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Vacuolar H + -adenosine triphosphatase (ATPase) plays important roles in urinary acid excretion, vesicular acidification to activate enzymes, and the membrane recycling of transporters in the kidney. As acidosis stimulates renal gluconeogenesis, we investigated the effect of blockade of H + -ATPase on renal gluconeogenesis in diabetic rats. Diabetes mellitus was induced by a single injection of streptozotocin, and a group of DM rats was treated with bafilomycin B1 intraperitoneally for 8 days. In diabetic rats, the renal expression and activity of H + -ATPase were increased with elevated urinary ammonium excretion. The blockade of H + -ATPase by bafilomycin B1 reduced the renal H + -ATPase activity and urinary ammonium excretion in diabetic rats. Treatment with bafilomycin suppressed the enhancement of the renal gluconeogenesis enzymes phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in diabetic rats and reduced the renal cytoplasmic glucose levels, whereas hepatic gluconeogenesis did not change significantly. After a 24-h starvation period, bafilomycin decreased the plasma glucose level to a normal level in diabetic rats. The suppression of renal gluconeogenesis by an H + -ATPase inhibitor may therefore be a new therapeutic target for the treatment of diabetes mellitus.

Background: Even though longer stented lengths may increase the risk of restenosis, full coverage of diffuse long lesions with longer stents seems to be the optimal strategy for percutaneous coronary intervention (PCI) in the new drug-eluting stent (DES) era. However, it remains unclear whether this strategy will indicate favorable outcome or not. This study evaluated the impact of stent length on two-year clinical outcomes after PCI with the XIENCE Alpine everolimus-eluting stent., Methods: This was a retrospective, non-randomized, observational study. Four patient groups were classified according to implanted overall total stent length (short, <15mm; middle, 15-23mm; long, 24-32mm; and ultra-long, >32mm). The primary outcome of this study was major adverse cardiac events (MACE), defined as the composite of cardiac death, recurrent myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis (ST). Angiographic restenosis by quantitative coronary angiography was defined as >50% diameter stenosis at 10 months after PCI., Results: A total of 730 patients who received intravascular ultrasound (IVUS)-guided PCI were enrolled. The short, middle, long, and ultra-long stent groups included 138 patients (149 lesions), 210 patients (235 lesions), 190 patients (209 lesions), and 192 patients (208 lesions), respectively. The primary outcome at two years did not differ among the four groups (MACE: 4.4% in short, 3.3% in middle, 4.7% in long, and 4.7% in ultra-long groups, p=0.402); TVR, ST, MI, and cardiac mortality also did not differ among groups., Conclusions: Long stenting using the XIENCE stent which was guided by IVUS for diffuse, long lesions was associated with favorable clinical outcomes at two years in daily clinical practice., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Aims: The aim of the present study was to demonstrate evidence of reduced thrombin generation at the trough plasma rivaroxaban concentration., Methods: A single-centre, prospective, nonrandomized, drug-intervention, self-controlled study was conducted in 51 anticoagulation therapy-naïve patients with nonvalvular atrial fibrillation. Plasma rivaroxaban concentration was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and the anti-factor Xa chromogenic assay. Partial thrombin time (PT), protein C activity, and protein S antigen, prothrombin fragment 1 + 2 (F1 + 2), D-dimer, thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor-1 (PAI-1) and tissue factor pathway inhibitor (TFPI) levels were also measured at the trough steady state after 4 weeks of rivaroxaban treatment and compared with baseline., Results: Plasma concentrations obtained by the LC-MS/MS and anti-Xa assays were correlated (r = 0.841, P < 0.001). The mean concentration of rivaroxaban at the trough steady state was 23.6 ng ml -1 , at which F1 + 2, TAT and D-dimer had decreased from the baseline values (P < 0.0001, P = 0.029 and P < 0.005, respectively). PT was prolonged (+0.59 s, P < 0.0001). TFPI increased from baseline to the trough steady state in the first to third quartile groups (+0.79 pg ml -1 , P = 0.048). By contrast, PAI-1, protein C activity, protein S antigen and TM remained within the normal range at the trough steady state., Conclusions: Residual plasma rivaroxaban at the trough steady state may explain the antithrombin effect of rivaroxaban in patients with nonvalvular atrial fibrillation., (© 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Previous studies have demonstrated that patients with small coronary artery lesions are at increased risk for late cardiac events after percutaneous coronary intervention. It remains uncertain whether second-generation drug-eluting stents have an advantage over first-generation drug-eluting stents in patients with small vessel lesions. Our aim was to compare in the 3-year clinical impact between second-generation everolimus-eluting stents (EES) and first-generation sirolimus-eluting stents (SES) in small vessel lesions. Four-hundred forty-four patients with small vessel lesions defined as reference diameter <2.5 mm were treated with EES (237 patients, 265 lesions) or SES (207 patients, 220 lesions) and completed 3-year follow-up. We compared the major adverse clinical events (MACE) between the two groups. EES had no significant impact on the MACE rate compared with SES (4.6 vs. 7.2%, p = 0.14). No significant differences were observed in the individual components of cardiac death (1.7 vs. 1.9%, p = 0.78), myocardial infarction (1.3 vs. 3.4%, p = 0.12), and ischemia-driven target lesion revascularization (2.3 vs. 4.6%, p = 0.13) in EES and SES, respectively. Stent thrombosis, however, was significantly less in the EES group than in the SES group (0.7 vs. 3.4%, HR: 0.53, 95% CI 0.38-0.88, p < 0.05). EES implantation did not significantly impact 3-year MACE rates compared to SES implantation in small vessel lesions. A significant reduction in the overall rate of stent thrombosis was observed in recipients of EES. While the SES group showed increasing rates of late and very late thrombosis, the EES group did not. EES offers a safe and effective treatment for small vessel lesions.

A recent OCT study revealed that the lack of stent strut endothelial coverage is associated with late stent thrombosis after drug-eluting stent implantation. However, the sequential changes of stent strut endothelial coverage in the extremely early period have never been reported. Serial OCTs were performed in 35 patients with 35 EES (everolimus-eluting stent)-treated de novo lesions at 0, 2, 4, and 12 weeks after EES implantation. Serial changes in quantitative parameters of the neointima (neointimal thickness, stent strut coverage, and apposition of each strut) were analyzed. Mean neointimal thickness significantly increased from 35.9 to 51.8 and 108.2 μm at 2, 4, and 12 weeks, respectively (p < 0.001 for all), and the percentage of uncovered stent struts significantly decreased from 74.7 to 19.5% and 0.4% (p < 0.001, respectively). There was no stent malapposition at 4 weeks compared with immediate post-intervention (0 vs. 5.4 %, p = 0.031). This OCT study demonstrates that neointimal coverage of stent struts progresses to about 80 % and malapposition of stent struts completely disappears at 4 weeks after EES implantation. In addition, neointimal coverage of stent struts was almost complete within 12 weeks.

Aortic pulse wave velocity (PWV) has been accepted as the gold standard for arterial stiffness measurement. However, PWV depends on blood pressure (BP). To eliminate the BP dependency of PWV, the cardio-ankle vascular index (CAVI) was developed. This study aimed to define the relationship between CAVI and aortic atherosclerosis or structure on multidetector computed tomography (MDCT). Patients with (n = 49) or without (n = 49) coronary artery disease were studied. The lumen and vessel diameters and wall thickness were calculated from the cross-sectional area at the pulmonary bifurcation level by 64-slice MDCT. The CAVI was measured within 3 days before MDCT. Multivariate analysis showed that the vessel diameter of the ascending and descending aorta on MDCT depends on age, body surface area, and diastolic BP. The CAVI significantly correlated with the vessel diameter ( r = .453) and wall thickness ( r = .387) of the thoracic descending aorta ( P < .001, respectively). The CAVI was an independent predictor of the descending aortic wall thickness on multiple stepwise regression analysis. These data suggest that CAVI, a simple index, is useful for evaluating thoracic aortic atherosclerosis.

First-generation drug-eluting stents (DES) demonstrated delay in vascular healing and increase in incidence of late and very late stent thrombosis compared with bare-metal stents (BMS). Second-generation DES, however, have shown a reduction of late and very late stent thrombosis compared with first-generation DES. Thus, we decided to evaluate whether the second-generation everolimus-eluting stent (EES) has an advantage over BMS in Japanese patients with ST-segment elevation myocardial infarction (STEMI). This study was conducted in two centers, retrospective, non-randomized and observational design in patients with STEMI. Three-hundred eighty patients were randomly selected to receive EES (198 patients) or cobalt-chromium BMS (182 patients). The primary endpoints were cardiac death, recurrent myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), and stent thrombosis (ST). At 2 years, the rates of TLR, TVR, and recurrent MI were significantly lower in the EES group than in the BMS group (TLR 1.5 vs. 8.3 %, p < 0.05; TVR 2.5 vs. 9.4 %, p < 0.05; recurrent MI 1.0 vs. 4.1 %, p < 0.05), and the rate of ST was also significantly lower in the EES group than in the BMS group (0.5 vs. 4.3 %, p < 0.05). Thus, major adverse cardiac events defined at the composite cardiac death, MI, TLR, TVR, or ST were significantly lower in EES group than in BMS group (3.0 vs. 9.9 %, p = 0.008). The rate of cardiac death, however, did not differ between both groups. In STEMI patients, EES may be associated with improved outcomes-specifically, a significant reduction in TVR, ST, and recurrent MI compared to BMS throughout 2 years.

We investigated the molecular mechanism underlying the processing of pro-B-type natriuretic peptide (proBNP). Rat neonatal atrial and ventricular myocytes were cultured separately. We examined the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; levels of corin and furin mRNA in atrial and ventricular myocytes; the effect their knockdown on proBNP processing; plasma molecular forms of BNP from rats and humans with and without heart failure; and the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP, expressed in rat myocytes transfected with lentiviral vectors. BNP was the major molecular form secreted by atrial and ventricular myocytes. Transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes; however, transfection of corin siRNA did not reduce it. BNP was the major molecular form in rat plasma, whereas proBNP was the major form in human plasma. The relative fraction of human BNP in rat myocytes expressing human proBNP was about 60%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly. These results suggest that proBNP is processed into BNP intracellularly by furin. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the O-glycosylation and cleavage sites in humans., (Copyright © 2015 the American Physiological Society.)

The objective of this study was to investigate physicians' awareness and use of the Japanese Society of Hypertension (JSH) Guidelines for the Management of Hypertension (JSH2004 and JSH2009), and determine what changes need to be implemented in the future. A questionnaire was used to survey physicians' awareness and their use of JSH2004 and JSH2009. Physicians attending educational seminars on hypertension that were held during the months after the publication of JSH2009 (January-April 2009) were asked to participate in the survey. Of the 5795 respondents, 88% were aware of the JSH2009 publication. Furthermore, physicians were also aware of JSH2004, with about 90% using JSH2004 in their practice. A hypertension blood pressure (BP) reference value of 140/90 mm Hg was used by 55% in office BP, whereas 31% used 135/85 mm Hg for home BP. Target BP levels used by physicians were 130/80 mm Hg for patients with diabetes or kidney disease (52%) and for elderly patients with diabetes or kidney disease (45%), whereas 140/90 mm Hg was used for elderly patients with low cardiovascular disease risk (44%) and for patients with chronic-phase stroke (27%). Answers to the questionnaire varied among physicians according to sex, age, workplace and specialty. The majority of the participating Japanese physicians were familiar with both JSH2004 and JSH2009, with many following the guidelines in their practice. However, some physicians use different reference values for hypertension and target BP levels. Physicians' adherence to and use of the guidelines should be regularly examined and promoted.

Antiplatelet drugs, frequently used for cardiovascular events with thrombotic involvement, are also regarded as possible promising agents for cardiovascular primary prevention. The roles of P2Y12, an ADP receptor and the target of thienopyridine antiplatelet drugs, are not satisfactorily known in the vascular wall. We investigated the hypothesis that vascular smooth muscle cell (VSMC) P2Y12 is involved in vascular wall inflammatory changes by upregulating monocyte chemoattractant protein-1 (MCP-1) and promoting monocyte adhesion. ADP at 10(-5) M induced a 3.6 ± 0.3-fold upregulation of MCP-1 mRNA in cultured rat VSMCs, which was significantly inhibited by R-138727, the active metabolite of P2Y12 inhibitor prasugrel and siRNAs against P2Y12. ADP also induced MCP-1 protein upregulation, which was diminished by R-138727 and P2Y12 siRNAs. JNK (c-Jun NH2-terminal kinase) inhibition attenuated ADP-induced MCP-1 mRNA and protein upregulation. R-138727 and P2Y12 siRNAs inhibited ADP-induced JNK activation. The reactive oxygen species (ROS) inhibitors N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and Tempol also diminished MCP-1 upregulation and JNK activation induced by ADP. ADP induced MCP-1 promoter activation, which was inhibited by R-138727 and P2Y12 siRNAs. Nuclear factor-κB (NF-κB) consensus sites in the MCP-1 promoter region were involved in this activation. ADP-induced NF-κB pathway activation, examined by a plasmid containing multiple NF-κB sites, was diminished by P2Y12 inhibition. For cellular function analysis, stimulation of VSMC with ADP increased subsequent THP-1 monocyte adhesion. P2Y12 siRNAs and CCR2 antagonism diminished this ADP-induced monocyte adhesion. These data suggested that ADP, via the VSMC P2Y12 receptor, induces vascular inflammatory changes by upregulating MCP-1 and promoting monocyte adhesion., (Copyright © 2015 the American Physiological Society.)

Two-thirds of hypertensive patients need a combination antihypertensive therapy to achieve the target blood pressure (BP). The PARTNER (Practical combination therapy of Amlodin and angiotensin II Receptor blocker; Safety and efficacy in paTieNts with hypERtension) study is a prospective specific clinical use survey examining the efficacy and safety of 12-week treatment with amlodipine (AML) and Angiotensin II Receptor Blocker (ARB) in 5900 hypertensive patients. The current analysis was performed as to the BP control, adverse reactions, and the effects on laboratory data in patients treated with the combination of AML and irbesartan (IRB), namely the patients added AML to already taking IRB (AML add-on group, n = 1202) and the patients added IRB to AML (IRB add-on group, n = 1050). Both study groups showed distinct decreases in office BP at 4 week (p < 0.001) and the antihypertensive effects were sustained to 12 week (p < 0.001). The percentage of patients achieving BP < 140/90 mmHg was ∼70% in either group. Proteinuria and estimated glomerular filtration rate (eGFR) were significantly improved in hypertensive patients with baseline eGFR <60 ml/min/1.73 m(2). Serum uric acid was reduced either by adding AML or IRB, and the reductions were prominent in patients with serum uric acid >7 mg/dl. The incidence of adverse reactions was as few as 1.11% and there were no severe adverse reactions which hampered the continuation of combination therapy. In conclusion, combination antihypertensive therapy with AML and IRB effectively lowers BP without particular safety problems, reduces serum uric acid especially in patients with hyperuricemia and exhibits renoprotective effects in patients with chronic kidney disease.

Objective: The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, open-label, blinded endpoint trial., Methods: Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140 mmHg and/or DBP at least 90 mmHg with antihypertensive treatment, or SBP at least 160 mmHg and/or DBP at least 100 mmHg without antihypertensive treatment were randomized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. If SBP and/or DBP remained at least 140 and/or at least 90 mmHg, the other antihypertensive drug was added. The primary endpoint was a composite of fatal and nonfatal cardiovascular events. The median follow-up time was 3.3 years., Results: Blood pressure decreased similarly in both groups. The primary endpoint occurred in 116/2568 patients (4.5%) in the olmesartan plus CCB group and in 135/2573 patients (5.3%) in the olmesartan plus diuretic group [hazard ratio 0.83, 95% confidence interval (CI) 0.65-1.07, P = 0.16]. Rates of all-cause death and cardiovascular deaths were similar. Among patients aged at least 75 years, the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group (hazard ratio 0.63, 95% CI 0.38-1.02, P = 0.059, interaction P = 0.019). Fewer patients in the olmesartan plus CCB group (8.2%, 211/2568) than in the olmesartan plus diuretic group (9.8%, 253/2573; P = 0.046) experienced serious adverse events., Conclusion: Despite no significant difference in cardiovascular events, the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic.

Backgroud: Chronic kidney disease (CKD) is a staple risk factor not only for renal failure but also for cardiovascular diseases. In addition, because dyslipidemia facilitates atherosclerosis and renal dysfunction, antihyperlipidemic treatment is important to prevent cardiac and renal events in CKD patients., Methods: We compared the effects of a statin and an intestinal cholesterol transporter inhibitor in 20 dyslipidemic patients with CKD presenting with proteinuria and/or glomerular filtration rate <60 mL/min/1.73 m(2). Either 5-10 mg atorvastatin or 10 mg ezetimibe was given for 3 months each in a randomized crossover manner and the parameters of oxidative stress, inflammation and endothelial function were compared., Results: Atorvastatin lowered serum low-density lipoprotein (LDL) cholesterol more prominently than ezetimibe (103 ± 38 vs 130 ± 45 mg/dL, p < 0.001), while serum γ-glutamyl transpeptidase was higher in atorvastatin than in ezetimibe (29 ± 16 vs 25 ± 11 U/L, p = 0.013). On the other hand, serum oxidized LDL and high-sensitivity C-reactive protein were lower in the atorvastatin treatment period than in the ezetimibe treatment period (109 ± 38 vs 146 ± 67 U/L, p = 0.002; 1.02 ± 1.46 vs 1.47 ± 1.77 µg/mL, p = 0.003). Although serum adiponectin was not significantly different between the two drugs, the reactive hyperemia index, an index of endothelial function, was higher in atorvastatin than in ezetimibe (1.94 ± 0.58 vs 1.60 ± 0.44, p = 0.023)., Conclusion: It is concluded that atorvastatin is more potent than ezetimibe in improving the serum lipid profile, reducing oxidative stress, suppressing inflammation and preserving endothelial function, while ezetimibe may be advantageous in reducing the hepatic lipid load.

Background: The cardio-ankle vascular index (CAVI) is an arterial stiffness index based on the stiffness parameter β, which is essentially independent of blood pressure. The objective of this study was to determine whether CAVI correlates with the regional stiffness parameter β and pulse wave velocity (PWV) in the thoracic aorta calculated from ECG-gated multi-detector row computed tomography (MDCT)., Methods and Results: Forty-nine patients who underwent coronary MDCT for suspicious coronary artery disease were recruited. The largest and smallest vessel luminal cross-sectional areas of the thoracic aorta were measured from MDCT images to calculate PWV and stiffness parameter β of the ascending and descending aorta. CAVI was also measured by VaSera VS-1000. In univariate analysis, CAVI significantly correlated with regional stiffness parameter β and PWV, which was influenced by the inevitable part of the aging process in the ascending (r = 0.485, P < 0.001; r = 0.483, P < 0.001) and descending aortas (r = 0.304, P = 0.034; r = 0.327, P = 0.022), respectively. The regional stiffness parameter β did not correlate with systolic blood pressure (SBP), although the PWV correlated with SBP. In multivariate analysis, CAVI independently correlated with the stiffness parameter β, but not with the PWV., Conclusion: These data suggest that CAVI, which correlated with stiffness parameter β in the thoracic aorta, has a potential role in evaluating integrated arterial stiffness including that of the central aorta., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Gallstone ileus (GI) results from the passage of a stone through a cholecystoenteric fistula, subsequently causing a bowel obstruction. The ideal treatment procedure for GI remains controversial., Presentation of Case: A 63-year-old female was admitted to our hospital following persistent nausea and vomiting for 7 days. Computed tomography revealed a partially calcified 4-cm circular object in the jejunum, and the proximal intestine was dilated, with concomitant pneumobilia. Based on the preoperative diagnosis of GI, enterotomy with stone extraction by single-incision laparoscopic surgery (SILS) was performed. The patient's postoperative course was uneventful, and the cholecystoduodenal fistula closed spontaneously 4 months after the surgery., Discussion: Recent studies have reported that enterotomy with stone extraction alone is associated with better outcomes than with more invasive techniques. This case also suggests that enterotomy with stone extraction alone and careful postoperative follow-up is feasible for the management of GI. Although the use of laparoscopy in the management of GI has been described previously, laparoscopic surgery has not been widely performed, and SILS is not generally performed. When only this less demanding procedure is required, laparoscopic surgery, including SILS, can be a viable option., Conclusion: SILS can be an alternative surgical procedure for the management of GI., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB)., Methods: We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine., Results: SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication., Conclusion: Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension.

The renin-angiotensin-aldosterone system is not necessarily suppressed in end-stage renal disease patients undergoing dialysis. Of all the inhibitors of this system, the clinical efficacy of the renin inhibitor, aliskiren, has not been well demonstrated in dialysis patients. We evaluated the antihypertensive effect of aliskiren, administered as a single daily dose of 150 mg for 24 weeks, in 23 chronic hemodialysis patients (age 65 ± 12 years, 15 men and eight women) with blood pressure ≥140/90 mm Hg, and assessed the factors relating to blood pressure reduction. At 4 weeks, the average systolic blood pressure before the dialysis session was insignificantly reduced from 163 ± 10 mm Hg to 160 ± 15 mm Hg, while it was significantly lowered at 12 (154 ± 13 mm Hg) and 24 weeks (155 ± 10 mm Hg), although the pulse rate was not significantly altered. Serum K increased at 24 weeks from 4.9 ± 0.6 mEq/L to 5.2 ± 0.8 mEq/L. Only 10 out of 23 patients showed systolic blood pressure reduction by ≥10 mm Hg. Naturally, plasma renin immunoreactivity increased, while plasma renin activity, along with angiotensin II and aldosterone levels decreased. Basal levels of the components of the renin-angiotensin-aldosterone system were not significantly different in patients showing systolic blood pressure reduction by ≥10 mm Hg (n = 10) vs. those with <10 mm Hg changes (n = 13). The reduction in systolic blood pressure in all 23 patients taken as a whole correlated with changes in plasma renin activity (r = -0.432, P < 0.05) and angiotensin II (r = 0.467, P < 0.05). In chronic hemodialysis patients, aliskiren modestly lowers blood pressure over the long term, although the antihypertensive effect seems dependent on the changes, but not on the basal levels of plasma renin activity and angiotensin II., (© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.)

Background: SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP fatty) rats create a new animal model of metabolic syndrome. However, the renoprotective effect of telmisartan therapy and its underlying mechanisms in SHRSP fatty rats remain unknown. We evaluate the effects of long-term telmisartan therapy on renal dysfunction, podocyte injury, inflammation, and transforming growth factor-β1 (TGF-β1)/Smad, epithelial-mesenchymal transition (EMT), mitogen-activated protein kinase (MAPK), Rho-kinase, and cell-cycle progression pathway in the renal cortex of SHRSP fatty rats., Methods: Seven-week-old male SHRSP fatty rats were treated with vehicle, telmisartan, and hydralazine for 8 weeks. Age-matched male Wistar-Kyoto/Izumo rats served as a control group., Results: Vehicle-treated SHRSP fatty rats developed proteinuria and renal dysfunction, which in the telmisartan group was less than the vehicle and hydralazine group without changing blood pressure. Glomerulosclerosis and interstitial fibrosis were impaired in SHRSP fatty rats, and the renal damage in the telmisartan group was less than the vehicle and hydralazine groups. Decreased expression of nephrin and podocin and increased desmin-positive area in SHRSP fatty rats were restored by telmisartan but not hydralazine. TGF-β1/Smad, EMT marker, MAPK, Rho-kinase, and cell-cycle progression pathways were upregulated in SHRSP fatty rats, and these increased proteins in the telmisartan group were less than the vehicle and hydralazine group. Telmisartan administration resulted in significant suppression in tumor necrosis factor-α expression and nuclear factor-κB phosphorylation., Conclusion: Long-term telmisartan therapy may improve renal dysfunction, glomerulosclerosis, podocyte injury, and inflammation associated with EMT, TGF-β/Smad, MAPK, Rho-kinase pathway in SHRSP fatty rats. Thus, telmisartan may have significant therapeutic potential for metabolic syndrome.

Because systemic inflammation after coronary intervention places patients at increased risk of subsequent cardiac events, we aimed to compare clinical outcomes and chronic serum inflammation markers of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) in hemodialysis patients. Paclitaxel-eluting stents and SES were implanted in 36 patients with 46 lesions, and 32 patients with 40 lesions, respectively. In addition to 1-year major adverse cardiac event (MACE) rates, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), neopterin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were also compared before and 9 months after percutaneous coronary intervention (PCI). The incidence of MACE was significantly lower in the PES group than in the SES group (11.1 vs. 25.0 %, respectively, P = 0.042), mainly due to the reduction of target lesion revascularization in the PES group (6.5 vs. 17.5 %, P = 0.003). The logarithm of hs-CRP as well as IL-6 decreased significantly 9 months post-PCI compared with pre-PCI in the PES group (hs-CRP: 3.65 ± 0.35 vs. 2.91 ± 0.48, P = 0.007; IL-6: 6.73 ± 3.66 vs. 2.61 ± 2.29, P = 0.017) but not in the SES group (hs-CRP: 3.33 ± 0.29 vs. 3.42 ± 0.27, P not significant; IL-6: 6.08 ± 4.97 vs. 5.66 ± 4.29, P not significant). However, neopterin, ICAM-1, and VCAM-1 remained unchanged both pre-PCI and 9 months post-PCI in both groups. Moreover, MACE were less frequent in patients with decreased hs-CRP levels 9 months post-PCI compared with patients without decreased hs-CRP levels (P = 0.002) in all patients. Paclitaxel-eluting stents appear to be more effective than SES in reducing MACE rates, especially target lesion revascularization, and may be able to stabilize local inflammatory changes of target lesions specifically in patients on hemodialysis. Thus PES, which inhibit in-stent restenosis and cardiac events in hemodialysis patients, may play an important role in suppression of chronic inflammatory response in target lesions as compared with SES. Chronic continuous inflammation plays an important role after implantation of both types of stent with regard to in-stent restenosis in patients on hemodialysis.

Tolvaptan is a highly selective and orally effective arginine vasopressin V2 receptor antagonist, and is potentially useful for the treatment of heart failure (HF) patients. However, the renoprotective effect of long-term tolvaptan therapy and its underlying mechanisms remain unknown. We evaluated the effects of chronic treatment with tolvaptan on renal dysfunction, podocyte injury, inflammation, oxidative stress, Rho-kinase, epithelial-mesenchymal transition (EMT), and the extracellular signal-regulated protein kinase (ERK1/2) pathway in the renal cortex of Dahl salt-sensitive hypertensive (DS) rats with end-stage severe HF. DS and Dahl salt-resistant rats were fed a high-salt diet at 6 weeks of age. DS rats were treated with vehicle and tolvaptan (0.05% concentration in diet) from the age of 11 to 18 weeks. Vehicle-treated DS rats developed proteinuria, renal dysfunction, glomerulosclerosis, and interstitial fibrosis, which were ameliorated by tolvaptan without changing blood pressure. Decreased expression of nephrin and podocin and increased desmin-positive area in failing rats were restored by tolvaptan. Upregulation of NAD(P)H oxidase p22(phox), p47(phox), and gp91(phox), EMT markers such as transforming growth factor-β1, vimentin, and fibronectin expression, and Rho-kinase and ERK1/2 phosphorylation in DS rats were significantly suppressed by tolvaptan. Tolvaptan administration resulted in significant inhibition of tumor necrosis factor-α and monocyte chemoattractant protein-1 expression, and nuclear factor-κB phosphorylation. We concluded that long-term tolvaptan therapy may improve renal dysfunction, glomerulosclerosis, podocyte injury, and inflammation associated with oxidative stress, as well as EMT, ERK, and the Rho-kinase pathway in the failing heart of DS rats. Thus, tolvaptan may be a therapeutic strategy for end-stage severe HF.

Objective: Pro-brain natriuretic peptide (proBNP)-108 and N-terminal proBNP-76 (NT-BNP) contain seven sites for O-linked oligosaccharide attachment. Currently, levels of glycosylated NT-BNP are probably underestimated because it is not recognised by one antibody in the sandwich assay system. The pathophysiological significance of cardiac and plasma levels of non-glycosylated (nonglyNT-BNP) and glycosylated NT-BNP (glyNT-BNP) in heart failure (HF) and chronic renal failure (CRF) was investigated., Methods: Plasma samples from 186 patients with HF and 76 patients with CRF on haemodialysis were studied, together with 11 atrial tissue samples. To measure nonglyNT-BNP and glyNT-BNP, samples were incubated with or without deglycosylating enzymes and NT-BNP was measured using Roche Elecsys proBNP I. The percentage glyNT-BNP was calculated as glyNT-BNP/(glyNT-BNP + nonglyNT-BNP)., Results: In HF, plasma BNP, nonglyNT-BNP and glyNT-BNP levels all increased with increasing disease severity (New York Heart Association class; p<0.0001), though the molar ratio remained constant (molar ratio, BNP:nonglyNT-BNP:glyNT-BNP = 1:2.4:9.6). Before haemodialysis for CRF, plasma BNP and nonglyNT-BNP were somewhat elevated, and glyNT-BNP was markedly increased (molar ratio, BNP:nonglyNT-BNP:glyNT-BNP = 1:8.5:82). After haemodialysis, plasma BNP, nonglyNT-BNP, atrial natriuretic protein and cGMP all declined (p<0.0001), but glyNT-BNP was unchanged. Notably, the percentage of glyNT-BNP was elevated before haemodialysis, and was further increased after haemodialysis (p<0.0001). Atrial tissue levels of BNP, nonglyNT-BNP and glyNT-BNP were similar., Conclusion: THE findings suggest that most endogenous plasma NT-BNP is glycosylated and therefore undetectable with the current assay system, and that the relative glycosylation level is increased by haemodialysis.

Background: Apelin and its cognate G protein-coupled receptor, APJ, constitute a signaling pathway with a positive inotropic effect on cardiac function. Recently, we and other investigators demonstrated that a reduction in myocardial apelin/APJ expression might play a critical role in experimental models of end-stage heart failure (HF). Therefore, we evaluated whether exogenous apelin infusion restores apelin/APJ expression and improves cardiac function in the failing heart of Dahl salt-sensitive hypertensive (DS) rats., Methods and Results: High salt-loaded DS rats were treated with vehicle and pyroglutamylated apelin-13 (Pyr-AP13; 200µg·kg(-1)·day(-1), IP) from the age of 11 to 18 weeks. Decreased end-systolic elastance and percent fractional shortening in failing rats was significantly ameliorated by Pyr-AP13. Pyr-AP13 effectively inhibited vascular lesion formation and suppressed expression of inflammation factors such as tumor necrosis factor-α and interleukin-1β protein. Downregulation of apelin and APJ expression, and phosphorylation of endothelial nitric oxide synthase at Ser(1177) and Akt at Ser(473) in failing rats was significantly increased by Pyr-AP13. Upregulation of NAD(P)H oxidase p22(phox), p47(phox), and gp91(phox) in DS rats was significantly suppressed by Pyr-AP13., Conclusions: Exogenous apelin-13 may ameliorate cardiac dysfunction and remodeling and restore apelin/APJ expression in DS rats with end-stage HF. Thus, apelin-13 may have significant therapeutic potential for end-stage HF.

In this study, the effect of nifedipine controlled-release tablets at a dose of 80 mg/day (NCR80) on blood pressure (BP) and safety was investigated. In essential hypertension (n = 50, >140/90 mm Hg) despite a combined therapy with antihypertensive agents, NCR80 was administered instead of the previous antihypertensive agents and changes in BP and pulse rate (PR), side effects, and changes in laboratory test values were examined for 24 months. Thirty-three patients switched to NCR80 as the initial dose from the previous antihypertensive agents (Initial), while 17 patients started treatment at NCR40 and increased to NCR80 after 1-3 months (Up-titration). In the Initial group, BP decreased significantly and this significant reduction continued for 24 months, but not in the case of PR. In the Up-titration group, BP decreased significantly during the treatment with NCR40, and further reduced in 1-2 month(s) after NCR80. This significant reduction continued for 12 months, but not in the case of PR. The mean change in BP after increasing NCR40 to NCR80 was -16/-6 mm Hg at 6 months. When patients who received NCR80 were stratified into three grades according to the baseline systolic blood pressure level (SBP) (≥180, 160-179, and 140-159 mm Hg), the mean change in BP at 1 month was -55, -27, and -16 mm Hg, respectively. None of the 50 patients treated with NCR80 experienced any side effects and no abnormal change was observed in their laboratory test values. These findings suggested that NCR80 demonstrated the ability to control BP appropriately depending on the severity with favorable safety.

Aim: Rho-kinase plays a critical role in various cellular functions. p38 mitogen-activated protein kinase (p38 MAPK) plays a central role in the inflammatory cytokine response to immune challenge. We evaluated the effects of a combination of fasudil, a Rho-kinase inhibitor, and FR167653, a p38 MAPK inhibitor, on cardiovascular remodeling, inflammation, and oxidative stress in Dahl salt-sensitive hypertensive (DS) rats., Methods: DS and Dahl salt-resistant (DR) rats were fed a high-salt diet at 6 weeks of age. Vehicle, fasudil (100 mg/kg per day), FR167653 (2 mg/kg per day), and a combination of fasudil and FR167653 were administered to 6-week-old DS rats for 5 weeks., Results: At the age of 11 weeks, in the left ventricle, DS rats were characterized by increased myocardial fibrosis, phosphorylation of p38 MAPK, and myosin phosphatase targeting subunit (MYPT-1), and NAD(P)H oxidase p22(phox), p47(phox), gp91(phox), tumor necrosis factor-α and interleukin-1β expression compared with DR rats. Fasudil improved cardiovascular remodeling, inflammation, NAD(P)H oxidase subunits, and phosphorylation of p38 MAPK and MYPT-1. FR167653 also similarly ameliorated these indices but not MYPT-1 phosphorylation. Compared with either agent alone, a combination of fasudil and FR167653 was more effective for the improvement of myocardial damage, inflammation and oxidative stress., Conclusion: These findings suggest that the Rho-kinase and p38 MAPK pathways may play a pivotal role in ventricular hypertrophy; thus, we obtained the first evidence that a combination of Rho-kinase inhibitor and p38 MAPK inhibitor may provide a potential therapeutic target in hypertension with cardiovascular remodeling.

To address whether hospital antimicrobial use influences surgical site infection (SSI), we investigated factors including antimicrobial homogeneity index (AHI), an indicator of prescription diversity, with a retrospective study during 120 months for patients undergoing lung, breast, and general surgery (n = 4,510). We analyzed the odds ratios of background factors for SSI and the correlation between AHI and drug susceptibility in isolates of SSI. A total of 243 cases of SSI (5.4%) occurred. Factors that significantly contributed for SSI were operative time [odds ratio (OR), 1.78; 95% confidence interval (CI), 1.33-2.39; P < 0.001], American Society of Anesthesiologists' score (OR, 1.68, 95% CI, 1.23-2.28; P < 0.001), endoscopic use (OR, 0.10, 95% CI, 0.04-0.24; P < 0.001), lung and breast surgery versus general surgery (OR, 0.12, 95% CI, 0.06-0.22; P < 0.001), increased AHI (OR, 0.72, 95% CI, 0.55-0.95; P = 0.020), and older age (OR, 2.08, 95% CI, 1.39-3.11; P < 0.001). AHI showed a positive correlation coefficient (CC, P < 0.05) with susceptibility to ampicillin (CC = +0.327), cefotaxime (CC = +0.142), imipenem/cilastatin (CC = +0.101), and sulbactam/cefoperazone (CC = +0.145). AHI, which has been described to help prevent drug resistance, was associated with increased susceptibility in microbes of SSI. This finding in part may explain that increase in AHI reduced SSI.

Hypertension facilitates development and progression of cardiac diseases such as left ventricular hypertrophy (LVH), coronary artery disease (CAD), arrhythmia and heart failure. Strict blood pressure control over 24 hours is essential for the primary and secondary prevention of these cardiac diseases. Inhibitors of renin-angiotensin system(RASI) such as ACE inhibitors and angiotensin II receptor blockers(ARB) and long-acting calcium channel blockers(CCB) are effective in improving LVH. CCB and beta-blockers are preferentially chosen for CAD. RASI is expected to reduce the incidence of atrial fibrillation. RASI, beta-blockers and aldosterone blockers have been shown to improve the prognosis of heart failure patients. In addition, diuretics and long-acting CCB are used for the adequate control of body fluid volume and blood pressure.

Cardio-ankle vascular index (CAVI) using the volume plethysmographic method is a noninvasive atherosclerotic indicator which is not influenced by blood pressure. Coronary intravascular ultrasound (IVUS) is a reliable technique to measure progression of atherosclerosis. The association between CAVI and IVUS has not been reported. The aim of this study was to evaluate the association between CAVI and the plaque burden measured by IVUS in the left main coronary artery (LMCA) in patients with coronary heart disease and normal LMCA. Cardio-ankle vascular index was significantly correlated with percentage plaque area (r = .649, P < .0001) measured by IVUS in the most diseased segment of LMCA. Cardio-ankle vascular index remained significant among cardiovascular disease risk factors included in the multiple regression analysis predicting percentage plaque area. Cardio-ankle vascular index was a good atherosclerotic indicator and associated with the plaque burden in nonculprit and angiographically normal LMCA.

Esophageal rupture is a rare entity. Delay in the diagnosis and treatment may threaten the patient's life. The decision for surgical or nonsurgical treatment, however, remains controversial because advocates of both treatments have reported comparable results. To quantify the decision making, we suggest the systemic inflammatory response syndrome (SIRS) score for triage of an esophageal rupture. Using this criterion for 12 patients resulted in the survival of all of them. Therefore, we advocate use of the SIRS score for triage of an esophageal rupture.

Objective: Urinary liver-type fatty acid-binding protein (L-FABP) is a promising indicator of tubular but not glomerular damage. The aim of this study was to evaluate the clinical usefulness of urinary L-FABP as a prognostic biomarker in impaired diabetic nephropathy in type 2 diabetes., Research Design and Methods: This investigation involved a cross-sectional and longitudinal analysis of the relationship between urinary L-FABP levels and progressive nephropathy. Urinary L-FABP was measured with enzyme-linked immunosorbent assay. In the cross-sectional analysis, the association of urinary L-FABP, with the severity of diabetic nephropathy, was investigated in 140 patients with type 2 diabetes and in 412 healthy control subjects. Of the patients in the former study, 104 have been followed for 4 years. The progression of diabetic nephropathy was defined as progressive albuminuria, end-stage renal disease, or induction of hemodialysis., Results: Urinary L-FABP levels were progressively increased in subjects with normo-, micro-, or macroalbuminuria and further increased in patients with end-stage renal disease. In the longitudinal analysis, high urinary L-FABP levels were associated with the increase in albuminuria, progression to end-stage renal disease, or induction of hemodialysis. This was particularly demonstrated in the subgroup of patients without renal dysfunction (n = 59), where high urinary L-FABP levels were associated with the progression of diabetic nephropathy., Conclusions: Urinary L-FABP accurately reflected the severity of diabetic nephropathy in type 2 diabetes, and its level was high in the patients with normoalbuminuria. Moreover, higher urinary L-FABP was a risk factor for progression of diabetic nephropathy.

We compared treatment with an angiotensin II receptor antagonist (ARB) and a calcium channel blocker (CCB) combination and a fixed-dose ARB and thiazide diuretic in 18 chronic kidney disease (CKD) patients. A randomized crossover study was performed using a fixed-dose combination of losartan-hydrochlorothiazide or losartan combined with controlled-release nifedipine. Both systolic blood pressure (SBP) and diastolic blood pressures (DBPs) were lower during the nifedipine period than during the diuretic period. No significant difference was observed in urinary albumin excretion, but the estimated glomerular filtration rate was higher in the nifedipine than in the diuretic period. Serum uric acid and low-density lipoprotein cholesterol were higher in the diuretic than in the nifedipine period. A significantly low cardio-ankle vascular index, an index of arterial wall stiffness, was observed in the nifedipine period. A combination of ARB and a controlled-release nifedipine at 20-40 mg used showed a superior antihypertensive effect in CKD patients compared to a fixed-dose combination of losartan 50 mg-hydrochlorothiazide 12.5 mg in terms of blood control. The former combination is considered advantageous for maintaining renal function and artery wall elasticity without influencing uric acid or lipid metabolism.

Background: Growing evidence suggests that the epicardial adipose tissue may have local interactions with coronary arteries. In addition, vasoactive peptides such as adrenomedullin and natriuretic peptide has an interaction with adipose tissue. In this study, we investigated the relationship between adipokines, adipocytokines, and vasoactive peptides expressed in epicardial adipose tissue and subcutaneous adipose tissue in patients with and without coronary artery disease (CAD)., Methods: We studied 20 patients with CAD and 14 patients without CAD. We obtained blood samples and epicardial and subcutaneous adipose tissue at open-heart surgery. We measured serum cytokine levels and used real-time polymerase chain reaction (PCR) to measure mRNA levels of various molecules in epicardial and subcutaneous tissue and investigated the relation between mRNA levels and clinical parameters., Results: The mRNA levels of IL-6, IL-1beta, MCP-1, and TNF-alpha were significantly higher in epicardial adipose tissue than in subcutaneous adipose tissue. Interestingly, the mRNA levels of IL-6, IL-1beta, MCP-1, natriuretic peptide receptor-C (NPR-C), adrenomedullin, and leptin in epicardial adipose tissue were higher in patients with CAD than those without CAD. In contrast, mRNA levels of adiponectin, PPAR-gamma, and NPR-A were similar in the two groups. In subcutaneous tissue, mRNA expressions of IL-6, IL-1beta, MCP-1, NPR-C, adrenomedullin, and leptin were modestly higher in patients with CAD than in those without CAD. There were no differences in plasma cytokine levels between the two groups., Conclusion: The mRNA levels of inflammatory cytokines, adipokines, neurohumoral factors and their receptors appear to be increased in epicardial adipose tissue independent of plasma levels of these molecules. Further studies are necessary to elucidate the pathophysiological role of these molecules in CAD., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: We have demonstrated that angiotensin II receptor blocker (ARB) improved endothelial progenitor cells (EPCs) dysfunction through the antioxidative mechanism. Therefore, we investigate whether the selective mineralocorticoid receptor (MR) antagonist eplerenone improves EPCs function in rat hindlimb ischemia., Methods: Unilateral hindlimb ischemia was surgically induced in Wistar rats. After induced ischemia, rats received eplerenone (30 mg/kg/day), valsartan (3 mg/kg/day), or vehicle for 3 weeks. Peripheral blood mononuclear cells were isolated, subjected to flow cytometric analysis to determine the number of circulating EPCs, cultured to assay EPC colony formation, and subjected to a migration chamber assay to evaluate EPCs migration., Results: Blood perfusion by laser Doppler image was significantly higher in eplerenone than in vehicle. Capillary density by isolectin B4 stained of ischemic muscle was significantly increased in eplerenone compared with vehicle. Eplerenone significantly increased the number, colony formation, and migration of EPCs. Levels of endothelial nitric oxide synthase (eNOS) and angiogenic factor such as vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2) protein expression by western blot were significantly higher in eplerenone than in vehicle. Eplerenone significantly decreased the NAD(P)H oxidase p22(phox), p47(phox), gp91(phox) and MR expression and expression of aldosterone effector kinase serum and glucocorticoid-induced protein kinase 1 (Sgk1). These effects of eplerenone are similar extent as valsartan., Conclusions: This study showed that eplerenone improves the proliferation and function of EPCs in rat hindlimb ischemia, suggesting that eplerenone may provide a novel and effective therapeutic strategy for the repair of cardiovascular diseases.

We and others recently reported that long-term Rho-kinase inhibition has renoprotective effects. This study was designed to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (imidapril), a Rho-kinase inhibitor (fasudil) and a combination of them both on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved. Imidapril (50 mg l(-1)), fasudil (1 g l(-1)) or a combination of them both was given in drinking water to mice, and their effects were compared on renal interstitial fibrosis induced by UUO. We assessed histological findings, monocyte/macrophage infiltration, myofibroblast differentiation, oxidative stress and the expression of various mRNA in the kidney by UUO. Eleven days after UUO, wild-type kidney was characterized by increased fibrotic area, dihydroethidium (DHE)-positive area, alpha-smooth muscle actin (SMA)-positive area, F4/80-positive area and the increased expression of various mRNA. Fasudil and imidapril similarly improved fibrotic area (-23%, -15%), DHE-positive area (-13%, -11%), alpha-SMA-positive area (-22%, -15%), F4/80-positive area (-42%, -34%) and the expression of various mRNA, most of which were significant (P<0.05). The combination of imidapril and fasudil further improved fibrotic area (-52%), DHE-positive area (-26%), alpha-SMA-positive area (-33%), F4/80-positive area (-62%) and the expression of various mRNA (all P<0.05 vs. monotherapy). Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor was more effective for the prevention of renal interstitial fibrosis because of the inhibition of transforming growth factor-beta/collagen, monocyte/macrophage infiltration, myofibroblast differentiation, inflammation and the oxidative stress pathway.

Components of the renin-angiotensin-aldosterone system such as angiotensin II and aldosterone are believed to contribute to the development and progression of cardiovascular tissue and organ injuries. We compared the effects of two calcium channel blockers, efonidipine and amlodipine, on the renin-angiotensin-aldosterone system in patients with end-stage renal diseases on maintenance hemodialysis. Twenty hypertensive patients on chronic hemodialysis were given efonidipine 20-60 mg twice daily and amlodipine 2.5-7.5 mg once daily for 12 weeks each in a random crossover manner. The average blood pressure was comparable between the efonidipine and amlodipine periods (151 + or - 15/77 + or - 8 versus 153 + or - 15/76 + or - 8 mmHg). The pulse rate did not change significantly during the administration periods. Although the plasma renin activity and plasma angiotensin II were not significantly different between the efonidipine and amlodipine periods, plasma aldosterone was significantly lower in the efonidipine period than in the amlodipine period (123 + or - 118 versus 146 + or - 150 pg/mL, P = 0.027). The findings suggest that efonidipine reduces plasma aldosterone levels in patients on maintenance hemodialysis, and this seems to be an additional benefit to the cardiovascular protection by antihypertensive therapy with efonidipine in patients with end-stage renal disease.

Background: Nicorandil has cardioprotective effects in the ischemic myocardium, mimicking ischemic preconditioning, and is thus expected to improve the prognosis of ischemic heart disease (IHD). As part of the Japanese Coronary Artery Disease (JCAD) Study, a multicenter collaborative prospective observational study of a large cohort of coronary artery disease patients, the effect of nicorandil on outcome was examined., Methods and Results: In total, 2,558 patients with nicorandil treatment and controls subjected to propensity score matching were eligible among 13,812 patients registered in the JCAD study. The mean follow-up interval was 2.7 years. The primary endpoint, death from all causes, was significantly lower, by 35% (hazard ratio 0.65, P=0.0008), in the nicorandil group than in the control group. There were also significant reductions in secondary endpoints, including cardiac death (56%), fatal myocardial infarction (56%), cerebral or vascular death (71%), and congestive heart failure (33%) in the nicorandil group, with no excess of deaths from other non-cardiovascular causes. Treatment with nicorandil reduced the number of deaths from all causes to a similar extent with or without treatment with sulfonylureas., Conclusions: The reduction in cardiovascular death with nicorandil was large in patients with IHD, which has important implications for treatment.

Objective: Recent studies have shown that plasma levels of brain natriuretic peptide (BNP)-32 and proBNP-108 are increased in heart failure (HF) and that the BNP-32 assay kit in current clinical use cross-reacts with proBNP-108. We investigated why proBNP is increased without processing in HF was investigated., Design, Setting and Patients: Plasma BNP-32 and proBNP-108 in normal individuals (n=10) and in patients with atrial fibrillation (AF) (n=18) and HF (n=132) was measured. BNP-32 and proBNP-108 in ventricular and atrial tissue and in pericardial fluid using a specific fluorescent enzyme immunoassay following Sep-Pak C18 (Waters, Milford, Massachusetts, USA) cartridge extraction and gel filtration was also measured., Main Outcome Measures: Levels of both BNP-32 and proBNP-108 were higher in HF than in control or AF (both p<0.01), and the levels of these peptides significantly correlated (r=0.94, p<0.001). The proBNP-108/total BNP (BNP-32+proBNP-108) ratio was widely distributed and lower in HF (0.33 (0.17)) than in control (0.41 (0.06), p<0.05) and AF (0.45 (0.04), p<0.002). The proBNP-108/total BNP ratio was higher in HF with ventricular than in HF with atrial overload (0.45 (0.10) vs 0.20 (0.11), p<0.001). Consistent with this finding, the major molecular form were proBNP-108 and BNP-32 in ventricular (n=6, 0.67 (0.04)) and atrial (n=7, 0.76 (0.05), p<0.0001) tissues, respectively. ProBNP-108 was also the major molecular form of BNP in pericardial fluid (n=8, 0.82 (0.05)). The proBNP-108/total BNP ratio increased and decreased with HF deterioration and improvement, respectively., Conclusion: These results suggest that BNP-32 and proBNP-108 is increased in HF and that the proBNP/total BNP ratio increases in association with pathophysiological conditions such as ventricular overload.