Masahide Hara

Pioglitazone attenuates inflammatory atrial fibrosis and vulnerability to atrial fibrillation induced by pressure overload in rats

BACKGROUND Inflammatory processes are involved in the pathogenesis of atrial fibrillation (AF). OBJECTIVE The purpose of this study was to test the hypothesis that atrial fibrosis and enhanced vulnerability to AF evoked by pressure overload can be attenuated by pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, via suppression of inflammatory profibrotic signals. METHODS Male Sprague-Dawley rats were subjected to abdominal aortic constriction (AAC). Pioglitazone 3 mg/kg/day or vehicle was orally administered for 4 weeks. RESULTS Western blot analysis revealed that AAC enhanced expression of monocyte chemoattractant protein (MCP)-1, transforming growth factor-β1 and α-smooth muscle actin in the left atrium (LA), which was suppressed by pioglitazone. Messenger RNA expression of collagen type 1 and atrial natriuretic peptide in the LA was increased by AAC, which was suppressed by pioglitazone. Gelatin zymography demonstrated that activity of matrix metalloproteinase-9 was increased by AAC, which was suppressed by pioglitazone. Pioglitazone attenuated AAC-induced LA fibrosis. In isolated-perfused heart experiments, AAC did not alter the refractory period of the LA or the right atrium (RA), but it did prolong the interatrial conduction time. Programmed extrastimuli from the RA induced AF in all of the AAC-treated rats (8/8 [100%]). This was suppressed by pioglitazone (2/8 [25%], P <.05) with normalization to interatrial conduction time. CONCLUSION The results of this study suggest that inflammatory profibrotic mechanisms are involved in this pressure-overloaded AF model. The results also suggest that pioglitazone is effective at attenuating atrial fibrosis, possibly via suppression of MCP-1-mediated inflammatory profibrotic processes.

Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants.

Moderate consumption of red wine has been shown to exert cardioprotection against ischemia/reperfusion. Because oxidant-dependent leukocyte infiltration plays a critical role in ischemia/reperfusion-induced tissue injury, we hypothesized that resveratrol, a red wine constituent polyphenol would attenuate postischemic leukocyte recruitment and subsequent endothelial dysfunction. Intravital microscopic approaches were used to quantify leukocyte/endothelial cell interactions and venular protein leakage in rat mesenteries exposed to either 20 min ischemia and 60 min reperfusion (I/R), oxidants generated by the reaction of hypoxanthine and xanthine oxidase (HX/XO), platelet-activating factor (PAF), or leukotriene B4 (LTB4). I/R or HX/HX produced marked increases in the number of adherent (LA) and emigrated (LE) leukocytes, which were associated with significant increases in venular albumin leakage (VAL). Intravenous administration of resveratrol or superoxide dismutase (SOD) attenuated these increases in LA, LE, and VAL. Superfusion of the mesentery with PAF or LTB4 also markedly increased LA, LE, and VAL. While resveratrol attenuated the proinflammatory effects of PAF, LTB4-induced changes were not affected by resveratrol. Resveratrol prevents leukocyte recruitment and endothelial barrier disruption induced by a number of superoxide-dependent proinflammatory stimuli, including I/R, HX/XO, or PAF. These salutary effects appear to be related to the antioxidant properties of resveratrol and contribute to the cardioprotective actions associated with consumption of red wine.

Gender differences in various types of idiopathic ventricular tachycardia.

Gender Differences in Idiopathic VT. Introduction: The aim of this study was to evaluate gender differences in the incidence and age distribution of various types of idiopathic ventricular tachycardia (VT).

Gender differences in autonomic modulation of ventricular repolarization in humans.

Background: Gender differences in the incidence of ventricular arrhythmias have been reported and torsades de pointes associated with long QT syndrome are more common in women than men. Although increased sympathetic tone has an important role in vulnerability to arrhythmia, little is currently known regarding gender differences in the dynamic electrophysiological response to sympathetic stimulation. Therefore, we investigated whether there is a gender difference in humans with respect to the dynamic response of ventricular repolarization to β‐adrenergic stimulation and to autonomic blockade.

Effect of essential hypertension on cardiac autonomic function in type 2 diabetic patients.

OBJECTIVES The aim of this study was to examine the effects of essential hypertension on cardiac autonomic function in type 2 diabetic patients. BACKGROUND Hypertension is common in type 2 diabetic patients and is associated with a high mortality. However, the combined effects of type 2 diabetes and essential hypertension on cardiac autonomic function have not been fully elucidated. METHODS Thirty-three patients with type 2 diabetes were assigned to a hypertensive diabetic group (n = 15; age: 56 +/- 8 years, mean +/- SD) or an age-matched normotensive diabetic group (n = 18, 56 +/- 6 years). Cardiac autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability (HRV), plasma norepinephrine concentration and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS Baroreflex sensitivity was lower in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.05). The early and delayed myocardial uptake of 123I-MIBG was lower (p < 0.01 and p < 0.05, respectively), and the percent washout rate of 123I-MIBG was higher (p < 0.05) in the hypertensive diabetic group. However, the high frequency (HF) power and the ratio of low frequency (LF) power to HF power (LF/HF) of HRV and plasma norepinephrine concentration were not significantly different. The homeostasis model assessment index was higher in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.01). CONCLUSIONS Our results indicate that essential hypertension acts synergistically with type 2 diabetes to depress cardiac reflex vagal and sympathetic function, and the results also suggest that insulin resistance may play a pathogenic role in these processes.

Evaluation of Autonomic Influences on QT Dispersion Using the Head-Up Tilt Test in Healthy Subjects

Our objective was to examine the autonomic influence on QT interval dispersion using the head‐up tilt test in healthy subjects. RR and QT intervals, heart rate variability, and plasma norepinephrine concentration were measured in the supine position and tilting to 70± for 20 minutes using a footboard support in 15 healthy male volunteers (mean age ± SD: 28.0 ± 4.5 years). The rate‐corrected QT interval (QTc) was calculated using Bazetts formula, and QT and QTc dispersions were defined as the maximum minus minimum values for the QT and QTc, respectively, from the 12‐lead ECG. Spectral analysis of the heart rate variability generated values for the low‐ and high‐frequency powers (LF and HF) and their ratio (LF/HF). Compared with values obtained in the supine position, tilting significantly increased QT (P < 0.05) and QTc dispersion (P < 0.01), the LF/HF ratio (P < 0.0001), and plasma norepinephrine concentration (P < 0.0001), and significantly decreased HF (P < 0.0001). QTc dispersion was positively correlated with the LF/HF ratio and plasma norepinephrine concentration, and negatively correlated with HF. These results suggest that head‐up tilt testing increases QT dispersion by increasing sympathetic tone and/or decreasing vagal tone in healthy subjects.

Phosphatidylinositol 3-kinase-dependent activation of akt, an essential signal for hyperthermia-induced heat-shock protein 72, is attenuated in streptozotocin-induced diabetic heart

We tested the hypothesis that phosphatidylinositol 3-kinase (PI 3-kinase)-dependent activation of Akt is essential for the expression of cardiac heat-shock protein 72 (HSP72) and that this pathway is impaired in the streptozotocin (STZ)-induced diabetic heart. STZ-induced male diabetic rats were treated with insulin (STZ-insulin group, n = 26) or vehicle (STZ-vehicle group, n = 61) for 3 weeks. Whole-body hyperthermia (43°C for 20 min) was applied, and the heart was isolated 24 h later. Compared with control heart, hyperthermia-induced HSP72 expression and phosphorylation of Akt were attenuated in the STZ-vehicle heart. Pretreatment with wortmannin attenuated hyperthermia-induced HSP72 expression and phosphorylation of Akt. In isolated perfused heart experiments, the hyperthermia-treated STZ-vehicle heart showed poor left ventricular functional recovery during reperfusion after no-flow global ischemia compared with hyperthermia-treated control heart. Insulin treatment restored HSP72 expression and reperfusion-induced functional recovery. In cultured neonatal rat cardiomyocytes, hyperthermia-induced HSP72 expression was enhanced by insulin, together with tolerance against hypoxia-reoxygenation injury. Wortmannin and LY294002 inhibited hyperthermia-induced HSP72 expression and phosphorylation of Akt. Our results indicate that activation of Akt, in a PI 3-kinase–dependent manner, is essential for hyperthermia-induced HSP72 expression in association with cardioprotection, suggesting impairment of this signaling pathway in the STZ-induced diabetic heart, probably due to insulin deficiency.

Reduced 24 hour ambulatory blood pressure and abnormal heart rate variability in patients with dysorexia nervosa

Dysorexia nervosa (DN) includes two types of eating disorder: anorexia nervosa (AN) and bulimia nervosa (BN). AN is a syndrome characterised by changes in eating habits, distortions of body shape, and a refusal to maintain even minimally normal body weight. BN is a syndrome encompassing repeated episodes of binge eating, followed by inappropriate compensatory behaviours such as self induced vomiting, misuse of laxatives and diuretics, fasting or excessive exercise. Both AN and BN predominantly affect young females, in whom the prevalence is approximately 10 times higher than in males, and both are important social health concerns in developed countries.1 The following study was designed to explore the underlying autonomic dysfunction in DN; six patients with AN, eight with BN and 11 healthy subjects were assessed. The circadian changes in blood pressure (BP), heart rate (HR), and heart rate variability (HRV) of the patients were measured. Twenty four hour ambulatory BP and HR were recorded using a portable multibiomedical recorder (TM-2425, A&D Co, Tokyo, Japan). The measurements of BP and HR were repeated every 30 minutes in the waking period from 6 am to 11 …

Measurement of the Brachial-Ankle Pulse Wave Velocity and Flow-Mediated Dilatation in Young, Healthy Smokers

The brachial-ankle pulse wave velocity (PWV) is a quick test which adequately estimates arterial stiffness. Because flow-mediated dilatation (FMD) of the brachial artery assesses an essential endothelial function, we tested the hypothesis that the brachial-ankle PWV could reflect the early stages of endothelial dysfunction caused by smoking in young, healthy subjects. Fifty-seven healthy subjects (13 females and 44 males; mean 29.9±5.6 years) were enrolled. Twenty-six of the subjects (30.4±5.7 years) were active smokers, with a mean cumulative nicotine consumption of 10.0±8.6 pack/years, and thus were assigned to the smoking group. Thirty-one subjects without a history of smoking (29.5±5.5 years) were assigned to the non-smoking group. The brachial-ankle PWV and arterial blood pressure were simultaneously measured using a recently established, non-invasive automatic device (model BP-203RPE; Nihon Colin, Tokyo, Japan). Endothelium-dependent FMD was induced by reactive hyperemia, while endothelium-independent vasodilation of the brachial artery was induced by administration of sublingual nitroglycerin spray. The FMD was lower in the smoking group than in the non-smoking group (p<0.05). There was no significant difference between the two groups with respect to the brachial-ankle PWV. In the non-smoking group, multiple stepwise regression analysis revealed that FMD was predicted by the systolic blood pressure (F=16.351). In the smoking group, statistical analysis revealed that FMD was independently predicted by either the brachial-ankle PWV (F=8.108) or the subjects age (F=4.381). Our results suggest that a reduction in FMD is closely associated with the early stages of endothelial dysfunction caused by cigarette smoking in young, healthy subjects, which is at least partly reflected by the PWV value.

Role of leptin signaling in the pathogenesis of angiotensin II-mediated atrial fibrosis and fibrillation.

Background—We examined the hypothesis that leptin signaling contributes to the atrial fibrosis and atrial fibrillation (AF) evoked by angiotensin II (AngII). Methods and Results—Eight-week-old male CL57/B6 (CNT) and leptin-deficient ob/ob mice (Ob) were subcutaneously infused with AngII (2.0 mg/kg per day). Two weeks later, transesophageal burst pacing and an electrophysiological study using isolated perfused hearts were performed. Left-atrial tissues were collected to determine interstitial fibrosis by Masson trichrome staining, and the expressions of mRNAs related to inflammatory profibrotic signals were assessed. Left-atrial fibroblasts were isolated from adult Sprague-Dawley and Zucker rats. The effects of leptin (100 ng/mL) or AngII (100 nmol/L) treatment were evaluated. In CNT-AngII mice, leptin expression in the left atrium was upregulated (P<0.01). Transesophageal burst pacing induced atrial fibrillation in 88% (7/8) of CNT-AngII mice, but not in Ob-AngII mice (0/8; P<0.01). In isolated perfused hearts, atrial fibrillation was induced only in CNT-AngII mice (4/6; 67%). Interatrial conduction time was prolonged in CNT-AngII mice (P<0.01), but not in Ob-AngII mice. The upregulation of collagen 1, collagen 3, transforming growth factor-&bgr;1, &agr;-smooth muscle actin, MCP-1, F4/80, and RANTES mRNA, which was seen in CNT-AngII mice, was attenuated in Ob-AngII mice. In cultured Sprague-Dawley rat atrial fibroblasts, AngII treatment increased leptin expression (P<0.01). Addition of leptin increased transforming growth factor-&bgr;1, &agr;-smooth muscle actin, MCP-1, and RANTES expressions in Sprague-Dawley rat atrial fibroblasts, but not in Zucker rat atrial fibroblasts. Conclusions—Our results demonstrate for the first time that leptin signaling is essential for the development of atrial fibrosis and atrial fibrillation evoked by AngII.