Mikiko Nakagawa

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.

Influence of menstrual cycle on QT interval dynamics

Objectives: The aim of this study was to investigate the effects of the menstrual cycle on QT interval dynamics and the autonomic tone in healthy women.

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).

Circadian Variation of QT Interval Dispersion Correlation with Heart Rate Variability

The circadian variation of QT interval dispersion and its correlation with heart rate variability (HRV) was examined in 17 normal subjects by using 24-hour recordings of three-lead electrocardiograms. Measurements of HRV, R-R intervals, and QT intervals were made for the first 6 minutes of each hour over a 24-hour period. Spectral analysis of HRV yielded low-frequency power (LF) (0.04-0.15 Hz), high-frequency power (HF) (0.15-0.40 Hz), and the ratio of LF to HF (LF/HF). A rate-corrected QT interval (QTc) was calculated by Bazetts formula, and QT and QTc dispersion was defined as the difference between the maximum and minimum values in any two leads. High-frequency power and QT interval were greater at night than during the day: conversely, LF/HF and dispersion of QT and QTc were greater during the day. The QTc interval remained virtually unchanged throughout the 24-hour period. The dispersion of QTc showed a significant negative correlation with HF and a significant positive correlation with LF/HF. The results suggest that an increased sympathetic tone or a decreased vagal tone increases QT dispersion in healthy subjects.

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.

Circadian rhythm of the signal averaged electrocardiogram and its relation to heart rate variability in healthy subjects

Objective To examine the circadian variation in the signal averaged electrocardiogram (saECG) and heart rate variability and investigate their relations in healthy subjects. Methods 24 hour ECGs were obtained with a three channel recorder using bipolar X, Y, and Z leads in 20 healthy subjects. The following variables were determined hourly: heart rate, filtered QRS (f-QRS) duration, low and high frequency components of heart rate variability (LF and HF), and the LF/HF ratio. Results Heart rate, f-QRS duration, HF, and the LF/HF ratio showed significant circadian rhythms, as determined by the single cosinor method. Heart rate and the LF/HF ratio increased during daytime, and f-QRS duration and HF increased at night. f-QRS duration was negatively correlated with heart rate (r = 0.95, p < 0.001) and the LF/HF ratio (r = 0.94, p < 0.001) and positively with HF (r = 0.93, p < 0.001). Conclusions f-QRS duration has a significant circadian rhythm in healthy subjects and is closely related to the circadian rhythm of autonomic tone.

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.

Mechanism of β-Adrenergic Receptor Upregulation Induced by ACE Inhibition in Cultured Neonatal Rat Cardiac Myocytes Roles of Bradykinin and Protein Kinase C

Background—Although bradykinin is thought to contribute to the effects of ACE inhibitors on the cardiovascular system, its precise role remains to be elucidated. Evidence suggests that bradykinin might be important in the upregulation of β-adrenergic receptors (β-ARs) induced by ACE inhibitors, and the role of bradykinin in this effect has now been investigated with cultured neonatal rat cardiac myocytes. Methods and Results—The density of β-ARs on the myocyte surface was determined with a binding assay with [3H]CGP-12177. Incubation of cultured myocytes for 24 hours with the ACE inhibitor captopril (1 μmol/L) increased β-AR density by 35% and enhanced the response of cells to isoproterenol but not to forskolin. Neither an angiotensin-II type 1 (AT1) receptor antagonist, CV-11974, nor angiotensin-I affected β-AR density. However, the bradykinin B2 receptor antagonist Hoe 140 abolished the effect of captopril on β-AR upregulation in a dose-dependent manner. The protein kinase C inhibitor staurosporine (20 ...