The Contributions Of NOX4,GDF-15and NRG-1to Atrial Fibrillation And Effects Of Probucol On Atrial Fibrillation Progression In Patients With Paroxysmal Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, which can increase the risk of stroke and death. It has become a major public health problem that seriously damaged to people’s health. However, the etiology of AF is various and the pathophysiology of AF is very complex. Recently accumulating evidence suggests the involvement of inflammation and oxidative stress in the development and maintenance of AF. The research about potential association between serum nicotinamide adenine dinucleotide phosphate-oxidase4(NOX4), growth differentiation factor-15(GDF-15), and neuregulin-1(NRG-1) levels, as inflammatory or oxidative stress biomarkers, and AF was rarely reported. In addition, the overall treatment effect of AF is not very satisfactory. In recent years, people found that some anti-inflammatory or anti-oxidant drugs may have potentially anti-arrhythmic effects, what is called "the upstream treatment of AF". Probucol has a significant anti-oxidant effect that is5-6times that of vitamin E. The phenol hydroxyl contained in molecular of probucol is easy to be oxidated, break and combine with oxygen radicals, which can effectively reduce the serum concentration of oxygen free radicals. Our previous study suggested probucol attenuated atrial myocyte hypertrophy and atrial interstitial fibrosis, reduced the dispersion of atrial effective refactory period and decreased vulnerability of AF caused by diabetes mellitus. Therefore, the research would be divide into two parts:one is to investigate circulating level of GDF-15, NOX4and NRG-1in patients with AF; The other is to investigate the effects of probucol on atrial structural remodeling, oxidative stress and on AF promotion in the patients with paroxysmal AF. Section Ⅰ. The contributions of NOX4, GDF-15and NRG-1to atrial fibrillationObjective:To investigate circulating level of NOX4, GDF-15and NRG-1in patients with non-valvular atrial fibrillation (AF).Methods:We enrolled104consecutive patients with AF (paroxysmal AF with67, persistent AF with37) and67subjects as controls matched for sex, age and atherosclerotic risk factors that presented to our hospital between August2012and June2013. Comorbidities, laboratory items and echocardiographic characteristics were carefully recorded. Serum levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), myeloperoxidase (MPO), NOX4, GDF-15and NRG-1were measured in each patient.Results:No significant difference in age, history of hypertension, coronary heart disease, and stroke was found among three groups. Compared with the control group, left atrial diameter (LAD), serum level of MDA, MPO, NOX4, NRG-1, and GDF-15were increased, while left ventricular ejection fraction (LVEF), serum level of CAT and SOD were decreased in paroxysmal AF or persistent AF group. Comparision between any two groups, NOX4, NRG-1, GDF-15had significant difference between patients with paroxysmal AF and controls. Multivariable analysis demonstrated that LAD (OR:1.10,95%CI:1.007-1.201, P=0.034), MDA (OR:1.438,95%CI:1.108-1.867, P=0.006)and GDF-15(OR:1.002,95%CI:1.000-1.003, P=0.031) were associated with paroxysmal AF (OR:1.002,95%CI:1.000-1.003, P<0.05). The area under the receiver-operating characteristic curve of GDF-15was0.636(95%CI:0.532-0.740, P=0.015) to predict paroxysmal AF and the best cut-off value was1249.09pg/ml with sensitivity58.6%and specificity60%.Conclusions:Patients with AF have a higher serum level of NOX4, GDF-15and NRG-1compared with controls, however, only serum GDF-15was independently associated with paroxysmal AF in multivariable analyses. Undoubtedly, larger studies should further examine this potential association as well as the underlying pathophysiological mechanisms. Section Ⅱ. Effects of probucol on atrial fibrillation progression in patients with paroxysmal atrial fibrillationObjective: To investigate the effects of probucol on atrial structural remodeling, oxidative stress and on atrial fibrillation (AF) promotion in the patients with paroxysmal AF.Methods:We enrolled40consecutive patients with paroxysmal AF that presented to our hospital between August2012and June2013. Patients were randomly divided into two groups using the random seal envelope method: probucol group (n=20), control group (n=20). Two groups of patients took conventional beta blockers as atrial fibrillation drug treatment, and patients in probucol group added probucol at a dose of500mg/times,2times/d. The primary end point of this study was to occur persistent AF that is more than7d. Patients underwent12-lead electrocardiography (ECG), asked any arrhythmia-related symptoms and recorded end events at1,2,3,6,9and12months after enrollment. Subsequently, a12-lead ECG and a24-hour Holter were also recorded whenever patients reported palpitations. Each patient measured serum level of CAT, MDA, NOX4and GDF-15before and after treatment. ECG,24-hour Holter and echocardiography were recorded at the baseline and the end of the follow up.Results:The average follow-up was8.5±2.9months, two patients in control group withdrew from the study because of occurring end point events. Left atrial diameter (LAD) reduced, P wave dispersion (Pd) shortened and AF episodes decreased at the end of the follow up compared to before taking medicine in patients with probucol group (P<0.05), however, it had no significant difference in patients with control group. The serum level of MDA, NOX4and GDF-15were lower while CAT was higher at the end of the follow up compared to before taking medicine in patients with probucol group, but the difference was not statistically significant.Conclusions:Probucol through its powerful anti-inflammatory and antioxidant activity attenuated atrial structural remodeling and decreased vulnerability of AF caused by oxidase stress in patients with paroxysmal AF, which provided new strategy for diagnosis and treatment of AF.In summary, patients with AF have a higher serum level of MDA, NOX4, NRG-1, GDF-15and a lower level of CAT compared with controls. However, multivariable analysis demonstrated that only MDA and GDF-15were the risk factors of paroxysmal AF/AF, larger studies should further examine this potential association as well as the underlying pathophysiological mechanisms. In addition, probucol can reduce LAD, shorten Pd and decrease AF episodes in patients with paroxysmal AF. Probucol through its powerful anti-inflammatory and antioxidant activity attenuated atrial structural remodeling, expected to become the upstream treatment of AF.