Optimization of cardiac metabolism in heart failure.

The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utilization of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential of modifying substrate utilization to optimize cardiac metabolism in heart failure.

Pioglitazone enhances cholesterol efflux from macrophages by increasing ABCA1/ABCG1 expressions via PPARγ/LXRα pathway: findings from in vitro and ex vivo studies.

OBJECTIVE: Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, reportedly reduces cardiovascular events in diabetic patients. ATP cassette binding transporters (ABC) A1 and G1 are pivotal molecules for cholesterol efflux (ChE) from macrophages and high density-lipoprotein biogenesis, and the A1 transporter is regulated by a PPARγ-liver receptor X (LXR) pathway. Also, pioglitazone induces ABCG1 expression, though the exact mechanism remains unclear. We therefore investigated the effects of pioglitazone on ABCA1/G1 expression in vitro and ex vivo. METHODS: The effects of pioglitazone on ChE and ABCA1/G1 expressions in macrophages were assessed. Then, mRNA was quantified in macrophages when PPARγ/LXR inhibition by siRNA or overexpression of oxysterol sulfotransferase was performed. ABCA1/G1 promoter activity with mutated LXR-responsive elements was also measured. As an ex vivo study, 15 type 2 diabetic patients were administered pioglitazone or placebo, and ChE assays and protein expressions were determined using macrophages cultured with the corresponding sera. RESULTS: Pioglitazone increased LXRα/ABCA1/G1 expressions, which enhanced ChE from macrophages. Inhibition of PPARγ/LXR pathways revealed that LXR was primarily involved in pioglitazone's transactivation of ABCA1 but only partially involved for ABCG1. Promoter assays showed that ABCG1 was regulated more by the promoter in intron 4 than that upstream of exon 1 but both promoters were responsive to LXR activation. Sera obtained after pioglitazone treatment promoted ChE and ABCA1/G1 expressions in macrophages. CONCLUSION: Pioglitazone enhanced ChE from macrophages by increasing ABCA1/G1 in LXR-dependent and -independent manners. Our comparable in vitro and ex vivo results shed new light on pioglitazone's novel anti-atherogenic property.

Effect of sulfonylurea agents on reverse cholesterol transport in vitro and vivo.

AIM: Reverse cholesterol transport (RCT) is a critical mechanism for the anti-atherogenic property of HDL. The inhibitory effect of the sulfonylurea agent (SUA) glibenclamide on ATP binding-cassette transporter (ABC) A1 may decrease HDL function but it remains unclear whether it attenuates RCT in vivo. We therefore investigated how the SUAs glibenclamide and glimepiride affected the functionality of ABCA1/ABCG1 and scavenger receptor class B type I (SR-BI) expression in macrophages in vitro and overall RCT in vivo. METHODS: RAW264.7, HEK293 and BHK-21 cells were used for in vitro studies. To investigate RCT in vivo, 3H-cholesterol-labeled and acetyl LDL-loaded RAW264.7 cells were injected into mice. RESULTS: High dose (500µM) of glibenclamide inhibited ABCA1 function and apolipoprotein A-I (apoA-I)-mediated cholesterol efflux, and attenuated ABCA1 expression. Although glimepiride maintained apoA-I-mediated cholesterol efflux from RAW264.7 cells, like glibenclamide, it inhibited ABCA1-mediated cholesterol efflux from transfected HEK293 cells. Similarly, the SUAs inhibited SR-BI-mediated cholesterol efflux from transfected BHK-21 cells. High doses of SUAs increased ABCG1 expression in RAW264.7 cells, promoting HDL-mediated cholesterol efflux in an ABCG1-independent manner. Low doses (0.1-100 µM) of SUAs did not affect cholesterol efflux from macrophages despite dose-dependent increases in ABCA1/G1 expression. Furthermore, they did not change RCT or plasma lipid levels in mice. CONCLUSION: High doses of SUAs inhibited the functionality of ABCA1/SR-BI, but not ABCG1. At lower doses, they had no unfavorable effects on cholesterol efflux or overall RCT in vivo. These results indicate that SUAs do not have adverse effects on atherosclerosis contrary to previous findings for glibenclamide.

Gender differences in the effects of angiotensin receptor blockers on cardiovascular disease.

Women tend to develop hypertension later as they transition into menopause, and during and after menopause the development of hypertension in women is independent of age and body mass index (BMI) but is related to menopause itself. One of the mechanisms of hypertension development in postmenopausal women is believed to be the lack of estrogen leading to vasoconstriction due to both renin-angiotensin-aldosterone (RAA)-sensitive and sodium-sensitive pathways. Nowadays, we have many medications of antihypertensive therapy, including angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) in addition to diuretics, beta-blockers, calcium channel blockers. The present review summarizes gender differences in the effects of ARB on blood pressure lowering and cardiovascular outcomes from the published reports of large-scaled, randomized clinical trials and its substudy on sex-specific difference. Many antihypertensive drugs have been developed, and the benefit of blood pressure lowering therapy for the prevention of cardiovascular disease would be expected not only in men but also in women as indicated in the large-scaled clinical studies with ARB.

Long-term event monitoring study of fluvastatin in Japanese patients with hypercholesterolemia: Efficacy and incidence of cardiac and other events in elderly patients (≥ 65 years old).

OBJECTIVE: This long-term event monitoring (LEM) study was designed to evaluate the long-term lipid-lowering efficacy and safety of fluvastatin (Lochol®, Novartis A.G.) along with the incidence of cardiac and other events, and safety of fluvastatin in Japanese patients with hypercholesterolemia. METHODS: Patients (n = 21,139) who started fluvastatin between April 1, 2000 and March 31, 2002, across 2563 centers in Japan were prospectively registered and followed up for 3 years (secondary prevention cohort) or 5 years (primary prevention cohort). RESULTS: Of the patients registered, 19,084 were included in this analysis. Levels of low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) decreased significantly in the primary (-27.1% and -18.8%) and secondary (-25.3% and -18.4%) prevention cohorts. Reductions in LDL-C (-22.1 vs. -18.2%, p < 0.0001) and TC (-16.1 vs. -13.1%, p < 0.0001) levels were significantly greater among patients aged ≥ 65 than < 65 years old. Overall, 1.7% (146/8563) and 1.1% (93/8563) of patients aged ≥ 65 years old experienced confirmed cardiac and cerebral events, compared with 1.1% (112/10,517) and 0.3% (28/10,517) of patients aged < 65 years old (p = 0.0002 and < 0.0001, respectively). Incidence of cardiac and cerebral events was lowest in patients aged < 65 years old in the primary prevention cohort and highest among patients aged ≥ 65 years old in the secondary prevention cohort. Adverse events were reported in 7.9% (1501/19,084) of patients. CONCLUSION: This large-scale, prospective, uncontrolled study confirmed the lipid-lowering efficacy and safety of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients aged ≥ 65 years old. The higher incidence of cardiac and cerebral events in patients aged ≥ 65 years old in the secondary prevention cohort reflects a high-risk clinical profile with multiple classic risk factors warranting multifactorial interventions.

Gender and the renin-angiotensin-aldosterone system.

Premenopausal women are protected to some extent from cardiovascular and kidney diseases. Because this protection weakens after menopause, sex hormones are believed to play an important role in the pathogenesis of cardiovascular and kidney diseases. The cardiovascular system and the kidneys are regulated by the renin-angiotensin-aldosterone system (RAAS), which in turn, appears to be regulated by sex hormones. In general, oestrogen increases angiotensinogen levels and decreases renin levels, angiotensin-converting enzyme (ACE) activity, AT(1) receptor density, and aldosterone production. Oestrogen also activates counterparts of the RAAS such as natriuretic peptides, AT(2) receptor density, and angiotensinogen (1-7). Progesterone competes with aldosterone for mineralocorticoid receptor. Less is known about androgens, but testosterone seems to increase renin levels and ACE activity. These effects of sex hormones on the RAAS can explain at least some of the gender differences in cardiovascular and kidney diseases.

Sex differences in effects of valsartan administration on cardiovascular outcomes in hypertensive patients: findings from the Jikei Heart Study.

OBJECTIVES: The randomized Jikei Heart Study has demonstrated that the addition of valsartan to conventional treatments prevents more cardiovascular events in Japanese patients with hypertension. This substudy analyses the sex difference in cardiovascular disease risk reduction in the Jikei Heart Study. METHODS: Treatment effects were evaluated by sex (1038 women and 2043 men) as hazard ratios with 95% confidence intervals (CIs) using Cox regression models adjusted for age, BMI, smoking, dyslipidemia, diabetes, antihypertensives, and statin use at baseline. RESULTS: Women were older, had higher SBP, total and low-density lipoprotein cholesterol but were less frequently smokers or diabetics, and had a lower DBP and incidence of coronary artery disease. A greater incidence of primary endpoint, a composite of cardiovascular events, occurred in men versus women [hazard ratio 1.37 (95% CI 1.02-1.85)]. Men in the valsartan group had a significant reduction in the primary endpoint [hazard ratio 0.6 (95% CI 0.44-0.82), P = 0.001], whereas a nonsignificant effect was found in women [hazard ratio 0.64 (95% CI 0.39-1.06), P = 0.075]. However, statistical heterogeneity of this valsartan effect was not found between sexes, and women of at least 55 years of age, mostly after menopause, in the valsartan group showed a significant risk reduction for the primary endpoint [hazard ratio 0.60 (95% CI 0.36-0.99)]. CONCLUSION: The valsartan effect was significant in men and in elderly women but consistent in both sexes. A potential cardiovascular protection by valsartan therapy might be attributed to the cardiovascular risk level but not to the sex difference.

Myocardial Ca2+ handling and cell-to-cell coupling, key factors in prevention of sudden cardiac death.

Using whole-heart preparations, we tested our hypothesis that Ca(2+) handling is closely related to cell-to-cell coupling at the gap junctions and that both are critical for the development and particularly the termination of ventricular fibrillation (VF) and hence the prevention of sudden arrhythmic death. Intracellular free calcium concentration ([Ca(2+)](i)), ECG, and left ventricular pressure were continuously monitored in isolated guinea pig hearts before and during development of low K(+)-induced sustained VF and during its conversion into sinus rhythm facilitated by stobadine. We also examined myocardial ultrastructure to detect cell-to-cell coupling alterations. We demonstrated that VF occurrence was preceded by a 55.9% +/- 6.2% increase in diastolic [Ca(2+)](i), which was associated with subcellular alterations indicating Ca(2+) overload of the cardiomyocytes and disorders in coupling among the cells. Moreover, VF itself further increased [Ca(2+)](i) by 58.2% +/- 3.4% and deteriorated subcellular and cell-to-cell coupling abnormalities that were heterogeneously distributed throughout the myocardium. In contrast, termination of VF and its conversion into sinus rhythm was marked by restoration of basal [Ca(2+)](i), resulting in recovery of intercellular coupling linked with synchronous contraction. Furthermore, we have shown that hearts exhibiting lower SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase) activity and abnormal intercellular coupling (as in older guinea pigs) are more prone to develop Ca(2+) overload associated with cell-to-cell uncoupling than hearts with higher SERCA2a activity (as in young guinea pigs). Consequently, young animals are better able to terminate VF spontaneously. These findings indicate the crucial role of Ca(2+) handling in relation to cell-to-cell coupling in both the occurrence and termination of malignant arrhythmia.

Significantly lower incidence of early definite stent thrombosis of drug-eluting stents after unrestricted use in Japan using ticlopidine compared to western countries using clopidogrel: a retrospective comparison with western mega-studies.

BACKGROUND AND OBJECTIVES: The incidence of definite stent thrombosis (ST) after use of drug-eluting stents (DES), as defined by the Academic Research Consortium, is known to be lower in Japan than in western countries. However, a statistical difference in the incidence of early definite ST (EDST) associated with the unrestricted use of DES has not yet been documented. Therefore, the incidence of EDST in our Japanese institute after unrestricted use of DES was retrospectively compared with those reported in western mega-studies. METHODS AND RESULTS: During the 40 months from August 2004 to November 2007 (before approval of clopidogrel in Japan), DES were implanted in 3605 lesions in 1885 patients in our institute; lesion- and patient-associated percentages of DES use were 95.2% and 94.7%, respectively. Mean stent length per lesion was 33.2 mm, emergent procedures and ST-elevation myocardial infarctions made up 33.7% and 16.4% of the procedures, respectively, intravascular ultrasonography was used 96.0% of the time, a distal protection device for acute coronary syndrome was used 68.7% of the time, and the mean maximum inflation pressure was 19.5 atm. EDST was observed in five lesions (0.139%) in four patients (0.212%). The incidence of patient-associated EDST at our center was significantly lower than in four western mega-studies (0.736%, 66 of 8970 patients; 0.634%, 149 of 23,500; 0.595%, 52 of 8402; 0.997%, 20 of 2006) (p<0.05, <0.01, <0.05, <0.01, respectively, using a chi(2)-test). CONCLUSION: Due to differences in procedural approaches in Japan, the incidence of EDST after unrestricted use of DES was significantly lower than in western countries.

Telmisartan predominantly suppresses cardiac fibrosis, rather than hypertrophy, in renovascular hypertensive rats.

Angiotensin II receptor blockers have beneficial effects in patients with cardiac diseases. We examined the effects of an angiotensin II receptor blocker, telmisartan, on cardiac remodeling in renovascular hypertensive rats. Telmisartan was administered to renovascular hypertensive rats at either a high dose (5 mg per kg per day; high-T group) or a low dose (0.5 mg per kg per day; low-T group). After 4 weeks, histomorphological studies, including an evaluation of cardiac fibrosis, hypertrophy, vascular changes and measurement of the serum aldosterone concentration, were performed. A significant reduction in systolic blood pressure was obtained in the high-T group, and the heart weight to body weight ratio in the high-T and low-T groups was significantly lower than that in the control renovascular hypertensive group. Cardiac and perivascular fibrosis and the accumulation of collagen were significantly suppressed in the high-T and low-T groups. An increase in the cross-sectional area of the myocytes and vessel hypertrophy were significantly prevented in the high-T group, but not in the low-T group. The dependence of myocyte lengthening on the blood pressure was also prevented in the high-T group, but not to a significant degree. The elevation of the serum aldosterone level observed in the renovascular hypertensive group was prevented in both the high-T and low-T groups.Treatment with telmisartan strongly suppresses the progression of cardiac fibrosis, rather than cardiac hypertrophy, in a manner that is independent of the blood pressure.

Inhibitory effect of valsartan against progression of left ventricular dysfunction after myocardial infarction: T-VENTURE study.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) reduce the mortality in the chronic phase of myocardial infarction (MI), and similar effects of angiotensin receptor blockers (ARB) have been reported. However, these effects of ARB have not yet been established in Japanese patients. A multicenter randomized study was designed for the present study to examine the effect of valsartan as compared to that of ACEI against left ventricular dysfunction after MI. METHODS AND RESULTS: Patients with acute MI were randomly allocated to either the valsartan group (n=120; mean age 63 +/-1.0) or the ACEI group (n=121; mean age 62.9 +/-1.0) and followed up until 6 months. Left ventriculography was performed during hospital admission and at 6 months. The blood pressure was similar in the 2 groups throughout the study. The incidences of cardiovascular events and target vessel revascularization were similar, although that of adverse events was significantly higher in the ACEI (12.4%) than in the valsartan group (3.3%; P<0.05). There were no differences in left ventricular ejection fraction and left ventricular end-diastolic volume index between the groups. CONCLUSIONS: Valsartan exhibits similar efficacy effective to that of ACEI in preventing left ventricular dysfunction in Japanese patients with acute MI, and is, in addition, better tolerated than ACEI.

Impact of pulmonary vein isolation on the autonomic modulation in patients with paroxysmal atrial fibrillation and prolonged sinus pauses.

AIMS: The efficacy of catheter-based pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (AF) and prolonged sinus pauses [bradycardia-tachycardia syndrome (BTS)] has been already described. However, the effects of PVI on autonomic modulation in BTS patients remain to be determined. We, therefore, examined the alteration in the autonomic modulation through the PVI procedure by using a heart rate variability (HRV) analysis of 24 h ambulatory monitoring. METHODS AND RESULTS: This study consisted of 26 symptomatic paroxysmal AF patients either with prolonged sinus pauses on termination of AF (>3.0 s, BTS group, n = 11) or without any evidence of sinus node dysfunction (control group, matched for sex and age, n = 15) who underwent PVI. All 11 BTS patients became free from both AF and prolonged sinus pauses without pacemaker implantation (23 +/- 14 months of observation). The mean heart rate significantly increased in the control group (P < 0.05), but not in the BTS group after the PVI procedure, although the HRV parameters of root-mean-square successive differences in the adjacent NN intervals, standard deviation of the NN intervals, and high frequency did significantly decrease in both groups (P < 0.05). CONCLUSION: Although the parasympathetic modulation was significantly attenuated after the PVI procedure, the mean heart rate did not increase in the BTS patients, probably due to the pre-existing sinus node dysfunction.

A hypoxic inducible factor-1 alpha hybrid enhances collateral development and reduces vascular leakage in diabetic rats.

BACKGROUND: Diabetes mellitus is a common comorbidity of atherosclerosis. Hypoxia-inducible factor-1 (HIF-1) is the master regulator of the angiogenic response to hypoxia. METHODS: We studied the effects of adenoviral vectors expressing a constitutively active HIF-1 alpha hybrid (Ad2/HIF-1 alpha/VP16) or vascular endothelial growth factor (Ad2/VEGF) on collateral development and vascular leakiness in a diabetic rat model of hindlimb ischemia. RESULTS: After the removal of the right femoral artery, the mRNA levels of VEGF, angiopoietin-1 and angiopietin-4 in the calf muscles, as measured by Taqman reverse transcriptase-polymerase chain reaction, were transiently elevated in Zucker lean (ZL) but not Zucker diabetic fatty (ZDF) rats. The angiographic score, as determined by post-mortem angiography, was significantly lower in ZDF animals 35 days after surgery compared to their ZL counterparts. In separate animals, intramuscular injection of Ad2/HIF-1a/VP16 and Ad/2VEGF into the thigh muscles significantly increased the angiographic score and capillary density 21 and 35 days after the injection compared to Ad2/CMVEV (a vector expressing no transgene) or vehicle. After the injection of Ad2/CMVEV or vehicle, the Evans-blue dye content in the thigh muscles was significantly higher in ZDF rats than their ZL counterparts. Ad2/HIF-1 alpha/VP16 but not Ad2/VEGF reduced tissue Evans blue dye content. CONCLUSIONS: The endogenous angiogenic response to ischemia was impaired in ZDF rats, possibly due to down-regulation of angiogenic factors. Ad2/HIF-1 alpha/VP16 enhanced collateral development and reduced vascular leakage in the ischemic hindlimb of ZDF rats indicating that hybrid HIF-1 alpha angiogenic therapy may be efficacious for peripheral vascular disease with a diabetic comorbidity.

High incidence of repeat anginal attacks despite treatment with calcium-channel blockers in patients with coronary spastic angina.

BACKGROUND: Calcium-channel blockers (CCBs) are highly effective in suppressing coronary spasm and are widely used as the standard therapy for coronary spastic angina, but it is unclear if CCB treatment completely suppresses the symptoms. METHODS AND RESULTS: The clinical course of the symptoms caused by coronary spasm was investigated in patients taking CCBs: 90 patients were evaluated and 80 patients were followed. The mean follow-up period was 1,796+/-1,169 days. There were no cardiac deaths, but 3 patients were admitted to the hospital, 1 because of the onset of non-Q wave myocardial infarction and 2 because of repeat anginal attacks. In those 2 patients, medical therapy was discontinued at their discretion. In the follow-up analysis, we found that the incidence of symptoms caused by repeat anginal attacks was 37.0% (27/73) in the first year and was increasing every year. CONCLUSIONS: CCBs are strongly recommended for improving the prognosis of coronary spasm, but in many cases they do not suppress completely symptoms.

Cardiac metabolism in diabetes mellitus.

Diabetes mellitus is one of the most common chronic illnesses throughout the world. Diabetic cardiomyopathy is a specific syndrome, consisting of cardiomegaly, left ventricular dysfunction, electrical remodeling of the ventricle, and symptoms of congestive heart failure, that is seen in diabetic patients in the absence of other predisposing factors. Many researchers have suggested that inhibition of the renin-angiotensin-aldosterone system and the sympathetic nervous system may exert a therapeutic effect in individuals with diabetic cardiomyopathy. Indeed, angiotensin II and aldosterone blockade may be effective, partly because aldosterone blockade down-regulates Na(+)/H(+) exchanger 1 activity. Further study of the alterations in ion channel physiology in the context of diabetic cardiomyocytes may be of benefit.

Prevalence, morphological and electrophysiological characteristics of confluent inferior pulmonary veins in patients with atrial fibrillation.

BACKGROUND: Although the common trunk of left pulmonary veins (PVs) has been reported as a relatively popular anatomical variation of PVs, little is known about the coalescence of contralateral PVs. The present study was conducted to reveal the prevalence and electrophysiologic characteristics of the confluent inferior common PVs. METHODS AND RESULTS: Anatomical variation in the PV drainage to the left atrium (LA) was assessed using the multidetector computed tomography scan in 326 patients with atrial fibrillation (AF) who underwent the PV isolation procedure. Coalescence of inferior PVs was observed in 5 cases (1.5%). Both inferior PVs conjoined prior to the junction with the LA in 3 cases, while they coalesced at the LA junction in the other 2 cases. The arrhythmogenic activities of the confluent inferior PVs were generally low in all cases without any ectopic firings triggering the observed AF. All inferior PVs, as well as the superior PVs, were successfully isolated either en bloc at the common trunk or individually at the orifice of each PV. CONCLUSIONS: Confluent inferior PVs were present in 1.5% of cases in patients with AF who underwent the PV isolation procedure. Preoperative recognition of this venous anomaly by 3-dimensional imaging is important for smooth and safe ablation.

Interaction of scaffolding adaptor protein Gab1 with tyrosine phosphatase SHP2 negatively regulates IGF-I-dependent myogenic differentiation via the ERK1/2 signaling pathway.

Grb2-associated binder 1 (Gab1) coordinates various receptor tyrosine kinase signaling pathways. Although skeletal muscle differentiation is regulated by some growth factors, it remains elusive whether Gab1 coordinates myogenic signals. Here, we examined the molecular mechanism of insulin-like growth factor-I (IGF-I)-mediated myogenic differentiation, focusing on Gab1 and its downstream signaling. Gab1 underwent tyrosine phosphorylation and subsequent complex formation with protein-tyrosine phosphatase SHP2 upon IGF-I stimulation in C2C12 myoblasts. On the other hand, Gab1 constitutively associated with phosphatidylinositol 3-kinase regulatory subunit p85. To delineate the role of Gab1 in IGF-I-dependent signaling, we examined the effect of adenovirus-mediated forced expression of wild-type Gab1 (Gab1(WT)), mutated Gab1 that is unable to bind SHP2 (Gab1(DeltaSHP2)), or mutated Gab1 that is unable to bind p85 (Gab1(Deltap85)), on the differentiation of C2C12 myoblasts. IGF-I-induced myogenic differentiation was enhanced in myoblasts overexpressing Gab1(DeltaSHP2), but inhibited in those overexpressing either Gab1(WT) or Gab1(Deltap85). Conversely, IGF-I-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation was significantly repressed in myoblasts overexpressing Gab1(DeltaSHP2) but enhanced in those overexpressing either Gab1(WT) or Gab1(Deltap85). Furthermore, small interference RNA-mediated Gab1 knockdown enhanced myogenic differentiation. Overexpression of catalytic-inactive SHP2 modulated IGF-I-induced myogenic differentiation and ERK1/2 activation similarly to that of Gab1(DeltaSHP2), suggesting that Gab1-SHP2 complex inhibits IGF-I-dependent myogenesis through ERK1/2. Consistently, the blockade of ERK1/2 pathway reversed the inhibitory effect of Gab1(WT) overexpression on myogenic differentiation, and constitutive activation of the ERK1/2 pathway suppressed the enhanced myogenic differentiation by overexpression of Gab1(DeltaSHP2). Collectively, these data suggest that the Gab1-SHP2-ERK1/2 signaling pathway comprises an inhibitory axis for IGF-I-dependent myogenic differentiation.

Angiographic and clinical outcomes after sirolimus-eluting stent implantation to de novo ostial lesion of the right coronary artery: a retrospective study.

BACKGROUND: Although ostial lesion (defined as being within 3 mm of the ostia) of the right coronary artery (RCAos) has been a limitation of percutaneous coronary intervention after using previous various devices, the angiographic and clinical outcomes after the deployment of a sirolimus-eluting stent (SES) to RCAos have not been fully estimated. Therefore, the incidences of binary restenosis (BR; % diameter stenosis at chronic phase

Clinical significance of B-type natriuretic Peptide in the assessment of untreated hypertension.

BACKGROUND: Recent studies suggest that B-type natriuretic peptide (BNP) is an important predictor of cardiac events in hypertensive patients. METHODS AND RESULTS: The relationship between the plasma BNP level and various clinical parameters was examined in 154 untreated hypertensive patients without heart failure or atrial fibrillation (mean age: 58.0+/-10.7; mean blood pressure: 164.5+/-15.2/99.1+/-9.7 mmHg; mean BNP: 32.7+/-36.7 pg/ml). First, the patients were divided into 2 groups based on BNP: normal (<18.5 pg/ml, mean 9.7+/-5.7, n=69); or elevated (>18.5 pg/ml, mean 51.4+/-40.4, n=85). The elevated BNP group had a significantly greater electrocardiographic voltage index (SV1+RV5; 3.7+/-1.2 vs 3.2+/-0.8 mV, p=0.0029), cardiothoracic ratio/chest radiography (CTR; 49.1 vs 46.9%, p=0.0037), left ventricular mass index (LVMI; 122.2+/-31.7 vs 103.1+/-26.4 g/m2, p=0.0005) and deceleration time (DT; 241+/-39 vs 208+/-30 ms, p=0.0001), as well as a smaller E-wave to A-wave (E/A ratio) (0.80+/-0.22 vs 0.96+/-0.28, p=0.0003), compared with the normal BNP group. There were no significant differences in casual blood pressure, body mass index, serum creatinine and ejection fraction between the 2 groups. Next, the patients were divided into 3 groups based on BNP: normal (<18.5, n=69), moderate (18.5 to 40, mean 27.0+/-5.7, n=43) and high (40<, mean 76.3+/-45.3, n=42). In the high BNP group, most clinical parameters indicated the most severe organ damage compared with other groups, including SV1+RV5, DT and LVMI. In all patients, logarithmic BNP was positively correlated with the age, pulse pressure, SV1+RV5, CTR, ventricular wall thickness, DT, LVMI and negatively correlated with hemoglobin, renin and E/A ratio. Using multiple regression analysis, renin and DT were significantly associated with BNP. No gender differences in the relationship between BNP and clinical parameters were found. CONCLUSIONS: Results suggest that BNP is a useful indicator for the initial assessment of the severity of essential hypertension, detecting both cardiac hypertrophy and diastolic dysfunction, and may also be valuable for risk stratification.

The insulin sensitizer pioglitazone improves the deterioration of ischemic preconditioning in type 2 diabetes mellitus rats.

We investigated the effects of ischemic preconditioning (IP) on reperfusion arrhythmias in type 2 diabetic rats as well as the effects of the insulin sensitizer pioglitazone. Thirty-week-old OLETF rats with or without pioglitazone (10 mg/kgBW, orally) were used as a model for type 2 diabetes. LETO rats served as controls. The incidences and durations of reperfusion ventricular tachyarrhythmias (RVT) were evaluated using a working heart method. After 5 minutes of initial perfusion, the rats were divided into the following groups: 1) control rats without IP (CIP(-)), 2) control rats with IP (CIP(+)), 3) diabetic rats without IP (DIP(-)), 4) diabetic rats with IP (DIP(+)), 5) pioglitazone-treated diabetic rats without IP (TDIP(-)), and 6) pioglitazone-treated diabetic rats with IP (TDIP(+)). Three 2-minute cycles of global diastolic ischemia and 5 minutes of reperfusion before long ischemia were performed as IP. The incidence and duration of RVT in CIP(+) were significantly lower than in CIP(-). There was no significant difference in the duration of RVT between DIP(+) and DIP(-). However, the duration of RVT in TDIP(+) was significantly shorter than TDIP(-). These results suggested that the effects of IP on reperfusion arrhythmias are deteriorated in type 2 diabetic rats. The insulin sensitizer pioglitazone can improve the deterioration of IP against reperfusion arrhythmias in type 2 diabetic rats.