永井 良三

During fasting, animals maintain their energy balance by shifting their energy source from carbohydrates to triglycerides. However, the trigger for this switch has not yet been entirely elucidated. Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve-mediated lipolysis in adipose tissue. Hepatic glycogen pre-loading by the adenoviral overexpression of glycogen synthase or the transcription factor TFE3 abolished this liver-brain-adipose axis activation. Moreover, the blockade of glycogenolysis [corrected] through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry. These results demonstrate that liver glycogen shortage activates a liver-brain-adipose neural axis that has an important role in switching the fuel source from glycogen to triglycerides under prolonged fasting conditions.

Background: Endothelial dysfunction and autonomic nervous system imbalance are both risk markers of atherosclerotic vascular damage. The relationship between these 2 factors, however, has not been clarified concisely. Methods and Results: Flow-mediated dilation (FMD) was measured in 47 patients with ischemic heart disease (IHD mean age, 68.1±7.1 years) using an ultrasound semi-automatic measuring system (UNEXEF18G), and autonomic nervous system activity was evaluated by simultaneous measurements of heart rate variability. FMD was significantly correlated with standard deviation of normal-to-normal beats (r=0.33, P=0.022) and the power ratio of low-frequency power to high-frequency power (LF/HF r=-0.38, P=0.0087). Furthermore, multiple regression analysis indicated that LF/HF was the most important predictor of the magnitude of FMD. This interaction was severely blunted by β-blockers and the presence of diabetes. Moreover, standardized FMD according to autonomic nervous system activity was a better predictor of future cardiovascular events than FMD. Subjects with cardiovascular events had a significantly smaller corrected FMD (event (+), 3.62±0.41 event (-), 5.10±2.35 P=0.001), and the higher corrected FMD was associated with longer event-free survival. Conclusions: Autonomic nervous system activity is an important regulatory factor of FMD in subjects with IHD. Assessment of this interaction can help provide more accurate risk stratification of subjects with IHD.

BACKGROUND: Differences in regulating factors and the clinical implications of body temperature variability (BTV) between subjects with and without diabetes have not been clarified to date. METHODS AND RESULTS: In 66 subjects with ischemic heart disease (33 with diabetes and 33 without diabetes), BTV, the difference between the highest and lowest temperature measurements, and body temperature standard deviation (BT SD) were measured from axillary body temperature (ABT) records of 3 consecutive days and followed for 16.4±8.4 months. In subjects without diabetes BTV and BT SD were closely associated with endothelial function as evaluated on flow-mediated dilation (BTV, R=0.33, P=0.026; BT SD, R=0.41, P=0.029), whereas there was a poor association in subjects with diabetes. In the absence of an interrelationship between vascular function and thermoregulation, the contribution of inflammation to BTV was increased in subjects with diabetes (BTV, 0.59±0.21°C for C-reactive protein [CRP] <0.08 mg/dl vs. 0.79±0.28°C for CRP >0.08 mg/dl, P=0.014). Event-free survival analysis showed that in subjects with diabetes higher BT SD was associated with shorter event-free survival (log-rank P=0.012), but this relationship was not found in subjects without diabetes. CONCLUSIONS: In subjects with diabetes, the interrelationship between thermoregulation and vascular function was disrupted and the effect of inflammation on thermoregulation was enhanced, so that BTV had a sufficient predictive value for cardiovascular events in diabetic subjects.

There have been few reports concerning the trends in antidiabetic drug use in Japan. In 2009, a dipeptidyl peptidase- 4 inhibitor (DPP4I), an antidiabetic with a new mechanism of action, was made available. This study was conducted to analyze the antidiabetic prescription trends in Japan in recent years and the influence of DPP4Is on those trends. We used monthly claims data obtained from a database company. Data from patients 20 years of age or older and who were prescribed antidiabetics were extracted and analyzed. A total of 18,457 patients were prescribed antidiabetics (mean age, 53.6 ± 11.0). The sulfonylurea prescription rate decreased while that of biguanides increased. After the introduction of DPP4Is, use of these agents rapidly increased and the rate further increased one year after DPP4I introduction. DPP4Is also became the most prescribed antidiabetics for those prescribed antidiabetics for the first time. The decrease in the use of sulfonylureas and the increase in the use of biguanides are in accordance with trends observed in the United States and Europe, and probably reflect Japanese physicians' awareness of cumulating evidence gained from studies such as the UK Prospective Diabetes Study (UKPDS). The rapid increase in the DPP4I prescription rate might be the result of several factors including their safety profiles, which were highlighted in clinical studies published just prior to the drugs becoming available. However, there is little data regarding the efficacy of DPP4Is in reducing diabetes related complications, which should be determined in future studies.

Pressure overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor (NF)-κB is a key factor in the progression of cardiac hypertrophy, its pathophysiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-κB activation improves pressure overload-induced cardiac dysfunction. To assess the effect of inhibition on NF-κB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IκB via inhibition of IκB kinase-β. IMD-1041 (100 mg·kg(-1)·day(-1)) or vehicle was administered orally into mice once a day, and mice were euthanized on day 42 after TAC. TAC resulted in left ventricular wall thickening, cardiac dysfunction, and increases of heart and lung weight, whereas IMD-1041 significantly suppressed the development of cardiac hypertropy 6 wk after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle-treated group, whereas IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65-positive cells and nuclear translocation of p65 induced by TAC compared with vehicle. Matrix metalloproteinase-2 activity increased in the vehicle + TAC-treated group; however, it was suppressed in the IMD-1041 + TAC-treated group. IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease in the percentage of fractional shortening and cardiac fibrosis without an antihypertrophic effect. In conclusion, IMD-1041 may be useful for preventing pressure overload-induced cardiac dysfunction and the transition of cardiac hypertrophy to contraction failure via suppression of NF-κB activation.

For the time being, in Japan, two recently approved implantable ventricular assist devices (VADs) are indicated only when a patient has been listed for heart transplantation or approved to be eligible for heart transplantation by in-hospital committee. The reversibility of end-organ dysfunction must be expected before VAD implantation, but it is often hard to prove during worsening clinical status. We report two patients whose end-organ dysfunction had been eventually demonstrated to be reversible by invasive procedures such as transluminal liver biopsy or transient insertion of intra-aortic balloon pumping.

Tamibarotene-loaded biodegradable matrices with antithrombogenic and drug-releasing properties were prepared in a crosslinking reaction between amino groups of alkali-treated collagen (AlCol) and active ester groups of trisuccinimidyl citrate. The resulting matrices were characterized by their residual amino group concentrations, swelling ratios and thermal, antithrombogenic and drug-releasing properties. It was clarified that the addition of tamibarotene does not inhibit matrix formation. After immersion in water, the swelling ratio of a matrix became lower than that prior to immersion. Thermal analysis indicated that AlCol interacted with tamibarotene. The addition of tamibarotene to the matrix did not influence the antithrombogenic property of the resulting matrix. A matrix with a high crosslinking density had a prolonged tamibarotene elution time. These results demonstrate that tamibarotene-loaded matrices have great potential as a coating material for drug-eluting stents.

SUS316L stainless steel and cobalt-chromium and platinum-chromium alloys are widely used platforms for coronary stents. These alloys also contain nickel (Ni), which reportedly induces allergic reactions in some subjects and is known to have various cellular effects. The effects of Ni on neointima formation after stent implantation remain unknown, however. We developed coronary stents made of Ni-free high-nitrogen austenitic stainless steel prepared using a N2-gas pressurized electroslag remelting (P-ESR) process. Neointima formation and inflammatory responses following stent implantation in porcine coronary arteries were then compared between the Ni-free and SUS316L stainless steel stents. We found significantly less neointima formation and inflammation in arteries implanted with Ni-free stents, as compared to SUS316L stents. Notably, Ni2+ was eluted into the medium from SUS316L but not from Ni-free stainless steel. Mechanistically, Ni2+ increased levels of hypoxia inducible factor protein-1α (HIF-1α) and its target genes in cultured smooth muscle cells. HIF-1α and their target gene levels were also increased in the vascular wall at SUS316L stent sites but not at Ni-free stent sites. The Ni-free stainless steel coronary stent reduces neointima formation, in part by avoiding activation of inflammatory processes via the Ni-HIF pathway. The Ni-free-stainless steel stent is a promising new coronary stent platform.

The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin-angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.

Macrolide antibiotics are broadly used for the treatment of various microbial infections. However, they are also known to have multiple biologic effects, such as alteration of inflammatory factors and matrix metalloproteinases (MMPs). Because of controversial results in clinical trials, the effects of macrolides on cardiovascular diseases are still to be elucidated. It has been reported that MMP activity is upregulated in various cardiovascular diseases, such as myocarditis, cardiac transplant rejection and myocardial infarction. However, little is known about the effects of macrolides on cardiovascular diseases. We have reported that clarithromycin suppressed the development of myocarditis, cardiac rejection and myocardial ischemia using animal models. In this article, we reviewed the roles of MMPs in cardiovascular diseases and the effects of macrolides on the prevention of adverse tissue remodeling.

BACKGROUND: Inflammatory markers such as serum C-reactive protein (CRP), serum amyloid A (SAA), and plasma pentraxin 3 (PTX3), which belong to the pentraxin superfamily, increase due to various inflammatory diseases. Some studies demonstrated that serum CRP and SAA are predictors of cardiovascular diseases, and cardiac rehabilitation (CR) induces anti-inflammatory effects. In the present study, we investigated the effects of CR on pentraxins (serum CRP, SAA, and plasma PTX3) in patients with cardiovascular diseases. METHODS: Fifty patients with cardiovascular diseases [61 ± 13 (mean ± SD) years old, male/female 44/6] participated. Each subject performed CR using aerobic bicycle exercise two or three times per week for 3-6 months. We measured resting serum high-sensitivity CRP (hsCRP), SAA, and plasma PTX3 before and 3 and 6 months after CR, and compared them with VO(2peak) determined using a standard increment cycle ergometer protocol, B-type natriuretic peptide (BNP), and other biochemical data such as HbA1c. RESULTS: There was a significant positive correlation between hsCRP and SAA (r = 0.92, p < 0.001), but no relations between these parameters and PTX3. Plasma PTX3 significantly decreased time dependently during CR (at baseline 3.2 ± 2.0 ng/ml, at 3 months 2.3 ± 0.8 ng/ml, at 6 months 2.1 ± 0.7 ng/ml; all p < 0.05). Serum hsCRP tended to decrease, but not statistically significantly. At baseline, plasma PTX3 was negatively correlated with the percentage of the predicted values of VO(2peak) and positively correlated with BNP. CR significantly increased the percentage of the predicted values of VO(2peak) and decreased BNP. CONCLUSIONS: Plasma PTX3, an inflammatory marker, which was quite different from CRP and SAA, decreased during cardiac rehabilitation with an improvement of exercise capacity in patients with cardiovascular diseases.

Modulator recognition factor-2 (Mrf2/AT-rich interaction domain (Arid)5b) has been revealed to be involved in pathogenesis of atherosclerosis and adipogenesis. Single-nucleotide polymorphisms (SNPs) in the MRF2/ARID5B gene are associated with coronary artery disease (CAD) and has been proposed as a candidate gene for type 2 diabetes (T2D). The study was aimed to determine whether any of the four MRF2/ARID5B SNPs (rs2893880, rs10740055, rs7087507 and rs10761600) associated with susceptibility to CAD are also associated with T2D, and to determine whether SNP genotype influences the levels of adiponectin and other clinical factors. Association of MRF2/ARID5B SNPs was investigated in 500 diabetic patients from the Department of Metabolic Diseases at the University of Tokyo and 243 hospital-based nondiabetic individuals from the Institute for Adult Disease Asahi Life Foundation Hospital and 500 community-based nondiabetic individuals from the Hiroshima Atomic Bomb Casualty Council Health Management Center. Associations of haplotypes of these SNP with levels of adiponectin and other clinical factors were evaluated when the data was available. We found rs2893880C, rs10740055A, rs7087507A and rs10761600T were increasingly associated with T2D in terms of allele/genotype frequencies of each SNP and their haplotype combinations. Individuals with haplotype CAAT indicated an 1.86 times higher prevalence of diabetes compared with individuals with GCGA (OR 1.86 (95% confidence interval (CI) 1.43-2.41)). Furthermore, CAAT significantly associated with adiponectin levels and other clinical factors. In conclusion, polymorphisms on the MRF2/ARID5B gene were associated with susceptibility to T2D as well as adiponectin and other clinical factors, which was in a completely concordant way with their associations with CAD.

STEMIはPCIを主とした再灌流療法の普及によって、院内死亡率はこの数十年でほぼ10%以下までの低減が達成された。一方依然として高い院外死亡率の低減のためには、発症者を可及的速やかに正確な診断によって適切な施設に搬送するための救急診療連携が非常に重要である。そのためにプレホスピタル心電図診断は有効であるがいまだ広く普及するには至っていない。そこでわれわれは、近年急速に発達したモバイルクラウドICTにより低コストのシステムCloud Cardiologyを開発し、プレホスピタル診断の普及を図り循環器救急の臨床アウトカム改善を目標とした試みを開始した。コンパクトな心電図ユニット、Tablet型モバイル端末とクラウドにより簡便実用性化したシステムとしてSTEMIの臨床的アウトカムを改善する可能性がある。(著者抄録)

BACKGROUND: Several groups have reported that an elevated ratio of early (E) to late (A) diastolic filling velocities is observed in patients after heart transplantation. However, the mechanism has not been fully analyzed. METHODS: Serial echocardiography and hemodynamic study were performed in 16 patients who had received heart transplantation and had no evidence of rejection during 1 month after the operation. RESULTS: On Day 1 after the surgery, E/A ratio was higher and peak velocity of A wave was lower than normal range among the patients after heart transplantation. E/A ratio and peak velocity of A wave gradually normalized during 1 moth after the surgery. Meanwhile, early mitral annular velocity and pulmonary capillary wedge pressure remained within normal range during the study period. CONCLUSIONS: Longer ischemic time during heart transplantation procedure may cause atrial stunning, but it appears to recover within 1 month. We have to be alert to misinterpretation of this "psuedo-psuedonormal" mitral inflow pattern early after transplantation.

The molecular mechanism that leads to age-related macular degeneration (AMD) is poorly understood. Gene expression profiling identified adrenomedullin (ADM) as a possible molecular target for the treatment of AMD and expression of ADM was upregulated in eyes with laser-induced choroidal neovascularization (CNV). In vivo experiments strongly indicated that ADM inhibits laser-induced CNV. In vitro tube formation assay demonstrated that neither ADM nor conditioned medium from the retinal pigment epithelial (RPE) cells, D407 cells, treated with ADM affected the capillary-formation of human umbilical vein endothelial cells. In contrast, in vitro macrophage migration assay clearly demonstrated that the conditioned medium of D407 inhibited macrophage migration. Furthermore, the expression of C-C motif chemokine 2 (CCL2) was significantly inhibited in D407 cells after ADM treatment. In vivo experiments using a laser-induced CNV model in ADM(+/-) mice demonstrated that CCL2 expression was upregulated in ADM(+/-) mice with concomitant increase in macrophage migration in the subretinal space. Additionally, the effect of ADM was abrogated in CCL2 knockout mice. These results suggest that administration of ADM inhibits macrophage migration in the subretinal space and leads to the suppression of laser-induced CNV in an animal model. The inhibition of macrophage migration occurred through the CCL2 from RPE. This study provides a novel potential therapeutic target for AMD which does not substantially disrupt VEGF-A signaling mediated vasculogenesis. (Am J Pathol 2012, 181:14641472 http://dx.dot.org/10.1016/j.ajpath.2012.06.028)

Refractory ventricular tachyarrhythmias are life threatening, especially in patients with stage D heart failure, and left ventricular assist device therapy is virtually the sole option to resolve the fatal conditions in many cases. The Interagency Registry for Mechanically Assisted Circulatory Support defines modifier A as complicating recurrent ventricular tachyarrhythmias. However, the optimal timing to implant a left ventricular assist device remains to be determined in less sick patients with modifier A. We experienced three patients with stage D heart failure with revised modifier A, i.e., at least two appropriate operations of implantable cardiac defibrillators within 2 weeks. Two of them were rescued by extracorporeal left ventricular assist device implantation, but one died because of an electrical storm before left ventricular assist device support was available. We would like to emphasize that we should consider implantable left ventricular assist device therapy as soon as possible for those who are assigned modifier A to prevent sudden arrhythmic death.

Intravenous cyclophosphamide pulse therapy (IVCY) exerts its efficacy against interstitial lung disease (ILD) associated with systemic sclerosis (SSc) by restoring vascular injuries as well as aberrant immune activation. We recently experienced two patients with SSc-ILD in whom the values of brachial flow-mediated dilation (FMD) reflected the efficacy of IVCY. We herein report the details of these cases and discuss the potential of FMD to predict and evaluate the effect of IVCY on SSc-ILD.

BACKGROUND: Telmisartan is an angiotensin II receptor blocker, which acts as a partial agonist of peroxisome proliferator activator receptor-γ (PPAR-γ). Because PPAR-γ initiates a variety of antiinflammatory responses, the effect on myocardial ischemia is to be elucidated. METHODS AND RESULTS: The left anterior descending arteries were ligated to induce myocardial infarction in rats. The animals were assigned to 4 groups: (1) control (saline, n = 6), (2) telmisartan (10 mg·kg·d, n = 6), (3) telmisartan + GW9662 (PPAR-γ-antagonist) (10 mg·kg·d of telmisartan and 1 mg·kg·d of GW9662, n = 6), and (4) amlodipine (10 mg·kg·d, n = 8) groups. Telmisartan reduced mean blood pressure compared with that in the control group. There was no statistical difference among the telmisartan, telmisartan + GW9662 and amlodipine groups. The end-diastolic left ventricular diameter was smaller in telmisartan group compared with that in the control group; GW9662 negated the effect of telmisartan. The thickness of the ventricular septum was kept in the telmisartan group compared with that in the control group; GW9662 negated the effect. Histopathologic analyses showed that telmisartan suppressed myocardial fibrosis compared with that of the control, whereas GW9662 negated the telmisartan effect. CONCLUSIONS: Telmisartan suppresses pathological remodeling by PPAR-γ agonistic activities independent of its antihypertensive effects.

Left ventricular outflow tract obstruction (LVOTO) is commonly observed in patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy (LVH). While some patients develop LVOTO at rest, it can also be provoked by physical exertion, and hence termed latent LVOTO (L-LVOTO). Recent reports demonstrated that L-LVOTO develops not only in LVH patients, but also in patients without LVH (non-LVH). However, the prevalence and clinical prognosis of non-LVH patients with L-LVOTO are not yet elucidated. In this study, we retrospectively investigated the echocardiographic features of patients with malignancy who underwent dobutamine stress echocardiography (DSE) to evaluate preoperative cardiac risk. One hundred ninety-nine patients were found not to have LVH or coronary artery disease. Among them, 106 patients exhibited L-LVOTO after DSE. We next compared the baseline echocardiographic features of L-LVOTO (+) patients with those of L-LVOTO (-) patients, and identified the left ventricular outflow tract (LVOT) ratio (systolic LVOT diameter/diastolic LVOT diameter) as a significant predictor of L-LVOTO. An LVOT ratio &lt;= 0.83 was the best cutoff value to detect the presence of L-LVOTO, with a sensitivity of 81.1% and specificity of 80.6%. Overall, L-LVOTO was found to develop in almost half of non-LVH patients with malignancy, in addition, the baseline LVOT ratio was strongly related to the presence of L-LVOTO in non-LVH patients. Therefore, patients with dynamic LVOT narrowing may benefit from DSE to detect the presence of L-LVOTO. (Int Heart J 2012; 53: 230-233)

BACKGROUND: Little is known about depressive symptoms in heart failure with preserved ejection fraction (HFpEF, EF ≥50%). We aimed to assess the prevalence of depression, to clarify the impact of depressive symptoms upon clinical outcomes, and to identify factors associated with these symptoms in HF with reduced EF (HFrEF, EF <50%) and HFpEF. METHODS AND RESULTS: A total of 106 HF outpatients were enrolled. Of them, 61 (58%) had HFpEF. Most patients were male (HFrEF 80%, HFpEF 70%) and the mean of plasma B-type natriuretic peptide (BNP) level in the HFrEF group was similar to that in the HFpEF group (164.8 ± 232.8 vs. 98.7 ± 94.8 pg/mL). HFrEF patients were treated more frequently with beta-blockers compared with HFpEF patients (71% vs. 43%, p=0.004). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The prevalence of depression (CES-D score ≥16), and CES-D score did not significantly differ between HFrEF and HFpEF (24% vs. 25%, 14.1 ± 8.3 vs. 12.1 ± 8.3, respectively). During the 2-year follow-up, depressed patients had more cardiac death or HF hospitalization in HFrEF (55% vs. 12%, p=0.002) and HFpEF (35% vs. 11%, p=0.031). Cox proportional hazard analysis revealed that a higher CES-D score, indicating increased depressive symptoms, predicted cardiac events independent of BNP in HFrEF [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.01-1.13] and HFpEF (HR 1.09, 95% CI 1.04-1.15). Multiple regression analyses adjusted for BNP showed that independent predictors of depressive symptoms were non-usage of beta-blockers and being widowed or divorced in HFrEF. On the other hand, usage of warfarin was the only independent risk factor for depressive symptoms in HFpEF (all, p<0.05). CONCLUSIONS: Depressive symptoms are common and independently predict adverse events in HFrEF/HFpEF patients. This study suggests that beta-blockers reduce depressive symptoms in HFrEF. In contrast, treatment for depression remains to be elucidated in HFpEF.

Postoperative right ventricular failure is usually apparent perioperatively or soon after left ventricular assist device insertion. Here, we report a case complicated by right ventricular failure that manifested 3 weeks after HeartMate II implantation. This case is also unique because the postoperative right ventricular failure was progressive over the years. We discuss how the smaller size of the left ventricle and untreated tricuspid regurgitation contributed to the development of right ventricular failure in this case.

An excess of lipids may accumulate in the kidney in conditions such as diabetes and hypertension, and can potentially cause renal injury. We previously reported that an infusion of angiotensin II into a rat induced deposition of lipids in the renal tubular epithelial cells. Here we have examined the effect of pioglitazone, an agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), on renal lipid accumulation and renal injury induced by angiotensin II infusion. Pioglitazone treatment (2.5 mg/kg/day) reduced the amount of triglycerides in the kidney of the angiotensin II-induced hypertensive rat without significantly altering either blood pressure levels or mRNA expression of lipogenic genes in the kidney. In addition, pioglitazone, either alone or in conjunction with angiotensin II, increased the expression of phosphorylated, but not total, AMP-activated protein kinase (AMPK). Proteinuria and kidney weight in the angiotensin II-infused rat were significantly decreased by pioglitazone treatment. In addition, pioglitazone suppressed iron deposition and ferritin protein induction, but did not alter upregulated expression of the antioxidative molecule, heme oxygenase-1, in the kidney of the angiotensin II-infused rat. These findings suggested that pioglitazone suppressed the angiotensin II-induced increase in renal lipid content by inhibiting its proteinuric action, but not by direct alteration of the expression or activity of lipid metabolism-related genes. Reduction of lipotoxic renal damage may represent one of the renoprotective effects provided by pioglitazone in hypertension with activation of the renin-angiotensin system. (C) 2012 Elsevier B.V. All rights reserved.

Objectives: A strong degree of co-existence between coronary artery disease (CAD) and abdominal aortic aneurysm (AAA) is widely acknowledged, however, it remains to be elucidated whether the existence of CAD is associated with an accelerated expansion rate of AAA. Also, the relationship between preoperative CAD and postoperative major adverse cardiovascular events (MACE) has not been examined in Japanese patients. The aim of this study was to investigate the deleterious effects of CAD on the progression of AAA and the onset of postoperative MACE after elective AAA repair. Methods and results: A retrospective cohort study of 665 consecutive Japanese patients who underwent elective surgical repair for infrarenal AAA at 2 high-volume Tokyo hospitals from 2003 through 2010 was performed. Preoperative CAD was shown to be a significant determinant of postoperative MACE (HR 2.29; 95% CI, 1.12-4.66; p = 0.02). In the analysis of 510 patients for whom there were at least 2 follow-up CT scans of the size of their AAA before repair, the existence of CAD was shown to be inversely associated with the accelerated expansion rate of AAA. Conclusion: This study on the patients undergone elective repair for infrarenal AAA identified an inverse association between the existence of CAD and progression of AAA as well as the significant impact of preoperative CAD on the occurrence of postoperative MACE after elective AAA repair. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Consumption of foods high in saturated fatty acids (FAs) as well as elevated levels of circulating free FAs are known to be associated with T2D. Though previous studies showed inflammation is crucially involved in the development of insulin resistance, how inflammation contributes to β cell dysfunction has remained unclear. We report here the saturated FA palmitate induces β cell dysfunction in vivo by activating inflammatory processes within islets. Through a combination of in vivo and in vitro studies, we show β cells respond to palmitate via the TLR4/MyD88 pathway and produce chemokines that recruit CD11b(+)Ly-6C(+) M1-type proinflammatory monocytes/macrophages to the islets. Depletion of M1-type cells protected mice from palmitate-induced β cell dysfunction. Islet inflammation also plays an essential role in β cell dysfunction in T2D mouse models. Collectively, these results demonstrate a clear mechanistic link between β cell dysfunction and inflammation mediated at least in part via the FFA-TLR4/MyD88 pathway.

Cardiac allograft rejection can be accompanied by diastolic dysfunction, but the hemodynamic change is usually compensated and hard to be recognized noninvasively. Here we report on two transplanted patients who showed electrocardiogram (ECG) changes suggesting right ventricular overload. Hemodynamic measurement revealed increased right ventricular pressure and endomyocardial biopsy confirmed grade 3R rejection. After rejection was treated with steroid pulse, the ECG alterations were reversed and right ventricular pressure was normalized. In such cases, asymptomatic rejection may be diagnosed by ECG changes that are reversible along with the treatment of rejection, although those ECG changes are apparently non-specific.

Background: The ratio of early diastolic transmitral flow velocity (E) to tissue Doppler (TD) mitral annular early diastolic velocity (E/E'VEL-TD) has been widely used for the noninvasive assessment of LV diastolic filling pressures. However, it has been reported that E/E'VEL-TD is not accurate particularly when being applied to patients with advanced heart failure. Methods: Fifty-six ICU patients with decompensated heart failure underwent simultaneous echocardiography and PCWP measurements. Patients with elevated PCWP (n = 41) were compared with patients normal PCWP (n = 15) as well as age-matched healthy controls (n = 32). In the apical 4-chamber view, the ratio of E to speckle tracking (ST) mitral annular velocity (E/E'VEL-ST) and early diastolic global LV longitudinal strain rate (E/E'SR-ST) were evaluated as new surrogate markers of elevated PCWP. Results: Correlations with PCWP were observed for speckle tracking derived E/E'VEL-ST (r = 0.40,P = 0.002) and E/E'SR-ST (r = 0.56, P &lt; 0.001), although the traditional E/E'VEL-TD did not show a significant correlation (r = 0.23, P = 0.082). Compared with controls, patients with elevated PCWP had significant increases in all variables. The best cutoff values and diagnostic accuracies for identifying elevated PCWP were E/E'VEL-TD&gt;12 (Sensitivity/Specificity/area under the ROC curve: 0.58/0.90/0.78), E/E'VEL-ST &gt; 14 (0.60/0.85/0.80), and E/E'SR-ST &gt; 93 (0.80/0.88/0.89). Conclusion: Speckle tracking derived E/E'SR-ST may be a robust surrogate marker of elevated LV filling pressure. In ICU patients, E/E'SR-ST showed better correlation with PCWP and higher diagnostic accuracy than the tissue Doppler approach. (Echocardiography 2012;29:404-410)

BACKGROUND: Angiotensin converting enzyme inhibitors have been used clinically to prevent myocardial infarction (MI). The angiotensin converting enzyme inhibitors attenuated ventricular remodeling and improved cardiac function by inhibition of matrix metalloproteinases after MI. Although the effect is thought to be a class effect, there are significant differences among the drugs. The aim of this study was to compare the effects of imidapril and ramipril on ventricular remodeling after MI. METHODS: The middle portion of left anterior descending artery was ligated to induce a moderate size MI in rats (moderate MI group). The proximal portion of the artery was ligated to induce a large size MI (large MI group). The animals were assigned to subgroups in moderate MI group and large MI group: (1) nontreated group, (2) ramipril group (1 mg/kg daily), and (3) imidapril group (1 mg/kg daily). All rats were killed on day 28 after the MI operation. RESULTS: Although the nontreated MI group showed impaired ventricular contraction and severe fibrosis, imidapril significantly negated ischemia-induced changes. Imidapril had a superior effect for preventing ventricular remodeling characterized by fibrosis and collagen accumulation in left ventricle compared with ramipril in the moderate and large MI groups, even though the dosage used in this study was too small to reduce systemic blood pressure. CONCLUSIONS: Imidapril can be used as a substitute for ramipril to prevent ventricular remodeling after MI.

Hyaluronic acid (HA) has been implicated in the proliferation and metastasis of tumor cells. However, most previous studies were conducted on extracellular matrix or pericellular HA, and the role of circulating HA in vivo has not been studied. HA is rapidly cleared from the bloodstream. The scavenger receptor Stabilin-2 (Stab2) is considered a major clearance receptor for HA. Here we report a dramatic elevation in circulating HA levels in Stab2- deficient mice without any overt phenotype. Surprisingly, the metastasis of B16F10 melanoma cells to the lungs was markedly suppressed in the Stab2-deficient mice, whereas cell proliferation was not affected. Furthermore, administration of an anti-Stab2 antibody in Stab2+ mice elevated serum HA levels and prevented the metastasis of melanoma to the lung, and also suppressed spontaneous metastasis of mammary tumor and human breast tumor cells inoculated in the mammary gland. Administration of the antibody or high-dose HA in mice blocked the lodging of melanoma cells to the lungs. Furthermore, HA at high concentrations inhibited the rolling/tethering of B16 cells to lung endothelial cells. These results suggest that blocking Stab2 function prevents tumor metastasis by elevating circulating HA levels. Stab2 may be a potential target in antitumor therapy.