Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats.

Uncoupling of nitric oxide (NO) synthase (NOS) has been implicated in left ventricular (LV) hypertrophy (LVH) and dilatory remodeling induced by pressure overload. We investigated whether administration of sepiapterin, a substrate of the salvage pathway of tetrahydrobiopterin synthesis, prevents LVH and dilatory LV remodeling by inhibiting NOS uncoupling and increasing bioavailable NO. Pressure overload was induced in rats by transverse aortic constriction (TAC). Concentric LVH developed during 8 wk after TAC, and dilatory LV remodeling and dysfunction developed between 8 and 16 wk after TAC associated with a decrease in capillary density. Oral administration of sepiapterin or the superoxide/peroxynitrite scavenger N-(2-mercaptopropionyl)-glycine for 8 wk after TAC inhibited oxidative stress, but only sepiapterin increased bioavailable NO and inhibited cardiomyocyte hypertrophy associated with a further increase in capillary density. When sepiapterin was administered between 8 and 16 wk after TAC, cardiomyocyte hypertrophy was regressed and capillary density was restored. This was associated with the inhibition of interstitial fibrosis and dilatory LV remodeling. N-nitro-l-arginine methyl ester abrogated all the beneficial effects of sepiapterin in rats with TAC. These results suggest that sepiapterin prevents concentric LVH and dilatory remodeling after TAC primarily by increasing the bioavailability of NO.

Safety of exercise-based cardiac rehabilitation and exercise testing for cardiac patients in Japan: a nationwide survey.

BACKGROUND: The safety of exercise-based cardiac rehabilitation (CR) has not been investigated in Japan, so a nationwide survey was conducted to investigate the incidence of adverse events (AEs) associated with CR and exercise testing. METHODS AND RESULTS: In total, 136 hospitals reported operating recovery-phase CR programs, amounting to 383,096 patient-hours of exercise training. The incidence rates of all AEs and life-threatening AEs (LAE: death, cardiac arrest, acute myocardial infarction, cardiac rupture) during exercise sessions were 12 and 1 event/383,096 patient-hours (3.13 and 0.26 events/100,000patient-hours), respectively. When CR programs were categorized as "Formal" in which an exercise prescription based on exercise testing was issued to individual patients or "Non-formal" without exercise prescription, the incidence of AEs during and within the 24 h after an exercise session was significantly lower in the Formal than the Non-formal CR programs (P<0.001), despite similar hospital size and coronary intervention volumes between the 2 category hospitals. Moreover, LAEs did not occur in 277,721 patient-hours in Formal CR, whereas 2 LAEs occurred in 105,375 patient-hours in Non-formal CR (P<0.05). During 469,215 exercise testing sessions, 3 LAEs (0.64 event/100,000tests) and 31 non-LAEs (6.61 events/100,000tests) occurred. CONCLUSIONS: This first nationwide survey in Japan revealed that both exercise-based CR and exercise testing are generally safe, and that Formal CR, in which an individual exercise prescription is determined by exercise testing, is particularly safe.

[Incidence and clinical outcome of contrast-induced nephropathy in the elderly patients].

BACKGROUND: Aging is an established risk factor for contrast-induced nephropathy (CIN). However, little information is available on the incidence and clinical outcome of CIN for the elderly patients in Japan. OBJECTIVES: We determined the incidence and clinical outcome of CIN in the Japanese elderly patient. METHODS: We studied 292 patients who had mild renal dysfunction (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)) at baseline and underwent coronary angiography. Patients were divided into two groups base on their age: the elderly group (age ≥ 75, n=108) and the control group (age<75, n=184). CIN was defined as a 25% increase in serum creatinine or an increase in serum creatinine by>0.5 mg/dl above the baseline value at or within 2 days post procedure. RESULTS: Patients in the elderly group had a higher incidence of CIN (14%) than those in the control group (9%). In patients who developed CIN, there was no significant difference between the two groups in baseline GFR and GFR on days 1, 2, 7 and 30 after the procedure. However, the relative increase in GFR above baseline on day 7 (-4.0 ± 6.1 vs -8.3 ± 8.0 ml/min P=0.096) and day 30 (1.5 ± 9.4 vs -10.1 ± 9.6 ml/min P=0.0017) in the elderly group was higher than that in the control group. Furthermore, death occurred in 3 patients in the elderly group (20%) whereas no patient died in the control group (P=0.092). CONCLUSION: Aging (age ≥ 75) is a risk factor for CIN in Japanese. CIN in the elderly patients may be associated with prolonged renal dysfunction and poor prognosis.

Urinary liver-type fatty acid-binding protein level as a predictive biomarker of contrast-induced acute kidney injury.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a well-known complication of contrast medium exposure in patients with chronic kidney disease. However, there are no biological markers to accurately predict the onset of CI-AKI. Liver-type fatty acid-binding protein (L-FABP), an intracellular carrier protein for free fatty acids, is markedly upregulated and abundantly expressed in the proximal tubules after renal ischaemia. We prospectively investigated whether urinary L-FABP is a suitable marker for the prediction of CI-AKI. METHODS: We performed a prospective study of 220 consecutive patients with chronic kidney disease who underwent elective catheterization [serum creatinine (Cr) ≥ 1.2 mg/dL (106 M)]. Serum Cr and L-FABP levels were measured immediately before and 1 and 2 days after the procedure. CI-AKI was defined as an increase in serum Cr level of ≥ 0.3 mg/dL within 48 h after the procedure. RESULTS: We observed the development of CI-AKI in 19 patients (8.6%). Urinary L-FABP levels were significantly higher in patients with CI-AKI than those without CI-AKI before contrast medium exposure. Receiver operating characteristic analysis showed that baseline urinary L-FABP level exhibited 82% sensitivity and 69% specificity, at a cut-off value of 24.5 µg/g Cr. Using multivariate analysis, we found that independent predictors of CI-AKI development were L-FABP level of ≥ 24.5 µg/g Cr [odds ratio (OR): 9.10; 95% confidence interval (CI), 3.20-28.9], and left ventricular ejection fraction ≤ 40% (OR, 3.42; 95% CI, 1.07-10.8). CONCLUSIONS: Urinary L-FABP level is useful for predicting the onset of CI-AKI before contrast medium exposure.

Effect of pioglitazone on arterial baroreflex sensitivity and sympathetic nerve activity in patients with acute myocardial infarction and type 2 diabetes mellitus.

Pioglitazone has been shown to reduce the occurrence of fatal and nonfatal myocardial infarction (MI) in type 2 diabetes mellitus (DM). However, the mechanisms of such favorable effects remain speculative. The aim of this study was to investigate the effect of pioglitazone on arterial baroreflex sensitivity (BRS) and muscle sympathetic nerve activity (MSNA) in 30 DM patients with recent MI. Patients were randomly assigned to those taking pioglitazone (n = 15) and those not taking pioglitazone (n = 15) at 4 weeks after the onset of MI. BRS, MSNA, calculated homeostasis model assessment of insulin resistance index (HOMA-IR), and plasma adiponectin were measured at baseline and after 12 weeks. Pioglitazone increased plasma adiponectin (from 6.9 ± 3.3 µg/dL to 12.2 ± 7.1 µg/dL) and reduced HOMA-IR (from 4.0 ± 2.2 to 2.1 ± 0.9). In the pioglitazone group, MSNA decreased significantly (from 37 ± 7 bursts/min to 25 ± 8 bursts/min) and BRS increased significantly (from 6.7 ± 3.0 to 9.9 ± 3.2 ms/mm Hg) after 12 weeks. Furthermore, a significant relationship was found between the change in MSNA and HOMA-IR (r = 0.6, P = 0.042). Thus, pioglitazone decreased the sympathetic nerve traffic through the improvement of insulin resistance in DM patients with recent MI, which indicate that the sympathoinhibitory effects of pioglitazone may, at least in part, have contributed to the beneficial effects of pioglitazone.

Prognostic value of normal stress-only technetium-99m myocardial perfusion imaging protocol. Comparison with standard stress-rest protocol.

BACKGROUND: Patients with a normal stress image on technetium-99m (Tc-99m) single-photon emission computed tomography (SPECT) have a good prognosis for diagnosing coronary artery disease. However, current guidelines recommend stress and rest imaging to confirm that a stress image is normal. METHODS AND RESULTS: We determined all-cause of cardiac events (acute coronary syndrome and sudden death) in 1,939 patients undergoing stress myocardial perfusion SPECT with Tc-99m radiotracers. Patients with an abnormal stress image were excluded, so we focused on 1,125 patients in whom the stress SPECT study was interpreted as normal. A stress-only protocol was used in 726 patients (adenosine=339; exercise=387), whereas 399 had both stress and rest imaging (adenosine=294; exercise=105). Mean follow-up was 1,252 days. At the end of follow-up, there were 39 cardiac events in the stress-only cohort and 19 in the stress-rest cohort. Kaplan-Meier analysis revealed that there were no differences for the entire cohort of cardiac events not only between the stress-only and stress-rest protocols but also for stressor modality, despite the fact that the stress-rest cohort showed higher coronary risk factors. CONCLUSIONS: Patients determined as having a normal SPECT on the basis of stress imaging alone have a similar cardiac event rate as those who have a normal SPECT on the basis of evaluation of both stress and rest images. This imaging strategy will significantly reduce radiation exposure in a substantial number of patients.

Radiofrequency catheter ablation of posterior paraseptal accessory pathway with atresia of the coronary sinus ostium.

A 42-year-old man was referred to our hospital for an electrophysiologic study because of recurrent episodes of palpitation. On coronary angiogram, an anomalous atresia of the coronary sinus (CS) ostium was discovered. The ablation catheter was inserted from the right femoral artery to the accessory pathway (AP) of posterior paraseptal area. The earliest retrograde atrial activation was recorded in the 5-6 o'clock region of the mitral annulus. Radiofrequency energy was delivered to this site, resulting in elimination of the AP. After this application, there was persistent ventriculoatrial dissociation and led to successful ablation of the AP.

Accumulation of visceral fat in maintenance hemodialysis patients.

BACKGROUND: In hemodialysis (HD) patients, obesity has been recognized as a serious risk factor for mortality and morbidity for cardiovascular diseases. In addition, abnormalities of lipid profiles exist in these patients. METHODS: In patients undergoing maintenance HD, incidences of abnormality of lipid profiles and visceral obesity determined by computed tomography scans were compared. In addition, the relationship between visceral fat area (VFA) and brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, or carotid intima-media thickness (IMT), an index of atherosis, was examined. RESULTS: The incidence of high VFA (27.0%) was significantly greater than that of high body mass index (BMI) (9.7%), high low-density-lipoprotein cholesterol (LDL-C) (4.8%), and high triglyceride (12.7%). In patients with diabetes mellitus (DM), waist circumference and VFA showed a significant positive relationship with baPWV. baPWV was significantly higher in patients with high VFA and DM than in patients with low VFA without DM, those with high VFA without DM, and those with low VFA and DM. Carotid IMT was significantly greater in patients with high VFA and DM than in those with low VFA without DM and those with low VFA and DM. CONCLUSIONS: The incidence of high VFA was much greater than that of high BMI, high LDL-C, or high triglyceride. Visceral fat accumulation may be related to both arterial stiffness and atherosis in diabetic patients on maintenance HD.

Granulocyte colony-stimulating factor does not enhance recruitment of bone marrow-derived cells in rats with acute myocardial infarction.

Despite the potential benefit of granulocyte colony-stimulating factor (G-CSF) therapy in patients with acute myocardial infarction (MI), the efficacy of G-CSF in regenerating the heart after MI remains controversial. The authors hypothesize that the limited efficacy of G-CSF is related to its inhibitory effect on recruitment of bone marrow-derived cells (BMCs) to the infarcted tissue. MI was induced in rats with intrabone marrow-bone marrow transplantation from syngenic rats expressing green fluorescence protein to track BMCs. G-CSF was administered for five days after the onset of MI. G-CSF increased the number of CD45(+) cells in the peripheral circulation but did not increase their recruitment to the heart. G-CSF had no effect on myocardial stromal-derived factor-1 alpha and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in mononuclear cells in the peripheral blood and CXCR4(+) cells in the heart. G-CSF had no effect on angiogenesis, myocardial fibrosis or left ventricular function four weeks after MI. These results suggest that G-CSF mobilizes BMCs to the peripheral circulation but does not increase recruitment to the infarcted myocardium despite preservation of the stromal-derived factor-1 alpha/CXCR4 axis.

Pseudoaneurysm with left-to-right shunt in a patient with myocardial infarction: evaluation by three-dimensional echocardiography.

It is often difficult to noninvasively differentiate a post-infarction left ventricular (LV) pseudoaneurysm from a post-infarction true aneurysm. A 66-year-old woman with a past history of inferior acute myocardial infarction was admitted to our hospital because of acute decompensated heart failure. Two-dimensional transthoracic echocardiography showed an aneurysm with a narrow orifice in the inferoposterior basal area. The pulmonary to systemic flow ratio (Q p/Q s) was 2.2:1, which corresponded to moderate left-right shunting. Three-dimensional transesophageal echocardiography (3D-TEE) showed the orifice in the perforated right ventricular basal area with a color jet through the orifice from the LV to the right ventricle. Collectively, based on the 3D-TEE findings, we diagnosed the case as inferoposterior pseudoaneurysm with a left-to-right shunt caused by myocardial infarction.

Reversal of inducible nitric oxide synthase uncoupling unmasks tolerance to ischemia/reperfusion injury in the diabetic rat heart.

The diabetic heart is known to be susceptible to ischemia/reperfusion (I/R) injury by increased oxidative stress. Although oxidative stress upregulates inducible nitric oxide (iNOS), the role of iNOS in I/R injury in the diabetic heart has been poorly understood. Because iNOS-derived nitric oxide (NO) plays a crucial role in cardioprotection against I/R injury, we hypothesized that inhibition of iNOS uncoupling would restore tolerance to I/R injury in the diabetic heart. The present study demonstrated that iNOS-derived superoxide generation was reduced, and that the NO bioavailability was increased, by treatment with the NOS-cofactor, tetrahydrobiopterin (BH4), before I/R in the hearts isolated from diabetic rats. This was associated with a reduction of infarct size and improvement of left ventricular (LV) function after I/R. The cardioprotective effect of BH4 was abrogated by treatment with a thiol reducing agent dithiothreitol (DTT), but not a NO-sensitive guanylyl cyclase inhibitor ODQ, suggesting that iNOS-derived NO-mediated cardioprotection occurs through protein S-nitrosylation but not cGMP-dependent signaling in the diabetic heart. Indeed, protein S-nitrosylation was increased by treatment with BH4 in the diabetic heart and was inhibited by DTT. These results suggest that the inhibition of iNOS uncoupling unmasks tolerance to I/R injury through enhanced protein S-nitrosylation in the diabetic rat heart.

Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction.

Uncoupling of nitric oxide synthase (NOS) has been implicated in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). We hypothesized that inducible NOS (iNOS) plays a crucial role in LV remodeling after MI, depending on its coupling status. MI was created in wild-type, iNOS-knockout (iNOS(-/-)), endothelial NOS-knockout (eNOS(-/-)), and neuronal NOS-knockout (nNOS(-/-)) mice. iNOS and nNOS expressions were increased after MI associated with an increase in nitrotyrosine formation. The area of myocardial fibrosis and LV end-diastolic volume and ejection fraction were more deteriorated in eNOS(-/-) mice compared with other genotypes of mice 4 wk after MI. The expression of GTP cyclohydrolase was reduced, and tetrahydrobiopterin (BH(4)) was depleted in the heart after MI. Oral administration of sepiapterin after MI increased dihydrobiopterin (BH(2)), BH(4), and BH(4)-to-BH(2) ratio in the infarcted but not sham-operated heart. The increase in BH(4)-to-BH(2) ratio was associated with inhibition of nitrotyrosine formation and an increase in nitrite plus nitrate. However, this inhibition of NOS uncoupling was blunted in iNOS(-/-) mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS(-/-), and nNOS(-/-) but not iNOS(-/-) mice. N(ω)-nitro-L-arginine methyl ester abrogated sepiapterin-induced increase in nitrite plus nitrate and angiogenesis and blocked the beneficial effects of sepiapterin on LV remodeling and function. These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH(4) synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS.

Decreased plasma level of vitamin C in chronic kidney disease: comparison between diabetic and non-diabetic patients.

BACKGROUND: A decreased plasma level of vitamin C has been reported to be associated with an increased risk of cardiovascular morbidity and mortality. Here, we sought to determine the vitamin C status of patients with chronic kidney disease and the pathophysiological role of vitamin C in these patients. METHODS: We studied 58 patients and evaluated the relationship between renal function and plasma vitamin C concentration, as well as the effect of diabetes on this relationship. Endothelium-dependent flow-mediated dilation of brachial artery was measured to assess the endothelial function. Serum malondialdehyde low-density lipoprotein was measured as a marker for oxidative stress. RESULTS: Plasma vitamin C concentration had a positive linear relationship with eGFR in both diabetic and non-diabetic patients (P = 0.006 and P = 0.004, respectively). When vitamin C concentration and eGFR relationships were compared in the two groups, vitamin C concentration was significantly lower in diabetic patients at every eGFR (P = 0.006). Flow-mediated vasodilatation of the brachial artery was positively correlated with vitamin C concentration in non-diabetic patients (P = 0.047) but not in diabetic patients. There was a negative correlation between serum malondialdehyde low-density lipoprotein and vitamin C concentration in non-diabetic patients (P = 0.044) but not in diabetic patients. CONCLUSIONS: Renal dysfunction was associated with a decrease in plasma vitamin C level. Moreover, decreased vitamin C may cause endothelial dysfunction via an increase in oxidative stress in non-diabetic chronic kidney disease patients.

Olmesartan induces renoprotective effects by stimulating angiotensin type 2 receptors and reducing oxidative stress in diabetic nephropathy.

BACKGROUND: Angiotensin receptor blockers reduce the progression of diabetic nephropathy primarily by inhibiting angiotensin type 1 (AT(1)) receptors. In the present study, we investigated the role of angiotensin type 2 (AT(2)) receptors on the renoprotective effects of olmesartan in diabetic nephropathy. METHODS: Six-week-old mice were treated with streptozotocin and divided into four groups: the OLM group (mice treated with olmesartan), the OLM+Ang II group (mice treated with olmesartan and angiotensin II), the OLM+PD group (mice treated with olmesartan and the AT(2) antagonist PD 123319), and the vehicle group. Nondiabetic mice were used as controls. We measured blood glucose levels and urinary excretions of albumin and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is a marker for oxidative stress. RESULTS: Although urinary albumin excretion in the OLM and OLM+Ang II groups showed a tendency to be reduced compared to the vehicle group, it was significantly lower compared to the OLM+PD group. Urinary excretion of 8-OHdG was also significantly lower in the OLM and OLM+Ang II groups compared to the OLM+PD group. CONCLUSIONS: In diabetic nephropathy, the renoprotective effects of olmesartan are due not only to the blockade of AT(1) receptors, but also to a reduction in oxidative stress via stimulation of AT(2) receptors.

Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice.

1. Uncoupling of nitric oxide synthase (NOS) has been implicated in the pathogenesis of left ventricular (LV) dysfunction in diabetes mellitus. In the present study, we investigated the role of NOS uncoupling in oxidative/nitrosative stress and LV dysfunction in the diabetic mouse heart. 2. Diabetes was induced in wild-type (WT), endothelial (e) NOS knockout (eNOS(-/-)), inducible (i) NOS knockout (iNOS(-/-)) and neuronal (n) NOS knockout (nNOS(-/-)) mice by streptozotocin (STZ) treatment. 3. In the diabetic heart, iNOS, but not eNOS or nNOS, expression was increased. Levels of malondialdehyde (MDA), 4-hydroxy-noneal (HNE) and nitrotyrosine (NT), as markers of oxidative/nitrosative stress, were increased in the diabetic mouse heart, but the increase in oxidative/nitrosative stress was significantly repressed in the iNOS(-/-) diabetic mouse heart. Levels of nitrite and nitrate (NO(x)), as an index of nitric oxide, bioavailability were significantly decreased in the iNOS(-/-) diabetic mouse heart. 4. Oral administration of sepiapterin (10 mg/kg per day), a precursor of tetrahydrobiopterin (BH(4)), significantly increased BH(4) and the BH(4)/BH(2) ratio in diabetic mouse heart. Similarly, sepiapterin inhibited the formation of HNE, MDA and NT in diabetic hearts from all three genotypes, but the increase in NO(x) following sepiapterin treatment was significantly attenuated in the iNOS(-/-) diabetic mouse heart. Percentage fractional shortening (FS), evaluated by echocardiography, decreased significantly in all genotypes of diabetic mice. Sepiapterin significantly increased percentage FS in diabetic mice, except in iNOS(-/-) mice. 5. These results suggest that sepiapterin inhibits uncoupling of NOS and improves LV function presumably by increasing iNOS-derived nitric oxide in the diabetic heart.

A Japanese case of proteinase 3 antineutrophil cytoplasmic autoantibody-associated pauci-immune-type crescentic glomerulonephritis without valvular endocarditis.

A 74-year-old male without recent medical treatment visited our hospital complaining of fever and lack of appetite. Upon examination severe azotemia, proteinuria, and urinary occult blood were noted, and the patient was admitted. Results of a blood test showed that his proteinase 3 antineutrophil cytoplasmic autoantibody (PR3-ANCA) level was high. A transthoracic echocardiogram indicated normal cardiac function and no valvular regurgitation or stenosis. Necrotizing glomerulonephritis accompanied by cellular crescentic bodies, but not granuloma, was noted on renal biopsy. An immunofluorescence study demonstrated no immunofluorescence staining in the glomerulus or in the tubulointerstitial or vascular compartments. No lesion was present in the lung or upper respiratory tract. The patient was diagnosed with PR3-ANCA-associated pauci-immune-type crescentic glomerulonephritis and treated with steroids. This treatment resulted in rapid normalization of C-reactive protein, and the PR3-ANCA level slowly decreased and converted to negative. The renal function, however, did not improve, and maintenance dialysis was introduced. No pulmonary or upper airway lesion has developed during 18 months of follow-up. PR3-ANCA-positive crescentic glomerulonephritis accompanied by valvular endocarditis has been described by several reports in Japan; however, this case was not complicated by valvular endocarditis. To our knowledge, this is the 4th case report describing PR3-ANCA-associated crescentic glomerulonephritis in Japan.

Comparison of metabolic profile and adiponectin level with pioglitazone versus voglibose in patients with type-2 diabetes mellitus associated with metabolic syndrome.

Type 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versus voglibose on physical and metabolic profiles and serum adiponectin level in patients with T2DM associated with MetS. Sixty patients who were diagnosed for the first time as T2DM associated with MetS were analyzed for insulin sensitivity, lipid profile, serum adiponectin and systemic inflammation. Those patients were randomly assigned to oral pioglitazone group (n = 30) or voglibose group (n = 30) in addition to conventional diet and exercise training. Body mass index and waist circumference did not change in the pioglitazone group, whereas these physical parameters significantly decreased in the voglibose group during a 6-month follow-up period. However, glycosylated hemoglobin, fasting plasma glucose, and HOMA-IR more significantly decreased in the pioglitazone group. The level of serum adiponectin especially high-molecular weight adiponectin markedly increased in the pioglitazone group. Moreover, high sensitive CRP significantly decreased only in the pioglitazone group. These results suggest that voglibose is superior in improving obesity, while pioglitazone is superior in ameliorating insulin sensitivity and increasing serum adiponectin in patients with an early stage of T2DM associated with MetS.

Effect of Exercise Training on Body Temperature in the Elderly: A Retrospective Cohort Study.

BACKGROUND: This study evaluated the effect of exercise training on body temperature and clarified the relationship between body temperature and body composition in the elderly. METHODS: In this retrospective cohort study, a total of 91 elderly participants performed aerobic and anaerobic exercise training twice a week for 2 years. Non-contact infrared thermometer and bioelectrical impedance analysis were performed at baseline and at 2 years. RESULTS: Mean age of study participants was 81.0 years. The participants were divided into two groups by baseline body temperature of 36.3 °C; lower body temperature group (n = 67) and normal body temperature group (n = 24). Body temperature rose significantly after exercise training in the lower body temperature group (36.04 ± 0.11 °C to 36.30 ± 0.13 °C, p < 0.0001), whereas there was no significant difference in the normal body temperature group (36.35 ± 0.07 °C to 36.36 ± 0.13 °C, p = 0.39). A positive correlation was observed between the amount of change in body temperature and baseline body temperature (r = -0.68, p < 0.0001). Increase in skeletal muscle mass was an independent variable related to the rise in body temperature by the multivariate logistic regression analysis (odds ratio: 4.77, 95% confidence interval: 1.29-17.70, p = 0.02). CONCLUSIONS: Exercise training raised body temperature in the elderly, especially those with lower baseline body temperature.

Inhibition of contractile activity during postconditioning enhances cardioprotection by restoring sarcolemmal dystrophin through phosphatidylinositol 3-kinase.

BACKGROUND: Although ischemic postconditioning (IPost) confers cardioprotection by protecting the mitochondria though the activation of phosphatidylinositol 3-kinase (PI3K), a potential drawback of IPost is impairment of aerobic ATP generation during reperfusion by repeated ischemia. This decrease in ATP might inhibit the restoration of sarcolemmal dystrophin, which is translocated during ischemia, and render cardiomyocytes susceptible to contraction-induced oncosis. METHODS AND RESULTS: Isolated rat hearts were subjected to 30 min ischemia and 120 min reperfusion. IPost induced by 20 cycles of 10-s reperfusion and 10-s ischemia enhanced the activation of PI3K as evidenced by the increased phosphorylation of Akt, but had no effect on myocardial ATP, restoration of sarcolemmal dystrophin, or cardiomyocyte oncosis during IPost. Administration of the contractile blocker, 2,3-butanedione monoxim (BDM), during IPost increased myocardial ATP and facilitated the redistribution of dystrophin to the sarcolemma. This led to reduced cardiomyocyte oncosis and infarct size, and improved the left ventricular function. The anti-oncotic effect of BDM occurred without changing the anti-apoptotic effect of IPost. The PI3K inhibitor, LY294002, prevented the phosphorylation of Akt, decreased the recovery of ATP and restoration of sarcolemmal dystrophin, and blocked the anti-oncotic and anti-apoptotic effects of IPost. CONCLUSIONS: These results suggest that the inhibition of contractile activity during IPost prevents cardiomyocyte oncosis and enhances cardioprotection through PI3K-dependent restoration of sarcolemmal dystrophin.

Soluble TRAIL prevents RANTES-dependent restenosis after percutaneous coronary intervention in patients with coronary artery disease.

Some factors play pathogenic roles in the development of restenosis after percutaneous coronary intervention (PCI). We measured and compared the ratio of elevated levels of regulated on activation normally T-cell expressed and secreted (RANTES), soluble (s) P-selectin, sE-selectin, s vascular cell adhesion molecule (VCAM)-1, s interleukin-2 receptor (IL-2R) and s tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) after PCI. Plasma levels of chemokines and soluble markers were measured before and 30 days after PCI in 85 patients (61 males and 24 females, aged 61 +/- 7 years) who underwent PCI and who had repeated angiograms at a 6-month follow-up. Restenosis occurred in 29 (34.1%) patients. The significant and time-dependent increases in RANTES, sIL-2R and sVCAM-1 were observed in the restenosis group. However, there were no significant differences in sP-selectin and sE-selectin levels with or without restenosis. sTRAIL levels in patients with coronary artery disease were significantly higher than levels in normal controls. Furthermore, unlike the restenosis group, sTRAIL levels after PCI were significantly increased in the non-restenosis group, and sTRAIL levels correlated significantly with sVCAM-1 and sE-selectin. These findings suggest that restenosis development after PCI in patients with coronary artery disease involve the participation of RANTES and activated T-lymphocyte expressing CD25 after PCI, and sTRAIL may prevent this RANTES-dependent restenosis.