Article

Oxidative Stress Markers Are Associated with Persistent Atrial Fibrillation

October 2007
Clinical Chemistry 53(9):1652-7

October 2007
53(9):1652-7

DOI:10.1373/clinchem.2006.083923

Source
PubMed

Authors:

Heather Bloom

Emory University

Irfan Shukrullah

University of Illinois at Chicago

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Atrial fibrillation (AF) has been associated with myocardial oxidative stress, and antioxidant agents have demonstrated antiarrhythmic benefit in humans. We compared serum markers of oxidation and associated inflammation in individuals with or without AF. Serum markers of oxidative stress and inflammation were compared in a cross-sectional, case-control design study of 40 male individuals, with or without persistent or permanent AF, who were matched for age, sex, diabetes, and smoking status, known confounding variables for the measurement of oxidative stress. We used derivatives of reactive oxidative metabolites (DROMs) and ratios of oxidized to reduced glutathione (E(h) GSH) and cysteine (E(h) CySH) to quantify oxidative stress. We also measured inflammatory markers, including high-sensitivity C-reactive protein, interleukins 1beta and 6, and tumor necrosis factor alpha. Univariate, conditional logistical regression analysis showed that oxidative stress but not inflammatory markers were statistically associated with AF (P <0.05). The increase in the odds ratios for AF for E(h) GSH, E(h) CySH, and DROMs were 6.1 (95% CI, 1.3-28.3; P = 0.02), 13.6 (95% CI, 2.5-74.1; P = 0.01), and 15.9 (95% CI, 1.7-153.9; P = 0.02), respectively. There was a stronger correlation between E(h) GSH and E(h) CySH (r = 0.66) than between E(h) GSH and DROMs (r = 0.41). In multivariate analysis corrected for statins and other AF risk factors differing between the groups, the association of AF and oxidative stress remained significant. These data suggest that oxidative stress markers may have predictive value in AF management.

Developing Pharmacological Therapies for Atrial Fibrillation Targeting Mitochondrial Dysfunction and Oxidative Stress: A Scoping Review

Preprint

Full-text available

Nov 2023

Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and comorbidities. A direct relation exists between AF and altered mitochondrial activity resulting from membrane potential loss, contractile dysfunction, or decreased ATP levels. This review aimed to elucidate the role of mitochondrial oxidative mechanisms in AF pathophysiology, the impact of mitochondrial oxidative stress on AF initiation and perpetuation, and current therapies. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews. PubMed, Excerpta Medica Database, and Scopus were explored until June 2023 using "MESH terms." Bibliographic references from relevant papers were also included. Oxidative stress is an imbalance that causes cellular damage from excessive oxidation, resulting in conditions such as AF. An imbalance in reactive oxygen species production and elimination can cause mitochondrial damage, cellular apoptosis, and cardiovascular diseases. Oxidative stress and inflammation are intrinsically linked, and inflammatory pathways are highly correlated with the occurrence of AF. AF is an intricate cardiac condition that requires innovative therapeutic approaches. The involvement of mitochondrial oxidative stress in the pathophysiology of AF introduces novel strategies for clinical treatment.

Elevated 8-isoprostane concentration is associated with thromboembolic events in patients with atrial fibrillation

Article

Full-text available

Jul 2022
INT J CARDIOL

Background Enhanced oxidative stress occurs in atrial fibrillation (AF), however its impact on the efficacy and safety of anticoagulation is unknown. We sought to evaluate whether 8-isoprostaglandin F2 (8-isoprostane) levels are associated with clinical outcomes in anticoagulated AF patients. Methods In a study involving 243 AF patients (median age 69 years), we measured serum 8-isoprostane, along with prothrombotic markers, including plasma fibrin clot permeability, clot lysis time (CLT), endogenous thrombin potential (ETP), von Willebrand factor (VWF), and fibrinolytic proteins. Ischemic cerebrovascular events, major bleeding, and death were recorded during a median follow-up of 53 months while on anticoagulation, largely on non-vitamin K antagonist oral anticoagulants (NOACs). Results Increased 8-isoprostane levels were observed in women, in patients with arterial hypertension, and those with paroxysmal or persistent AF. Patients with 8-isoprostane levels ≥559 pg/mL (the top quartile) compared with those with 8-isoprostane <250 pg/mL (the bottom quartile) had higher fibrinogen, lower VWF, higher plasminogen activator inhibitor 1, along with lower fibrin clot permeability with no difference in CHA2DS2-VASc score, CLT or ETP. Patients who experienced thromboembolic events (n = 20, 1.9%/year) had 48.6% higher 8-isoprostane concentrations compared to the remainder (P < 0.01). Levels of 8-isoprostane >459 pg/mL based on the optimal cut-off value were associated with thromboembolic events during follow-up (hazard ratio 2.87, 95% confidence interval 1.17–7.03, P = 0.02). There were no associations between 8-isoprostane and major bleeding (2.0%/year) or all-cause mortality (1.9%/year). Conclusions Increased 8-isoprostane levels partly through altered fibrin clot structure are associated with thromboembolic events despite anticoagulant therapy in AF patients.

Melatonin to Rescue the Aged Heart: Antiarrhythmic and Antioxidant Benefits

Article

Full-text available

Mar 2021
OXID MED CELL LONGEV

Aging comes with gradual loss of functions that increase the vulnerability to disease, senescence, and death. The mechanisms underlying these processes are linked to a prolonged imbalance between damage and repair. Damaging mechanisms include oxidative stress, mitochondrial dysfunction, chronodisruption, inflammation, and telomere attrition, as well as genetic and epigenetic alterations. Several endogenous tissue repairing mechanisms also decrease. These alterations associated with aging affect the entire organism. The most devastating manifestations involve the cardiovascular system and may lead to lethal cardiac arrhythmias. Together with structural remodeling, electrophysiological and intercellular communication alterations during aging predispose to arrhythmic events. Despite the knowledge on repairing mechanisms in the cardiovascular system, effective antiaging strategies able to reduce the risk of arrhythmias are still missing. Melatonin is a promising therapeutic candidate due to its pleiotropic actions. This indoleamine regulates chronobiology and endocrine physiology. Of relevance, melatonin is an antiaging, antioxidant, antiapoptotic, antiarrhythmic, immunomodulatory, and antiproliferative molecule. This review focuses on the protective effects of melatonin on age-induced cardiac functional and structural alterations, potentially becoming a new fountain of youth for the heart.

Preoperative monocyte‐to‐HDL‐cholesterol ratio predicts early recurrence after radiofrequency maze procedure of valvular atrial fibrillation

Article

Full-text available

Sep 2020
J CLIN LAB ANAL

Background Monocyte‐to‐high‐density lipoprotein (M/H) ratio has emerged as a novel cardiovascular prognostic biomarker. We aimed to evaluate the prognostic values of M/H with early recurrence in persistent valvular atrial fibrillation (AF) patients after radiofrequency (RF) maze procedure. Methods We retrospectively analyzed 131 consecutive persistent AF patients with valvular heart diseases who were followed up 3 months after RF maze procedure. Their clinical data were recorded. Logistic regression analyses were performed for significant predictors. Receiver operating characteristic analysis was used for validation with corresponding area under the curve. Results 70 (53.4%) patients experienced early recurrence after procedure. Patients with early recurrence were older, have longer AF duration history, larger left atria diameter (LAD), higher plasma C‐reactive protein (CRP), lower triglycerides (TG), lower cholesterol (TC), increased monocyte counts, lower HDL cholesterol, and increased M/H ratio. In multivariate analysis, age (OR 1.1 95% CI 1.0‐1.1 P = .003), LAD (OR 2.1, 95%CI 1.2‐3.5, P = .006), TG (OR 0.35, 95% CI 0.15‐0.84, P = .019), M/H (OR 6.1, 95% CI 2.9‐13.0, P < .001) were significantly independent predictors of AF early recurrence. M/H ratio demonstrated a significant predictive value (AUC = 0.77, sensitivity 89.0%, specificity 54%). Further, there was a positive correlation of M/H ratio with CRP and white blood cell. Conclusion Preoperative M/H ratio was an independent risk factor of AF early recurrence following RF maze operation. M/H ratio should be considered in prediction of early recurrence for valvular AF patients.

Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target

Article

Jun 2020

Ca²⁺ is a fundamental second messenger in all cell types and is required for numerous essential cellular functions, including cardiac and skeletal muscle contraction. The intracellular concentration of free Ca²⁺ ([Ca²⁺]) is regulated primarily by ion channels, pumps (ATPases), exchangers and Ca²⁺-binding proteins. Defective regulation of [Ca²⁺] is found in a diverse spectrum of pathological states that affect all the major organs. In the heart, abnormalities in the regulation of cytosolic and mitochondrial [Ca²⁺] occur in heart failure (HF) and atrial fibrillation (AF), two common forms of heart disease and leading contributors to morbidity and mortality. In this Review, we focus on the mechanisms that regulate ryanodine receptor 2 (RYR2), the major sarcoplasmic reticulum (SR) Ca²⁺-release channel in the heart, how RYR2 becomes dysfunctional in HF and AF, and its potential as a therapeutic target. Inherited RYR2 mutations and/or stress-induced phosphorylation and oxidation of the protein destabilize the closed state of the channel, resulting in a pathological diastolic Ca²⁺ leak from the SR that both triggers arrhythmias and impairs contractility. On the basis of our increased understanding of SR Ca²⁺ leak as a shared Ca²⁺-dependent pathological mechanism in HF and AF, a new class of drugs developed in our laboratory, known as rycals, which stabilize RYR2 channels and prevent Ca²⁺ leak from the SR, are undergoing investigation in clinical trials.

The relationship between red blood cell distribution width and atrial fibrillation in Asian population: A cross-sectional study

Article

Aug 2019

Background: Red blood cell distribution width (RDW) was related with increased risk of mortality and adverse cardiovascular outcomes. However, it is uncertain whether RDW is related to the prevalence of atrial fibrillation (AF) in Asian population. The aim of this study was to assess the relationship between RDW and AF in a large Chinese population. Methods: We performed a cross-sectional study to examine the relationship between RDW and AF among 106,998 subjects who were from the Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) Cohort Study. AF was diagnosed using electrocardiography, and RDW was measured using an automated hematology analyzer. Multiple logistic regression models were conducted to examine the relation between tertiles of RDW and AF. Results: The overall prevalence of AF was 0.1% (129/106,998). After adjustments for potential confounding factors, the odds ratios (95% confidence intervals) of AF across increasing tertiles of RDW were 1.00 (reference), 1.08 (0.69, 1.67), and 2.65 (1.75, 4.07) (P for trend <0.0001), respectively. Conclusions: The study demonstrated that elevated RDW is significantly related to higher prevalence of AF in a general Chinese population. Large prospective studies are needed to confirm this finding. This article is protected by copyright. All rights reserved.

The effect of hypertension on cerebrovascular carbon dioxide reactivity in atrial fibrillation patients

Article

Full-text available

Apr 2024

Atrial fibrillation (AF) and hypertension (HTN) are both associated with impaired cerebrovascular carbon dioxide reactivity (CVR CO2 ), an indicator of cerebral vasodilatory reserve. We hypothesised that CVR CO2 would be lower in patients with both AF and HTN (AF + HTN) compared to normotensive AF patients, due to an additive effect of AF and HTN on CVR CO2 . Forty AF (68 ± 9 years) and fifty-seven AF + HTN (68 ± 8 years) patients underwent transcranial Doppler ultrasound measurement of middle cerebral artery blood velocity (MCA V m ) during stepped increases and decreases in end-tidal carbon dioxide (P ET CO 2 ). A cerebrovascular conductance index (CVCi) was calculated as the ratio of MCA V m and mean arterial pressure (MAP). CVR CO2 was determined from the linear slope for MCA V m and MCA CVCi vs P ET CO 2 . Baseline MAP was higher in AF + HTN than AF (107 ± 9 vs. 98 ± 9 mmHg, respectively; p < 0.001), while MCA V m was not different (AF + HTN:49.6 [44.1–69.0]; AF:51.7 [45.2–63.3] cm.s ⁻¹ ; p = 0.075), and CVCi was lower in AF + HTN (0.46 [0.42–0.57] vs. 0.54 [0.44–0.63] cm.s ⁻¹ .mmHg ⁻¹ ; p < 0.001). MCA V m CVR CO2 was not different (AF + HTN: 1.70 [1.47–2.19]; AF 1.74 [1.54–2.52] cm/s/mmHg ⁻² ; p = 0.221), while CVCi CVR CO2 was 13% lower in AF + HTN (0.013 ± 0.004 vs 0.015 ± 0.005 cm.s ⁻¹ .mmHg ⁻¹ ; p = 0.047). Our results demonstrate blunted cerebral vasodilatory reserve (determined as MCA CVCi CVR CO2 ) in AF + HTN compared to AF alone. This may implicate HTN as a driver of further cerebrovascular dysfunction in AF that may be important for the development of AF-related cerebrovascular events and downstream cognitive decline.

Advancements in Gene Therapy approaches for Atrial Fibrillation: Targeted delivery, Mechanistic Insights and Future Prospects

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Feb 2024
CURR PROB CARDIOLOGY

Oxidative Stress, Inflammation, and Mitochondrial Dysfunction: A Link between Obesity and Atrial Fibrillation

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Jan 2024

The adipose tissue has long been thought to represent a passive source of triglycerides and fatty acids. However, extensive data have demonstrated that the adipose tissue is also a major endocrine organ that directly or indirectly affects the physiological functions of almost all cell types. Obesity is recognized as a risk factor for multiple systemic conditions, including metabolic syndrome, type 2 diabetes mellitus, sleep apnea, cardiovascular disorders, and many others. Obesity-related changes in the adipose tissue induce functional and structural changes in cardiac myocytes, promoting a wide range of cardiovascular disorders, including atrial fibrillation (AF). Due to the wealth of epidemiologic data linking AF to obesity, the mechanisms underlying AF occurrence in obese patients are an area of rich ongoing investigation. However, progress has been somewhat slowed by the complex phenotypes of both obesity and AF. The triad inflammation, oxidative stress, and mitochondrial dysfunction are critical for AF pathogenesis in the setting of obesity via multiple structural and functional proarrhythmic changes at the level of the atria. The aim of this paper is to provide a comprehensive view of the close relationship between obesity-induced oxidative stress, inflammation, and mitochondrial dysfunction and the pathogenesis of AF. The clinical implications of these mechanistic insights are also discussed.

The Usefulness of RDW as a Predictor of Atrial Fibrillation Recurrence after Cryoablation

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Sep 2023

Obesity and atrial fibrillation: a narrative review from arrhythmogenic mechanisms to clinical significance

Article

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Jul 2023
CARDIOVASC DIABETOL

The prevalence of obesity and atrial fibrillation (AF), which are inextricably linked, is rapidly increasing worldwide. Obesity rates are higher among patients with AF than healthy individuals. Some epidemiological data indicated that obese patients were more likely to develop AF, but others reported no significant correlation. Obesity-related hypertension, diabetes, and obstructive sleep apnea are all associated with AF. Additionally, increased epicardial fat, systemic inflammation, and oxidative stress caused by obesity can induce atrial enlargement, inflammatory activation, local myocardial fibrosis, and electrical conduction abnormalities, all of which led to AF and promoted its persistence. Weight loss reduced the risk and reversed natural progression of AF, which may be due to its anti-fibrosis and inflammation effect. However, fluctuations in weight offset the benefits of weight loss. Therefore, the importance of steady weight loss urges clinicians to incorporate weight management interventions in the treatment of patients with AF. In this review, we discuss the epidemiology of obesity and AF, summarize the mechanisms by which obesity triggers AF, and explain how weight loss improves the prognosis of AF.

Epidemiology of atrial fibrillation

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Jun 2009
SWISS MED WKLY

CM Albert

Insulin‐like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence

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Sep 2022

Aims Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results We have measured plasma IGFBP7 concentrations in 2250 subjects with new‐onset or worsening heart failure (BIOSTAT‐CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT‐proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all‐cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25–2.46; HR 1.71, 95% CI 1.39–2.11; and HR 1.44, 95% CI 1.23–1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT‐CHF validation cohort. Conclusions IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.

Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases

Article

Full-text available

Sep 2022
INT J MOL SCI

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading across the cardiac tissue. Dislocation of Cx43 to lateral membranes has been detected in numerous cardiac diseases leading to slowed conduction and high propensity for the development of arrhythmias. At the cellular level, arrhythmogenic diseases are associated with elevated levels of oxidative distress and gap junction remodeling affecting especially the amount and sarcolemmal distribution of Cx43 expression. So far, a mechanistic link between sustained oxidative distress and altered Cx43 expression has not yet been identified. Here, we propose a novel cell model based on murine induced-pluripotent stem cell-derived cardiomyocytes to investigate subcellular signaling pathways linking cardiomyocyte distress with gap junction remodeling. We tested the new hypothesis that chronic distress, induced by rapid pacing, leads to increased reactive oxygen species, which promotes expression of a micro-RNA, miR-1, specific for the control of Cx43. Our data demonstrate that Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression. This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Moreover, Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, we propose miR-1 as a novel target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart.

The Prognostic Value of Derivatives-Reactive Oxygen Metabolites (d-ROMs) for Cardiovascular Disease Events and Mortality: A Review

Article

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Aug 2022

Oxidative stress participates in the development and exacerbation of cardiovascular diseases (CVD). The ability to promptly quantify an imbalance in an individual reductive-oxidative (RedOx) state could improve cardiovascular risk assessment and management. Derivatives-reactive oxygen metabolites (d-ROMs) are an emerging biomarker of oxidative stress quantifiable in minutes through standard biochemical analysers or by a bedside point-of-care test. The current review evaluates available data on the prognostic value of d-ROMs for CVD events and mortality in individuals with known and unknown CVD. Outcome studies involving small and large cohorts were analysed and hazard ratio, risk ratio, odds ratio, and mean differences were used as measures of effect. High d-ROM plasma levels were found to be an independent predictor of CVD events and mortality. Risk begins increasing at d-ROM levels higher than 340 UCARR and rises considerably above 400 UCARR. Conversely, low d-ROM plasma levels are a good negative predictor for CVD events in patients with coronary artery disease and heart failure. Moreover, combining d-ROMs with other relevant biomarkers routinely used in clinical practice might support a more precise cardiovascular risk assessment. We conclude that d-ROMs represent an emerging oxidative-stress-related biomarker with the potential for better risk stratification both in primary and secondary cardiovascular prevention.

Risk Factors of Early Atrial Fibrillation Recurrence Following Electrical Cardioversion When Left Ventricular Ejection Fraction Is Preserved

Article

Full-text available

Aug 2022

Background and objectives: To identify clinical, echocardiographic, and laboratory parameters that affect the early recurrence of atrial fibrillation (AF) after restoring sinus rhythm (SR) by electrical cardioversion (ECV), and to determine whether left atrial (LA) strain, as a noninvasive indicator reflecting fibrosis, is associated with laboratory indicators affecting the development of fibrosis, interleukin 6 (IL-6) or tumor necrosis factor α (TNF-α). Materials and Methods: The study included 92 persistent AF patients who underwent elective ECV. The effective maintenance of SR was evaluated after 40 ± 10 days of ECV. Echocardiography, inflammatory markers (high-sensitivity c-reactive protein (hs-CRP), IL-6, and TNF-α), and natriuretic peptides (N-terminal pro b-type natriuretic peptide (NT-proBNP) and N-terminal pro a-type natriuretic peptide (NT-proANP)) were assessed. Results: After a 40 ± 10 days observation period, 51 patients (55.4%) were in SR. Patients with AF recurrence had a significantly longer duration of AF (p = 0.008) and of arterial hypertension (p = 0.035), lower LA ejection fraction (p = 0.009), lower LA strain (p < 0.0001), higher left ventricular global longitudinal strain (p = 0.001), and a higher E/e‘ ratio (p < 0.0001). LA strain was an independent predictor of early AF recurrence (OR: 0.65; 95% Cl 0.5–0.9, p = 0.004). LA strain < 11.85% predicted AF recurrence with 70% sensitivity and 88% specificity (AUC 0.855, 95% CI 0.77–0.94, p < 0.0001). LA strain demonstrated the association with NT-proBNP (r = −0.489, p < 0.0001) and NT-proANP (r = −0.378, p = 0.002), as well as with hs-CRP (r = −0.243, p = 0.04). Conclusions: LA strain appeared to be the most accurate predictor of early AF recurrence after ECV in patients with persistent AF. LA strain inversely correlated with NT-proBNP and NT-proANP, but no significant association with any of the inflammatory markers was identified.

Beneficial Effect of Edoxaban on Preventing Atrial Fibrillation and Coagulation by Reducing Inflammation via HBG1/HBD Biomarkers

Article

Full-text available

Jun 2022

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The effectiveness and mechanism of edoxaban in preventing stroke after atrial fibrillation remain unclear. Methods: The expressions of HBG1 and HBD in red blood cells were tested in AF. Sixty C57B/6J mice were randomly divided into the following groups: the control (CON) group, atrial fibrillation (AF) group, AF + edoxaban group, and AF + rivaroxaban group. H&E staining assay and reticular fiber staining were performed. Myocardial fibrosis was evaluated by the Masson staining assay, Sirius red staining assay, and immunohistochemical assay for the expressions of α-SMA and COL1A1. ELISA and RT-PCR assay were performed for the detection of inflammatory parameters (TNF-α, IL-1β, IL-6, and IL-10). Blood lipids were detected by using the Beckman automatic biochemical analyzer. Furthermore, four items of coagulation were detected, and molecular docking among HBG1, HBD, and MASP1 (Xa) was performed by PyMOL 2.1 software. The BP neural network model, cubic spline interpolation, and support vector machine model were constructed to predict prothrombin time based on HBG1 and HBD expressions. COIP assay was performed to construct the interaction between HBG1 and HBD. The functional enrichment analysis was performed by DAVID and Metascape tools. Results : The expressions of HBG1 and HBD in red blood cells of the patients with atrial fibrillation were decreased. The results showed a lower level of hemoglobin in red blood cells with HBG1-siRNA and HBG1-siRNA. Compared with the AF group, the collagen fiber percentage in the AF + edoxaban group was decreased ( p < 0.05). After using edoxaban, the expressions of TNF-α, IL-1β, IL-6, and IL-10 were significantly decreased ( p < 0.05). The LDL-C, TC, and TG levels were downregulated in the AF + edoxaban group. The PT and APTT levels in the AF + edoxaban group were more increasing than in the AF mice ( p < 0.05). Compared with the AF group, the expressions of HBG1 and HBD were downregulated in the AF + edoxaban group ( p < 0.05). HBG1 protein matched well with HBD and MASP1(Xa) protein surfaces. There exists a significant interaction between HBG1, HBD, and PT via the BP neural network and support vector machine. Enrichment analysis showed that HBG1 and HBD were mainly enriched in blood coagulation. Conclusion: Edoxaban could prevent atrial fibrillation and coagulation by reducing inflammation, lipids, and fibrosis via HBG1/HBD biomarkers effectively, and the effect was superior to that of rivaroxaban.

Oxidative stress: A bystander or a causal contributor to atrial remodelling and fibrillation?

Article

Apr 2021

Stress-driven cardiac calcium mishandling via a kinase-to-kinase crosstalk

Article

Full-text available

Mar 2021
PFLUG ARCH EUR J PHY

Calcium homeostasis in the cardiomyocyte is critical to the regulation of normal cardiac function. Abnormal calcium dynamics such as altered uptake by the sarcoplasmic reticulum (SR) Ca²⁺-ATPase and increased diastolic SR calcium leak are involved in the development of maladaptive cardiac remodeling under pathological conditions. Ca²⁺/calmodulin-dependent protein kinase II-δ (CaMKIIδ) is a well-recognized key molecule in calcium dysregulation in cardiomyocytes. Elevated cellular stress is known as a common feature during pathological remodeling, and c-jun N-terminal kinase (JNK) is an important stress kinase that is activated in response to intrinsic and extrinsic stress stimuli. Our lab recently identified specific actions of JNK isoform 2 (JNK2) in CaMKIIδ expression, activation, and CaMKIIδ-dependent SR Ca²⁺ mishandling in the stressed heart. This review focuses on the current understanding of cardiac SR calcium handling under physiological and pathological conditions as well as the newly identified contribution of the stress kinase JNK2 in CaMKIIδ-dependent SR Ca²⁺ abnormal mishandling. The new findings identifying dual roles of JNK2 in CaMKIIδ expression and activation are also discussed in this review.

Cardiac adaptation and cardioprotection against arrhythmias and ischemia-reperfusion injury in mammalian hibernators

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Full-text available

Mar 2021
PFLUG ARCH EUR J PHY

Hibernation allows animals to enter an energy conserving state to survive severe drops in external temperatures and a shortage of food. It has been observed that the hearts of mammalian hibernators exhibit intrinsic protection against ischemia-reperfusion (I/R) injury and cardiac arrhythmias in the winter whether they are hibernating or not. However, the molecular and ionic mechanisms for cardioprotection in mammalian hibernators remain elusive. Recent studies in woodchucks (Marmota monax) have suggested that cardiac adaptation occurs at different levels and mediates an intrinsic cardioprotection prior to/in the winter. The molecular/cellular remodeling in the winter (with or without hibernation) includes (1) an upregulation of transcriptional factor, anti-apoptotic factor, nitric oxide synthase, protein kinase C-ε, and phosphatidylinositol-4,5-bisphosphate 3-kinase; (2) an upregulation of antioxidant enzymes (e.g. superoxide dismutase and catalase); (3) a reduction in the oxidation level of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII); and (4) alterations in the expression and activity of multiple ion channels/transporters. Therefore, the cardioprotection against I/R injury in the winter is most likely mediated by enhancement in signaling pathways that are shared by preconditioning, reduced cell apoptosis, and increased detoxification of reactive oxygen species (ROS). The resistance to cardiac arrhythmias and sudden cardiac death in the winter is closely associated with an upregulation of the antioxidant catalase and a downregulation of CaMKII activation. This remodeling of the heart is associated with a reduction in the incidence of afterdepolarizations and triggered activities. In this short review article, we will discuss the seasonal changes in gene and protein expression profiles as well as alterations in the function of key proteins that are associated with the occurrence of cardioprotection against myocardial damage from ischemic events and fatal arrhythmias in a mammalian hibernator. Understanding the intrinsic cardiac adaptive mechanisms that confer cardioprotection in hibernators may offer new strategies to protect non-hibernating animals, especially humans, from I/R injury and ischemia-induced fatal cardiac arrhythmias.

Dietary supplementation of a sulforaphane-enriched broccoli extract protects the heart from acute cardiac stress

Article

Full-text available

Dec 2020

Cardiac arrythmias play a critical role in several pathological conditions. Importantly, increased arrhythmic risk is associated with systemic oxidative stress and activation of the autonomic nervous system. Thus, we hypothesized that dietary antioxidant supplementation may help in reducing cardiac stress-induced arrhythmias. Sulforaphane (SFN), an isothiocyanate present in Brassicaceaes, is recognized as a powerful health-promoting compound with known antioxidant properties. Then, we aimed to generate a broccoli extract (BE) enriched in SFN and determine whether oral BE supplementation induced cardio-protection during acute cardiac stress in rats. BE decreases cardiac sympathetic drive and increases parasympathetic cardiac modulation as evidenced by heart rate variability (HRV) shifts. In addition, isoproterenol-induced cardiac stress (a sympathomimetic agent) induced a ~ 4-fold increase in arrhythmia incidence and this effect was almost completely abolished by BE treatment. In conclusion, dietary supplementation with a BE regulates cardiac autonomic drive and protects the heart from acute cardiac stress.

Evidence for Inflammation as a Driver of Atrial Fibrillation

Article

Full-text available

Apr 2020

Atrial fibrillation (AF) is one of the most common types of arrhythmias and increases cardiovascular morbidity and mortality. Current therapeutic approaches to AF that focus on rhythm control have high recurrence rates and no life prolongation value. While possible explanations include toxicity of current therapies, another likely explanation may be that current therapies do not address fundamental mechanisms of AF initiation and maintenance. Inflammation has been shown to affect signaling pathways that lead to the development of AF. This paper reviews the roles of inflammation in the occurrence, development, and mechanisms of AF and reviews the therapeutic implications of the correlation of inflammation and AF.

Wenxin Keli Regulates Mitochondrial Oxidative Stress and Homeostasis and Improves Atrial Remodeling in Diabetic Rats

Article

Full-text available

Feb 2020
OXID MED CELL LONGEV

Mitochondrial dysfunction and oxidative stress play an important role in the pathogenesis of both atrial fibrillation (AF) and diabetes mellitus (DM). Wenxin Keli (WXKL), an antiarrhythmic traditional Chinese medicine, has been shown to prevent cardiac arrhythmias through modulation of cardiac ion channels. This study tested the hypothesis that WXKL can improve atrial remodeling in diabetic rats by restoring mitochondrial function. Primary atrial fibroblasts of neonatal SD rats were divided into four groups: control, hydrogen peroxide (H2O2), H2O2+WXKL 1 g/L, and H2O2+WXKL 3 g/L groups. Intracellular mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitochondrial oxygen consumption were measured. SD male rats were randomly divided into three groups: control, DM, and DM+WXKL groups. Rats in the DM+WXKL group were treated with daily gavage of WXKL at 3 g/kg. After eight weeks, echocardiography, hemodynamic examination, histology, electrophysiology study, mitochondrial respiratory function, and western blots were assessed. H2O2 treatment led to increased ROS and decreased intracellular MMP and mitochondrial oxygen consumption in primary atrial fibroblasts. WXKL improved the above changes. DM rats showed increased atrial fibrosis, greater left atrial diameter, lower atrial conduction velocity, higher conduction heterogeneity, higher AF inducibility, and lower mitochondrial protein expression, and all these abnormal changes except for left atrial diameter were improved in the DM+WXKL group. WXKL improves atrial remodeling by regulating mitochondrial function and homeostasis and reducing mitochondrial ROS in diabetic rats.

Anaphylaxis-induced atrial fibrillation and anesthesia: Pathophysiologic and therapeutic considerations

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Full-text available

Jan 2020

Atrial fibrillation is the most common cardiac arrhythmia in western society affecting more than 35 million individuals worldwide annually. It is a common postoperative complication and may also occur spontaneously during general and local anesthesia administration. Aging, diabetes mellitus, hypertension, and cardiovascular diseases including cardiomyopathies, congenital cardiac anomalies, heart failure, myocardial ischemia, pericarditis, previous cardiac surgery, vascular disease, and valvular heart disease are some correlated factors. Beyond age, increased incidence of atrial fibrillation has been correlated to autoimmune system activation as it is the underlying mechanism of persistent atrial fibrillation development. Current research supports an association between the complement system activation and lymphocyte-pro-inflammatory cytokines release with the cardiac conduction system and atrial fibrosis. The loss of CD28 antigen from CD4+ CD28+ T lymphocytes seems to play a major role in atrial fibrillation development and prognosis. Except atrial fibrillation, a variety of additional electrocardiographic changes, resembling those with digitalis intoxication may accompany anaphylaxis and particularly Kounis syndrome. Histamine is one well-known mediator in allergic and inflammatory conditions as physiologically regulates several cardiovascular and endothelial functions with arrhythmogenic potential. The increased oxidative stress, measured by the redox potentials of glutathione, has been correlated with atrial fibrillation incidence and prevalence. The use of antazoline, a first-generation antihistamine agent used for rapid conversion of recent-onset atrial fibrillation in patients with preserved left ventricular function and for rapid atrial fibrillation termination during accessory pathway ablation denotes that anaphylaxis-induced histamine production could be the cause of atrial fibrillation at least in some instances. The anaphylaxis diagnosis in anesthesia can be challenging owing to the absence of cutaneous manifestetions such as flushing, urticaria, or angioedema. Anticoagulation for stroke prevention, rate and rhythm control medications, invasive methods such as radiofrequency ablation or cryoablation of pulmonary veins as well surgical ablation constitute the treatment basis of atrial fibrillation. Understanding the underlying mechanisms of atrial fibrillation by cardiologists, anesthesiologists and surgeons, as well as potential treatments, to optimize care is of paramount importance.

Effects of N-acetyl cysteine, vitamin E and vitamin C on liver glutathione levels following amiodarone treatment in rats

Article

Full-text available

Jul 2019
KARDIOCHIR TORAKOCHI

Introduction: Amiodarone, a pharmaceutical extensively used to suppress atrial and ventricular tachyarrhythmias, is also known to cause many side effects on many tissues. N-acetyl-cysteine (NAC), vitamin E and vitamin C are known as antioxidants for their ability to minimize oxidative stress. In the peer-reviewed literature, there is no study reporting on the protective effects of these antioxidant agents against its hepatotoxicity. Aim: We investigated the oxidative effects of NAC, vitamins E and C on liver tissue after amiodarone treatment. Material and methods: Rats were randomly assigned to: control; amiodarone group; amiodarone + NAC treated group; amiodarone + Vit. E group and amiodarone + Vit. C group. Liver tissues were isolated from animals and total glutathione levels were measured. Results: In all time intervals, the level of glutathione increased. When all time intervals were compared, the amiodarone group revealed the lowest levels. The antioxidant co-administered group was studied; the glutathione levels were statistically significantly higher than the sole amiodarone group. When vitamins E, C or N-acetyl cysteine were examined, there was no statistically significant difference among them. Conclusions: In this study we found that hepatotoxicity capacity of amiodarone may be reduced by taking up antioxidants. In addition, the effect documented here may be reproducible and may be applied to clinical settings.

Biomarkers of Inflammation in Left Ventricular Diastolic Dysfunction

Article

Full-text available

Jun 2019
DIS MARKERS

Left ventricular diastolic dysfunction (LVDD) is an important precursor to many different cardiovascular diseases. Diastolic abnormalities have been studied extensively in the past decade, and it has been confirmed that one of the mechanisms leading to heart failure is a chronic, low-grade inflammatory reaction. The triggers are classical cardiovascular risk factors, grouped under the name of metabolic syndrome (MetS), or other systemic diseases that have an inflammatory substrate such as chronic obstructive pulmonary disease. The triggers could induce myocardial apoptosis and reduce ventricular wall compliance through the release of cytokines by multiple pathways such as (1) immune reaction, (2) prolonged cell hypoxemia, or (3) excessive activation of neuroendocrine and autonomic nerve function disorder. The systemic proinflammatory state causes coronary microvascular endothelial inflammation which reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes favoring hypertrophy development and increases resting tension. So far, it has been found that inflammatory cytokines associated with the heart failure mechanism include TNF- α , IL-6, IL-8, IL-10, IL-1 α , IL-1 β , IL-2, TGF- β , and IFN- γ . Some of them could be used as diagnosis biomarkers. The present review aims at discussing the inflammatory mechanisms behind diastolic dysfunction and their triggering conditions, cytokines, and possible future inflammatory biomarkers useful for diagnosis.

Ovulatory follicular fluid induces sperm phagocytosis by neutrophils, but oviductal fluid around oestrus suppresses its inflammatory effect in the buffalo oviduct in vitro

Article

Full-text available

Apr 2019

We have recently shown that the conditioned media from bovine oviductal epithelial cell culture suppress sperm phagocytosis by neutrophils, suggesting that the oviduct around oestrus supplies the anti‐inflammatory microenvironment. To investigate the immune response of neutrophils toward the sperm at ovulation in the buffalo oviduct, we examined (a) a detailed distribution of neutrophils in the oviduct in buffaloes, (b) the effect of ovulatory follicular fluid (FF) and oviductal fluid (OF) on sperm phagocytosis by neutrophils, and (c) the interaction of the ovulatory FF with OF on sperm phagocytosis by neutrophils in vitro. Buffalo oviducts were collected from healthy reproductive tracts at a local slaughterhouse. A detailed observation by histological examination and transmission electron microscopy revealed that neutrophils exist in the oviduct epithelium and lumen throughout the oestrous cycle in buffaloes. The number of neutrophils at the oestrus stage was higher in ampulla compared with those in isthmus, whereas they remained relatively constant at the dioestrus stage. Two hours of preincubation of neutrophils with FF enhanced sperm phagocytosis through the formation of neutrophil extracellular traps (NETs) together with H2O2 production, whereas OF around oestrus (eOF) suppressed sperm phagocytosis, NETs formation, and H2O2 production and relieved the above FFinduced inflammatory response. Our findings show that neutrophils exist in the healthy cyclic oviduct across bovine species, and the OF supplies a strong anti inflammatory environment that could minimize the inflammatory effect of the FF that flows into the oviduct lumen after ovulation and supports the occurrence of fertilization. KEYWORDS buffalo, follicular fluid, neutrophils, oviduct, phagocytosis, sperm

Estimation of Oxidative Stress Involvement by Superoxide Dismutase Variation in Cardiac Arrhythmias

Article

Full-text available

Apr 2017

Cardiac arrhythmias, commonly diagnosed in young people, involve multiple etiopathogenic factors, including oxidative stress. Purpose: Evaluation of superoxide dismutase (SOD) variations as an antioxidant enzyme (with a physiological role in the dismutation of highly reactive oxygen free radicals into oxygen and water) in young patients with cardiac arrhythmias. Material and method: The study was conducted on a group of 40 young patients with a mean age of 34 years old, of both sexes, with non-lesional cardiac dysrhythmias, compared to a control group of 40 healthy subjects, determining for both groups the SOD serum level. Diagnosis of cardiac rhythm disorder was supported by electrocardiogram, imaging and laboratory investigations. Results: SOD recorded a 61% decrease of mean values in patients compared to controls. The decreasing variation was found in all arrhythmia types, as follows: atrial fibrillation (51,54%), sinus bradycardia (54,86%), atrial flutter (55,71%), extrasystolic ventricular arrhythmia (64,20%), extrasystolic atrial arrhythmia (65,27%), combined arrhythmias (65,93%), supraventricular paroxysmal tachycardia (71,32%) and sinus tachycardia (74,24%). SOD deficiency demonstrates the involvement of oxidative stress in cardiac arrhythmic pathogenesis, excess oxygen radicals interfering with multiple mechanisms related to the onset of arrhythmogenesis. The SOD decrease was more important in females (60,57%) than in males (67,06%) and in those with nutrition poor in antioxidants. Conclusions: SOD estimation represents a biomarker whose decrease and deficiency implies occurrence of oxidative stress and implicitly highlights its role in cardiac arrhythmic pathology in young people, with the possibility of monitoring and correction by pharmacological or non-pharmacological therapeutic means.

Linking Arrhythmias and Adipocytes: Insights, Mechanisms, and Future Directions

Article

Full-text available

Dec 2018

Obesity and atrial fibrillation have risen to epidemic levels worldwide and may continue to grow over the next decades. Emerging evidence suggests that obesity promotes atrial and ventricular arrhythmias. This has led to trials employing various strategies with the ultimate goal of decreasing the atrial arrhythmic burden in obese patients. The effectiveness of these interventions remains to be determined. Obesity is defined by the expansion of adipose mass, making adipocytes a prime candidate to mediate the pro-arrhythmogenic effects of obesity. The molecular mechanisms linking obesity and adipocytes to increased arrhythmogenicity in both the atria and ventricles remain poorly understood. In this focused review, we highlight areas of potential molecular interplay between adipocytes and cardiomyocytes. The effects of adipocytes may be direct, local or remote. Direct effect refers to adipocyte or fatty infiltration of the atrial and ventricular myocardium itself, possibly causing increased dispersion of normal myocardial electrical signals and fibrotic substrate of adipocytes that promote reentry or adipocytes serving as a direct source of aberrant signals. Local effects may originate from nearby adipose depots, specifically epicardial adipose tissue (EAT) and pericardial adipose tissue, which may play a role in the secretion of adipokines and chemokines that can incite inflammation given the direct contact and disrupt the conduction system. Adipocytes can also have a remote effect on the myocardium arising from their systemic secretion of adipokines, cytokines and metabolites. These factors may lead to mitochondrial dysfunction, oxidative stress, autophagy, mitophagy, autonomic dysfunction, and cardiomyocyte death to ultimately produce a pro-arrhythmogenic state. By better understanding the molecular mechanisms connecting dysfunctional adipocytes and arrhythmias, novel therapies may be developed to sever the link between obesity and arrhythmias.

Diabetes and Arrhythmias: Pathophysiology, Mechanisms and Therapeutic Outcomes

Article

Full-text available

Nov 2018

Laurel A. Grisanti

The prevalence of diabetes is rapidly increasing and closely associated with cardiovascular morbidity and mortality. While the major cardiovascular complication associated with diabetes is coronary artery disease, it is becoming increasingly apparent that diabetes impacts the electrical conduction system in the heart, resulting in atrial fibrillation, and ventricular arrhythmias. The relationship between diabetes and arrhythmias is complex and multifactorial including autonomic dysfunction, atrial and ventricular remodeling and molecular alterations. This review will provide a comprehensive overview of the link between diabetes and arrhythmias with insight into the common molecular mechanisms, structural alterations and therapeutic outcomes.

Developing Pharmacological Therapies for Atrial Fibrillation Targeting Mitochondrial Dysfunction and Oxidative Stress: A Scoping Review

Article

Full-text available

Dec 2023
INT J MOL SCI

Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and comorbidities. A direct relationship exists between AF and altered mitochondrial activity resulting from membrane potential loss, contractile dysfunction, or decreased ATP levels. This review aimed to elucidate the role of mitochondrial oxidative mechanisms in AF pathophysiology, the impact of mitochondrial oxidative stress on AF initiation and perpetuation, and current therapies. This review followed the Preferred Reporting Items for Systematic Reviews and the Meta-Analysis Extension for Scoping Reviews. PubMed, Excerpta Medica Database, and Scopus were explored until June 2023 using “MESH terms”. Bibliographic references to relevant papers were also included. Oxidative stress is an imbalance that causes cellular damage from excessive oxidation, resulting in conditions such as AF. An imbalance in reactive oxygen species production and elimination can cause mitochondrial damage, cellular apoptosis, and cardiovascular diseases. Oxidative stress and inflammation are intrinsically linked, and inflammatory pathways are highly correlated with the occurrence of AF. AF is an intricate cardiac condition that requires innovative therapeutic approaches. The involvement of mitochondrial oxidative stress in the pathophysiology of AF introduces novel strategies for clinical treatment.

Redox imbalance in patients with heart failure and ICD/CRT-D intervention. Can it be an underappreciated and overlooked arrhythmogenic factor? A first preliminary clinical study

Article

Full-text available

Nov 2023

Introduction: Redox imbalance and oxidative stress are involved in the pathogenesis of arrhythmias. They also play a significant role in pathogenesis of heart failure (HF). In patients with HFand implanted cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D), the direct current shocks may be responsible for additional redox disturbances and additionally increase arrhythmia risk. However, the precise role of oxidative stress in potentially fatal arrhythmias and shock induction remains unclear. Methods: 36 patients with diagnosed HF and implanted ICD/CRT-D were included in this study. Patients were qualified to the study group in case of registered ventricular arrhythmia and adequate ICD/CRT-D intervention. The control group consisted of patients without arrhythmia with elective replacement indicator (ERI) status. Activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) in erythrocyte (RBC), SOD, GPx activity and reactive oxygen/nitrogen species (ROS/RNS) concentration in plasma were determined. The values were correlated with glucose, TSH, uric acid, Mg and ion concentrations. Results: In the perishock period, we found a significant decrease in RBC and extracellular (EC) SOD and RBC CAT activity (p = 0.0110, p = 0.0055 and p = 0.0002, respectively). EC GPx activity was also lower (p = 0.0313). In all patients, a decrease in the concentration of all forms of glutathione was observed compared to the ERI group. Important association between ROS/RNS and GSH, Mg, TSH and uric acid was shown. A relationship between the activity of GSH and antioxidant enzymes was found. Furthermore, an association between oxidative stress and ionic imbalance has also been demonstrated. The patients had an unchanged de Haan antioxidant ratio and glutathione redox potential. Conclusion: Here we show significant redox disturbances in patients with HF and ICD/CRT-D interventions. Oxidative stress may be an additional risk factor for the development of arrhythmia in patients with HF. The detailed role of oxidative stress in ventricular arrhythmias requires further research already undertaken by our team.

Preventive and Personalized Strategies in Ambulatory and Clinical Cardiac Electrophysiology

Chapter

Oct 2023

Predictive, Preventive, and Personalized Medicine (3P Medicine) in cardiac electrophysiology (EP) seems to be not a future but the reality. Management of atrial fibrillation (AF)—the most common type of arrhythmia—in the form of prolonged continuous electrocardiographic monitoring, exploiting preventive measures and a modern personalized multispecialty team approach for the development of the best diagnostic and therapeutic solutions, certainly will result in an effective prediction of AF episodes and morbidity and mortality prevention. Present guidelines on cardiac pacing therapy provide us with the assumption that asymptomatic patients do not require PPM implantation as a preventive strategy before transcatheter aortic valve replacement. However, the post-procedure risk of further conduction disturbances advancing in the future changed the approach for early preventive pacemaker implantation, especially in the form of leadless pacemaker (LP), as becoming more attractive and safer. One of the reasons is the improvement of the safety profile of LP technology. This is mainly because the pocket and leads of transvenous pacemakers account for two-thirds of complications. Their lack in LP technology is one of their most significant benefits. The perfect example is a reduction of the risk of infective endocarditis in patients with artificial valves. For many years up to now, the only therapeutic option for a patient with symptomatic bradycardia was pacemaker implantation. However, this method still has many limitations, i.e., infectious complications or lead damage with the need to perform extraction of a part or a whole of the pacing system. Cardioneuroablation (CNA) has become a new therapeutic option for patients with symptomatic bradycardia – a procedure which involves modification of the heart’s parasympathetic nerves. This allows physicians to offer a more personalized approach to bradycardia therapy, especially for younger and more active patients with longer lifespans, for whom there is a significant increase in the cumulative risk of long-term treatment complications with standard implantable devices. It requires a detailed analysis of individual therapy options with the participation of a multidisciplinary EP-Heart Team. The patient is involved in the decision-making process and informed about the risk associated with the pacemaker implantation or CNA procedure and the cumulative long-term risks and possible limitations resulting from the whole process. Recently, we have observed rising interest in physiological automated closed-loop control systems. It became possible due to essential developments in many areas of medicine and biomedical technology. The total intravenous anesthesia process with the use of a fully automated system can relieve a medical staff from continuous monitoring and help in this challenging process but not replace it. Personalized models could be exploited in the clinical electrophysiological setting during pulmonary vein isolation and cardioneuroablation procedures to predict the drug’s effect on each individual and minimize the negative impact on the patient. This personalized control scheme would warrant the preventive measure to reduce postoperative complications. This chapter aims to indicate how 3P Medicine is essential in modern cardiac electrophysiology. We will show already existing modalities and how the process of implementation of this approach becomes even more dynamic.

NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation

Article

Full-text available

Oct 2023

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and its prevalence increases with age. The irregular and rapid contraction of the atria can lead to ineffective blood pumping, local blood stasis, blood clots, ischemic stroke, and heart failure. NADPH oxidases (NOX) and mitochondria are the main sources of reactive oxygen species in the heart, and dysregulated activation of NOX and mitochondrial dysfunction are associated with AF pathogenesis. NOX- and mitochondria-derived oxidative stress contribute to the onset of paroxysmal AF by inducing electrophysiological changes in atrial myocytes and structural remodeling in the atria. Because high atrial activity causes cardiac myocytes to expend extremely high energy to maintain excitation-contraction coupling during persistent AF, mitochondria, the primary energy source, undergo metabolic stress, affecting their morphology, Ca2+ handling, and ATP generation. In this review, we discuss the role of oxidative stress in activating AF-triggered activities, regulating intracellular Ca2+ handling, and functional and anatomical reentry mechanisms, all of which are associated with AF initiation, perpetuation, and progression. Changes in the extracellular matrix, inflammation, ion channel expression and function, myofibril structure, and mitochondrial function occur during the early transitional stages of AF, opening a window of opportunity to target NOX and mitochondria-derived oxidative stress using isoform-specific NOX inhibitors and mitochondrial ROS scavengers, as well as drugs that improve mitochondrial dynamics and metabolism to treat persistent AF and its transition to permanent AF.

Oxidants and Antioxidants Interplay in the Modulation of Inflammation and Cardiovascular Disease

Chapter

Jul 2023

Blood Oxidant Ties: The Evolving Concepts in Myocardial Injury and Cardiovascular Disease is an update on the recent advances in the development of antioxidant-based therapies. It starts with an overview of the mechanisms underlying the genesis of oxidative stress, summarizing the link between oxidative stress and a number of cardiovascular conditions. This is followed by an explanation of how oxidative stress interacts with lipid metabolism and the placental environment. Three chapters on the role of antioxidant-based therapy for cardiovascular diseases round up the book. Key Features - Outlines several cell-signaling pathways that are modulated by the interplay between reducing and oxidizing agents (redox status) and gene expression in the cardiovascular disease process - Brings information about maternal programming environment in the placenta - Covers development of novel nanotechnology-based antioxidant delivery systems for effective drug delivery - Includes references for further reading The book is aimed at a broad readership of scientific and medical professionals involved in research on cardiovascular diseases, pathophysiology, pharmacy, pharmaceutical science and life sciences. It also serves as a reference for scholars who want to understand the complex biochemical mechanisms of antioxidant agents.

Elevated 8-Isoprostane Concentration is Associated with Thromboembolic Events in Patients with Atrial Fibrillation

Article

Jan 2022

Genome Editing and Atrial Fibrillation

Chapter

Dec 2022
ADV EXP MED BIOL

Michael D. Spartalis

Atrial fibrillation (AF) is a frequent rhythm disturbance that raises the possibility of heart failure (HF) and stroke. AF is a multifactorial disorder combining genetic and environmental etiologies. Over the last decade, advancements have been made regarding the genetic base of this arrhythmia. We present the existing knowledge of genetic analysis and genome editing for atrial fibrillation, indicating the existing gaps and future directions. We aim to elucidate how genome editing could be utilized for patients with atrial fibrillation.KeywordsGenome editingAtrial fibrillationGene therapyGeneticsArrhythmia

The Potential Prognostic, Diagnostic and Therapeutic Targets for Recurrent Arrhythmias in Patients with Coronary Restenosis and Reocclusions After Coronary Stenting

Article

Nov 2022

Background The interplay of oxidative stress, proinflammatory microparticles, and proinflammatory cytokines in recurrent arrhythmias is unknown in elderly patients with coronary restenosis and reocclusions after coronary stenting. Objective This research sought to investigate the potential diagnostic and therapeutic targets for recurrent arrhythmias in patients with coronary restenosis and reocclusions after coronary stenting. Methods We examined whether oxidative stress, proinflammatory microparticles, and proinflammatory cytokines could have effects that lead to recurrent arrhythmias in elderly patients with coronary restenosis and reocclusions. We measured the levels of malondialdehyde (MDA), CD31+ endothelial microparticle (CD31+ EMP), CD62E+ endothelial microparticle (CD62E+ EMP), high-sensitivity C-reactive protein (hs-CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), as well as oxidized low-density lipoprotein (OX-LDL), and assessed the effects of relationship between oxidative stress, proinflammatory microparticles, and proinflammatory cytokines on recurrent atrial and ventricular arrhythmias in elderly patients with coronary restenosis and reocclusions after coronary stenting. Results The levels of CD31+EMP, CD62E+EMP, MDA, hs-CRP, IL-1β, IL-6, IL-8, TNF-α and OX-LDL were found to be increased significantly in coronary restenosis+recurrent atrial arrhythmia group compared to without coronary restenosis and coronary restenosis+without recurrent atrial arrhythmia groups, respectively (P< 0.001). Patients in the coronary reocclusion+recurrent ventricular arrhythmia group also exhibited significantly increased levels of CD31+EMP, CD62E+EMP, MDA, hs-CRP, IL-1β, IL-6, IL-8, TNF-α and OX-LDL compared to without coronary reocclusion and coronary reocclusion+without recurrent ventricular arrhythmia groups, respectively (P< 0.001). Conclusion Proinflammatory microparticles, proinflammatory cytokines, and oxidative stress might act as potential targets for recurrent arrhythmias in patients with coronary restenosis and reocclusions after coronary stenting.

Stress Kinase Signaling in Cardiac Myocytes

Chapter

Sep 2022

Stress-response kinases, the mitogen-activated protein kinases (MAPKs), are activated in response to the challenge of a myriad of stressors. c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and MAPK p38 are the important members of the MAPK family in the heart. Extensive studies have revealed critical roles of activated MAPKs in the processes of cardiac injury, cardiac arrhythmias, heart failure, and other cardiovascular diseases. Advancing our understanding regarding the functional impacts of MAPKs in the development of heart diseases could shed new light on developing novel therapeutic approaches to improve cardiac function and prevent arrhythmia development in patients. This chapter summarizes relevant current knowledge on the pivotal roles of MAPKs in physiopathological and molecular remodeling in cardiac myocytes during the disease development and for the therapeutic potentials of developing MAPK inhibitors and/or activators.KeywordsMitogen-activated protein kinases Stress Arrhythmia Heart failure Calcium homeostasis Cardiovascular diseases

Antioxidants in Arrhythmia Treatment—Still a Controversy? A Review of Selected Clinical and Laboratory Research

Article

Full-text available

Jun 2022

Antioxidants are substances that can prevent damage to cells caused by free radicals. Production of reactive oxygen species and the presence of oxidative stress play an important role in cardiac arrhythmias. Currently used antiarrhythmic drugs have many side effects. The research on animals and humans using antioxidants (such as vitamins C and E, resveratrol and synthetic substances) yields many interesting but inconclusive results. Natural antioxidants, such as vitamins C and E, can reduce the recurrence of atrial fibrillation (AF) after successful electrical cardioversion and protect against AF after cardiac surgery, but do not affect the incidence of atrial arrhythmias in critically ill patients with trauma. Vitamins C and E may also effectively treat ventricular tachycardia, ventricular fibrillation and long QT-related arrhythmias. Another natural antioxidant—resveratrol—may effectively treat AF and ventricular arrhythmias caused by ischaemia–reperfusion injury. It reduces the mortality associated with life-threatening ventricular arrhythmias and can be used to prevent myocardial remodelling. Statins also show antioxidant activity. Their action is related to the reduction of oxidative stress and anti-inflammatory effect. Therefore, statins can reduce the post-operative risk of AF and may be useful in lowering its recurrence rate after successful cardioversion. Promising results also apply to polyphenols, nitric oxide synthase inhibitors and MitoTEMPO. Although few clinical trials have been conducted, the use of antioxidants in treating arrhythmias is an interesting prospect.

Alteration of serum biomarkers in patients with hypertrophic cardiomyopathy with and without atrial fibrillation

Article

Aug 2021

Aim: We sought to determine the relationship between presence of atrial fibrillation (AF) and serum biomarkers, including native thiol (antioxidant), disulphide/native thiol ratio, Hs-CRP and high-sensitivity Troponin-I (Hs-TnI) in hypertrophic cardiomyopathy (HCM). Materials & methods: We enrolled consecutive 121 HCM outpatients without AF and 40 HCM outpatients with AF. A 12-lead electrocardiogram, transthoracic echocardiography and 24/48-h ambulatory rhythm monitoring were performed for all patients. Fasting venous blood samples were taken from all study patients to measure serum thiol-disulphide homeostasis, Hs-CRP and Hs-TnI. Results: Serum-native thiol was lower and disulphide/native thiol ratio was more oxidized in HCM patients with AF (p < 0.001). Also, HCM patients with AF had higher Hs-TnI and Hs-CRP than no-AF HCM patients. Disulphide/native thiol ratio, serum-native thiol, age, NYHA functional class≥III, and advanced diastolic dysfunction were independently associated with the presence of AF in HCM. Conclusion: In addition to clinical and echocardiographic findings, oxidative stress is also associated with AF in HCM patients.

Natural and synthetic antioxidants targeting cardiac oxidative stress and redox signaling in cardiometabolic diseases

Article

Apr 2021

Cardiometabolic diseases (CMDs) are metabolic diseases (e.g., obesity, diabetes, atherosclerosis, rare genetic metabolic diseases, etc.) associated with cardiac pathologies. Pathophysiology of most CMDs involves increased production of reactive oxygen species and impaired antioxidant defense systems, resulting in cardiac oxidative stress (OxS). To alleviate OxS, various antioxidants have been investigated in several diseases with conflicting results. Here we review the effect of CMDs on cardiac redox homeostasis, the role of OxS in cardiac pathologies, as well as experimental and clinical data on the therapeutic potential of natural antioxidants (including resveratrol, quercetin, curcumin, vitamins A, C, and E, coenzyme Q10, etc.), synthetic antioxidants (including N-acetylcysteine, SOD mimetics, mitoTEMPO, SkQ1, etc.), and promoters of antioxidant enzymes in CMDs. As no antioxidant indicated for the prevention and/or treatment of CMDs has reached the market despite the large number of preclinical and clinical studies, a sizeable translational gap is evident in this field. Thus, we also highlight potential underlying factors that may contribute to the failure of translation of antioxidant therapies in CMDs.

Effects of perioperative oxygen concentration on oxidative stress in adult surgical patients: a systematic review

Article

Full-text available

Nov 2020

Background The fraction of inspired oxygen (FiO2) administered during general anaesthesia varies widely despite international recommendations to administer FiO2 0.8 to all anaesthetised patients to reduce surgical site infections (SSIs). Anaesthetists remain concerned that high FiO2 administration intraoperatively may increase harm, possibly through increased oxidative damage and inflammation, resulting in more complications and worse outcomes. In previous systematic reviews associations between FiO2 and SSIs have been inconsistent, but none have examined how FiO2 affects perioperative oxidative stress. We aimed to address this uncertainty by reviewing the available literature. Methods EMBASE, MEDLINE, and Cochrane databases were searched from inception to March 9, 2020 for RCTs comparing higher with lower perioperative FiO2 and quantifying oxidative stress in adults undergoing noncardiac surgery. Candidate studies were independently screened by two reviewers and references hand-searched. Methodological quality was assessed using the Cochrane Collaboration Risk of Bias tool. Results From 19 438 initial results, seven trials (n=422) were included. Four studies reported markers of oxidative stress during Caesarean section (n=328) and three reported oxidative stress during elective colon surgery (n=94). Risk of bias was low (four studies) to moderate (three studies). Pooled results suggested high FiO2 was associated with greater malondialdehyde, protein-carbonyl concentrations and reduced xanthine oxidase concentrations, together with reduced antioxidant markers such as superoxide dismutase and total sulfhydryl levels although total antioxidant status was unchanged. Conclusions Higher FiO2 may be associated with elevated oxidative stress during surgery. However, limited studies have specifically reported biomarkers of oxidation. Given the current clinical controversy concerning perioperative oxygen therapy, further research is urgently needed in this area.

Red Cell Distribution Width and Risk of Atrial Fibrillation and Subsequent Thromboembolism: The Tromsø Study

Article

Full-text available

Sep 2020

Introduction Red cell distribution width (RDW) is associated with cardiovascular diseases, including atrial fibrillation (AF) and venous thromboembolism (VTE). Whether RDW is a risk marker for thromboembolic events in AF patients is scarcely known. We aimed to assess the association between RDW and the risk of AF, and AF-related VTE and ischemic stroke, in a population-based cohort. Methods We measured RDW in 26,111 participants from the Tromsø Study (1994–1995), and registered incident AF cases through December 31, 2013. Among participants with AF, first-ever VTEs and ischemic strokes were registered from the date of AF diagnosis through the end of follow-up. We calculated hazard ratios (HRs) with 95% confidence intervals (CIs) for AF by quartiles of RDW. Furthermore, we calculated cause-specific HRs for VTE and ischemic stroke by tertiles of RDW for participants with AF. Results There were 2,081 incident AF cases during a median of 18.8 years of follow-up. Subjects with RDW in the highest quartile (RDW ≥ 13.3%) had 30% higher risk of AF than those in the lowest quartile (RDW ≤ 12.3%). Among those with AF, subjects with RDW in the upper tertile had a doubled risk of ischemic stroke (HR 2.07, 95% CI 1.20–3.57). In contrast, RDW was not associated with incident VTE in subjects with AF. Conclusion RDW was significantly associated with incident AF in a general population. Among subjects with AF, high RDW was associated with ischemic stroke, but not VTE.

Antiarrhythmic Properties of Non-Antiarrhythmic Drugs in Atrial Fibrillation: Upstream Therapy

Chapter

Feb 2020

Traditionally, antiarrhythmic strategies have focused almost exclusively on atrial electrophysiological alterations. Unfortunately, these interventions yield very limited success over the long-term and have a high side-effect profile. A number of ‘non-antiarrhythmic’ drugs (i.e., whose main effect is not exerted at ion channel level) have gained increasing attention due to their potential to prevent, delay, or even reverse atrial fibrillation (AF)-related atrial structural remodeling, while lacking the undesirable effects of ion channel blockers. By modifying the substrate upstream of AF, these new strategies are expected to prevent new-onset AF, to delay AF transition to more persistent forms, and/or to prevent recurrent AF. However, to date, with very few the exceptions, there is insufficient evidence to support the wide use of non-conventional antiarrhythmic drugs for AF prophylaxis in clinical practice. It still remains to be established whether this approach is truly effective, by itself or at least in addition to conventional rhythm control strategies. Clarification of the most adequate target population, of the most suitable drug, dose, and timing to intervene is also required.

Induction of atrial endothelial senescence by angiotensin II and thrombin : role of oxidative stress and characterization of pro-thrombotic, pro-adhesive, proteolytic and pro-fibrotic phenotype

Thesis

Nov 2018

Hira Hasan

Many studies documented strong relationship between ageing and development of atrial fibrillation (AF). Moreover, it has been found that senescence and senescence-associated- secretory-phenotype play an important role in development of overall atrial inflammation which can ultimately ends up in atrial structural remodeling paving the way to AF perpetuation and maintenance. Moreover, it has been known for decades that AF has been associated with the activation of local and circulating coagulation factors. However, little is known about the impact of coagulation-derived factors, in particular thrombin, on the onset of AF. The aim of the present study was to determine the link between atrial endothelial cells (AECs) senescence and the induction of pro-inflammatory, pro-adhesive, pro-fibrotic and pro-remodelling AECs patterns and also to evaluate the contribution of coagulation derived-factors such as thrombin.

The combined effect of Vitamin C and omega-3 polyunsaturated fatty acids on fatigue following coronary artery bypass graft surgery: A triple-blind clinical trial

Article

Aug 2019
J Compl Integr Med

Background Fatigue is a common compliant among patients who undergo coronary artery bypass graft (CABG) surgery. This may affect patients’ function in all aspects. A few studies have already assessed the influence of complementary therapies on minimizing fatigue. This study aimed to investigate the combined effect of vitamin C and omega-3 polyunsaturated fatty acids (n-3 PUFA) on fatigue following CABG surgery. Methods In this randomized, triple-blind placebo-controlled trial, 160 patients who already underwent CABG surgery were randomly assigned into an experimental or a control groups. Each group consisted of 80 patients. The experimental group was given both n-3 PUFA and vitamin C the day before surgery. They also received the same supplements in the first 5 days of operation. The control group received only placebo. Subjects in both groups responded to Multidimensional Fatigue Inventory (MFI-20) scale in the beginning, and at the end of the intervention as well as on the fifth day of the operation. Chi-square test and independent t-test were used for data analysis. Results The mean fatigue score in experimental and control groups came up to 62.01 ± 4.06 and 67.92 ± 4.95 (p<0.0001), respectively, which was greater than that of the values we had before intervention. The mean difference of fatigue score was 3.97 ± 3.49 and 9.56 ± 6.41 (p<0.0001) prior and following the intervention, correspondingly. Conclusion Combination of vitamin C and n-3 PUFA effectively reduces post-operative fatigue among patients who undergo CABG surgery.

Gene therapy for atrial fibrillation - How close to clinical implementation?

Article

Aug 2019
INT J CARDIOL

In this review we examine the current state of gene therapy for the treatment of cardiac arrhythmias. We describe advances and challenges in successfully creating and incorporating gene vectors into the myocardium. After summarizing the current scientific research in gene transfer technology we then focus on the most promising areas of gene therapy, the treatment of atrial fibrillation and ventricular tachyarrhythmias. We review the scientific literature to determine how gene therapy could potentially be used to treat patients with cardiac arrhythmias.

Change of HDL in Various Diseases

Chapter

May 2019

Kyung-Hyun Cho

It has been firmly established that coronary heart disease (CHD) is responsible for the vast majority of cases of unstable angina pectoris (AP), acute myocardial infarction (MI), and sudden death. MI is an acute and catastrophic event that results from acute coronary syndrome (ACS) and atherosclerosis, which chronically progresses to ACS (Thygesen et al. 2007). MI is a leading cause of morbidity and mortality in adults in western countries and Asia (Rosamond et al. 2007), and diagnostic biomarkers for MI have been developed and utilized clinically such as serum levels of GOT, LDH, creatine kinase (CK)-MB, and troponin I and T (Jaffe et al. 2000). However, the biomarkers have been limited to clinical use because they had insufficient specificity for predictive MI diagnosis. Furthermore, although many biomarkers have been reported to predict cardiovascular risk, there have been no specific and useful biomarkers developed for the early detection of MI (Pahor et al. 1999). Inflammation is a major risk factor of atherosclerosis, and several inflammatory biomarkers such as hsCRP, cytokines, biomarkers of endothelial cell activation, and proinflammatory enzymes have been established for the diagnosis of ACS (Hartford et al. 2007); however, no studies have been reported to determine if these biomarkers are useful for the prediction of acute MI.

N‐acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double‐blind controlled trial in healthy subjects

Article

Nov 2018

Paracetamol (APAP) may lead to hepatic changes even at therapeutic dosages. Glutathione (GSH) plays a pivotal role in APAP metabolism as it allows the detoxification of a toxic metabolite. N‐Acetylcysteine (NAC) is APAP antidote, is also largely used as a mucoactive drug and is often associated with APAP. This study aims at evaluating if 1‐ NAC modifies APAP pain efficacy and 2‐ NAC prevents glutathione depletion with APAP at therapeutic doses. This double‐blind randomized controlled study (NCT02206178) was carried out in 24 healthy volunteers. APAP was given for 4 days (1 gram x4 daily) with NAC or with placebo. Thermal pain tests, whole blood GSH and hepatic enzymes (ASAT, ALAT) were measured before (D0) and after (D4) oral APAP‐NAC or APAP‐placebo intake. ANOVA for repeated measures adapted to cross‐overdesign was performed and a two‐tailed type I error was fixed at 5%. The primary endpoint was the area under the curve (0‐240min) of pain intensity (Numerical Scale) after thermal pain stimulation using Pathway‐Medoc®. APAP antinociceptive effect was similar in both groups. GSH was maintained to its baseline value in the APAP/NAC group but diminished in the APAP/placebo group (p=0.033). This study shows for the first time that APAP antinociceptive effectiveness is not influenced by NAC. It also shows that the effect of APAP at therapeutic dosage on GSH may be counteracted by NAC. These issues are particularly important for patients as APAP is often prescribed for years as a first‐line pain treatment and further trials in patients are now warranted. This article is protected by copyright. All rights reserved.

Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: Population-based estimates

Article

Full-text available

Oct 1998
AM J CARDIOL

Atrial fibrillation (AF) is the most common of the serious cardiac rhythm disturbances and is responsible for substantial morbidity and mortality in the general population. Its prevalence doubles with each advancing decade of age, from 0.5% at age 50–59 years to almost 9% at age 80–89 years. It is also becoming more prevalent, increasing in men aged 65–84 years from 3.2% in 1968–1970 to 9.1% in 1987–1989. This statistically significant increase in men was not explained by an increase in age, valve disease, or myocardial infarctions in the cohort. The incidence of new onset of AF also doubled with each decade of age, independent of the increasing prevalence of known predisposing conditions. Based on 38-year follow-up data from the Framingham Study, men had a 1.5-fold greater risk of developing AF than women after adjustment for age and predisposing conditions. Of the cardiovascular risk factors, only hypertension and diabetes were significant independent predictors of AF, adjusting for age and other predisposing conditions. Cigarette smoking was a significant risk factor in women adjusting only for age (OR = 1.4), but was just short of significance on adjustment for other risk factors. Neither obesity nor alcohol intake was associated with AF incidence in either sex. For men and women, respectively, diabetes conferred a 1.4- and 1.6-fold risk, and hypertension a 1.5- and 1.4-fold risk, after adjusting for other associated conditions. Because of its high prevalence in the population, hypertension was responsible for more AF in the population (14%) than any other risk factor. Intrinsic overt cardiac conditions imposed a substantially higher risk. Adjusting for other relevant conditions, heart failure was associated with a 4.5- and 5.9-fold risk, and valvular heart disease a 1.8- and 3.4-fold risk for AF in men and women, respectively. Myocardial infarction significantly increased the risk factor-adjusted likelihood of AF by 40% in men only. Echocardiographic predictors of nonrheumatic AF include left atrial enlargement (39% increase in risk per 5-mm increment), left ventricular fractional shortening (34% per 5% decrement), and left ventricular wall thickness (28% per 4-mm increment). These echocardiographic features offer prognostic information for AF beyond the traditional clinical risk factors. Electrocardiographic left ventricular hypertrophy increased risk of AF 3–4-fold after adjusting only for age, but this risk ratio is decreased to 1.4 after adjustment for the other associated conditions. The chief hazard of AF is stroke, the risk of which is increased 4–5-fold. Because of its high prevalence in advanced age, AF assumes great importance as a risk factor for stroke and by the ninth decade becomes a dominant factor. The attributable risk for stroke associated with AF increases steeply from 1.5% at age 50–59 years to 23.5% at age 80–89 years. AF is associated with a doubling of mortality in both sexes, which is decreased to 1.5–1.9-fold after adjusting for associated cardiovascular conditions. Decreased survival associated with AF occurs across a wide range of ages.

Dual control of C-reactive protein gene expression by interleukin-I and interleukin-6

Article

Full-text available

Jan 1990

Human C-reactive protein (CRP) is the major acute phase reactant during acute inflammation. The human CRP promoter is expressed in an inducible and cell-specific manner when linked to the bacterial CAT gene and transfected into human hepatoma cell cultures. In this paper we analyze the effect of several recombinant cytokines or CRP promoter inducibility in human Hep3B cells. When cytokines are tested singly the major inducer of CRP-CAT fusions is interleukin-6 (IL-6). Maximal CAT gene expression, however, is only achieved when both interleukin-1 beta (IL-1 beta) and IL-6 are present. The response to the two cytokines is cooperative. Cooperativity is maintained when the CRP promoter is linked to a different coding region, that of the bacterial neomycin phosphotransferase II gene. With a series of 5' and 3' deletions we show the existence of two distinct and independent regions responsive to IL-6 and located upstream to the TATA box. The IL-1 effect is exerted at the level of downstream sequences that are probably important for optimal mRNA translatability or nuclear-cytoplasmic transport. Inducibility is not influenced by the activation of protein kinases C or A and does not require new protein synthesis.

Plasma glutathione and glutathione disulfide in the rat: Regulation and response to oxidative stress

Article

Full-text available

Jan 1984

Plasma GSH and GSSG concentrations were examined after the administration of compounds that deplete intracellular GSH either by adduct formation or by production of oxidative stress. A modified assay based on the GSSG reductase method was developed that minimizes the artifactual auto-oxidation of GSH to GSSG and mixed disulfides by rapid addition of bis(3-carboxy-4-nitrophenyl)disulfide or N-ethylmaleimide directly to whole blood or tissue samples. Control arterial plasma GSH and GSSG concentrations were found to be 16.5 +/- 0.7 and 0.3 +/- 0.1 microM, respectively. Depletion of GSH by fasting or by the administration of acetaminophen or diethyl maleate was associated with a proportional decrease in the arterial plasma GSH concentrations (r = 0.94) consistent with the hypothesis that the liver in vivo is a major source of plasma GSH. Diquat and t-butyl hydroperoxide, but not acetaminophen or diethyl maleate, elicited large increases in arterial plasma GSSG concentrations (17- and 115-fold, respectively) and several-fold increases in biliary GSSG levels without markedly increasing hepatic GSSG levels (2.7- and 1.2-fold, respectively). In contrast, treatment with paraquat produced substantial increases in arterial plasma GSSG levels (22-fold) without large increases in the bile (3-fold). Assessment of the arteriovenous difference for GSSG across the lungs after paraquat administration demonstrated that the lung may be a significant source of plasma GSSG. In conclusion, plasma GSH concentrations appear to reflect mainly intrahepatic GSH concentration, whereas plasma GSSG appears to arise from both hepatic and extrahepatic sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Independent Risk Factors for Atrial Fibrillation in a Population-Based CohortThe Framingham Heart Study

Article

Full-text available

Apr 1994

To determine the independent risk factors for atrial fibrillation. Cohort study. The Framingham Heart Study. A total of 2090 men and 2641 women members of the original cohort, free of a history of atrial fibrillation, between the ages of 55 and 94 years. Sex-specific multiple logistic regression models to identify independent risk factors for atrial fibrillation, including age, smoking, diabetes, electrocardiographic left ventricular hypertrophy, hypertension, myocardial infarction, congestive heart failure, and valve disease. During up to 38 years of follow-up, 264 men and 298 women developed atrial fibrillation. After adjusting for age and other risk factors for atrial fibrillation, men had a 1.5 times greater risk of developing atrial fibrillation than women. In the full multivariable model, the odds ratio (OR) of atrial fibrillation for each decade of advancing age was 2.1 for men and 2.2 for women (P < .0001). In addition, after multivariable adjustment, diabetes (OR, 1.4 for men and 1.6 for women), hypertension (OR, 1.5 for men and 1.4 for women), congestive heart failure (OR, 4.5 for men and 5.9 for women), and valve disease (OR, 1.8 for men and 3.4 for women) were significantly associated with risk for atrial fibrillation in both sexes. Myocardial infarction (OR, 1.4) was significantly associated with the development of atrial fibrillation in men. Women were significantly more likely than men to have valvular heart disease as a risk factor for atrial fibrillation. The multivariable models were largely unchanged after eliminating subjects with valvular heart disease. In addition to intrinsic cardiac causes such as valve disease and congestive heart failure, risk factors for cardiovascular disease also predispose to atrial fibrillation. Modification of risk factors for cardiovascular disease may have the added benefit of diminishing the incidence of atrial fibrillation.

Relation between left ventricular function and oxidative stress in patients undergoing bypass surgery

Article

Full-text available

Apr 1998

To determine whether preoperative left ventricular ejection fraction (LVEF) is related to the degree of myocardial oxidative stress during bypass surgery in man. Observational study. Tertiary care centre. 31 patients (LVEF range was 20% to 68%) undergoing elective coronary bypass surgery with blood cardioplegic reperfusion were studied. Arterial and coronary sinus blood was collected before aortic cross clamping (T0) and at 0 (T1), 15 (T2), and 30 (T3) minutes after unclamping. Transmural left ventricular biopsies were also obtained from 15 patients at T0 and at T1. Glutathione and adenine nucleotides were measured in myocardial biopsies, while coronary sinus-artery differences for glutathione, nucleotides, and products of lipid peroxidation were calculated from blood specimens. Creatine kinase (myocardial band; CK-MB) was measured in plasma at four and 12 hours after operation. Myocardial glutathione and adenine nucleotides were correlated (p < 0.02) with preoperative LVEF both at T0 (r = 0.909 and 0.672) and T1 (r = 0.603 and 0.605). Oxidised glutathione released from the heart during reperfusion was inversely correlated with LVEF (r = -0.448, -0.466, and -0461 at T1, T2, and T3, p < 0.01), while reduced glutathione (r = 0.519 and 0.640 at T1 and T2) and glutathione redox ratio (r = 0.647, 0.714, 0.645, and 0.702 at T0, T1, T2, and T3) showed a direct correlation (p < 0.01). Lipid peroxidation at T1 was negatively related to LVEF (r = -0.492). CK-MB was also negatively related to LVEF (r = -0.440 at 4 h and -0.462 at 12 h). The capacity to counterbalance oxidative burst following ischaemia and reperfusion appears to be related to the functional ability of the heart.

Tandem Promoters and Developmentally Regulated 5'- and 3'-mRNA Untranslated Regions of the Mouse Scn5a Cardiac Sodium Channel

Article

Full-text available

Feb 2005

The SCN5A gene encodes a voltage-sensitive sodium channel expressed in cardiac and skeletal muscle. Coding region mutations cause cardiac sudden death syndromes and conduction system failure. Polymorphisms in the 5′-sequence adjacent to the SCN5A gene have been linked to cardiac arrhythmias. We identified three alternative 5′-splice variants (1A, 1B, and 1C) of the untranslated exon 1 and two 3′-variants in the murine Scn5a mRNA. Two of the exon 1 isoforms (1B and 1C) were novel when compared with the published human and rat SCN5A sequences. Quantitative real time PCR results showed that the abundance of the isoforms varied during cardiac development. The 1A, 1B, and 1C mRNA splice variants increased 7.8 ± 1.7-fold (E1A), 6.0 ± 1.0-fold (E1B), and 20.6 ± 3.7-fold (E1C) from fetal to adult heart, respectively. Promoter deletion and luciferase reporter gene analysis using cardiac and skeletal muscle cell lines demonstrated a pattern of distinct cardiac-specific enhancer elements associated with exons 1A and 1C. In the case of exon 1C, the enhancer element appeared to be within the exon. A 5′-repressor preceded each cardiac enhancer element. We concluded that the murine Na+ channel has both 5′- and 3′-untranslated region mRNA variants that are developmentally regulated and that the promoter region contains two distinct cardiac-specific enhancer regions. The presence of homologous human splicing suggests that that these regions may be fruitful new areas of study in understanding cardiac sodium channel regulation and the genetic susceptibility to sudden death.

Is atrial fibrillation an inflammatory disorder?

Article

Full-text available

Feb 2006

There is mounting evidence to support the influence of inflammation in the pathogenesis of atrial fibrillation (AF). Indeed, AF is associated with increased levels of known inflammatory markers, even after adjustment for confounding factors. The renin-angiotensin-aldosterone system (RAAS) appears to play a key role in this process. Atrial biopsies from patients with AF have also confirmed the presence of inflammation. Furthermore, there is preliminary evidence to support a number of drug therapies that have the potential to reduce the clinical burden of AF. In this review, we present an overview of the evidence supporting a link between inflammation and AF, and some of the drug therapies, such as the angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, steroids, fish oils, and vitamin C, that might be efficacious in the prevention of AF by modulating inflammatory pathways.

Statins and Postoperative Risk of Atrial Fibrillation Following Coronary Artery Bypass Grafting

Article

Full-text available

Feb 2006
AM J CARDIOL

Atrial fibrillation (AF) is a common complication after coronary artery bypass grafting. Atrial remodeling has been observed in AF and has been associated with the development of this arrhythmia. Because 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) have been demonstrated to modify remodeling, we hypothesized a protective role of statins against postoperative AF. We also hypothesized that extracellular matrix turnover and brain natriuretic peptide (BNP) might be related to such atrial remodeling. We studied 234 consecutive patients who underwent coronary artery bypass grafting (173 men; 65 +/- 9 years of age) in whom the occurrence of postoperative AF was monitored. In a subgroup of 66 patients, we measured plasma levels of matrix metalloproteinase-1 (MMP-1), its inhibitor, tissue inhibitor matrix metalloproteinase-1 (TIMP-1; as indexes of extracellular matrix remodeling), and N-terminus pro-BNP (related to left ventricular function) at baseline and at 24 hours after surgery. Of 234 patients, 66 (28.2%) developed postoperative AF. In multivariate analysis, previous AF was related to an increase in the development of AF (odds ratio 11.92, 95% confidence interval 2.37 to 59.98, p = 0.026), whereas statin use was related to a decrease in arrhythmia (odds ratio 0.52, 95% confidence interval 0.28 to 0.96, p = 0.038). A higher TIMP-1/MMP-1 ratio at 24 hours after surgery was present in those who did not develop postoperative AF (p = 0.043). Statin use was associated with increased TIMP-1 levels and TIMP-1/MMP-1 ratio (p = 0.027 and 0.036, respectively). No significant relations to N-terminus pro-BNP were seen. In conclusion, previous AF and nonuse of statins are significantly associated with AF after coronary artery bypass grafting. Statin use may be protective against AF after coronary artery bypass grafting, possibly due to alterations in the extracellular matrix and remodeling after coronary artery bypass grafting.

Cellular antioxidant effects of atorvastatin in vitro and in vivo

Article

Jan 2002
ARTERIOSCL THROM VAS

Independent Risk Factors for Atrial Fibrillation in a Population-Based Cohort

Article

Mar 1994

Emelia Benjamin

Inflammation as a Risk Factor for Atrial Fibrillation

Article

Mar 2004

Glutathione measurement in human plasma

Article

Jul 1998
CLIN CHIM ACTA

Literature values for human plasma GSH vary over 10-fold despite the use of apparently valid analytical procedures for GSH measurement. The purpose of this study was to develop a procedure to minimize error in sample collection, processing and storage that could contribute to such differences. HPLC with fluorescence detection of dansyl derivatives was used for quantification. The results show that collection of blood with a butterfly needle and syringe reduces overestimation due to limited hemolysis and that use of a preservation solution designed to inhibit autooxidation and enzymatic degradation allows quantitative recovery of both GSH and GSSG. Stability tests showed that non-derivatized samples were stable for at least 2 months at −80° while dansyl derivatives were stable in the dark at 0–4° for 12 months. Results from 59 healthy individuals (20–43 years) provided a mean (±1 SD) GSH value of 2.09±1.14 micromolar.

Glutathione measurement in human plasma: Evaluation of sample collection, storage and derivatization conditions for analysis of dansyl derivatives by HPLC

Article

Aug 1998
CLIN CHIM ACTA

Activation of the Complement System During and After Cardiopulmonary Bypass Surgery : Postsurgery Activation Involves C-Reactive Protein and Is Associated With Postoperative Arrhythmia

Article

Dec 1997

Complement activation during cardiopulmonary bypass (CPB) surgery is considered to result from interaction of blood with the extracorporeal circuit. We investigated whether additional mechanisms may contribute to complement activation during and after CPB and, in particular, focused on a possible role of the acute-phase protein C-reactive protein (CRP). In 19 patients enrolled for myocardial revascularization, perioperative and postoperative levels of complement activation products, interleukin-6 (IL-6), CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation in vivo, were measured and related to clinical symptoms. A biphasic activation of complement was observed. The ratio between the areas under the curve of perioperative and postoperative C3b/c and C4b/c were 3:2 and 1:46, respectively. IL-6 levels reached a maximum at 6 hours post-surgery. CRP levels peaked on the second postoperative day. Each complement-CRP complex had peak levels on the second or third postoperative day. By multivariate analysis, maximum levels of CRP on the second postoperative day were mainly explained by C4b/c levels after protamine administration, leukocyte count on the second postoperative day, and preoperative levels of CRP. Peak levels of C4b/c after protamine administration (P=.0073) and on the second postoperative day correlated with the occurrence of arrhythmia on the same day (P=.0065). Cardiac surgery with CPB causes a biphasic complement activation. The first phase occurs during CPB and results from the interaction of blood with the extracorporeal circuit. The second phase, which occurs during the first 5 days after surgery, involves CRP, is related to baseline CRP levels, and is associated with clinical symptoms such as arrhythmia.

Glutathione in Human Plasma: Decline in Association with Aging, Age-Related Macular Degeneration, and Diabetes

Article

Mar 1998
FREE RADICAL BIO MED

Blood samples were analyzed for GSH and GSH redox state in 40 age-related macular degeneration (ARMD) patients (> 60 y), 33 non-ARMD diabetic patients (> 60 years), 27 similarly aged non-ARMD and nondiabetic individuals (> 60 years), and 19 younger individuals (< 60 years) without ARMD or diabetes. Results showed a significantly lower plasma GSH in older individuals (ARMD, diabetes, and controls) than in younger individuals (p < .01). Total GSH (GSHt) obtained following treatment with dithiothreitol was significantly lower only in diabetic cases (p < .05) but also approached significance for ARMD cases (p = .089). Estimation of redox potential indicated that the plasma GSH pool is considerably more oxidized in all of the older groups. Analyses of whole blood GSH showed that GSH was significantly lower in diabetic cases compared to the other groups, but did not reveal any difference associated with age or ARMD. In contrast, GSSG in whole blood was significantly higher in the older groups compared to the younger controls. The results suggest that in studies of age-related pathologies, oxidation of GSH may be a more important parameter than a decline in pool size, while in specific pathologies such as diabetes, both oxidation and a decline in pool size may be important.

Ascorbate Attenuates Atrial Pacing-Induced Peroxynitrite Formation and Electrical Remodeling and Decreases the Incidence of Postoperative Atrial Fibrillation

Article

Oct 2001
CIRC RES

Atrial fibrillation (AF), the most common chronic arrhythmia, increases the risk of stroke and is an independent predictor of mortality. Available pharmacological treatments have limited efficacy. Once initiated, AF tends to self-perpetuate, owing in part to electrophysiological remodeling in the atria; however, the fundamental mechanisms underlying this process are still unclear. We have recently demonstrated that chronic human AF is associated with increased atrial oxidative stress and peroxynitrite formation; we have now tested the hypothesis that these events participate in both pacing-induced atrial electrophysiological remodeling and in the occurrence of AF following cardiac surgery. In chronically instrumented dogs, we found that rapid (400 min(-1)) atrial pacing was associated with attenuation of the atrial effective refractory period (ERP). Treatment with ascorbate, an antioxidant and peroxynitrite decomposition catalyst, did not directly modify the ERP, but attenuated the pacing-induced atrial ERP shortening following 24 to 48 hours of pacing. Biochemical studies revealed that pacing was associated with decreased tissue ascorbate levels and increased protein nitration (a biomarker of peroxynitrite formation). Oral ascorbate supplementation attenuated both of these changes. To evaluate the clinical significance of these observations, supplemental ascorbate was given to 43 patients before, and for 5 days following, cardiac bypass graft surgery. Patients receiving ascorbate had a 16.3% incidence of postoperative AF, compared with 34.9% in control subjects. In combination, these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insight into the etiology and potential treatment of an enigmatic and difficult to control arrhythmia. The full text of this article is available at http://www.circresaha.org.

Cellular Antioxidant Effects of Atorvastatin In Vitro and In Vivo

Article

Mar 2002
ARTERIOSCL THROM VAS

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 micromol/L atorvastatin. Angiotensin II-induced and epidermal growth factor-induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription-polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by L-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins.

Heart Failure, Oxidative Stress, and Ion Channel Modulation

Article

May 2002

The balance of reactive oxygen species (ROS) and nitric oxide, the cell redox state, appears to be important in the mechanisms of heart failure. This balance has significant impact on calcium-handling proteins, affecting excitation-contraction coupling. Both ROS and nitric oxide appear to be elevated in heart failure and are accompanied by significant impairments in the number and function of calcium-handling proteins. These proteins contain sulfhydryl groups or disulfide linkages involving cysteine residues, making them susceptible to the action of oxidizing-reducing agents and nitrosylation, thereby altering their properties. Initial increases in nitric oxide may be an adaptive response to myocardial dysfunction, elevated cytokines, and increases in ROS, while a further increase in nitric oxide and overwhelming ROS can be damaging. Abundant nitric oxide and ROS can cause formation of peroxynitrite, a strong oxidant, or nitric oxide can activate alternate pathways aiding the ROS, causing impaired calcium handling contributing to contractile dysfunction.

Inflammation as a Risk Factor for Atrial Fibrillation

Article

Jan 2004
CIRCULATION

The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort. CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P<0.001). CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.

Oxidation of glutathione and cysteine in human plasma associated with smoking

Article

Dec 2003
FREE RADICAL BIO MED

Cigarette smoking contributes to the development or progression of numerous chronic and age-related disease processes, but detailed mechanisms remain elusive. In the present study, we examined the redox states of the GSH/GSSG and Cys/CySS couples in plasma of smokers and nonsmokers between the ages of 44 and 85 years (n = 78 nonsmokers, n = 43 smokers). The Cys/CySS redox in smokers (-64 +/- 16 mV) was more oxidized than nonsmokers (- 76 +/- 11 mV; p <.001), with decreased Cys in smokers (9 +/- 5 microM) compared to nonsmokers (13 +/- 6 microM; p <.001). The GSH/GSSG redox was also more oxidized in smokers (-128 +/- 18 mV) than in nonsmokers (-137 +/- 17 mV; p =.01) and GSH was lower in smokers (1.8 +/- 1.3 microM) than in nonsmokers (2.4 +/- 1.0; p <.005). Although the oxidation of GSH/GSSG can be explained by the role of GSH in detoxification of reactive species in smoke, the more extensive oxidation of the Cys pool shows that smoking has additional effects on sulfur amino acid metabolism. Cys availability and Cys/CySS redox are known to affect cell proliferation, immune function, and expression of death receptor systems for apoptosis, suggesting that oxidation of Cys/CySS redox or other perturbations of cysteine metabolism may have a key role in chronic diseases associated with cigarette smoking.

Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses

Article

Dec 2002
FREE RADICAL BIO MED

Oxidative stress is a component of diseases and degenerative processes associated with aging. However, no means are available to assess causative oxidative events separately from decline in function of protective antioxidant systems. Previous studies show that ongoing oxidative processes maintain plasma cysteine/cystine redox at a value that is more oxidized than the antioxidant glutathione/glutathione disulfide (GSH/GSSG) system, suggesting that redox analysis of these plasma thiols could allow separate evaluation of an increase in oxidative events from a decline in antioxidant function. The present study uses measurement of cysteine/cystine and GSH/GSSG redox in plasma of 122 healthy individuals aged 19-85 years to determine whether thiol-disulfide redox changes occur with age. The results show a linear oxidation of cysteine/cystine redox state with age at a rate of 0.16 mV/year over the entire age span. In contrast, GSH/GSSG redox was not oxidized prior to 45 years and subsequently was oxidized at a nearly linear rate of 0.7 mV/year. These data suggest that there is a continuous, linear increase in oxidative events throughout adult life but that the capacity of the GSH antioxidant system is maintained until 45 years and then declines rapidly. The data further suggest that redox states of cysteine/cystine and GSH/GSSG provide an approach to clinically distinguish between increased causative oxidative events and decreased GSH antioxidant function. In principle, such analyses can be used to assess efficacy of intervention strategies against oxidative stress prior to or early after onset of clinical symptoms in aging and age-related disease.

The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model

Article

Apr 2004

It has been recently reported that AF is associated with tissue inflammation. Statins reduce C-reactive protein (CRP) levels. However, the effect of statin on atrial fibrillation (AF) is unclear. The purpose of the present study was to evaluate the effect of statin on AF in a canine sterile pericarditis model. Sterile pericarditis was created in 20 dogs randomly assigned to two groups: a control group (10 dogs) and an atorvastatin treatment group (10 dogs). Atorvastatin was administered orally (2 mg/kg/day) beginning 1 week before the operation until the end of the study. Before and 2 days after the operation, CRP levels, the duration of induced AF, the atrial effective refractory period (AERP), and intra-atrial conduction time were determined. Before the operation, there were no significant differences in any of the parameters between the two groups. On the second postoperative day, the atorvastatin group had a lower CRP level (7.6+/-0.5 versus 11.7+/-1.3 mg/dl, P<0.0001), a shorter AF duration (177+/-57 versus 534+/-189 s, P<0.0001), a longer AERP (138+/-6 versus 130+/-6 ms, P<0.01), and a shorter intra-atrial conduction time (46+/-3 versus 51+/-5 ms, P<0.01) than the control group. Atorvastatin can prevent maintenance of AF by inhibiting inflammation in the canine sterile pericarditis model. Atorvastatin may thus be a novel therapeutic agent for AF.

Relationship of interleukin-6 and C-Reactive protein to the prothrombotic state in chronic atrial fibrillation

Article

Jun 2004
J AM COLL CARDIOL

We sought to test the hypothesis that there is a relationship between inflammation and the prothrombotic state in atrial fibrillation (AF). Atrial fibrillation is associated with a prothrombotic or hypercoagulable state, which may contribute to an increased risk of stroke and thromboembolism. Inflammation may be involved in the pathogenesis of AF, but the role of inflammation in the pathophysiology of the prothrombotic state of AF has not been studied in detail, despite evidence of a link between inflammation and arterial atherothrombotic disorders. We measured plasma indexes of inflammation (C-reactive protein [CRP] and interleukin-6 [IL-6]) and the prothrombotic state, including markers of platelet activation (soluble P-selectin), endothelial damage/dysfunction (von Willebrand factor), the coagulation cascade (tissue factor [TF], fibrinogen), and indexes of blood rheology (plasma viscosity, plasma fibrinogen, and hematocrit) in 106 patients with chronic AF and 41 healthy control subjects included in a cross-sectional analysis. Compared with controls, AF patients had higher levels of IL-6 (p = 0.034), CRP (p = 0.003), TF (p = 0.019), and plasma viscosity (p = 0.045). Plasma IL-6 levels were higher among AF patients at "high" risk of stroke (p = 0.003). After adjusting for potential confounding clinical variables (e.g., vascular disease), AF remained significantly associated with a raised logarithmic transformation (log) of TF (p = 0.04), but the relationships between AF and log IL-6, log CRP, and plasma viscosity became nonsignificant. Among AF patients, log TF (p < 0.001) and high stroke risk (p = 0.003) were independent associates of log IL-6 (adjusted r(2) = 0.443), whereas log fibrinogen (p < 0.001) and plasma viscosity (p = 0.04) were independent associates of log CRP (adjusted r(2) = 0.259). Increased plasma IL-6, CRP, and plasma viscosity support the case for the existence of an inflammatory state among "typical" populations with chronic AF. These indexes of inflammation are related to indexes of the prothrombotic state and may be related to the clinical variables of the patients (underlying vascular disease and co-morbidities), rather than simply to the presence of AF itself.

Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 122, 339-352

Article

Nov 2004

Reactive oxygen species (ROS), including superoxide (*O2-), hydrogen peroxide (H2O2), and hydroxyl anion (OH-), and reactive nitrogen species, such as nitric oxide (NO) and peroxynitrite (ONOO-), are biologically important O2 derivatives that are increasingly recognized to be important in vascular biology through their oxidation/reduction (redox) potential. All vascular cell types (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) produce ROS, primarily via cell membrane-associated NAD(P)H oxidase. Reactive oxygen species regulate vascular function by modulating cell growth, apoptosis/anoikis, migration, inflammation, secretion, and extracellular matrix protein production. An imbalance in redox state where pro-oxidants overwhelm anti-oxidant capacity results in oxidative stress. Oxidative stress and associated oxidative damage are mediators of vascular injury and inflammation in many cardiovascular diseases, including hypertension, hyperlipidemia, and diabetes. Increased generation of ROS has been demonstrated in experimental and human hypertension. Anti-oxidants and agents that interrupt NAD(P)H oxidase-driven *O2- production regress vascular remodeling, improve endothelial function, reduce inflammation, and decrease blood pressure in hypertensive models. This experimental evidence has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates, by decreasing generation of ROS and/or by increasing availability of antioxidants, may be useful in minimizing vascular injury and hypertensive end organ damage. The present chapter focuses on the importance of ROS in vascular biology and discusses the role of oxidative stress in vascular damage in hypertension.

Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs

Article

Nov 2004
CIRCULATION

There is evidence for a role of oxidant stress and inflammation in atrial fibrillation (AF). Statins have both antioxidant and antiinflammatory properties. We compared the effects of simvastatin with those of antioxidant vitamins on AF promotion by atrial tachycardia in dogs. We studied dogs subjected to atrial tachypacing (ATP) at 400 bpm in the absence and presence of treatment with simvastatin, vitamin C, and combined vitamins C and E. Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. Atrioventricular block was performed to control ventricular rate. Mean duration of induced AF was increased from 42+/-18 to 1079+/-341 seconds at terminal open-chest study after tachypacing alone (P<0.01), and atrial effective refractory period (ERP) at a cycle length of 300 ms was decreased from 117+/-5 to 76+/-6 ms (P<0.01). Tachypacing-induced ERP shortening and AF promotion were unaffected by vitamin C or vitamins C and E; however, simvastatin suppressed tachypacing-induced remodeling effects significantly, with AF duration and ERP averaging 41+/-15 seconds and 103+/-4 ms, respectively, after tachypacing with simvastatin therapy. Tachypacing downregulated L-type Ca2+-channel alpha-subunit expression (Western blot), an effect that was unaltered by antioxidant vitamins but greatly attenuated by simvastatin. Simvastatin attenuates AF promotion by atrial tachycardia in dogs, an effect not shared by antioxidant vitamins, and constitutes a potentially interesting new pharmacological approach to preventing the consequences of atrial tachycardia remodeling.

Association between novel oxidative stress markers and C-reactive protein among adults without clinical coronary heart disease

Article

Feb 2005
Atherosclerosis

Increases in the inflammatory marker C-reactive protein (CRP) have been associated with a higher risk of incident coronary heart disease (CHD). The causes of increased CRP, however, are not completely understood. Studies suggest that oxidative stress may have pro-inflammatory effects, but data on the relationship between oxidative stress and CRP in healthy persons is sparse. We conducted a cross-sectional study of oxidative stress markers and high sensitivity CRP (hsCRP) among 126 adults without CHD. Markers of oxidative stress included the free oxygen radical test (FORT), which reflects levels of organic hydroperoxides, and the redox potential of the reduced glutathione/glutathione disulfide couple, (Eh) GSH/GSSG. In a linear regression model that adjusted for age, sex, body mass index, and other potential hsCRP determinants, the FORT was positively associated with log-transformed hsCRP and explained 14% of log-transformed hsCRP variance (P < 0.001). In contrast, (Eh) GSH/GSSG showed little association with hsCRP. Among adults free of CHD, oxidative stress, as measured by the FORT, is significantly associated with higher hsCRP levels, independent of BMI and other CRP determinants. This result suggests that oxidative stress may be a determinant of CRP levels and promote pro-atherosclerotic inflammatory processes at the earliest stages of CHD development.

C-Reactive Protein is a Risk Indicator for Atrial Fibrillation After Myocardial Revascularization

Article

Jun 2005

Activation of the complement system after coronary artery bypass graft surgery involves C-reactive protein (CRP). This inflammatory response is related to baseline CRP levels and associated with postoperative arrhythmia, in particular atrial fibrillation (AF). We investigated whether baseline CRP levels are a risk indicator for the occurrence of AF and whether this phenomenon is cardiopulmonary bypass dependent. C-reactive protein was measured in perioperative blood samples of patients of the Octopus Study (coronary artery bypass graft surgery with [n = 73] or without cardiopulmonary bypass [n = 79]). Baseline CRP was dichotomized into a low and a high baseline group, using a cutoff value of 3.0 mg/L. After coronary artery bypass graft surgery with cardiopulmonary bypass 11 of 53 patients (21%) with low preoperative CRP levels had AF versus 11 of 20 patients (55%) with high baseline CRP levels (p = 0.01). In the off-pump group AF occurred in 4 of 52 patients (8%) who had low baseline CRP levels, versus 8 of 27 patients (30%) with high preoperative CRP levels (p = 0.002). After adjusting for age, the odds ratio (95% confidence interval) was 4.6 (1.4 to 15.3) with cardiopulmonary bypass, 3.7 (0.93 to 14.7) in the off-pump group, and 3.3 (1.4 to 7.6) for both groups together. Continuous baseline CRP was an independent predictor for AF in a multivariate logistic regression model (p = 0.02). Patients with high baseline CRP levels are at higher risk of having postoperative AF in both on-pump and off-pump surgery.

High-sensitivity C-reactive protein is predictive of successful cardioversion for atrial fibrillation and maintenance of sinus rhythm after conversion

Article

May 2006
INT J CARDIOL

Cardioversion for atrial fibrillation (AF) is the most effective treatment for the restoration of sinus rhythm (SR). Recently, an elevated level of hs-CRP has been shown to be associated with AF burden, suggesting that inflammation increases the propensity for persistence of AF. We examined whether the level of high-sensitivity C-reactive protein (hs-CRP) was predictive of the outcome of cardioversion for AF. One hundred and six patients with a history of symptomatic AF lasting > or =1 day (age 63+/-14 years, mean+/-S.D.) underwent cardioversion. Echocardiography and hs-CRP assay were performed immediately prior to cardioversion. SR was restored in 84 patients (79%). By using selected cutoff values, multiple discriminant analysis revealed significant associations between successful cardioversion and a shorter duration of AF (AF duration< or =36 days, odds ratio (OR), 0.98; 95% confidence interval (CI), 0.97-0.99), smaller left atrial diameter (left atrial diameter< or =40 mm, OR 0.82, 95% CI 0.71-0.94), better-preserved left ventricular ejection fraction (left ventricular ejection fraction> or =60%, OR 0.92, 95% CI 0.86-0.99), and lower hs-CRP level (hs-CRP< or =0.12 mg/dL, OR 0.33, 95% CI 0.21-0.51). During a follow-up period of 140+/-144 days, AF recurred in 64 patients (76%). By using a cutoff value of hs-CRP> or =0.06 mg/dL, Cox proportional-hazards regression model found that only hs-CRP level was an independent predictor of AF recurrence (OR 5.30, 95% CI 2.46-11.5) after adjustment for coexisting cardiovascular risks. When patients were divided by the hs-CRP level of 0.06 mg/dL, percentage of maintenance of SR below and above the cutoff was 53% and 4%, respectively (log-rank test, p<0.0001). hs-CRP level determined prior to cardioversion represents an independent predictor of both successful cardioversion for AF and the maintenance of SR after conversion.

A Myocardial Nox2 Containing NAD(P)H Oxidase Contributes to Oxidative Stress in Human Atrial Fibrillation

Article

Oct 2005
CIRC RES

Human atrial fibrillation (AF) has been associated with increased atrial oxidative stress. In animal models, inhibition of reactive oxygen species prevents atrial remodeling induced by rapid pacing, suggesting that oxidative stress may play an important role in the pathophysiology of AF. NAD(P)H oxidase is a major source of superoxide in the cardiovascular system; however, whether this enzyme contributes to atrial oxidative stress in AF remains to be elucidated. We investigated the sources of superoxide production (using inhibitors and substrates of a range of oxidases, RT-PCR, immunofluorescence, and immunoblotting) in tissue homogenates and isolated atrial myocytes from the right atrial appendage (RAA) of patients undergoing cardiac surgery (n=54 in sinus rhythm [SR] and 15 in AF). A membrane-bound gp91phox containing NAD(P)H oxidase in atrial myocytes was the main source of atrial superoxide production in SR and in AF. NADPH-stimulated superoxide release from RAA homogenates was significantly increased in patients with AF in the absence of changes in mRNA expression of the p22phox and gp91phox subunits of the NAD(P)H oxidase. In contrast with findings in SR patients, NO synthases (NOSs) contributed significantly to atrial superoxide production in fibrillating atria, suggesting that increased oxidative stress in AF may lead to NOS "uncoupling." These findings indicate that a myocardial NAD(P)H oxidase and, to a lesser extent, dysfunctional NOS contribute significantly to superoxide production in the fibrillating human atrial myocardium and may play an important role in the atrial oxidative injury and electrophysiological remodeling observed in patients with AF.

Atrial Fibrillation Increases Production of Superoxide by the Left Atrium and Left Atrial Appendage Role of the NADPH and Xanthine Oxidases

Article

Aug 2005
CIRCULATION

Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO*) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO* levels observed in AF may be associated with increased superoxide (O2*-) production. After a week of AF induced by rapid atrial pacing in pigs, O2*- production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase-inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O2*- production was increased 2.7-fold (P<0.01) and 3.0-fold (P<0.02) in the LA and LAA, respectively. A similar 3.0-fold (P<0.01) increase in LAA O2*- production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O2*-, implying that NADPH and xanthine oxidases both contributed to increased O2*- production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase (P=0.04) and xanthine oxidase (P=0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase. AF increased O2*- production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O2*- production. This increase in O2*- and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Article

Jan 2006
CIRC RES

Sudden cardiac death attributable to ventricular tachycardia/fibrillation (VF) remains a catastrophic outcome of myocardial ischemia and infarction. At the same time, conventional antagonist drugs targeting ion channels have yielded poor survival benefits. Although pharmacological and genetic models suggest an association between sodium (Na+) channel loss-of-function and sudden cardiac death, molecular mechanisms have not been identified that convincingly link ischemia to Na+ channel dysfunction and ventricular arrhythmias. Because ischemia can evoke the generation of reactive oxygen species, we explored the effect of oxidative stress on Na+ channel function. We show here that oxidative stress reduces Na+ channel availability. Both the general oxidant tert-butyl-hydroperoxide and a specific, highly reactive product of the isoprostane pathway of lipid peroxidation, E2-isoketal, potentiate inactivation of cardiac Na+ channels in human embryonic kidney (HEK)-293 cells and cultured atrial (HL-1) myocytes. Furthermore, E2-isoketals were generated in the epicardial border zone of the canine healing infarct, an arrhythmogenic focus where Na+ channels exhibit similar inactivation defects. In addition, we show synergistic functional effects of flecainide, a proarrhythmic Na+ channel blocker, and oxidative stress. These data suggest Na+ channel dysfunction evoked by lipid peroxidation is a candidate mechanism for ischemia-related conduction abnormalities and arrhythmias.

Statin Use Is Associated With a Reduction in Atrial Fibrillation After Noncardiac Thoracic Surgery Independent of C-Reactive Protein

Article

Nov 2005

The level of C-reactive protein (CRP) has been shown to be elevated in patients with atrial fibrillation/flutter (AF) unrelated to surgery, and statins are known to lower the CRP level. To determine whether an elevated CRP level predisposes the patient to postoperative AF and whether statin use is associated with a reduced AF incidence, we studied a consecutive group of patients who were at risk for AF after undergoing thoracic surgery (age, > or = 60 years). A prospective study in a tertiary care cancer center of 131 patients (mean [+/- SD] age, 73 +/- 6 years) who had undergone major lung or esophageal resection. High-sensitivity CRP and interleukin (IL)-6 levels were measured before surgery, on arrival at the postanesthesia care unit, and on the first morning after surgery. Continuous telemetry was used for 72 to 96 h to detect AF. AF occurred in 38 of 131 patients (29%) at a median time after surgery of 3 days. Although CRP and IL-6 levels increased significantly (p < 0.001) in response to surgery, patients with or without AF did not differ in perioperative values. In a stepwise logistic regression, statin use was associated with a threefold decrease in the odds of developing AF (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.08 to 0.82; p = 0.022) and a greater PR interval (OR, 1.11 per 5-ms increments; 95% CI, 1.01 to 1.22; p = 0.027) predicted an increase in the risk of AF. The preoperative use of statins was associated with a protective effect against postoperative AF independent of CRP levels. In contrast to AF in the general population, early markers of inflammation did not predict the postoperative occurrence of AF.

Relation of inflammatory cytokines to atrial fibrillation after oo-pump coronary artery bypass grafting

Article

May 2006

It has been observed that a systemic inflammatory response after on-pump coronary artery bypass grafting (CABG) participates in the pathogenesis of postoperative atrial fibrillation (AF). In patients undergoing off-pump CABG, it is plausible that inflammation is associated with the development of postoperative AF. The present study examined relation of proinflammatory cytokines, which play an important role in the upstream of inflammatory cascade, to the development of AF after off-pump CABG. The present study included 39 patients undergoing off-pump CABG. Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8, were measured by enzyme-linked immunosorbent assay, on anesthetic induction, after sternotomy before anastomoses, at the completion of anastomoses, 3 and 6h thereafter, and on postoperative days (POD) 1-4. C-reactive protein (CRP) was also measured by turbidimetric immunoassay, preoperatively, and on POD 1, 2, 3, 6, 9, and 13. Eleven patients (28%) developed postoperative AF. Patients with postoperative AF were older (70+/-6.4 years vs 60+/-8.8 years, P=0.001); however, there was no difference in other pre- and perioperative variables. TNF-alpha level did not change during the study period. However, IL-8 and CRP levels significantly increased after the surgery, although there was no significant difference between the two groups. IL-6 level also increased after the surgery with its peak at 6h after the completion of anastomoses. IL-6 levels of 3 and 6h after anastomoses were significantly higher in patients with postoperative AF (360+/-143 pg/ml vs 230+/-94 pg/ml, P=0.0047, 435+/-175 pg/ml vs 247+/-102 pg/ml, P=0.0005, respectively). Logistic regression analysis indicated that the highest quartile of IL-6 level immediately after the surgery (odds ratio 7.63; 95% CI, 1.06-54.9; P=0.04) and age (odds ratio 1.18; 95% CI, 1.01-1.39; P=0.04) independently predict postoperative AF. Furthermore, the maximum level of IL-6 immediately after the surgery significantly correlated to age and intraoperative blood loss (r=0.04, P=0.01, and r=0.47, P=0.04, respectively). Advanced age was a major risk factor for postoperative AF. Furthermore, inflammatory response induced by surgical trauma was also associated with the development of AF after off-pump CABG.

Endothelial dysfunction and exercise performance in lone atrial fibrillation or associated with hypertension or diabetes: Different results with cardioversion

Article

Sep 2006

Endothelial dysfunction and underperfusion of exercising muscle contribute to exercise intolerance, hyperventilation, and breathlessness in atrial fibrillation (AF). Cardioversion (CV) improves endothelial function and exercise performance. We examined whether CV is equally beneficial in diabetes and hypertension, diseases that cause endothelial dysfunction and are often associated with AF. Cardiopulmonary exercise and pulmonary and endothelial (brachial artery flow-mediated dilation) function were tested before and after CV in patients with AF alone (n = 18, group 1) or AF with hypertension (n = 19, group 2) or diabetes (n = 19, group 3). Compared with group 1, peak exercise workload, O2 consumption (Vo2), O2 pulse, aerobic efficiency (Delta Vo2/Delta WR), and ratio of brachial diameter changes to flow changes (Delta D/Delta F) were reduced in group 2 and, to a greater extent, in group 3; exercise ventilation efficiency (Ve/Vco2 slope) and dead space-to-tidal volume ratio (Vd/Vt) were similar among groups. CV had less effect on peak workload (+7% vs. +18%), peak Vo2 (+12% vs. +17%), O2 pulse (+33% vs. +50%), Delta Vo2/Delta WR (+7% vs. +12%), Ve/Vco2 slope (-6% vs. -12%), Delta D/Delta F (+7% vs. +10%), and breathlessness (Borg scale) in group 2 than in group 1 and was ineffective in group 3. The antioxidant vitamin C, tested in eight additional patients in each cohort, improved flow-mediated dilation in groups 1 and 2 before, but not after, CV and was ineffective in group 3, suggesting that the oxidative injury is least in lone AF, greater in hypertension with AF, and greater still in diabetes with AF. Comorbidities that impair endothelial activity worsen endothelial dysfunction and exercise intolerance in AF. The advantages of CV appear to be inversely related to the extent of the underlying oxidative injury.

Relationship Between C-Reactive Protein Level and Early Recurrence of Atrial Fibrillation After Electrical Cardioversion

Article

Feb 2006

Atrial remodeling is responsible for the early recurrence of atrial fibrillation (AF) after cardioversion. Recently, it has been shown that the C-reactive protein (CRP) level is elevated in patients with AF, indicating that inflammation may play a role in the pathogenesis of this arrhythmia. We postulated that a high CRP level would predict early recurrence of AF after electrical cardioversion. Forty-two patients with persistent AF, but without known heart disease, who underwent elective electrical cardioversion were investigated. The CRP level was measured immediately before cardioversion. The study population comprised the 37 patients in whom sinus rhythm was restored. After a follow-up period of 30 days, 16 patients (43%) had recurrence of AF; the other 21 (57%) remained in sinus rhythm. The mean CRP level was significantly higher in patients with AF recurrence (6.3 [3.3] mg/L vs 2.4 [2.1] mg/L, P=.0001). On dividing patients according to whether their CRP level was < or =3 mg/L or >3 mg/L, it was observed that only 33% of those in sinus rhythm had a level >3 mg/L compared with 81% of those with AF recurrence (P=.004). Patients with a CRP level >3 mg/L had a significant increase in the 1-month risk of AF recurrence (RR=3.7; 95% CI, 1.3-10.8). There was no association between CRP level and left atrial diameter (P =.50) or AF duration (P=.458). A high CRP level is associated with early recurrence of AF after electrical cardioversion, suggesting that inflammation could play a role in atrial remodeling.

Effect of Atorvastatin on the Recurrence Rates of Atrial Fibrillation After Electrical Cardioversion

Article

May 2006
AM J CARDIOL

To study the effect of atorvastatin on recurrence of atrial fibrillation (AF) after electrical cardioversion (EC), 48 patients with AF lasting 48 hours who were scheduled for EC were randomized to the atorvastatin (group I) and control (group II) groups. Six patients in group I (25%) and 2 patients in group II (8.3%) had spontaneous conversion before EC (p >0.05). The end point was the recurrence of AF during 3 months of follow-up. Eighteen patients in group I (12.5%) and 11 patients in group II (45.8%) had recurrence (p = 0.01, log-rank test). With the Cox proportional model, the predictors of recurrence included a body mass index of 25 to 30 kg/m2 (relative risk [RR] 0.07, 95% confidence interval [CI] 0.008 to 0.59), body mass index > or = 30 kg/m2 (RR 0.24, 95% CI 0.08 to 0.72), AF duration of > or = 3 months (RR 0.28, 95% CI 0.09 to 0.83), diabetes mellitus (RR 0.34, 95% CI 0.12 to 0.98), and left atrial diameter of > or = 45 mm (RR 0.23, 95% CI 0.07 to 0.74). Atorvastatin was associated with a significantly reduced risk of developing AF (unadjusted RR 0.23, 95% CI 0.064 to 0.82, p = 0.024). This association remained significant after adjustment for these predictors (adjusted RR 0.19, 95% CI 0.052 to 0.72, p = 0.01). High-sensitivity C-reactive protein levels at baseline were not different between the 2 groups (p = 0.92). Although the high-sensitivity C-reactive protein levels decreased significantly 48 hours after EC compared with the baseline levels in group I (2.82 +/- 1.46 vs 2.56 +/- 1.3 mg/dl, p = 0.02), no significant change occurred in group II (2.87 +/- 0.8 vs 2.84 +/- 0.8 mg/dl, p = 0.09). In conclusion, atorvastatin decreased the recurrence rate of AF after EC.

Glutathione measurement in human plasma: evaluation of sample collection, storage and derivatization conditions for analysis of dansyl derivatives by HPLC

D P Jones
J L Carlson
P S Samiec
P Sternberg
Mody Jr
Vc
Jr
R L Reed

Oxidative Stress Markers Are Associated with Persistent Atrial Fibrillation

Abstract

No full-text available

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