Aging-Related Decline of Glutathione Peroxidase 3 and Risk of Cardiovascular Events in Patients With Atrial Fibrillation

BACKGROUND: Experimental studies demonstrated that glutathione peroxidase 3 (GPx3), an antioxidant enzyme that catabolizes hydrogen peroxide, protects against thrombosis. Little is known about its role in cardiovascular disease. METHODS AND RESULTS: A prospective cohort study was conducted in 909 atrial fibrillation patients. Serum activities of GPx3, superoxide dismutase (SOD), and catalase were measured at baseline to assess the risk of cardiovascular events during a mean follow-up of 43.4 months (3291 person-years). Serum Nox2 and urinary excretion of 11-deydro-thromboxane B2 were also measured. During follow-up 160 cardiovascular events occurred (4.9%/year). Significantly lower values of GPx3 (P<0.001) and SOD (P=0.037) were detected in patients with, compared to those without, cardiovascular events. A lower survival rate was observed in patients with GPx3 (P<0.001) and SOD (P=0.010) activities below the median, as compared to those above. In a fully adjusted Cox regression model, GPx3 was the only antioxidant enzyme predictor of cardiovascular events (hazard ratio 0.647, 95% confidence interval 0.524-0.798, P<0.001). GPx3 was inversely associated with urinary 11-dehydro-thromboxane B2 (B -0.337, P<0.001) and serum Nox2 (B: -0.423, P<0.001). GPx3 activity progressively decreased with decades of age (P<0.001), with a progressive reduction in people aged ≥70 years. CONCLUSIONS: This study provides evidence that a low antioxidant status, as depicted by reduced levels of GPx3, increases the risk of cardiovascular events in patients with atrial fibrillation. The age-related decline of GPx3 may represent a mechanism for the enhanced cardiovascular risk in the elderly population

Minimizing drug-drug interactions between dabigatran and levetiracetam through clinical management. a case report

Background Direct oral anticoagulants (DOACs) are useful for stroke prevention in atrial fibrillation (AF) patients. However, the concomitant administration of Levetiracetam limited their use in clinical practice, although some authors raise doubts about clinical relevance of the interaction. Case summary We report a case of a 54-year-old male with AF, cirrhosis and seizures, in which the assessment of Dabigatran plasma concentration was needed due to the concomitant use of Levetiracetam. In this case no relevant reduction of trough Dabigatran plasma concentration was found. An increased peak serum level of dabigatran may be obtained delaying levetiracetam administration. The patient was then followed in our clinic and during 32 months of follow up no ischemic or haemorrhagic events occurred. Discussion The evaluation of DOACs concentration could be helpful to start a tailored therapy in frailty 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 &lt; 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 &lt; 0.001), logGPx3 (above median, HR: 0.629, p &lt; 0.05), and Med-Diet score (HR: 0.547, p &lt; 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 &lt; 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 &lt; 0.001), logGPx3 (above median, HR: 0.629, p &lt; 0.05), and Med-Diet score (HR: 0.547, p &lt; 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

Gut-Derived Serum Lipopolysaccharide is Associated With Enhanced Risk of Major Adverse Cardiovascular Events in Atrial Fibrillation: Effect of Adherence to Mediterranean Diet

Gut microbiota is emerging as a novel risk factor for atherothrombosis, but the predictive role of gut-derived lipopolysaccharide (LPS) is unknown. We analyzed (1) the association between LPS and major adverse cardiovascular events (MACE) in atrial fibrillation (AF) and (2) its relationship with adherence to a Mediterranean diet (Med-diet)

Oxidative stress and cardiovascular disease: new insights

The role of oxidative stress in the onset and progression of atherosclerosis and its impact on the development of cardiovascular events has been widely described. Thus, increased oxidative stress has been described in several atherosclerotic risk factors, such as hypertension, dyslipidaemia, peripheral artery disease, metabolic syndrome, diabetes, and obesity. Among others, specific oxidative pathways involving both pro-oxidant and antioxidant enzymes seem to play a major role in the production of reactive oxidant species (ROS), such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidase, superoxide dismutase, and glutathione peroxidase. In this review, we will discuss: 1) the most relevant enzyme systems involved in the formation and detoxification of ROS, 2) the relationship between oxidative stress and cardiovascular risk, and 3) therapeutic implications to modulate oxidative stress

Tailored Practical Management of Patients With Atrial Fibrillation: A Risk Factor-Based Approach

The management of antithrombotic therapy for thromboprophylaxis in patients with atrial fibrillation (AF) has been recently evolved by the progressive replacement of vitamin K antagonists with the non-vitamin K antagonist oral anticoagulants (NOACs). However, while these drugs are effective in reducing ischemic stroke/systemic embolism, a still high rate of cardiovascular events is present in the AF population. A tailored integrated approach to patients with AF is therefore necessary to reduce both thromboembolic events and cardiovascular disease. This approach should consist in the assessment of individual risk factors for ischemic and bleeding events in order to choose the most appropriate anticoagulant treatment according to patient's characteristics and preference. To this purpose, several risk scores have been developed and validated to stratify thromboembolic and hemorrhagic risk. This review provides an individual-based strategy for the management of patients with AF, from a risk-factor based approach to a tailored prescription and monitoring of NOACs. In particular, we reported an updated practical management strategy for AF patients in specific clinical situations such as those (1) experiencing a major bleeding, (2) requiring a switch to another antithrombotic regimen, (3) restarting anticoagulation after acute ischemic stroke, (4) suffering from an acute coronary artery disease (acute coronary syndrome or undergoing cardiac revascularization)

Inositol and Non-Alcoholic Fatty Liver Disease: A Systematic Review on Deficiencies and Supplementation

Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials

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

Mediterranean Diet: A Tool to Break the Relationship of Atrial Fibrillation with the Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease

Atrial fibrillation (AF) is the most common supraventricular arrhythmia associated with increased cardiovascular and non-cardiovascular morbidity and mortality. As multiple factors may predispose the onset of AF, the prevention of the occurrence, recurrence and complications of this arrhythmia is still challenging. In particular, a high prevalence of cardio-metabolic comorbidities such as the metabolic syndrome (MetS) and in its hepatic manifestation, the non-alcoholic fatty liver disease (NAFLD), have been described in the AF population. A common pathogenetic mechanism linking AF, MetS and NAFLD is represented by oxidative stress. For this reason, in the past decades, numerous studies have investigated the effect of different foods/nutrients with antioxidant properties for the prevention of, and their therapeutic role is still unclear. In this narrative comprehensive review, we will summarize current evidence on (1) the association between AF, MetS and NAFLD (2) the antioxidant role of Mediterranean Diet and its components for the prevention of AF and (3) the effects of Mediterranean Diet on MetS components and NAFLD