Yajuan Yang

Warfarin-related nephropathy: Prevalence, risk factors and prognosis

Warfarin has been the most commonly prescribed oral anticoagulantsince its approval in 1954 [1]. Warfarin is widely used in the preventionand treatment of deep venous thrombosis and pulmonary embolism,thromboembolismpreventioninthepatientswithatrial fibrillation,pros-thetic heart valves and indwelling central venous catheters. It interruptsthe synthesis of coagulation factors (II, VII, IX, and X) by inhibiting thevitamin K epoxide reductase (VKOR) and causes disruption of the extrin-sicclottingcascade.Warfarinisstillun deruseinclinicalpracticeespeciallyin China despite the strong evidence of this drug for thromboembolismprevention [2].Thismaybeduetoitsnarrowtherapeuticrange,potentialinteractions with a variety of commonly used drug and food [3], and itspropensity to cause hemorrhage. Also, different warfarin-relatedgenotypes were also related to over-anticoagulation and hemorrhagiccomplications [4].Warfarin-relatednephropathy(WRN)isarecentlyrecognizedcom-plication during warfarin anticoagulation therapy, in which excessivewarfarinization [international normalized ratio (INR) N3.0] leads toacute kidney injury (AKI) by causing glomerular hemorrhage andrenal tubular obstruction by red blood cell (RBC) casts [5,6]. Brodskyet al. [7] was the first to describe this entity through kidney biopsy ina subset of patients with warfarin overdose, hematuria, and AKI, andeachbiopsyspecimendemonstratedtheevidenceofacutetubularinju-ry, glomerular hemorrhage and renal tubular obstruction by RBC casts.They termed clinical WRN as an episode of unexplained acute renalinjury defined as a serum creatinine increase greater than 0.3 mg/dlwithin one week of an INR measurement greater than 3.0 in a patientbeing treated with warfarin without clinical evidence of hemorrhage[5,6]. They also established an animal model of WRN, and showed theexcessive anticoagulation increased serum creatinine levels andhematuriainthe5/6nephrectomyratsbutnotincontrols,whichresultedin the formation of obstructing tubular RBC casts [8].However, WRN could be the result of a problem more widespreadthan complete tubular obstruction by RBCs. Other potential mecha-nismsmayparticipateintheoccurrenceofWRN(Fig.1).First,oxidativestress damage to tubules by RBC, even though the RBC did not obstructthetubule,couldleadtoWRN[9].Thepatientswithchronickidneydis-ease have reduced plasma antioxidant enzyme activities, such as gluta-thioneperoxidaseandcatalase,whichmaycontributetoahigherriskofWRN. Other important mechanisms, including atheroembolism [10],interstitial nephritis [11], apoptosis of glomerular endothelial cells [8]and direct effects of warfarin on the glomerulus [12] may also contrib-ute to the development of WRN. Warfarin has been shown to affectglomerular mesangial cells by interfering with the activation of theproduct of growth arrest-specificgene6[11]. This could affect glomer-ular hemodynamics or aggravate the underlying glomerular disease.Brodsky et al. [5] further investigated the prevalence, risk factors,and consequence of WRN in a large cohort of patients who initiatedwarfarin therapy during a 5-year period at the Ohio State UniversityMedical Center, WRN occurred in 20.5% of the entire cohort, 33.0% ofthe CKD cohort, and 16.5% of the non-CKD cohort, which indicatedthat patients with CKD are at much greater risk of WRN than thosewithout CKD. It suggests that CKD patients may be prone to over-anticoagulation as spend less time within the target range, requiredmorefrequentadjustmentsandhadhigherbleedingrisk.Otherriskfac-torsfor WRNincludedage, diabetesmellitus,hypertension,andcardio-vascular disease. Therefore, WRN may be a common complication ofwarfarin therapy in high-risk patients, especially in the CKD patients.Recently, An et al. [13] showedWRNdeveloped in19.3% of thepatientshavingexcessivewarfarinization.Alowerbaselineserumalbumin,highserum AST at post INR elevation, and heart failure were independentrisk factors for WRN. In contrast, atrial fibrillation significantlydecreased the risk of WRN. However, neither the presence of CKD norbaseline estimated glomerular filtration rate (eGFR) was an indepen-dent risk factor for WRN.The occurrence of WRN also increased long-term mortality in pa-tients with and without CKD. Brodsky et al. [5] reported that one-yearmortality was significantly higher in the patients with WRN compared

Meta‐analysis of Vitamin D Deficiency and Risk of Atrial Fibrillation

There are accumulating studies investigating the association between vitamin D status and the risk of atrial fibrillation (AF). However, the results in these studies were inconsistent in regard to the role of vitamin D deficiency in predicting the development of AF.

Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits

Background There is increasing evidence implicating atrial mitochondrial dysfunction in the pathogenesis of atrial fibrillation. In this study, we explored whether alogliptin, a dipeptidyl peptidase‐4 inhibitor, can prevent mitochondrial dysfunction and atrial remodeling in a diabetic rabbit model. Methods and Results A total of 90 rabbits were randomized into 3 groups as follows: control group (n=30), alloxan‐induced diabetes mellitus group (n=30), and alogliptin‐treated (12.5 mg/kg per day for 8 weeks) diabetes mellitus group (n=30). Echocardiographic and hemodynamic assessments were performed in vivo. The serum concentrations of glucagon‐like peptide‐1, insulin, and inflammatory and oxidative stress markers were measured. Electrophysiological properties of Langendorff‐perfused rabbit hearts were assessed. Mitochondrial morphology, respiratory function, membrane potential, and reactive oxygen species generation rate were assessed. The protein expression of transforming growth factor β1, nuclear factor κB p65, and mitochondrial biogenesis–related proteins were measured by Western blot analysis. Diabetic rabbits exhibited left ventricular hypertrophy and left atrial dilation without obvious hemodynamic abnormalities, and all of these changes were attenuated by alogliptin. Compared with the control group, higher atrial fibrillation inducibility in the diabetes mellitus group was observed, and markedly reduced by alogliptin. Alogliptin decreased mitochondrial reactive oxygen species production rate, prevented mitochondrial membrane depolarization, and alleviated mitochondrial swelling in diabetic rabbits. It also improved mitochondrial biogenesis by peroxisome proliferator–activated receptor‐γ coactivator 1α/nuclear respiratory factor‐1/mitochondrial transcription factor A signaling regulated by adiponectin/AMP‐activated protein kinase. Conclusions Dipeptidyl peptidase‐4 inhibitors can prevent atrial fibrillation by reversing electrophysiological abnormalities, improving mitochondrial function, and promoting mitochondrial biogenesis.

NADPH oxidase inhibitor apocynin prevents atrial remodeling in alloxan-induced diabetic rabbits

OBJECTIVES Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The role of the NADPH oxidase (NOX) signaling in the setting of DM and the potential benefits of apocynin on diabetic atrial remodeling remain unknown. METHODS Sixty Japanese rabbits were randomized into 3 groups as follows: Control group (Control, n=20), alloxan-induced diabetic group (DM, n=20) and apocynin-treated diabetic group (APO, n=20). Rabbits in the APO group were orally administered apocynin (15mg/kg/day) for 8weeks. Serum malonaldehyde (MDA), superoxide dismutase (SOD) levels, and left atrial tissue NADPH oxidase (NOX) activities were measured. Isolated rabbit hearts were Langendorff perfused. Atrial refractory effective period (AERP), atrial effective refractory period dispersion (AERPD), interatrial conduction time (IACT) and vulnerability to AF were assessed. Atrial interstitial fibrosis was evaluated by Massons trichrome staining. The protein expression of NF-κB, TGF-β, p38, P-p38, JNK, P-JNK, ERK and P-ERK was measured by Western blot analysis. RESULTS There were no significant differences regarding SBP, DBP, LVEDP and AERP in the three groups. Compared with the Control group, AF inducibility was increased in the DM group (46/450 vs. 5/450, P<0.05), and markedly reduced by apocynin (46/450 vs. 12/450, P<0.05). Apocynin also attenuated atrial structural remodeling in diabetic rabbits. Western-blot analysis indicated that apocynin reduced the DM-induced increased protein expression of TGF-β, NF-κB, P-p38, P-JNK, ERK and P-ERK. CONCLUSIONS Apocynin, a NADPH oxidase inhibitor, prevents AF and attenuates atrial remodeling in alloxan-induced diabetic rabbits.

Association of Plasma Transforming Growth Factor-β1 Levels and the Risk of Atrial Fibrillation: A Meta-Analysis.

Introduction Numerous studies have demonstrated that plasma transforming growth factor-β1 (TGF-β1) may be involved in the pathogenesis of atrial fibrillation (AF), but some discrepancy remained. We performed a meta-analysis to evaluate the association between the plasma level of TGF-β1 and the risk of AF. Methods Published clinical studies evaluating the association between the plasma level of TGF-β1 and the risk of AF were retrieved from PubMed and EMBASE databases. Two reviewers independently evaluated the quality of the included studies and extracted study data. Subgroup analysis and sensitivity analysis were performed to evaluate for heterogeneity between studies. Results Of the 395 studies identified initially, 13 studies were included into our analysis, with a total of 3354 patients. Higher plasma level of TGF-β1 was associated with increased risk of AF when evaluated as both a continuous variable (SMD 0.67; 95%CI 0.29–1.05) and a categorical variable (OR 1.01, 95% CI 1.01–1.02). Conclusions This meta-analysis suggests an association between elevated plasma TGF-β1 and new onset AF. Additional studies with larger sample sizes are needed to further investigate the relationship between plasma TGF-β1 and the occurrence of AF.

Notching early repolarization pattern in inferior leads increases risk of ventricular tachyarrhythmias in patients with acute myocardial infarction: a meta-analysis

The aim of this of this meta-analysis was to examine the potential association between certain early repolarization (ER) characteristics and ventricular tachyarrhythmias (VTAs) in patients with acute myocardial infarction (AMI). We searched PubMed, Embase and Web of Science databases for records published until December 2014. Of the 658 initially identified records, 7 studies with a total of 1,565 patients (299 with ER and 1,266 without ER) were finally analyzed. Overall, patients with ER displayed a higher risk of VTAs following AMI compared to patients without ER [odds ratio (OR): 3.75, 95% CI: 2.62–5.37, p < 0.00001]. Subgroup analyses showed that the diagnosis of ER prior to AMI onset is a better predictor of VTAs (OR: 5.70, p < 0.00001) compared to those diagnosed after AMI onset (OR: 2.60, p = 0.00001). Remarkably, a notching morphology was a significant predictor of VTAs compared to slurring morphology (OR: 3.85, p = 0.002). Finally, an inferior ER location (OR: 8.85, p < 0.00001) was significantly associated with increased risk of VTAs in AMI patients. In conclusion, our meta-analysis suggests that ER pattern is associated with greater risk of VTAs in patients with AMI. A notched ER pattern located in inferior leads confers the highest risk for VTAs in AMI.

Apocynin attenuates left ventricular remodeling in diabetic rabbits

Introduction Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are responsible for the generation of reactive oxygen species, producing vascular and myocardial dysfunction in diabetes mellitus. However, the potential benefits of the NADPH oxidase inhibitor, apocynin, on left ventricular (LV) remodeling remain unknown. Results In the diabetic group, interventricular septal thickness and left ventricular posterior wall thickness were markedly increased compared to control. These changes were accompanied by increased LV cardiomyocyte cross-sectional area and greater degree of interstitial fibrosis. NO, myeloperoxidase, and malonaldehyde levels in the serum were significantly increased Moreover, protein expression levels of rac1, nuclear factor-κB, transforming growth factor-β, p38, P-p38, and metalloproteinase-9 were also raised. Apocynin treatment prevented all of these structural, histological and biochemical changes and additionally increased superoxide dismutase levels. Methods Thirty Japanese rabbits were randomized into three groups: control, alloxan-induced diabetes with and without apocynin treatment at 15 mg/kg/day for 8 weeks (n = 10 for each group). Echocardiography was performed and hemodynamics were assessed by carotid and LV catheterization. LV cardiomyocyte cross-sectional area and interstitial fibrosis were evaluated by histology. Serum nitric oxide (NO), malonaldehyde, myeloperoxidase, superoxide dismutase (SOD) levels, and activity of LV tissue NADPH oxidases was assessed. Expression of proteins involved in pro-inflammatory and pro-fibrotic signaling were determined by Western blotting. Conclusions Inhibition of NADPH oxidase using apocynin is an effective upstream therapy for preventing diabetes-induced adverse remodeling of the left ventricular myocardium.

Association between serum uric acid and atrial fibrillation recurrence following catheter ablation: A meta-analysis.

a Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, Peoples Republic of China b First Department of Cardiology, University Hospital of Ioannina, Ioannina, Greece c Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, “Evangelismos” General Hospital of Athens, Athens, Greece

The Chinese herb extract Wenxin Keli: A promising agent for the management of atrial fibrillation.

Keyword: Wenxin Keli Atrial fibrillation Chinese herb cardiac arrhythmias in vivo rat myocardial infarction model. Recent experimental evidence has proven the sodium channel blockers are capable of producing atrial-selective electrophysiological effects. Ranolazine and amiodarone can suppress AF without exerting markedly inhibition of electrophysiological parameters in the ventricles. Alexander et al. confirmed thatWXKL possesses anti-AF properties due to atrial-selective depression of INa-dependent parameters in canine isolated coronary-perfused preparations. The atrial-selective selectivity ofWXKL likely contributes to its usefulness for effectivemanagement of

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Background There are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes. Methods and Results Ninety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol‐treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage‐clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial‐related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment. Conclusions Allopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM‐related increases in oxidative stress.