Hidekazu Kondo

Glucose fluctuations increase the incidence of atrial fibrillation in diabetic rats.

AIMS We investigated whether glucose fluctuations aggravate cardiac fibrosis and increase the occurrence of atrial fibrillation (AF) in rats with diabetes mellitus (DM). METHODS AND RESULTS Streptozotocin-induced diabetic rats were randomly divided into three groups: uncontrolled DM (U-STZ) group, controlled DM (C-STZ) group, and DM with glucose fluctuations (STZ-GF) group. Glucose fluctuations were induced by fasting for 24 h and additional regular insulin injections (0.5 IU/kg) administered three times per week for three consecutive weeks. C-STZ rats were administered long acting insulin (20 IU/kg) twice a day to control blood glucose levels. Cardiac fibrosis evaluated by Masson trichrome staining and the expressions of collagen type 1, collagen type 3, and α-smooth muscle actin were increased in U-STZ rats compared with C-STZ rats, which were more pronounced in STZ-GF rats. The inducibility of AF was significantly larger in U-STZ rats than C-STZ rats and was greatest in STZ-GF rats. To explore the mechanism of cardiac fibrosis, we investigated the levels of reactive oxygen species (ROS) and apoptosis. The expression of malondialdehyde, an indicator of ROS levels, was significantly upregulated in STZ-GF rats compared with U-STZ rats, along with increased thioredoxin-interacting protein (Txnip) expression in STZ-GF rats. Furthermore, caspase-3 expression and the number of TUNEL-positive cells were significantly increased in STZ-GF rats compared with U-STZ and C-STZ rats. CONCLUSION Glucose fluctuations increase the incidence of AF by promoting cardiac fibrosis. Increased ROS levels caused by upregulation of Txnip expression may be a mechanism whereby in glucose fluctuations induce fibrosis.

Role of Indoxyl Sulfate as a Predisposing Factor for Atrial Fibrillation in Renal Dysfunction.

Background Renal dysfunction is a major risk factor for atrial fibrillation (AF). The uremic toxin indoxyl sulfate may contribute to the progression of cardiac fibrosis and AF substrate in renal dysfunction. Methods and Results Male Sprague–Dawley rats were assigned randomly to the following groups: 5/6 nephrectomy (5/6Nx) with vehicle, 5/6Nx with AST‐120, sham procedure with vehicle, and sham procedure with AST‐120. Vehicle and AST‐120 were administered for 4 weeks. Serum levels of IS were significantly increased in 5/6Nx groups. Expression of malondialdehyde, an indicator of oxidative stress, was upregulated in the left atrium of 5/6Nx groups and was accompanied by an increase in expression of NADPH oxidase 2 and 4. Monocyte‐mediated inflammatory signals such as CD68, monocyte chemoattractant protein 1, and vascular cell adhesion molecule 1 were also upregulated in 5/6Nx groups. Interstitial fibrosis was promoted heterogeneously, and expression of profibrotic indicators such as transforming growth factor β1, α‐smooth muscle actin, and collagen type 1 was upregulated in left atrium tissue of 5/6Nx groups. In cultured atrial fibroblasts, incubation with IS upregulated expression of the markers of oxidative stress, inflammation, and profibrotic factors. These results suggest the direct effects of IS on the progression of AF substrate. AF was consistently and invariably induced by atrial extrastimuli in 5/6Nx groups in electrophysiological experiments. AST‐120 treatment significantly alleviated renal dysfunction–induced oxidative stress, inflammation, and atrial fibrosis and, consequently, attenuated AF inducibility. Conclusions Indoxyl sulfate facilitates atrial fibrosis and AF and thus is a novel therapeutic target for prevention of renal dysfunction–induced AF.

Glucose Fluctuations Aggravate Cardiac Susceptibility to Ischemia/Reperfusion Injury by Modulating MicroRNAs Expression.

BACKGROUND The influence of glucose fluctuations (GF) on cardiovascular complications of diabetes mellitus (DM) has been attracting much attention. In the present study, whether GF increase susceptibility to ischemia/reperfusion in the heart was investigated. METHODS AND RESULTS Male rats were randomly assigned to either a control, DM, and DM with GF group. DM was induced by an injection of streptozotocin, and glucose fluctuation was induced by starvation and insulin injection. One sequential program comprised 2 hypoglycemic episodes during 4 days. The isolated hearts were subjected to 20-min ischemia/30-min reperfusion. The infarct size was larger in hearts with GF than those with sustained hyperglycemia. Activities of catalase and superoxide dismutase were decreased, and expressions of NADPH oxidase and thioredoxin-interacting protein were upregulated by GF accompanied by an increase of reactive oxygen species (ROS). Swollen mitochondria with destroyed cristae were observed in diabetic hearts; they were further devastated by GF. Microarray analysis revealed that the expressions of microRNA (miRNA)-200c and miRNA-141 were abundant in those hearts with GF. Overexpression of miRNA-200c and miRNA-141 decreased mitochondrial superoxide dismutase and catalase activities, and increased ROS levels. Meanwhile, knockdown of miRNA-200c and miRNA-141 significantly decreased ROS levels in cardiomyocytes exposed to GF. CONCLUSIONS GF increased ROS generation and enhanced ischemia/reperfusion injury in the diabetic heart. Upregulated miRNA-200c and miRNA-141 may account for the increased ROS.

Splenectomy exacerbates atrial inflammatory fibrosis and vulnerability to atrial fibrillation induced by pressure overload in rats: Possible role of spleen-derived interleukin-10

BACKGROUND The spleen is important for cardiac remodeling induced by myocardial infarction. However, the role of the spleen in inflammatory atrial fibrosis induced by pressure overload is unknown. OBJECTIVE The purpose of this study was to investigate whether splenectomy (SPX) attenuates or exacerbates pressure overload-induced atrial inflammatory fibrosis and vulnerability to atrial fibrillation (AF) in rats. METHODS Male Sprague-Dawley rats (6 weeks old) were divided into Sham+Sham, Sham+SPX, abdominal aortic constriction (AAC)+Sham, and AAC+SPX groups, and were evaluated for inflammation, fibrosis, and AF on days 2, 4, 14, and 28. RESULTS On day 4, an AAC-induced rise in interleukin-10 (IL-10) level was observed in the spleen, serum, and left atrium (LA), with SPX showing inhibitory effects in the latter 2 instances. In addition, AAC-induced M2 macrophage recruitment into the LA was decreased by SPX, as determined by immunofluorescence labeling (P <.05). On day 28, AAC-induced heterogeneous interstitial fibrosis of the LA was enhanced by SPX (P <.05). Electrophysiologic recordings revealed that the duration of AF and prolongation of interatrial conduction time induced by AAC were increased by SPX (P < .01 and P <.05, respectively). Furthermore, in the AAC+SPX group, the number of macrophages infiltrating into the LA on day 2 was marginal, but increased on day 28 relative to the AAC+Sham group. IL-10 administration attenuated the AAC-induced atrial remodeling that was aggravated by SPX. CONCLUSION The study results suggest that SPX exacerbates AAC-induced inflammatory atrial fibrosis and increases vulnerability to AF after 4 weeks, likely because of depletion of spleen-derived IL-10.

Hyperleptinemia Exacerbates High‐Fat Diet‐Mediated Atrial Fibrosis and Fibrillation

Obesity including metabolic syndrome is an independent risk factor of atrial fibrillation (AF). Although hyperleptinemia is usually a characteristic of obese subjects, the relationship with atrial fibrosis and AF is unknown. We tested the hypothesis that high‐fat diet (HFD)‐induced hyperleptinemia exacerbates atrial fibrosis and AF.

Outcome of Patients With Cardiac Sarcoidosis Who Received Cardiac Resynchronization Therapy: Comparison With Dilated Cardiomyopathy Patients

Cardiac resynchronization therapy (CRT) has been shown to be effective for patients with chronic heart failure; however, the efficacy of CRT in patients with cardiac sarcoidosis (CS) has not been established.

A case of short-coupled premature ventricular beat-induced ventricular fibrillation with early repolarization in the inferolateral leads

This case report describes a 19‐year‐old man with early repolarization (ER) in the inferolateral leads and a normal QT interval who survived a cardiac arrest that was likely related to polymorphic ventricular tachycardia (VT). Electrocardiograms (ECGs) also showed unifocal premature ventricular beats (PVBs) with a relatively narrow QRS duration. A Holter ECG documented occasional short‐coupled PVBs following non‐sustained VTs. Pharmacological stress testing was also performed to assess the effects of anti‐arrhythmic drugs on ER (the J wave) and PVBs. We performed successful radiofrequency catheter ablation to prevent the recurrence of ventricular fibrillation after cardioverter‐defibrillator implantation.

Exaggerated Reactivity of Parasympathetic Nerves is Involved in Ventricular Fibrillation in J‐Wave Syndrome

Brugada syndrome (BrS) and early repolarization syndrome (ERS) are termed the J‐wave syndrome. In most cases of J‐wave syndrome, ventricular fibrillation (VF) often occurs around midnight or in the early morning when parasympathetic tone is augmented.

Interleukin-6 as an Independent Predictor of Future Cardiovascular Events in Patients with Type-2 Diabetes without Structural Heart Disease

Background: An increased serum interleukin-6 (IL-6) level is associated with a risk of cardiovascular disease. Elevated IL-6 levels are also involved in the pathogenesis of insulin resistance and can predict the development of type-2 diabetes. We tested the hypothesis that elevated IL-6 levels can predict the incidence of cardiovascular events in type-2 diabetes. Methods: Eighty-two patients with type-2 diabetes without structural heart disease (48 males; 60 ± 12 years). The initial onset of a major adverse cardiovascular event was investigated. Results: During a mean of 3.4 ± 2.0 years of follow-up, 11 patients developed cardiovascular events (3 cardiovascular deaths, 2 non-fatal myocardial infarctions, 2 coronary revascularizations, and 4 strokes). Univariate analyses revealed that elevated IL-6 level, fasting immunoreactive insulin level, and the HOMA-R were associated with cardiovascular events. Based on multivariate analyses, elevated IL-6 levels independently predicted the incidence of cardiovascular events (HR 1.17, 95% CI 1.04–1.31, P=0.015). Kaplan–Meier curves revealed that patients with a high IL-6 concentration (>2.6 pg/mL) had a higher incidence of cardiovascular events than those with non-high IL-6 concentration (≤2.6 pg/mL, P=0.031). Conclusions: These results suggest that measurement of serum IL-6 concentration is a useful tool to identify high-risk patients for cardiovascular events in type-2 diabetes.

Association of fibrotic remodeling and cytokines/chemokines content in epicardial adipose tissue with atrial myocardial fibrosis in patients with atrial fibrillation

BACKGROUND Epicardial adipose tissue (EAT) is associated with atrial fibrillation (AF), but the underlying mechanisms remain to be fully elucidated. OBJECTIVE The purpose of this study was to examine, using human left atrial appendage (LAA) samples, the interactive relationship between the EAT profile and atrial myocardial fibrosis through histologic and biochemical analyses. METHODS LAA samples were obtained from 59 consecutive AF patients during cardiovascular surgery. In histologic analysis, adipose tissue, atrial myocardial fibrosis, EAT fibrosis, macrophage infiltration, and matrix metalloproteinase-2 and hypoxia-inducible factor-1α (Hif-1α) expression were evaluated in LAA sections. In biochemical analysis, proinflammatory/fibrotic proteins in EAT, total collagen in left atrial (LA) myocardium, angiopoietin-like protein-2 (Angptl2)-related proteins in EAT, and proinflammatory/fibrotic proteins in serum were evaluated. RESULTS Histology revealed that the severity of fibrotic remodeling of EAT was associated with LA myocardial fibrosis. Immunohistochemical and electron microscopic findings revealed that fibrotic remodeling of EAT was associated with infiltration of macrophages and myofibroblasts. Protein concentration analysis demonstrated that the total collagen in the LA myocardium was positively correlated with proinflammatory and profibrotic cytokines/chemokines, including interleukin-6, monocyte chemoattractant protein-1, tumor necrosis factor-α, vascular endothelial growth factor, and matrix metalloproteinase-2 and matrix metalloproteinase-9 in EAT. The proinflammatory and profibrotic cytokines/chemokines in EAT and the total collagen in the LA were also positively correlated with Angptl2 in EAT. CONCLUSION Our study demonstrated that fibrotic remodeling and cytokines/chemokines in peri-LA EAT were associated with atrial myocardial fibrosis as a substrate of AF. Our results also suggested that overexpression of Hif-1α and Angptl2 may be involved in these processes.