The Role of Ranolazine in Heart Failure-Current Concepts.

Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation have gained research interest especially after the introduction of sodium-glucose co-transporter 2 inhibitors in the treatment of heart failure. Ranolazine or N-(2,6-dimethylphenyl)-2-(4-[2-hydroxy-3-(2-methoxyphenoxy) propyl] piperazin-1-yl) acetamide hydrochloride is an active piperazine derivative which inhibits late sodium current thus minimizing calcium overload in the ischemic cardiomyocytes. Ranolazine also prevents fatty acid oxidation and favors glycose utilization ameliorating the "energy starvation" of the failing heart. Heart failure with preserved ejection fraction is characterized by diastolic impairment; according to the literature ranolazine could be beneficial in the management of increased left ventricular end-diastolic pressure, right ventricular systolic dysfunction and wall shear stress which is reflected by the high natriuretic peptides. Fewer data is evident regarding the effects of ranolazine in heart failure with reduced ejection fraction and mainly support the control of the sodium-calcium exchanger and function of sarcoendoplasmic reticulum calcium adenosine triphosphatase. Ranolazine's therapeutic mechanisms in myocardial ion channels and energy utilization are documented in patients with chronic coronary syndromes. Nevertheless, ranolazine might have a broader effect in the therapy of heart failure and further mechanistic research is required.

Non-Alcoholic Fatty Liver Disease and Echocardiographic Parameters of Left Ventricular Diastolic Function: A Systematic Review and Meta-Analysis.

The cardiovascular implications of non-alcoholic fatty liver disease (NAFLD) have been associated with heart failure with preserved ejection fraction (HFpEF). The purpose of this review was to conduct a bibliographic search regarding the correlation between NAFLD and the echocardiographic parameters of left ventricular diastolic function. A systematic literature search was conducted in PubMed and Embase for original research data reporting on the association of NAFLD with diastolic function markers [E/e', left atrial volume index (LAVi), left ventricular mass index (LVMi)]. Meta-analysis was performed using the meta and dmetar packages in R studio v.1.4.1106, with p < 0.05 values being considered significant. Results are expressed as the standardized mean difference (SMD) for continuous variables and as the odds ratio (OR) for categorical variables, with respective 95% confidence intervals (CI). Heterogeneity between studies was expressed with index Ι2. From the preliminary search, 2619 articles were found from which 31 studies were included in the final statistical analysis. The meta-analysis of 8 studies which reported on the prevalence of diastolic dysfunction showed that it was increased in patients with NAFLD (OR: 2.07, 95% CI 1.24-3.44 with p = 0.01, I2: 80% with p < 0.01). The meta-analysis of 21 studies showed significantly higher E/e' in NAFLD patients (SMD 1.02, 95% CI 0.43-1.61 with p < 0.001, I2: 97% with p < 0.001). Individuals with NAFLD had increased LAVi (SMD: 0.87, 95% CI 0.38-1.37 with p < 0.001, I2: 96% with p < 0.001) and LVMi (SMD: 0.89, 95% CI 0.31-1.48 with p = 0.003, I2: 100% with p < 0.001). To conclude, in the meta-analysis of 31 observational studies, NAFLD patients were found to have affected left ventricular diastolic function, supporting the hypothesis of NAFLD being associated with HFpEF.

Prolonged impact of anti-cancer therapy on endothelial function and arterial stiffness in breast cancer patients.

BACKGROUND: Cardiotoxicity restricts anthracycline and trastuzumab treatment of Human Epidermal Growth Factor Receptor 2 positive early breast cancer. Endothelial dysfunction and arteriosclerosis are significant cardiovascular risk factors. OBJECTIVES: We studied the effect of anthracycline-based chemotherapy, with or without trastuzumab, on endothelium and arteriosclerosis in patients with breast cancer. METHODS: In this case-control study, 52 women with breast cancer and 104 women without breast cancer were examined longitudinally up to 15 months following (in the breast cancer group) initiation of chemotherapy. Arterial stiffness was evaluated through pulse wave velocity (PWV), while endothelial function via flow-mediated dilatation (FMD) at baseline (T0), 3 (T1), 6 (T2), and 15 (T3) months later. RESULTS: There was no difference between subjects with breast cancer and control in PWV and FMD at baseline. Longitudinally, participants with breast cancer exhibited considerable impairment of PWV and FMD compared to the control group (p for interaction <0.001 for both parameters). In breast cancer patients, there was a significant increase from T0 to T3 in PWV (7.43 ± 1.68 m/s vs. 8.18 ± 2.00 m/s, p = 0.01) and decrease in FMD (6.95 ± 2.86% vs. 5.03 ± 2.83%, p = 0.006). The addition of trastuzumab in the treatment did not have any effect on PWV (p = 0.74) or FMD (p = 0.91). CONCLUSIONS: In patients with breast cancer, there is progression of endothelial dysfunction and arteriosclerosis up to 15 months following initiation of anthracycline-based chemotherapy. Trastuzumab has no additive effect on endothelial function or arterial stiffness.

Novel Approaches to the Management of Diabetes Mellitus in Patients with Coronary Artery Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with diabetes mellitus (DM). Although benefit has been attributed to the strict control of hyperglycemia with traditional antidiabetic treatments, novel antidiabetic medications have demonstrated cardiovascular (CV) safety and benefits by reducing major adverse cardiac events, improving heart failure (HF), and decreasing CVD-related mortality. Emerging data underline the interrelation between diabetes, as a metabolic disorder, and inflammation, endothelial dysfunction, and oxidative stress in the pathogenesis of microvascular and macrovascular complications. Conventional glucose-lowering medications demonstrate controversial CV effects. Dipeptidyl peptidase- 4 inhibitors have not only failed to prove to be beneficial in patients with coronary artery disease, but also their safety is questionable for the treatment of patients with CVD. However, metformin, as the first-line option for type 2 DM (T2DM), shows CVD protective properties for DM-induced atherosclerotic and macrovascular complications. Thiazolidinedione and sulfonylureas have questionable effects, as evidence from large studies shows a reduction in the risk of CV events and deaths, but with an increased rate of hospitalization for HF. Moreover, several studies have revealed that insulin monotherapy for T2DM treatment increases the risk of major CV events and deaths from HF, when compared to metformin, although it may reduce the risk of myocardial infarction. Finally, this review aimed to summarize the mechanisms of action of novel antidiabetic drugs acting as glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors that show favorable effects on blood pressure, lipid levels, and inflammation, leading to reduced CVD risk in T2DM patients.

Lipoprotein(a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment.

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a). Increased Lp(a) levels are an independent, heritable causal risk factor for atherosclerotic cardiovascular disease (ASCVD) as they are largely determined by variations in the Lp(a) gene (LPA) locus encoding apo(a). Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), and its role adversely affects vascular inflammation, atherosclerotic lesions, endothelial function and thrombogenicity, which pathophysiologically leads to cardiovascular (CV) events. Despite this crucial role of Lp(a), its measurement lacks a globally unified method, and, between different laboratories, results need standardization. Standard antilipidemic therapies, such as statins, fibrates and ezetimibe, have a mediocre effect on Lp(a) levels, although it is not yet clear whether such treatments can affect CV events and prognosis. This narrative review aims to summarize knowledge regarding the mechanisms mediating the effect of Lp(a) on inflammation, atherosclerosis and thrombosis and discuss current diagnostic and therapeutic potentials.

Expression of Tissue microRNAs in Ascending Aortic Aneurysms and Dissections.

Little is known about the role of serum and tissue mediators in the progression of ascending aortic aneurysms and dissections. We examined how the tissue expression of microRNAs and matrix metalloproteinases (MMPs), as well as the serum levels of osteoprotegerin, adiponectin, and high sensitivity C-reactive protein (hsCRP) are associated with these entities. We enrolled 21 patients with ascending aortic aneurysm, 11 with acute Stanford type A aortic dissection and 18 controls. The serum levels of osteoprotegerin, adiponectin, and hsCRP, as well as the tissue expression of MMPs 2 and 9 and tissue microRNAs 29 and 195 were compared among groups. There was no difference regarding serum osteoprotegerin, adiponectin, and tissue MMP2 and MMP9 levels. hsCRP was higher in the dissection group (P = .03). Tissue expression of microRNA 29 was 2.11-fold higher in the dissection (P = .001) and 2.99-fold higher in the aneurysm group (P < .001), compared with the control group. Tissue expression of microRNA 195 was 2.72-fold higher in the dissection (P < .001) and 2.00-fold lower in the aneurysm group (P = .08), compared with to the control group. These findings support the contribution of microRNAs in the progression of aneurysm formation and dissection, suggesting a role as potential biomarkers and future therapeutic targets.

The Association of Depression With QT Duration: A Comparison Between Individuals Younger or Older Than 65 Years.

OBJECTIVE: The electrocardiogram-derived corrected QT (QTc) interval is an indicator of cardiac autonomic activity that has been proposed as a biological measure to investigate the interplay between depression and cardiovascular diseases. This study assesses whether depression is associated with a longer QTc interval across age groups. METHODS: Assessment of depressive symptoms was performed in 1637 participants of the cross-sectional Corinthia study with the Zung Self-Rating Depression Scale in those younger than 65 years (group 1) and with the Geriatric Depression Scale in elderly individuals (≥65 years, group 2). The QT interval was obtained from electrocardiogram recordings and corrected for heart rate (QTc). RESULTS: Individuals in group 1 with depression were predominantly women and had a higher prevalence of coronary artery disease and diabetes mellitus. Group 1 individuals with depression had longer QTc duration (no depression versus depression, 389.3 [27.0] versus 401.1 [32.9] milliseconds; p < .001) and percentage of abnormal QTc (no depression versus depression, 2.0% versus 10.8%; p = .001) compared with those without depression. Elderly individuals (group 2) had similar values of QTc and percentage of abnormal QTc irrespective of depression status. Even after adjustment for known QT-prolonging factors, the presence of depression in younger individuals was associated with an increased QTc by 11.1 milliseconds and with an approximately 10.6-fold higher prevalence of abnormal QTc duration. CONCLUSIONS: Depression was associated with a longer QTc interval especially in individuals younger than 65 years. These findings may indicate an interrelationship between depression and autonomic dysregulation as potential risk factors for cardiovascular disease and sudden cardiac death.

COVID-19, Endothelium and the Cardiometabolic Patient: A Possible Role for Capillary Leak Syndrome.

Capillary leak syndrome is an under-diagnosed condition leading to serious hypoalbuminemia with diffuse edema, pulmonary edema, severe hypotension, and possibly death. Sepsis leading to hemophagocytic lymphohistiocytosis (HLH) is a major risk factor; however, capillary hyper-permeability is the core underlying pathophysiological mechanism. Endothelial dysfunction plays a major role in cardiometabolic disease through insulin resistance, lipotoxicity, and, eventually, oxidative stress and chronic inflammation. We review the literature concerning the aforementioned mechanisms as well-established risk factors for adverse COVID-19 outcomes. We especially focus on data regarding the underlying endothelial effects of SARS-CoV-2 infection, including direct damage and increased vascular leakage through a hyper-inflammatory cascade and diminished nitric oxide bioavailability. Interestingly, an increased incidence of hypoalbuminemia has been observed in patients with severe COVID-19, especially those with underlying cardiometabolic disease. Importantly, low albumin levels present a strong, positive association with poor disease outcomes. Therefore, in this review article, we highlight the important role of cardiovascular risk factors on endothelium integrity and the possible link of endothelial damage in the hypoalbuminemia-associated adverse prognosis of COVID-19 patients.

The Association of Physical Activity with Arterial Stiffness and Inflammation: Insight from the "Corinthia" Study.

Diminished physical activity is a frequent phenomenon leading to a higher incidence of cardiovascular morbidity and mortality. Our study aimed to assess the impact of physical activity on arterial stiffness and inflammation. Classification of physical activity was performed in 1945 individuals of the cross-sectional "Corinthia" study using the International Physical Activity Questionnaire. Demographic and clinical characteristics were obtained via a standardized questionnaire. Arterial stiffness was estimated via carotid-femoral pulse wave velocity evaluation, and the inflammatory burden was assessed via high sensitivity C reactive protein (hsCRP) measurement. Participants with low physical activity had the most impaired carotid-femoral pulse wave velocity values while abnormally increased measurements-adjusted for age and blood pressure-were more frequently encountered in individuals with low physical activity. Participants characterized as having vigorous physical activity had the lowest inflammatory burden, as estimated by hsCRP levels. The results remained unaffected even after adjustment for confounders. In a subgroup analysis according to sex, increased arterial stiffness and inflammatory burden were noted similarly in female and male subjects within the lowest percentile of physical activity. In conclusion, a significant association between physical activity, arterial stiffness, and inflammation was observed, even after adjusting for known cardiovascular risk factors.

The association of diabetes mellitus with carotid atherosclerosis and arterial stiffness in the Corinthia study.

BACKGROUND AND AIMS: Evaluation of arterial stiffness and carotid atherosclerotic burden can provide important prognostic information regarding the risk of future cardiovascular events. The aim of this study was to assess these vascular properties in patients with diabetes mellitus (DM). METHODS AND RESULTS: In the context of the observational "Corinthia" study, we analyzed 1757 participants with determined DM status. Carotid ultrasonography was performed to evaluate intima-media thickness (cIMT) and carotid plaque burden. Arterial stiffness was estimated via assessment of carotid-to-femoral pulse wave velocity (cfPWV). Individuals with DM had increased mean cIMT, maximum cIMT, carotid plaque burden, and cfPWV compared to those without DM. After multivariable regression analysis, the presence of DM was still associated with significantly increased mean cIMT (by 0.074 mm, p = .004), maximum cIMT (by 0.134 mm, p = .007), cfPWV (by 0.929 m/s, p < .001), and a higher prevalence of carotid plaques (odds ratio 1.52, 95% confidence intervals 1.11, 2.10, p = .01). In a propensity score-matched cohort, mean cIMT, maximum cIMT, and carotid plaque burden were significantly higher in individuals with DM. Analysis according to territory of cIMT measurement displayed substantial differences in left (DM: 1.32 ± 0.78 mm vs. no DM: 1.20 ± 0.66 mm, p = .04) and right carotid bulbs (DM: 1.33 ± 0.82 mm vs. no DM: 1.18 ± 0.69 mm, p = .02) with respect to DM status while non-significant variations were observed in left (DM: 0.98 ± 0.49 mm vs. no DM: 0.91 ± 0.35 mm, p = .06) and right common carotid artery (DM: 0.95 ± 0.50 mm vs. no DM: 0.92 ± 0.40 mm, p = .36). CONCLUSIONS: Diabetes mellitus is associated with increased cfPWV and cIMT, with more pronounced lesions in the carotid bulb.

The Role of Endothelial Related Circulating Biomarkers in COVID-19. A Systematic Review and Meta-analysis.

BACKGROUND: Several studies have revealed the link between Coronavirus Disease 2019 (COVID-19) and endothelial dysfunction. To better understand the global pattern of this relationship, we conducted a meta-analysis on endothelial biomarkers related to COVID-19 severity. METHODS: We systematically searched the literature up to March 10, 2021, for studies investigating the association between COVID-19 severity and the following endothelial biomarkers: Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), E-selectin, P-selectin, Von Willebrand Factor Antigen (VWFAg), soluble Thrombomodulin (sTM), Mid-regional pro-adrenomedullin (MR-proADM), and Angiopoietin-2 (Ang-2). Pooled estimates and mean differences (PMD) for each biomarker were reported. RESULTS: A total of 27 studies (n=2213 patients) were included. Critically ill patients presented with higher levels of MR-proADM (PMD: 0.71 nmol/L, 95% CI: 0.22 to 1.20 nmol/L, p=0.02), E-selectin (PMD: 13,32 pg/ml, 95% CI: 4,89 to 21,75 pg/ml, p=0.008), VCAM-1 (PMD: 479 ng/ml, 95% CI: 64 to 896 ng/ml, p=0.03), VWF-Ag (PMD: 110.5 IU/dl, 95% CI: 44.8 to 176.1 IU/dl, p=0.04) and Ang-2 (PMD: 2388 pg/ml, 95% CI: 1121 to 3655 pg/ml, p=0.003), as compared to non-critically ill ones. ICAM-1, P-selectin and thrombomodulin did not differ between the two groups (p>0.05). CONCLUSION: Endothelial biomarkers display significant heterogeneity in COVID-19 patients, with higher MR-proADM, E-selectin, VCAM-1, VWF-Ag, and Ang-2 levels being associated with increased severity. These findings strengthen the evidence on the key role of endothelial dysfunction in disease progress.

The impact of sleeping duration on atherosclerosis in the community: insights from the Corinthia study.

PURPOSE: Sleep is an essential physiologic process whose disturbances have been regarded as a risk factor in various pathophysiologic processes, including atherosclerosis and cardiovascular disease. Although the negative influence of short sleep duration has been well-established, recent data suggest a possible harmful effect of prolonged sleeping pattern. METHODS: In the setting of the Corinthia cross-sectional study, self-reported night sleep duration was recorded in 1752 apparently healthy individuals and was classified as normal sleep duration (NSD, 7-8 h), short sleep duration (SSD, 6-7 h), very short sleep duration (VSSD, < 6 h), and long sleep duration (LSD, > 8 h). Carotid duplex ultrasonography was performed in order to measure the mean and maximum carotid intima-media thickness (cIMT) as a non-invasive marker of atherosclerosis. RESULTS: Subjects with LSD and VSSD had significantly higher mean cIMT (VSSD: 1.02 ± 0.45 mm, SSD: 0.95 ± 0.35, NSD: 0.96 ± 0.38 mm, LSD: 1.07 ± 0.52 mm; p < 0.001) and maximum cIMT (VSSD: 1.39 ± 0.9 mm, SSD: 1.25 ± 0.71 mm, NSD: 1.23 ± 0.76 mm, LSD: 1.41 ± 0.93 mm). Following a regression analysis adjusting for known cardiovascular risk factors, individuals with LSD and VSSD had higher mean cIMT by 0.054 mm and 0.067 mm respectively compared to those with NSD. CONCLUSION: A balanced sleeping duration of 6-8 h is associated with decreased mean and maximum IMT while both very short sleep duration and long sleep duration are associated with increased carotid intima-media thickness, a marker of subclinical atherosclerosis.

Pro-inflammatory Cytokines in Acute Coronary Syndromes.

BACKGROUND: Over the last decades, the role of inflammation and immune system activation in the initiation and progression of coronary artery disease (CAD) has been established. OBJECTIVES: The study aimed to present the interplay between cytokines and their actions preceding and shortly after ACS. METHODS: We searched in a systemic manner the most relevant articles to the topic of inflammation, cytokines, vulnerable plaque and myocardial infarction in MEDLINE, COCHRANE and EMBASE databases. RESULTS: Different classes of cytokines (intereleukin [IL]-1 family, Tumor necrosis factor-alpha (TNF-α) family, chemokines, adipokines, interferons) are implicated in the entire process leading to destabilization of the atherosclerotic plaque, and consequently, to the incidence of myocardial infarction. Especially IL-1 and TNF-α family are involved in inflammatory cell accumulation, vulnerable plaque formation, platelet aggregation, cardiomyocyte apoptosis and adverse remodeling following the myocardial infarction. Several cytokines such as IL-6, adiponectin, interferon-γ, appear with significant prognostic value in ACS patients. Thus, research interest focuses on the modulation of inflammation in ACS to improve clinical outcomes. CONCLUSION: Understanding the unique characteristics that accompany each cytokine-cytokine receptor interaction could illuminate the signaling pathways involved in plaque destabilization and indicate future treatment strategies to improve cardiovascular prognosis in ACS patients.

Diagnostic performance of electrocardiographic criteria in echocardiographic diagnosis of different patterns of left ventricular hypertrophy.

BACKGROUND: Electrocardiogram (ECG) is considered the initial screening method for the detection of left ventricular hypertrophy (LVH) despite its low sensitivity. However, there are no data on how ECG criteria for LVH perform in patients with concentric (cLVH) and eccentric LVH (eLVH). METHODS: In the setting of the Corinthia cross-sectional study, ECGs were analyzed in 1,570 participants of the study. Seven ECG LVH criteria were calculated (Sokolow-Lyon voltage, index, and product, sex-specific Cornell voltage and product, Lewis voltage, and the Framingham), whereas LVH was defined, based on echocardiographic data, as left ventricular mass indexed for body surface area (BSA) of at least 125 g/m2 in men and at least 110 g/m2 in women. RESULTS: Regarding the frequency encountered for each ECG LVH criterion, there was no difference between eLVH and cLVH. However, when ECG criteria were compared as continuous variables between LVH groups, Cornell voltage and product were higher in cLVH individuals, with a value of Cornell voltage >13.95 mV having 61% sensitivity and 62% specificity to differentiate cLVH from eLVH (p = .05). Even after adjustment for age, sex, body mass index, and hypertension, the occurrence of Cornell voltage or product increased the odds of cLVH by 1.6 times (p = .001). CONCLUSION: Cornell voltage and product criteria disclosed a superior discriminative ability for the detection of LVH via ECG. When further categorizing LVH as concentric and eccentric, Cornell product depicted the higher discriminative ability for cLVH.

Alcohol Consumption and Aortic Root Dilatation: Insights from the Corinthia Study.

Aortic diameter and progression to thoracic aortic aneurysm are influenced by several factors. In this study, we investigated the association of alcohol consumption with aortic root and ascending aorta dilatation. In the context of the Corinthia study, we examined 1751 patients with echocardiography. Several demographic and clinical characteristics were recorded. Alcohol consumption was assessed based on a questionnaire of frequency, type, and quantity. Accordingly, patients were categorized as everyday alcohol consumers (EDACs) and as social drinkers (SoD). Everyday alcohol consumers were further categorized to group 1: 0 to 1 drink/d; group 2: 1 to 2 drinks/d; and group 3: ≥3 drinks/d. From the study population, 40% were categorized as EDAC and had an increased aortic root diameter (AoRD) and an elevated AoRD index compared with SoD. Interestingly, there was a stepwise increase in aortic root and ascending aorta diameter according to daily alcohol consumption. Specifically, patients consuming ≥3 drinks of alcohol/d had increased indexed aortic by 1.4 mm/m2 compared with SoD even after adjustment for possible confounders. Daily alcohol consumption is associated with increased aortic root diameter. These findings may have important clinical implications, especially in patients with borderline or dilated aortic root, and merit further investigation.

The impact of sedentary behavior patterns on carotid atherosclerotic burden: Implications from the Corinthia epidemiological study.

BACKGROUND AND AIMS: Sedentary lifestyle, unlike leisure time physical activity (PA), is associated with atherosclerosis progression. Regarding the interrelationship between television watching, as a sedentary behavior pattern, and cardiovascular disease burden, few data exist. METHODS: In this cross-sectional epidemiological study based on 2043 inhabitants of the Corinthia region, in Greece, ultrasonography was used to measure carotid intima-media thickness (IMT) in both carotid arteries. The average (meanIMT) and maximum thickness (maxIMT) were determined as representative values of subclinical atherosclerosis. We evaluated PA using the self-reported International Physical Activity Questionnaire (IPAQ). Based on specific questions, the average hours per week spent on watching television (TV), videos or DVD was calculated for each participant. RESULTS: According to TV viewing time, subjects were categorized into the low (≤7 h/week), moderate (7˃ TV hours/week ≤21) and high (˃21 h/week) TV viewing time groups. Prevalence of carotid atheromatic plaque was lower in the low TV viewing time group compared to the moderate and high TV viewing time groups (p = 0.02). TV viewing time was associated with increased carotid IMT (p = 0.03) and the prevalence of carotid atheromatic plaque (p = 0.02), even after adjustment for age, body mass index, cardiovascular risk factors or history of cardiovascular disease. Subjects in the high TV viewing time group have 80% increase odds of carotid atheromatic plaque compared to patients categorized in the low TV viewing time group (p = 0.01). CONCLUSIONS: The present findings have important public health implications, providing a better understanding of the components of sedentary behavior that are associated with atherosclerotic progression.

Redox State in Atrial Fibrillation Pathogenesis and Relevant Therapeutic Approaches.

BACKGROUND: Myocardial redox state is a critical determinant of atrial biology, regulating cardiomyocyte apoptosis, ion channel function, and cardiac hypertrophy/fibrosis and function. Nevertheless, it remains unclear whether the targeting of atrial redox state is a rational therapeutic strategy for atrial fibrillation prevention. OBJECTIVE: To review the role of atrial redox state and anti-oxidant therapies in atrial fibrillation. METHOD: Published literature in Medline was searched for experimental and clinical evidence linking myocardial redox state with atrial fibrillation pathogenesis as well as studies looking into the role of redoxtargeting therapies in the prevention of atrial fibrillation. RESULTS: Data from animal models have shown that altered myocardial nitroso-redox balance and NADPH oxidases activity are causally involved in the pathogenesis of atrial fibrillation. Similarly experimental animal data supports that increased reactive oxygen / nitrogen species formation in the atrial tissue is associated with altered electrophysiological properties of atrial myocytes and electrical remodeling, favoring atrial fibrillation development. In humans, randomized clinical studies using redox-related therapeutic approaches (e.g. statins or antioxidant agents) have not documented any benefits in the prevention of atrial fibrillation development (mainly post-operative atrial fibrillation risk). CONCLUSION: Despite strong experimental and translational data supporting the role of atrial redox state in atrial fibrillation pathogenesis, such mechanistic evidence has not been translated to clinical benefits in atrial fibrillation risk in randomized clinical studies using redox-related therapies.