Impact of Age on Gender Differences in the Acute Myocardial Infarction Onset-Weather Association　- Oita AMI Registry.

Background: The onset of acute myocardial infarction (AMI) is related to weather conditions, but the impact of age on gender differences in the AMI onset-weather association has not been elucidated. Methods and Results: We analyzed the Oita AMI Registry and obtained data for 403 enrolled patients. To examine the impact of age, we categorized the patients into 4 groups: young (age ≤65 years) women (n=20); young men (n=123); elderly (age >65 years) women (n=84); and elderly men (n=176). The analyzed meteorological factors were maximum and minimum temperature, intraday temperature difference, average humidity, and average atmospheric pressure. The young women group had a higher minimum temperature (17.7±5.7℃ vs. 13.8±8.2℃, P=0.04), lower intraday temperature difference (7.0±2.6℃ vs. 8.4±2.9℃, P=0.03), higher average humidity (74.5±12.1% vs. 68.1±12.0%, P=0.03), and lower average atmospheric pressure (1,009.5±5.0 hPa vs. 1,012.9±5.8 hPa, P=0.01) than the young men group on the onset day. In the elderly groups, there was no significant difference in meteorological variables except for the intraday temperature difference 2 days before AMI onset. Conclusions: AMI onset appears to be more sensitive to weather conditions (i.e., minimum temperature, average atmospheric pressure, and average humidity) in young patients than in elderly patients. In particular, young women had AMI on days with low intraday temperature difference and high humidity relative to men.

Seasonal variations of weather conditions on acute myocardial infarction onset: Oita AMI Registry.

The onset of acute myocardial infarction (AMI) has been reportedly related to weather conditions. The aim of this study was to investigate the impact of weather conditions on AMI onset. Our study population consisted of 274 patients enrolled in the Oita AMI Registry who were admitted with AMI between June 2012 and May 2013. We divided the 365 days of the year into the four seasons: spring (March, April, May), summer (June, July, August), autumn (September, October, November), and winter (December, January, February). We classified each day as a day of onset of AMI (onset day) or a day of non-onset of AMI (non-onset day). Information on maximum temperature, minimum temperature, mean humidity, and mean atmospheric pressure was obtained from the Japan Meteorological Agency. In summer, the temperatures and intraday temperature differences were significantly lower on onset days than on non-onset days. Receiver operating characteristic analysis for predicting AMI onset in each season showed that the maximum temperature 2 days before AMI onset in summer had the largest area under the curve (AUC = 0.72, p = 0.0005). Our analysis demonstrated that there exist specific weather conditions that influence AMI onset in each season in Oita prefecture. AMI onset in summer was particularly associated with the maximum temperature 2 days before AMI onset.

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-ß1, α-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-ß1, α-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.

Comparison of autonomic J-wave modulation in patients with idiopathic ventricular fibrillation and control subjects.

BACKGROUND: Although J-waves are seen in both patients with idiopathic ventricular fibrillation (IVF) and the general population, their genesis remains unclear. To assess the relationship between J-waves and autonomic tone we investigated the circadian variation of J-waves in individuals with and without IVF. METHODS AND RESULTS: In study 1, we obtained resting 12-lead ECG and Holter ECG recordings in 258 individuals undergoing screening for heart disease. In 60 of these subjects (23.3%), we detected J-waves on Holter ECGs; 40 of them (66.7%) had shown no J-waves on 12-lead ECGs. In study 2, we measured the J-wave amplitude, heart rate (HR), and HR variability [high frequency (HF) and the ratio of low- to high-frequency (LF/HF)] on Holter ECGs recorded in 5 patients with IVF and 20 control subjects who had manifested J-waves. The J-wave amplitude increased at night and decreased during the day in both groups; it was significantly higher in the IVF patients (P<0.0001). In both groups, the J-wave amplitude showed a significant negative correlation with HR and LF/HF and a significant positive correlation with HF. The slope of the J/HR and J/(LF/HF) relationship was significantly steeper in the IVF patients. CONCLUSIONS: The J-wave amplitude was more significantly influenced by the autonomic balance in IVF patients than in the controls. Autonomic J-wave modulation may yield important information on the genesis of J-waves.

Combined assessment of baroreflex sensitivity with iodine 123 metaiodobenzylguanidine scintigraphic findings strengthens the power of predictive value for cerebral and cardiovascular events in type 2 diabetic patients.

BACKGROUND: We previously reported that baroreflex sensitivity (BRS) or cardiac iodine 123 metaiodobenzylguanidine ((123)I-MIBG) scintigraphic findings can predict cardiovascular prognosis in type 2 diabetic patients. We therefore tested the hypothesis that the combination of BRS and (123)I-MIBG scintigraphic findings could strengthen the predictive power for major adverse cerebral and cardiovascular events (MACCE). METHODS AND RESULTS: From 1998, we have evaluated both BRS and (123)I-MIBG scintigraphy in 165 type 2 diabetic patients (77 females, 88 males, mean age 59 ± 12 years). Based on the ROC curves, depressed BRS was defined as <5.63 mmHg/s, and enhanced washout ratio (WR) was defined as ≥ 41.4%. Each patient was divided into 3 groups based on the "BRS-MIBG combination score" as follows: 0, patients having both preserved BRS and preserved WR; 1, patients having either depressed BRS or enhanced WR; 2, patients having both depressed BRS and enhanced WR. During the mean of 4.7 ± 2.7 years of follow-up, 19 patients developed MACCE. The MACCE-free ratio was significantly higher in the lower BRS-MIBG combination score group (log-rank 16.41, P=0.0003). Cox proportional hazards regression analysis revealed that BRS-MIBG combination score was independently associated with the incidence of MACCE (hazard ratio 4.06, P=0.0237). CONCLUSIONS: Our results suggest that combined assessment of the BRS and (123)I-MIBG scintigraphic findings is more useful for identifying the type 2 diabetic patients at high risk for MACCE.

Novel strategy to prevent atrial fibrosis and fibrillation.

To explore a novel strategy of preventing atrial fibrosis and atrial fibrillation (AF), we have established 3 appropriate experimental models of AF. Firstly, atrial fibrosis was induced by pressure overload by abdominal aortic constriction (AAC). AAC enhanced left atrial (LA) expression of monocyte chemoattractant protein-1. Scanning electron microscopy revealed that LA endothelial cells were irregularly hypertrophied, with disarrangement of lines of cells. Possible "arrested" leukocyte-derived cells were observed on the surface of LA endothelial cells. Treatment with pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, resulted in attenuation of pressure overload-induced LA fibrosis. Secondly, LA fibrosis was induced by continuous infusion of angiotensin II (AII). Repeated whole-body hyperthermia led to the induction of heat shock protein (HSP) 72, which resulted in attenuation of AII-induced LA fibrosis. Thirdly, atrial fibrosis was induced by 5/6 nephrectomy as a model of AF associated with chronic kidney disease. Because the amount of nicotinamide adenine dinucleotide phosphate oxidase was increased and the potent antioxidant agent was effective, oxidative stress may be involved in the pathogenesis of LA fibrosis and enhanced AF vulnerability in this model. These observations suggest that inflammatory profibrotic processes are essential for the development of atrial fibrosis in these 3 models. Pioglitazone, induction of HSPs and antioxidant agent could be novel therapeutic approaches to preventing atrial fibrosis and AF.

Establishment of a model of atrial fibrillation associated with chronic kidney disease in rats and the role of oxidative stress.

BACKGROUND: An animal model of atrial fibrillation (AF) associated with chronic kidney disease (CKD) has not been available. OBJECTIVE: The purpose of this study was to test the validity of 5/6 nephrectomy (5.6Nx) as an appropriate model of AF associated with CKD and to investigate the role of oxidative stress. METHODS: Male Sprague-Dawley rats were subjected to 5.6Nx. A novel derivative of lipoic acid, sodium zinc dihydrolipoylhistidinate (DHLHZn), was subcutaneously infused. Four weeks later, hearts were isolated. RESULTS: We observed 5 main findings. (1) 5.6Nx induced renal dysfunction with elevation of systolic blood pressure and impaired glucose tolerance. (2) In the left atrium (LA), expressions of α-smooth muscle action and collagen type I, the compositional proteins of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and malondialdehyde were increased by 5.6Nx, which was reversed by DHLHZn treatment. (3) In the LA, the tissue content of angiotensin II was elevated by 5.6Nx, which was also reversed by DHLHZn. (4) Masson trichrome staining revealed that heterogeneous LA interstitial fibrosis was induced by 5.6Nx, which was attenuated by DHLHZn. (5) In isolated perfused heart experiments, 5.6Nx caused slowing of interatrial conduction. In the hearts of rats of the 5.6Nxgroup, right atrial extrastimuli invariably induced AF (8/8 [100%]), which were suppressed by DHLHZn (3/8 [38%], P <.05). CONCLUSION: We successfully established an appropriate model of AF associated with CKD in rats. Because the amount of NADPH oxidase was increased and the potent antioxidant agent DHLHZn was effective, oxidative stress may be involved in the pathogenesis of LA fibrosis and enhanced AF vulnerability in our model.

Wolff-Parkinson-White syndrome concomitant with idiopathic ventricular fibrillation associated with inferior early repolarization.

We encountered a 39-year-old man with documented ventricular fibrillation (VF). His ECGs showed intermittent Wolff-Parkinson-White (WPW) syndrome pattern. During electrophysiological study, no ventricular preexcitation was observed. An accessory pathway located at the posterior mitral annulus was identified, and successfully eliminated by radiofrequency catheter ablation. VF was not induced. His ECGs in the absence of delta waves demonstrated early repolarization in the inferior leads. This case raises the possibility that patients with manifest WPW syndrome may have an arrhythmogenic substrate associated with early repolarization, and the characteristic J waves can be masked by the presence of ventricular preexcitation.

Activation of CaMKII as a key regulator of reactive oxygen species production in diabetic rat heart.

Diabetes mellitus is a risk factor for heart failure. Increased reactive oxygen species (ROS) have been proposed as a possible mechanism of cardiac dysfunction in diabetic patients. However, the mechanisms of ROS increase are still elusive. We hypothesized that activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) induced by impaired intracellular Ca(2+) ([Ca(2+)](i)) metabolism may stimulate ROS production in the diabetic heart. Cultured cardiomyocytes from neonatal rats were exposed to high glucose concentrations (25 mmol/L) and ROS levels were analyzed in 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H(2)DCFDA)-loaded cells by flow cytometry analysis. Exposure to high glucose concentrations for 24h significantly increased CM-H(2)DCFDA fluorescence, which was significantly inhibited by 1,2-bis (o-aminophenoxy) ethane- N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM), a [Ca(2+)](i) chelator, and KB-R7943, an inhibitor of the Na(+)-Ca(2+) exchanger (NCX) in the reverse mode. These results indicate that [Ca(2+)](i) increase by NCX activation may induce ROS increase following exposure to high glucose concentrations. We confirmed that exposure to high glucose concentrations significantly increased [Ca(2+)](i), which was inhibited by KB-R7943. Na(+)-H(+) exchanger (NHE) is a key factor in [Ca(2+)](i) metabolism, and is known to activate NCX by increasing the intracellular Na(+) ([Na(+)](i)) level. We showed that the expression of NHE isoform 1 and NHE activity increased following exposure to high glucose concentrations by evaluating protein expressions and intracellular pH recovery from acid loading. Exposure to high glucose concentrations up-regulated phosphorylated CaMKII expression in cardiomyocytes that was inhibited by KB-R7943. Further, autocamtide 2-related inhibitory peptide (AIP), a CaMKII inhibitor, significantly attenuated the ROS increase following exposure to high glucose concentrations. We confirmed these results obtained in in vitro experiments in an animal model of diabetes. ROS level and components of NADPH oxidase, p47phox and p67phox were up-regulated in streptozotocin-induced diabetic rat heart, which were attenuated by KN-93, a CaMKII inhibitor. Consistently, expression of phosphorylated CaMKII was increased in the diabetic heart. Activation of CaMKII by impaired [Ca(2+)](i) metabolism may be a mechanism of ROS increase in the heart with diabetes mellitus.

Cardiac iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy parameter predicts cardiac and cerebrovascular events in type 2 diabetic patients without structural heart disease.

BACKGROUND: Cardiac iodine-123 metaiodobenzylguanidine ((123)I-MIBG) scintigraphy is an established method of assessment of cardiovascular sympathetic function. The aim of the present study was to investigate the long-term cardiovascular predictive value of cardiac (123)I-MIBG scintigraphy parameters in Japanese type 2 diabetic patients without structural heart disease. METHODS AND RESULTS: Cardiac (123)I-MIBG scintigraphy in 108 patients with type 2 diabetes who did not have structural heart disease, was evaluated. The washout rate (WR) was considered enhanced if it was ≥40%. Accurate follow-up information for 4.6 years was obtained in 54 enhanced WR patients (27 male; mean age, 61 ± 11 years) and in 54 sex- and age-matched preserved WR patients (27 male; mean age, 61 ± 10 years). Major adverse cardiac and cerebrovascular events (MACCE) were investigated. During follow-up, 10 enhanced WR patients developed MACCE including cardiac death, coronary revascularization, stroke, and congestive heart failure, while MACCE occurred in only 3 male patients. The Kaplan-Meier curves indicated that enhanced WR patients had higher incidence of MACCE than those with preserved WR (P<0.05). Cox proportional hazards regression analysis showed that age and enhanced WR were independently associated with the incidence of MACCE (hazard ratio, 4.06; 95% confidence interval: 1.194-18.76, P = 0.0237). CONCLUSIONS: Abnormal WR of cardiac (123)I-MIBG scintigraphy at baseline has long-term cardiovascular predictive value in Japanese patients with type 2 diabetes without structural heart disease.

Candesartan restored cardiac Hsp72 expression and tolerance against reperfusion injury in hereditary insulin-resistant rats.

AIMS: We tested the hypothesis that candesartan, an angiotensin II (AII) type 1 receptor antagonist, would restore the depressed phosphatidylinositol 3 (PI3) kinase-dependent Akt phosphorylation, an essential signal to induce heat-shock protein 72 (Hsp72) in response to hyperthermia, in Otsuka Long-Evans Tokushima fatty (OLETF) rats. METHODS AND RESULTS: At 14 weeks of age, male OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats were treated with candesartan (0.25 mg/kg/day) for 2 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. We observed the following: (i) Candesartan did not improve insulin sensitivity in OLETF rats. (ii) Candesartan restored depressed PI3 kinase-dependent Akt phosphorylation and Hsp72 expression in OLETF rat hearts. (iii) Cardiac ventricular tissue contents of AII were greater in OLETF rats, which were suppressed by candesartan. (iv) Cardiac levels of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphorylation were greater in OLETF rats, which were suppressed by candesartan. In cultured cardiomyocytes, application of AII induced PTEN phosphorylation, which was suppressed by candesartan. (v) In high-fat diet insulin-resistant rats, similar results were observed with respect to Hsp72 expression, Akt phosphorylation and PTEN phosphorylation. (vi) In isolated, perfused heart experiments, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by candesartan. CONCLUSION: Our results suggest that the depression of PI3 kinase-dependent Akt activation in response to hyperthermia in OLETF rats can be restored by candesartan. Substantial activation of the renin-angiotensin system, represented by increased myocardial AII content and subsequent PTEN phosphorylation, may underlie the pathogenesis which is ameliorated by candesartan.

Effect of cardiac resynchronization therapy on cardiac sympathetic nervous dysfunction and serum C-reactive protein level.

BACKGROUND: Cardiac autonomic dysfunction is associated with a poor prognosis in patients with heart failure (HF). Systemic inflammation is elevated in patients with HF. We hypothesized that cardiac resynchronization therapy (CRT) improves cardiac sympathetic nervous dysfunction and systemic inflammation. To test our hypothesis, we evaluated cardiac sympathetic activity and serum levels of high sensitive C-reactive protein (hs-CRP) before and after CRT. METHODS: Twenty-seven patients with chronic HF (19 men, eight women; mean age 67 ± 10 years) with nonischemic cardiomyopathy who underwent CRT were evaluated. Each patient was evaluated before and 6 months after CRT. Responders were defined as patients showing ≥15% absolute decrease in left ventricular end-systolic volume. Cardiac sympathetic activity was estimated with cardiac (123) I-metaiodobenzylguanidine (MIBG) scintigrams. RESULTS: Patients were categorized as responders (n = 19) and nonresponders (n = 8) according to echocardiographic findings. In responders, the mean heart-to-mediastinum (H/M) ratio at the delayed phase in cardiac (123) I-MIBG scintigraphic findings was significantly increased (P<0.05) and serum levels of hs-CRP were decreased (P <0.01). Such improvements were not observed in nonresponders. Stepwise multiple regression analysis showed that the reduction in hs-CRP level was independently associated with the increase in the H/M ratio at delayed phase. CONCLUSIONS: Our results demonstrated that cardiac sympathetic nervous dysfunction and systemic inflammation were improved in responder HF patients to CRT. Furthermore, the reduction in systemic inflammation was associated with the improvement in cardiac sympathetic nervous dysfunction.

Cardioprotective effects of pravastatin against lethal ventricular arrhythmias induced by reperfusion in the rat heart.

BACKGROUND: Statins are reported to reduce mortality in patients with coronary artery disease and that mortality benefit might be related to the drugs' antiarrhythmic properties. METHODS AND RESULTS: Male rats were fed with or without pravastatin (0.1 mg·kg⁻¹·day⁻¹) for 7 days, and thereafter subjected to 10 min of ischemia by coronary artery ligation followed by 20 min reperfusion. Treatment with pravastatin reduced the frequency and duration of ventricular tachycardia and fibrillation (VT/VF) and improved the arrhythmia score after reperfusion. To investigate the rapid effects of pravastatin, isolated perfused rat hearts were subjected to 20 min of global ischemia followed by 30 or 60 min of reperfusion. Treatment with pravastatin (10 nmol/L) from 10 min before ischemia shortened the total duration of reperfusion-induced VT/VF. Interestingly, pravastatin administered from the beginning of reperfusion also exerted antiarrhythmic effects. These results indicate that pravastatin exerts antiarrhythmic effects not only with daily oral intake but also when administered just before ischemia or even after ischemia. Intracellular calcium ([Ca²âº](i)) overload and collapse of mitochondrial inner membrane potential (Δψ(m)) are associated with the arrhythmogenesis during ischemia-reperfusion. In cultured cardiomyocytes, pretreatment with pravastatin (10 nmol/L) suppressed [Ca²âº](i) overload and prevented Δψ(m) loss induced by H2O2. CONCLUSIONS: Pravastatin attenuated reperfusion-induced lethal ventricular arrhythmias. Inhibition of [Ca²âº](i) overload and preserving Δψ(m) may be the mechanisms of the observed antiarrhythmic effects of pravastatin.

Gender difference in baroreflex sensitivity to predict cardiac and cerebrovascular events in type 2 diabetic patients.

BACKGROUND: Cardiovascular autonomic neuropathy is a major complication in patients with diabetes mellitus (DM), and baroreflex sensitivity (BRS) reportedly can predict cardiovascular prognosis in type 2 DM patients. The hypothesis that cardiovascular events are associated with gender differences in BRS was tested in the present study. METHODS AND RESULTS: From 1998, we have evaluated BRS by phenylephrine methods in 185 consecutive type 2 DM patients. The long-term prognostic value of BRS was compared between 91 female (5812 years) and 94 male patients (5811 years). There was no significant difference in age or severity and duration of DM between the 2 groups. When compared to male, the BRS value in female patients was significantly lower (9.266.0 vs. 5.975.0 ms/mmHg, P < 0.0001). During a mean of 62.7 months of follow-up, 16 female patients developed cardiovascular events (17.6%) including stroke, acute myocardial infarction, angina pectoris requiring percutaneous coronary intervention or coronary artery bypass grafting and congestive heart failure requiring admission, while only 4 male patients developed events (4.3%, P < 0.005). In females, the Kaplan-Meier curves revealed that those with depressed BRS (< 6 ms/mmHg) had a higher incidence of cardiovascular events than those with preserved BRS (P < 0.05), but this relationship was not observed in male patients. CONCLUSIONS: Although the reason why females had a more depressed BRS remains unclear, our findings demonstrated that a depressed BRS value can accurately predict cardiovascular events, especially in female patients with type 2 DM.

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-ß1 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.

Telmisartan effectively improves insulin sensitivity in hypertensive patients with insulin resistance.

OBJECTIVE: The angiotensin II receptor blocker (ARB) telmisartan has been shown to activate peroxisome proliferator-activated receptor γ and increase adiponectin protein content in adipocytes. We tested the hypothesis that telmisartan can increase the serum level of adiponectin and improve insulin resistance. METHODS: The study participants were 25 consecutive hypertensive patients (8 females, 17 males; 65 ± 10 years). Insulin resistance was defined as a patient showing ≥2.5 in the homeostasis model assessment (HOMA) index. We divided subjects into non-insulin resistance (n = 10) and insulin resistance groups (n = 15) based on the HOMA index. Telmisartan was administered (40 mg/day) was administered for 24 weeks. RESULTS: In the insulin resistance group, telmisartan treatment resulted in a significant decrease in the HOMA index and serum level of C-reactive protein, and it increased the serum level of adiponectin (P < 0.05, respectively). Such improvements were not observed in the non-insulin resistance group. Stepwise multiple regression analysis showed that the increase in the serum level of adiponectin was independently associated with reduction in the HOMA index. CONCLUSIONS: Our findings suggest that telmisartan improves insulin resistance that parallels an increase in the serum level of adiponectin in hypertensive patients with insulin resistance. It may therefore have advantages in treating such populations.

High-glucose condition reduces cardioprotective effects of insulin against mechanical stress-induced cell injury.

AIMS: Mechanical stress induces cardiomyocyte injury and contributes to the progression of heart failure in patients with hypertension. In this study, we investigated whether insulin exerts cardioprotective effects against mechanical stretching-induced cell injury, and whether the protective effect is influenced by high-glucose condition. MAIN METHODS: Cultured neonatal rat cardiomyocytes were plated on silicone chambers, and the cells were mechanically stretched by 15% to induce cell injury. KEY FINDINGS: Mechanical stretching increased reactive oxygen species (ROS) and decreased mitochondrial inner membrane potential (DeltaPsi(m)), eventually leading to cell death by apoptosis and necrosis. Insulin activated the phosphoinositide 3 (PI3) kinase/Akt pathway and reduced apoptosis and necrosis by suppressing ROS increase and preserving DeltaPsi(m). However, high-glucose condition attenuated the insulin-induced Akt phosphorylation and cardioprotection. To investigate the mechanisms that attenuated the effects of insulin in high-glucose condition, we examined the expression of tensin homologue deleted on chromosome 10 (PTEN), which is a negative regulator of the PI3 kinase/Akt pathway. The expressions of PTEN and phosphorylated PTEN were significantly decreased by insulin, and those effects were attenuated in high-glucose condition. SIGNIFICANCE: The present results suggest that insulin prevents mechanical stress-induced cell injury which otherwise lead to heart failure. Furthermore, we found that high-glucose condition prevented the decrease in PTEN expression and the cardioprotective effects induced by insulin.

Baroreflex sensitivity predicts cardiovascular events in patients with type 2 diabetes mellitus without structural heart disease.

BACKGROUND: Cardiovascular autonomic neuropathy is a major complication in patients with diabetes mellitus (DM). However, the relationship between cardiovascular autonomic neuropathy and the incidence of cardiovascular events has been poorly investigated in type 2 DM. The present study aimed to assess the long-term cardiovascular predictive value of baroreflex sensitivity (BRS) in Japanese patients with type 2 DM without structural heart disease. METHODS AND RESULTS: BRS was evaluated using the phenylephrine method in 210 patients with type 2 DM who did not have structural heart disease or other severe complications. BRS was considered depressed if <6 ms/mmHg. Accurate follow-up information for 3-10 years (mean 4.7 years) was obtained in 184 patients (90 females, 94 males; mean age 58+/-12 years). The initial onset of a major adverse cardiovascular event (MACE) was investigated. During follow-up, 19 patients presented with a MACE (4 cardiovascular deaths, 3 nonfatal myocardial infarctions, 4 coronary revascularizations, 5 strokes, 2 congestive heart failures). Cox proportional hazards regression analysis revealed that depressed BRS was independently associated with the incidence of MACE (hazard ratio 1.93, 95% confidence interval 1.09-3.82, P=0.0236). CONCLUSIONS: Depressed BRS at baseline has long-term cardiovascular predictive value in Japanese patients with type 2 DM without structural heart disease.

Mitochondrial K(ATP) channels-derived reactive oxygen species activate pro-survival pathway in pravastatin-induced cardioprotection.

Reactive oxygen species (ROS) are important intracellular signaling molecules and are implicated in cardioprotective pathways including ischemic preconditioning. Statins have been shown to have cardioprotective effects against ischemia/reperfusion injury, however, the precise mechanisms remain to be elucidated. We hypothesized that ROS-mediated signaling cascade may be involved in pravastatin-induced cardioprotection. Cultured rat cardiomyocytes were exposed to H(2)O(2) for 30 min to induce cell injury. Pravastatin significantly suppressed H(2)O(2)-induced cell death evaluated by propidium iodide staining and the MTT assay. Incubation with pravastatin activated catalase, and prevented a ROS burst induced by H(2)O(2), which preserved mitochondrial membrane potential. Protective effects were induced very rapidly within 10 min, which was concordant with the up-regulation of phosphorylated ERK1/2. L-NAME, 5HD, N-acetylcysteine (NAC) and staurosporine inhibited ERK1/2 phosphorylation and also reduced pravastatin-induced cardioprotection, suggesting NO, mitochondrial K(ATP) (mitoK(ATP)) channels, ROS and PKC should be involved in the cardioprotective signaling. We also demonstrated that pravastatin moderately up-regulated ROS generation in a 5HD-inhibitable manner. In isolated perfused rat heart experiments, pravastatin administered 10 min prior to no-flow global ischemia significantly improved left ventricular functional recovery, and also reduced infarct size, which were attenuated by the treatment with NAC, 5HD, L-NAME or staurosporine. Administration of pravastatin from the beginning of reperfusion also conferred cardioprotection. Pravastatin protected the cardiomyocytes against oxidative stress by preventing the ROS burst and preserving mitochondrial function. Moderately up-regulated ROS production by mitoK(ATP) channels opening is involved in the pro-survival signaling cascade activated by pravastatin.

Hyperthermia-induced cardioprotection is potentiated by ischemic postconditioning in rats.

We tested the hypothesis that the protective effects of hyperthermia (HT) could be augmented by ischemic postconditioning (PostC) via enhancement of reperfusion-induced Akt phosphorylation. The role of the mitoKATP channel as an effecter to protect hearts against ischemia/reperfusion injury was also investigated. In isolated perfused heart experiments using a Langendorff apparatus, 30 min of no-flow global ischemia was followed by 120 min of reperfusion. Ischemic PostC, 5 cycles of 10-sec reperfusion/10-sec ischemia, was achieved at the initial moment of reperfusion. Hyperthermia (HT, 43 degrees C for 20 min) was applied 24 hr before ischemia onset. Ischemic PostC alone did not show significant protection, but HT did. The HT-induced protection in terms of infarct size, recovery of left ventricular performance, amount of released creatine kinase and apoptosis were enhanced by ischemic PostC. These protective effects were consistent with the levels of Akt phosphorylation 7 min after reperfusion and were completely blocked by the pretreatment with the phosphatidylinositol 3-kinase inhibitor wortmannin. HT-induced protection was also completely abolished by concomitant perfusion with 5-hydroxydecanoate (5HD, 100 microM), an inhibitor of the mitochondrial ATP-sensitive potassium (mitoKATP) channel. However, the potentiated protection by ischemic PostC remained, even in the presence of 5HD. In conclusion, ischemic PostC could potentiate the protective effects of HT possibly via enhancement of reperfusion-induced Akt phosphorylation. Although the opening of the mitoKATP channel is predominantly involved as an effecter in HT-induced protection, potentiated protection by ischemic PostC may involve mechanisms other than the mitoKATP channel.