Search

Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown etiology. Although a number of investigators have attempted to determine biomarkers for diagnosing TAK, there exist no specific serological markers of this intractable disease. We undertook the exploration of novel serological markers which could be useful for an accurate diagnosis of TAK using an unbiased proteomics approach. The purified plasma samples from untreated patients with TAK and healthy individuals were separated by two-dimensional electrophoresis. The differentially expressed protein spots were detected by gel comparison and identified using matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MS). Next, we validated plasma concentrations of identified proteins by enzyme-linked immunosorbent assay (ELISA). Two-dimensional electrophoresis and numerical analysis revealed 19 spots and 3 spot clusters whose sum of the sample averages was ≥ 0.01, and the average concentrations were ≥ 1.5 times in the patient group compared with the control group. Among them, 10 spots and spot clusters that met the condition of the average spot concentration being 2.5 times more than that in the control group were selected. After processing these spots using MS and conducting MS/MS ion search, we identified 10 proteins: apolipoprotein C-2 (ApoC-2), actin, apolipoprotein A-1, complement C3, kininogen-1, vitronectin, α2-macroglobulin, 14–3–3 protein ζ/δ, complement C4, and inter-α-trypsin inhibitor heavy chain H4 isoform 1 precursor. Finally, ELISA demonstrated that plasma ApoC-2 level was significantly elevated in patients with TAK compared with that in healthy individuals. Thus, ApoC-2 would be a promising candidate biomarker for TAK diagnosis. [ABSTRACT FROM AUTHOR]

Being overweight has been identified as independent risk factors for coronary artery disease. However, overweight patients have been reported frequently to have better mortality outcomes, and there is little data showing they are at a disadvantage regarding secondary prevention of cardiovascular events. We analyzed the influence of being overweight (defined as body mass index > 25 kg/m2) on adverse events in patients who underwent everolimus-eluting stent (EES) implantation using a multicenter registry with a maximum follow-up of 3 years. Propensity score matching was done for adjusting baseline characteristics. We defined primary end points as major adverse cardiac and cerebrovascular events (MACCE: a composite of mortality from all causes, nonfatal myocardial infarction, and nonfatal stroke) and "MACCE excluding non-cardiac mortality". Other adverse events were analyzed as key secondary end points. Out of 1918 patients, 450 pairs were obtained through propensity score matching. Overweight patients were superior to non-overweight patients regarding MACCE (event rates: 8.2 vs. 13.8% in overweight vs. non-overweight, respectively; log-rank p = 0.009) and "MACCE excluding non-cardiac mortality" (5.9 vs. 10.1%, p = 0.03). On secondary end points, not only did overweight patients have significantly fewer major bleeding events (2.2 vs. 4.8%, p = 0.02), but they also had smaller adverse event rates for almost all such events; the differences were not statistically significant. Overweight patients had better outcomes for MACCE, even on excluding non-cardiac mortalities. No result was supportive of an evident advantage to non-overweight EES-implanted patients in terms of secondary prevention of cardiovascular events. [ABSTRACT FROM AUTHOR]

Treatment of in-stent restenosis (ISR) is associated with a high incidence of recurrence. This study evaluated the clinical safety and 6-month efficacy of excimer laser coronary angioplasty (ELCA) before scoring balloon dilatation for the treatment of ISR. Twenty-three patients with ISR were included and treatment strategy of ISR was dependent on each operator. Twelve patients among those were treated with ELCA before scoring balloon dilatation (ELCA group) and 11 patients were treated with scoring balloon alone (non-ELCA group). Acute procedural results were evaluated by quantitative coronary angiography (QCA) and frequency domain optical coherence tomography (FD-OCT). Follow-up angiography was performed in all patients and the incidence of recurrent ISR and target lesion revascularization (TLR) was determined at 6 months after initial ISR treatment. Procedural success was achieved in all patients. Baseline clinical and angiographic characteristics were similar between groups. Maximum dilatation pressure of scoring balloon was significantly lower in the ELCA group than in the non-ELCA group (9.0 ± 3.1 vs. 14.9 ± 4.3 atm, p = 0.001). In follow-up angiography, the occurrence of TLR was similar between groups (16.7 vs. 45.5 %, p = 0.09), but the late luminal loss was significantly lower in the ELCA group (0.7 ± 0.6 vs. 1.3 ± 0.7 mm, p = 0.03). ELCA is a safe and feasible technique for the treatment of ISR and associated with a relatively low recurrent restenosis in comparison with scoring balloon dilatation alone. [ABSTRACT FROM AUTHOR]

Takayasu arteritis (TAK) is an acute and chronic vasculitis of unknown etiology. Recently, our group reported that SNP rs6871626 in the IL12B region had significant association with disease susceptibility to TAK. However, association of the SNP with clinical characteristics of TAK has yet to be determined. Therefore, we assessed whether this SNP was associated with TAK disease severity as represented by early onset and/or refractoriness to medical therapy. A total of 90 patients were genotyped for rs6871626 and their clinical charts were reviewed retrospectively. By examining the relationship between genotype and clinical profiles of patients, we found a strong association between the number of risk alleles and the frequency of severe cases as defined by (1) age at onset <20 years old, (2) steroid resistance, and/or (3) a relapse of disease [ p = 0.03; odds ratio 3.75 (95 % confidence interval 1.13-13.5)]. Thus, our study points to potential diagnostic use of SNP rs6871626 for predicting disease severity of TAK, with the goal of genotyping-oriented therapy in the near future. [ABSTRACT FROM AUTHOR]

Here we show that Mst1, a proapoptotic kinase, impairs protein quality control mechanisms in the heart through inhibition of autophagy. Stress-induced activation of Mst1 in cardiomyocytes promoted accumulation of p62 and aggresome formation, accompanied by the disappearance of autophagosomes. Mst1 phosphorylated the Thr108 residue in the BH3 domain of Beclin1, which enhanced the interaction between Beclin1 and Bcl-2 and/or Bcl-xL, stabilized the Beclin1 homodimer, inhibited the phosphatidylinositide 3-kinase activity of the Atg14L-Beclin1-Vps34 complex and suppressed autophagy. Furthermore, Mst1-induced sequestration of Bcl-2 and Bcl-xL by Beclin1 allows Bax to become active, thereby stimulating apoptosis. Mst1 promoted cardiac dysfunction in mice subjected to myocardial infarction by inhibiting autophagy, associated with increased levels of Thr108-phosphorylated Beclin1. Moreover, dilated cardiomyopathy in humans was associated with increased levels of Thr108-phosphorylated Beclin1 and signs of autophagic suppression. These results suggest that Mst1 coordinately regulates autophagy and apoptosis by phosphorylating Beclin1 and consequently modulating a three-way interaction among Bcl-2 proteins, Beclin1 and Bax. [ABSTRACT FROM AUTHOR]

To determine whether peroxisome proliferator-activated receptor (PPAR) γ ligands improve survival of patients with septic shock we treated a mouse model of sepsis [apolipoprotein (Apo) E) knockout mice] with pioglitazone, a PPAR-γ ligand. ApoE knockout mice have a high mortality rate due to sepsis because the endotoxin is not cleared. Prospective study in a university laboratory. We assorted 87 male ApoE knockout mice and 60 wild-type C57/B6 mice randomly into three groups (sepsis, pretreatment, posttreatment). Cecal ligation and puncture (CLP) was carried out in the sepsis and treatment groups. Mice were injected with pioglitazone (5 mg/kg per day) on the day before CLP or 6 h after surgery. Both pre- and post-CLP treatment with pioglitazone improved survival of ApoE knockout and wild-type mice. Serum levels of cytokines and chemokines and myeloperoxidase activity in lung and liver were suppressed in the pioglitazone-treated group. Pioglitazone also suppressed monocyte adhesion to vascular endothelium under flow conditions. Pioglitazone improved survival of ApoE knockout mice after onset of septic shock through suppression of inflammatory responses. [ABSTRACT FROM AUTHOR]

Background: [F-18]fluorodeoxyglucose positron emission tomography/computed tomography is routinely used for assessing Takayasu arteritis patients. However, extra-vessel [F-18]fluorodeoxyglucose uptake has not been evaluated in detail in these patients. We aimed to describe the extent and distribution of extra-vascular [F-18]fluorodeoxyglucose uptake on positron emission tomography/computed tomography in Takayasu arteritis patients. Seventy-three [F-18]fluorodeoxyglucose positron emission tomography/computed tomography scans from 64 consecutive Takayasu arteritis patients (59 women, mean age, 35.4 years; range, 13 to 71 years) and 40 scans from age-matched controls (36 women, mean age, 37.8 years; range, 13 to 70 years) were examined. We graded [F-18]fluorodeoxyglucose uptake in large vessels using a 4-point scale and evaluated extra-vessel findings. Factors correlated with disease activity were examined. We evaluated the relationship between disease activity according to the National Institutes of Health score with extra-vessel findings, as well as other inflammatory markers (e.g., white blood cell count and C-reactive protein level). Results: Extra-vessel involvement was present in 50 of 73 (68.4%) scans, specifically at the following sites: lymph nodes, 1.4%; thyroid glands, 17.8%; thymus, 11.0%; spleen, 1.4%; vertebrae, 45.2%; and pelvic bones, 9.6%. Takayasu arteritis patients had higher [F-18]fluorodeoxyglucose uptake in the spine (P = 0.03) and thyroid glands (P = 0.003) than did controls; uptake in other regions was comparable between groups. Compared with inactive patients, those with active Takayasu arteritis had a higher number of [F-18]fluorodeoxyglucose uptake sites in the vasculature (P = 0.001). Finally, patients with a National Institutes of Health score of ≥ 1 had significantly higher extra-vascular involvement (P = 0.008). Conclusions: Extra-vessel [F-18]fluorodeoxyglucose uptake may be present in the context of Takayasu arteritis-related inflammatory processes. Information on extra-vascular [F-18]fluorodeoxyglucose uptake may be useful for detecting and evaluating inflammatory processes when interpreting positron emission tomography/computed tomography scans obtained from Takayasu arteritis patients. [ABSTRACT FROM AUTHOR]

A peptide vaccine targeting angiotensin II (Ang II) was recently developed as a novel treatment for hypertension to resolve the problem of noncompliance with pharmacotherapy. Ang II plays a crucial role in the pathogenesis of cardiac remodeling after myocardial infarction (MI), which causes heart failure. In the present study, we examined whether the Ang II vaccine is effective in preventing heart failure. The injection of the Ang II vaccine in a rat model of MI attenuated cardiac dysfunction in association with an elevation in the serum anti-Ang II antibody titer. Furthermore, any detrimental effects of the Ang II vaccine were not observed in the rats that underwent sham operations. Treatment with immunized serum from Ang II vaccine-injected rats significantly suppressed post-MI cardiac dysfunction in MI rats and Ang II-induced remodeling-associated signaling in cardiac fibroblasts. Thus, our present study demonstrates that the Ang II vaccine may provide a promising novel therapeutic strategy for preventing heart failure. [ABSTRACT FROM AUTHOR]