Tatsuhiko Ooie

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.

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.

Role of protein kinase C in geranylgeranylacetone-induced expression of heat-shock protein 72 and cardioprotection in the rat heart.

We recently demonstrated that oral administration of geranylgeranylacetone (GGA), an antiulcer agent, induces heat-shock protein 72 (HSP72) in the rat heart and renders cardioprotection against ischemia/reperfusion injury. However, the signaling pathways remain to be elucidated. The present study tested the hypothesis that oral GGA would activate protein kinase C (PKC), leading to the phosphorylation and translocation of heat-shock factor 1 (HSF1), and thus, promote the expression of HSP72 protein. Rats were classified into four groups: a control (CNT) group (vehicle administration), a GGA group (GGA 200 mg/kg administration), a chelerythrine (CHE)-CNT group (pretreated with intravenous (i.v.) injection of 5 mg/kg CHE before vehicle administration), and a CHE-GGA group (pretreated with CHE before GGA administration). After 24 h administration, oral GGA-induced overexpression of HSP72, increased amount of the phosphorylated form of HSF1 in the nucleus, produced heat-shock element-specific DNA-HSF1 complex, and caused translocation of protein kinase C (PKC)delta, all of which were prevented by pretreatment with CHE. GGA also increased the PKC activity in a particulate fraction, which was prevented by pretreatment with rottlerin, a specific inhibitor of PKCdelta. Isolated-perfused heart experiments revealed that the better functional recovery observed in the GGA group during the reperfusion period following the 20 min of no-flow global ischemia, compared with the CNT group, was abolished by pretreatment with CHE. These results suggest that activation of PKC (translocation of PKCdelta), which primes the phosphorylation of HSF1, plays an essential role in the cardiac overexpression of HSP72 by GGA that leads to cardioprotection.

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.

Pioglitazone but Not Glibenclamide Improves Cardiac Expression of Heat Shock Protein 72 and Tolerance Against Ischemia/Reperfusion Injury in the Heredity Insulin-Resistant Rat

We tested the hypothesis that pioglitazone could restore expression of heat shock protein (HSP)72 in insulin-resistant rat heart. At 12 weeks of age, male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control (LETO) rats were treated with pioglitazone (10 mg · kg−1 · day−1) or glibenclamide (5 mg · kg−1 · day−1) for 4 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. In response to hyperthermia, the activation of serine/threonine kinase Akt depending on phosphatidylinositol 3 (PI3) kinase was necessary for cardiac expression of HSP72. Hyperthermia-induced activation of Akt and HSP72 expression were depressed in OLETF rat hearts. Pioglitazone but not glibenclamide improved insulin sensitivity in OLETF rats, which was associated with the restoration of Akt activation and HSP72 expression. In experiments with isolated perfused heart, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by pioglitazone but not glibenclamide. Our results suggest that PI3 kinase–dependent Akt activation, an essential signal for HSP72 expression, is depressed in the heart in insulin-resistant OLETF rats, and the results suggest also that the restoration of HSP72 expression and tolerance against ischemia/reperfusion injury by treatment with pioglitazone might be due to an improvement of insulin resistance, leading to restoration of impaired PI3 kinase–dependent Akt activation in response to hyperthermia.

Cardioprotection by streptozotocin-induced diabetes and insulin against ischemia/reperfusion injury in rats.

The effects of streptozotocin (STZ)-induced diabetes (DM) and insulin on cardiac performance were investigated during reperfusion after low-flow ischemia in rats. Hearts were isolated 4 weeks after intravenous injection of STZ (65 mg/kg) or vehicle and retrogradely perfused in the presence (throughout the perfusion period) or absence of 1 U/L insulin using a Langendorff apparatus. Normothermic low-flow global ischemia was instituted by reducing the flow rate to 5% of baseline for 30 min, followed by reperfusion for 30 min. Rate pressure product (left ventricular developed pressure x heart rate) was calculated as an index of cardiac performance. Myocardial concentrations of adenine nucleotides, creatine phosphate (CP) and glycogen were measured. Insulin perfusion increased preischemic myocardial glycogen content in both DM and control hearts. Recovery of cardiac performance and myocardial CP concentrations in the absence of insulin was greater in the DM hearts than in controls during reperfusion. Insulin perfusion improved recovery of cardiac performance and elevated CP concentrations in both DM and control hearts. These results demonstrate greater cardioprotection against ischemia/reperfusion injury in the STZ-DM state and with insulin perfusion. These protective effects may be associated with augmented resynthesis of high-energy phosphates during reperfusion.

Dynamics of T-U wave in patients with idiopathic ventricular tachycardia originating from the right ventricular outflow tract

Postextrasystolic U wave augmentation is observed in patients with long QT syndrome and those with organic heart disease. This phenomenon is considered a marker of increased risk of arrhythmia. However, the characteristics of the U wave have not been evaluated in patients with idiopathic VT originating from the right ventricular outflow tract (RVOT‐VT). The present study evaluated the dynamic change in the T‐U wave in patients with RVOT‐VT. Holter ECGs obtained from 14 patients with RVOT‐VT and 11 healthy control subjects were analyzed. The amplitude of T and U waves (Tamp and Uamp) and preceding RR intervals were measured during stable sinus rhythm (rate dependent change) and in the postextrasystolic sinus complex (pause dependent change). Uamp correlated negatively and significantly with the preceding RR interval in 13 (93%) RVOT‐VT patients but in only 2 (18%) control subjects. The average value of the slope of the Uamp/RR relationship was negative (−0.22 ± 0.10 mV/s) in the RVOT‐VT group, but was positive (0.04 ± 0.07 mV/s, P < 0.001) in the control group. Pause dependent U wave augmentation was observed in 12 (86%) of 14 patients. Increased frequency of consecutive preceding premature ventricular contractions (PVCs) was associated with a larger postextrasystolic Uamp. PVC or the first ventricular beat of VT arose from near the peak of augmented U waves. The dynamic changes in the T‐U wave were observed in patients with RVOT‐VT. Further investigations are required to elucidate the precise role of the U wave in arrhythmogenesis in those patients. (PACE 2004; 27:148–155)

Noninvasive assessment of the cardiac baroreflex: Response to downward tilting and comparison with the phenylephrine method

OBJECTIVES We studied the relation between changes in systolic blood pressure and RR interval during downward tilting in comparison with assessment of baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) and with measures of heart rate variability (HRV). BACKGROUND The method most extensively used for assessing BRS involves bolus injections of phenylephrine. Several noninvasive methods proposed to assess BRS have not been widely applied in the clinical setting. METHODS Sixteen healthy male volunteers were studied (mean age +/- SD 27.5+/-4.6 years). Arterial blood pressure using tonometry and electrocardiogram was simultaneously recorded. After 20 min of 70 degrees upright tilting, the table was returned to supine position at a speed of 3.2 degrees/s. Subsequently, BRS was assessed using an intravenous bolus injection of phenylephrine (2 to 3 microg/kg). Heart rate variability under resting conditions also was analyzed. RESULTS In all subjects, a beat to beat systolic blood pressure increase associated with corresponding RR interval lengthening was observed during downward tilting as well as during phenylephrine administration. During both testing procedures, these two variables showed linear correlation, and the slope of regression line during downward tilting (DT-BRS) correlated significantly with Phe-BRS (r = 0.79, p = 0.0003). The DT- and Phe-BRS also correlated significantly with the high frequency component of resting HRV (r = 0.70, p = 0.0023 for DT-BRS; r = 0.58, p = 0.0185 for Phe-BRS). CONCLUSIONS We conclude that in a small homogeneous group DT-BRS provided an assessment of reflex cardiac vagal function comparable to that obtained by the phenylephrine method.

H2-Blocker modulates heart rate variability

SummaryThe use of H2-blockers in the treatment of patients with peptic ulcer has become popular. However, this treatment has adverse cardiovascular effects. The aim of this study was to investigate proarrhythmic rhythm and autonomic nervous activity by analyzing heart rate variability in patients treated with omeprazole, ranitidine, and plaunotol. Nineteen patients (mean age 67.5 ± 2.7 years) with active gastric ulcer were treated with omeprazole (20 mg/day) for 8 weeks, then ranitidine (300 mg/day) for the next 4 months, and finally plaunotol (240 mg/day). At each stage of the treatment, Holter electrocardiography was performed, and heart rate variability and arrhythmias analyzed. Heart rate variability yielded power in the low- (0.04–0.15 Hz) and high-frequency components (0.15–0.4Hz). Although both ranitidine and omeprazole induced little change in cardiac rhythm, the high-frequency power was higher (10.3 ± 0.8 vs 8.6 ± 0.6 ms,P < 0.05) and the ratio of low-to-high frequency power was lower (1.41 ± 0.10 vs 1.59 ± 0.09,P < 0.05) during ranitidine than during plaunotol treatment. Cosinor analysis of heart rate variability revealed a decreased amplitude of lowfrequency power during omeprazole compared with during ranitidine and plaunotol treatment. Ranitidine modulated high-frequency power which may be related to the adverse cardiovascular effects of H2-blocker.

Oral administration of geranylgeranylacetone blunts the endothelial dysfunction induced by ischemia and reperfusion in the rat heart.

It has been shown that geranylgeranylacetone (GGA) protects heart against ischemia/reperfusion injury via enhanced heat shock protein 72 (HSP72) expression in rats. In the present study, we investigated the protective effect of GGA on ischemia/reperfusion-induced endothelial dysfunction. Rats were given oral GGA (GGA group) or vehicle (CON group), and 24 hours later their hearts were removed and placed in the Langendorff apparatus for 30-minute low-flow ischemia followed by 30-minute reperfusion. GGA improved the postischemic functional recovery (P < 0.01), which was abolished by NG-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor). NO production during both ischemia and reperfusion were increased in the GGA group, and the acetylcholine (ACh)-induced (endothelium-dependent) vasodilation, measured as the percentage decrease in coronary perfusion pressure after ischemia/reperfusion (14.9 ± 1.3%), was preserved as compared with that in the CON group (7.9 ± 1.4%). LY294002, a phosphatidylinositol 3 (PI3) kinase inhibitor, abolished the protective effects of GGA on endothelial-dependent coronary vasodilation and NO production, whereas Y27632 (Rho kinase inhibitor) increased endothelium-dependent coronary vasodilation and NO production in CON group toward the level seen in GGA group. The amount of adrenomedullin in the coronary effluent at basal condition was lower in the GGA group than in the CON group (P < 0.05), and during both ischemia and reperfusion there was no difference in the amount of adrenomedullin between the GGA and CON groups. In addition, no difference was observed in the amount of endothelin-1 between the GGA and CON groups. These results indicate that GGA attenuates the ischemia/reperfusion-induced coronary endothelial dysfunction, which may contribute to its cardioprotective effect. The PI3 kinase and/or Rho kinase pathways appear to be involved in this process, whereas adrenomedullin and endothelin-1 are not necessary for the GGA-induced cardioprotection.