consecutive CAP patients serum endotoxins were significantly higher compared to 10 controls (145 [115-187] vs 18 [6-21] pg/ml; p<0.01). Ex vivo study showed that agonist-stimulated platelets were associated with enhanced PA (p<0.01), Toll-like receptor 4 (TLR4) expression (p<0.05), thromboxane (Tx)A2 (p<0.01) and 8-iso-PGF2α-III (p<0.01) production in CAP patients compared to controls. The study provides evidence that LPS amplifies the platelet response to common agonists via TLR4-mediated eicosanoid production and suggests LPS as a potential trigger for PA in CAP

HIV-1 induces in vivo platelet activation by enhancing platelet NOX2 activity.

OBJECTIVES: HIV-1 patients show increased platelet activation, but the mechanisms involved are not completely clarified. We speculated that HIV-1 might induce in vivo platelet activation by enhancing platelet NOX2-related oxidative stress. METHODS: We measured soluble CD40 Ligand (sCD40L), a systemic marker of platelet activation, in 36 HIV-1 patients under effective combined antiretroviral therapy (cART) and in 10 naïve HIV-1 subjects. As control, 20 healthy subjects (HS) were included. Platelet oxidative stress was measured by platelet NOX2-derived peptide (sNOX2-dp), p47(phox) translocation to platelet membrane and platelet prostaglandin F2α (8-iso-PGF2α). RESULTS: sCD40L was increased both in HIV-1 naïve and cART patients compared to HS (p &lt; 0.001). Platelet sNOX2-dp and 8-iso-PGF2α were significantly higher in HIV-1 naïve subjects compared to those on cART and to HS, and both were mutually correlated (R = 0.734, p &lt; 0.001). A stepwise multivariable linear regression analysis showed that platelet sNOX2-dp (β: 0.803, p &lt; 0.001), HIV-1 infection (β: 0.146, p = 0.014) and age (β: 0.166, p = 0.001) were independently associated to sCD40L levels. CONCLUSIONS: HIV-1 infection is associated with increased platelet oxidative stress, which was related to the activation of NOX2. The independent association between platelet NOX2 activation and plasma levels of sCD40L suggest that in vivo platelet activation may be dependent upon platelet oxidative stress

Digoxin and platelet activation in patients with atrial fibrillation: In vivo and in vitro study

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 B2 (TxB2), 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‐TxB2 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‐TxB2 and SDC were correlated (rs=0.350, P<0.001). Patients in the upper tertile of SDC showed higher 11‐dehydro‐TxB2 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, TxB2 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 A2 phosphorylation. Our findings may have clinical implications for AF patients treated with digoxin

Extra virgin olive oil use is associated with improved post-prandial blood glucose and LDL cholesterol in healthy subjects

Extra virgin olive oil (EVOO) is a key component of the Mediterranean diet and seems to account for the protective effect against cardiovascular disease. However, the underlying mechanism is still elusive

Gut dysbiosis-derived low-grade endotoxemia: A common soil for liver and cardiovascular disease

Gut dysbiosis is characterized by bacteria overgrowth that ultimately leads to increased intestinal barrier permeability and bacteria or bacteria product translocation such as lipopolysaccharide (LPS) in the portal and eventually systemic circulation. Intestinal epithelial cells and hepatocytes encompass enzymatic armamentarium to counteract the LPS toxic effect, however impaired degradation results in LPS accumulation in hepatocytes and endothelial wall. Experimental and clinical study documented that in patients with liver disease, such as non-alcoholic fatty acid liver disease (NAFLD), low-grade endotoxemia by LPS is implicated in liver inflammation and thrombosis via interaction with its Toll-like receptor 4 (TLR4) expressed by hepatocytes and platelets. Furthermore, studies in patients with severe atherosclerosis documented that LPS localizes into atherosclerotic plaque in close association with activated macrophages expressing TLR4 suggesting a role for LPS in vascular inflammation, atherosclerotic progression, and thrombosis. Finally, LPS may directly interact with myocardial cells to induce electric and functional changes leading to atrial fibrillation or heart failure.  This review will focus on experimental and clinical evidence suggesting low-grade endotoxemia as mechanism potentially accounting for vascular damage occurring at level of hepatic and systemic circulation and myocardial cells.

Association of proprotein convertase subtilisin/kexin type 9 (PCSK9) levels with abnormally high ankle-brachial index in atrial fibrillation

BACKGROUND: High ankle-brachial index (ABI) has been associated with increased risk of worse outcomes in the general population. Few data on atrial fibrillation (AF) do exist. Experimental data suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) contribute to vascular calcification but clinical data on this association are lacking. AIMS: We want to investigate the relationship between circulating PCSK9 levels and abnormally high ABI in patients suffering from AF. METHODS: We analysed data from 579 patients included in the prospective ATHERO-AF study. An ABI ≥1.4 was considered as high. PCSK9 levels were measured coincidentally with ABI measurement. We used an optimized cut-offs of PCSK9 for both ABI and mortality obtained from ROC curve analysis. All-cause mortality according to the ABI value was also analysed. RESULTS: 115 (19.9%) had an ABI ≥1.4. The mean (SD) age was 72.1 (7.6) years and 42.1% of patients were women. Patients with ABI ≥1.4 were older, more frequently male and diabetic. Multivariable logistic regression analysis showed an association between ABI ≥1.4 and serum levels of PCSK9 &gt; 1150 pg/ml (odds ratio [OR], 1.649; 95% confidence interval [CI], 1.047–2.598; P = 0.031). During a median follow up of 41 months, 113 deaths occurred. At multivariable Cox regression analysis, ABI ≥1.4 (hazard ratio [HR], 1.626; 95% CI, 1.024–2.582; P = 0.039), CHA2DS2-VASc score (HR, 1.249; 95% CI, 1.088–1.434; P = 0.002), antiplatelet drug use (HR, 1.775; 95% CI, 1.153–2.733; P = 0.009), and PCSK9 &gt; 2060 pg/ml (HR, 2.200; 95% CI, 1.437–3.369; P &lt; 0.001) were associated with all-cause death. CONCLUSIONS: In AF patients, PCSK9 levels relate to an abnormally high ABI ≥1.4. Our data suggest a role for PCSK9 in favouring vascular calcification in AF patients