Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat : the PRIZE study

Background: Xanthine oxidase inhibitors are anti-hyperuricemic drugs that decrease serum uric acid levels by inhibiting its synthesis. Xanthine oxidase is also recognized as a pivotal enzyme in the production of oxidative stress. Excess oxidative stress induces endothelial dysfunction and inflammatory reactions in vascular systems, leading to atherosclerosis. Many experimental studies have suggested that xanthine oxidase inhibitors have anti-atherosclerotic effects by decreasing in vitro and in vivo oxidative stress. However, there is only limited evidence on the clinical implications of xanthine oxidase inhibitors on atherosclerotic cardiovascular disease in patients with hyperuricemia. We designed the PRIZE study to evaluate the effects of febuxostat on a surrogate marker of cardiovascular disease risk, ultrasonography-based intima-media thickness of the carotid artery in patients with hyperuricemia. Methods: The study is a multicenter, prospective, randomized, open-label and blinded-endpoint evaluation (PROBE) design. A total of 500 patients with asymptomatic hyperuricemia (uric acid >7.0 mg/dL) and carotid intima-media thickness ≥1.1 mm will be randomized centrally to receive either febuxostat (10–60 mg/day) or non-pharmacological treatment. Randomization is carried out using the dynamic allocation method stratified according to age (<65, ≥65 year), gender, presence or absence of diabetes mellitus, serum uric acid (<8.0, ≥8.0 mg/dL), and carotid intima-media thickness (<1.3, ≥1.3 mm). In addition to administering the study drug, we will also direct lifestyle modification in all participants, including advice on control of body weight, sleep, exercise and healthy diet. Carotid intima-media thickness will be evaluated using ultrasonography performed by skilled technicians at a central laboratory. Follow-up will be continued for 24 months. The primary endpoint is percentage change in mean intima-media thickness of the common carotid artery 24 months after baseline, measured by carotid ultrasound imaging. Conclusions: PRIZE will be the first study to provide important data on the effects of febuxostat on atherosclerosis in patients with asymptomatic hyperuricemia

インスリン テイコウセイ カラ ミタ sirolimus-eluting stent ト paclitaxel-eluting stent ノ ナイマク ゾウショク ノ ケントウ

(目的)虚血性心疾患の治療において経皮的冠動脈形成術は有用な治療であるが再狭窄が問題である.これに対し,近年薬剤溶出性ステント(Drug eluting stent:DES)が臨床応用され再狭窄は減少してきているが依然として認めている.現在数種類のDES が臨床使用されているが,病態によりどのDES を選択するか明確な指標はない.主に使用されているシロリムス溶出性ステント(sirolimus-eluting stent:SES)とパクリタキセル溶出性ステント(paclitaxel-eluting stent:PES)では塗布されている薬剤の作用機序が異なる.以前我々はDES 留置後においてもインスリン抵抗性が内膜増殖に関与していると報告してきた.本研究の目的は作用機序の異なるこれら2 つのDES において,内膜増殖とインスリン抵抗性の関与を比較検討することである.(方法)2007 年5 月から2009 年12 月までにPCI を施行しDES を留置した212 例をSES 留置例とPES 留置例それぞれで,インスリン抵抗性を認める群(P 群)と認めない群(N 群)に分けて再狭窄を検討した.(結果)再狭窄はSES 留置例,PES 留置例ともにP 群とN 群とで有意差を認めなかった.QCA 解析をするとPES 留置例では,最小血管径(minimum lumen diameter:MLD),%狭窄率(% stenosis),晩期損失径(late lumen loss)に有意差を認めなかったが,SES 留置例では最小血管径で2.18±0.77, 2.61±0.53(p=0.028),晩期損失径で0.36±0.56, 0.13±0.22 mm( p=0.048)と有意差を認め,%狭窄率では20.36±24.44,12.2±6.86(p=0.098)とP 群で狭窄率が高い傾向を認めた.(結語)PES 留置後は慢性期の内膜増殖にインスリン抵抗性の影響を受けないが,SES 留置後はインスリン抵抗性が内膜増殖に関与している.Percutaneous coronary intervention(PCI) has been widely adopted as an effective treatmentstrategy for patients with ischemic heart disease. However,the rate of coronary artery restenosis is still high. Drugelutingstent( DES) have been implanted in clinical practiceand reduced the incidence of restenosis. Nevertheless, restenosisof coronary artery still occurs in DES patients. Twotypes of DES, sirolimus-eluting stent:SES and paclitaxelelutingstent:PES are widely applied. Previously we reportedthat insulin resistance is one of the factors for stentrestenosis. The aim of this study is to investigate the diferenceof intimal hyperplasia in insulin resistant patients withthe two types of DES implantation.METHODS:We studied the 320 patients who underwentPCI to a new lesion using DES between May 2007 andDecember 2009.We divided these patients by presence ofinsulin resistance into Group P (positive:n=120) andGroup N( negative:n=92). Furthermore, we divided thesepatients into implantation of SES and PES. We measuredthe minimal lumen diameter( MLD) and late loss by quantitativecoronary angiography( QCA).RESULTS:In SES implantation Group and PES implantationGroup, the rate of restenosis was no difference betweenGroup P and Group N. In PES implantation Group,MLD and Late Loss had no difference. However in SES implantationGroup, MLD was significantly lower ( 2.18±0.77vs 2.61±0.53 mm, p<0.05) and Late Loss was significantlyhigher in Group P compared with Group N (0.36±0.56 vs0.13±0.22 mm, p<0.05).CONCLUSION:We suggest that in patients who wereimplanted the two types of DES, insulin resistance was relatedto intimal hyperplasia. Especially SES patients withpositive insulin resistance prone to show more intimal hyperplasia

Framingham Risk Score ト ドウミャク コウカ リスク ニ ツイテノ ケントウ

背景:冠動脈疾患において以前よりフラミンガムリスクスコア(Framingham Risk Score:FRS)は10 年以内の虚血性心疾患発症を予測することが知られている.また近年,冠動脈マルチスライスCT(MultisliceConputed Tomography:MSCT)により求められる冠動脈カルシウムスコア(Coronary Artery CalciumScore:CACS)や種々の炎症マーカーが冠動脈疾患予測因子として報告されている.目的:年齢,性別,総コレステロール値,High Density Lipoprotein Cholesterol (HDL-C)コレステロール値,収縮期血圧,喫煙の有無から簡易に求めることのできるFRS を算出し,FRS と冠動脈疾患各動脈硬化リスク因子について検討した.対象:2009 年6 月から2011 年9 月までに当院に虚血性心疾患精査目的に受診しMSCT および,冠動脈造影を施行した連続347 例(男性229 例,女性108 例)についてFRS を計測し15 以上の高リスク群(H 群)と15未満の低リスク群(L 群)に分類した.冠動脈造影における有病率と冠動脈疾患予測因子であるCT にて計測されるCACS,及び血液検査における炎症マーカーについて比較検討した.結果:対象はH 群149 例,L 群198 例に分けられた.冠動脈造影における冠動脈疾患有病率はH 群53.6%,L 群41.4%とH 群において有意に高値であった(P=0.023).CACS においてもH 群687.1±759.1,L 群489.8±725.6 とH 群において有意に高値であった(P=0.015).血液検査におけるマーカーにおいては高感度CRP(H 群 vs L 群:0.29±0.70 vs 0.17±0.29 mg/dl P=0.046)と酸化Low Density Lipoprotein Cholesterol(LDL)(H 群 vs L 群:110.2±47.0 vs 96.8±35.6 U/L P=0.007)において有意差を認めた.結語:FRS は簡便に計測でき,各種冠動脈疾患予測因子とも関連しており冠動脈疾患予測の一助となりうる可能性があると考えた.Background: The Framingham risk score (FRS) is widely used inclinical practice to identify subjects at high risk for developingischemic heart disease. However, FRS may not accuratelyidentify subjects at risk. Recently, coronary arterycalcium score (CACS) detected by multi-slice computedtomography (MSCT) and several atherosclerosis riskmarkers has been known to predict ischemic heart diseases.Subjects: The aim of this study is to clarify the relation betweenFRS and several coronary risk factors. We researched theclinical records of 347 patients who had been subjected toMSCT and coronary angiography( CAG) between Jun 2009and September 2011. We subdivided these patients by thevalue of FRS into a group H (n=149;FRS &#8805; 15) and agroup L( n=198;FRS<15), and examined the relationshipbetween FRS and the other coronary risk factors.Results: The prevalence of coronary heart disease by CAG wassignificantly higher in group H (53.6 %) than in group L(41.4%, p=0.023). CACS was significantly higher in groupH than in group L( 687.0±759.1 vs 489.8±725.6, p=0.015).In group H the level of high-sensitive CRP and MDL-LDLwere significantly higher than those in group L(0.29±0.70vs 0.17±0.29 p=0.046 and 110.18±47.0 vs 96.82±35.6 P=0.007).Conclusion: We suggest that the FRS is easy to calculate and usefulto predict ischemic heart disease compared with the othercoronary risk markers

コウド インスリン テイコウセイ ジョウタイ ニ オケル ヤクザイ ヨウシュツセイ ステント リュウチ ゴ サイキョウサク ノ ヨソク インシ ノ ケントウ

目的:虚血性心疾患に対する経皮的冠動脈形成術(Percutaneous coronary intervention:PCI)は有用な治療法として確立されている.薬剤溶出性ステント(Drug-eluting stent:DES)により,大きな問題であった再狭窄は減少したが,完全には克服されていない.最近糖尿病の前段階としてインスリン抵抗性が注目されており,再狭窄に影響を及ぼすことが示唆されている.今回我々はHomeostasis Model Assessment 指数(HOMA-IR)を用いてインスリン抵抗性の程度とDES 留置後の再狭窄の関連を検討した.方法:2007 年5 月から2010 年10 月までに待機的にPCI を施行しDES を留置した248 例について,HOMAIRより高度インスリン抵抗性を有する群(H 群:n=75)と中等度インスリン抵抗性を有する群(M 群:n=64)およびインスリン抵抗性を有さない群(L 群:n=109)に分類し,定量的冠動脈造影を用いて再狭窄率および再狭窄関連因子について検討した.結果:再狭窄率はH 群で有意に高かった(p=0.0005).慢性期最小血管径はH 群で他の2 群と比較して有意に小さかった(H:1.62±1.02 mm,M:2.42±0.48 mm,L:2.17±0.70 mm, p=0.0086).さらに%狭窄率はH 群で他の2 群と比較して有意に大きく(H:40.1±34.7%,M::14.7±10.4%,L:22.7±21.6%, p=0.0092),晩期損失径もH 群で他の2 群と比較して有意に大きかった(H:0.87±0.90 mm,M:0.19±0.17 mm,L:0.41±0.62 mm, p=0.0097).結論:高度インスリン抵抗性は,DES 留置後再狭窄の危険因子となりえると考えられた.INTRODUCTION: Percutaneous coronary intervention (PCI) has beenwidely adopted as an effective treatment strategy for patientswith ischemic heart disease;especially, restenosis issuppressed after drug-eluting stent (DES) implantation.However, coronary artery restenosis after DES implantationstill appear now and then. The aim of this study was toclarify the factors associated with coronary artery restenosisafter DES implantation and evaluate the homeostasismodel assessment of insulin resistance (HOMA-IR) indexas a predictor of restenosis.METHODS: We reserched the clinical records of 248 patients who hadbeen subjected to elective PCI and DES implantation betweenMay 2007 and December 2010. We divided these patientsby the value of HOMA-IR into three groups(GroupH;HOMA-IR≧5 . 0 , Group M;2 . 5≦HOMA-IRHOMA-IR), and examined the relationshipbetween coronary artery restenosis and HOMA-IR.RESULTS: The rate of restenosis was significantly higher in GroupH (26.7 %) than in the other two groups (M;7.8 % andL;8.3%, p=0.0005 %). Follow up MLD was significantlylower in Group H (H;1.62±1.02 mm v.s. M;2.42±0.48 mm v.s. L;2.17±0.70 mm, p=0.0086). Furthermore, %stenosis and late lumen loss was significantly higher inGroup H (H;40.1±34.7%, M;14.7±10.4%, L;22.7±21.6%, p=0.0092, and H;0.87±0.9 mm v.s. M;0.19±0.17 mmv.s. L;0.41±0.62 mm, P=0.0097). Logistic analysis showedthat the only independent predictor of restenosis was HOMA-IR over 5.0( OR 2.87;p=0.004).CONCLUSION: The results suggested that severe insulin resistance wasa predictor of restenosis after drug-eluting stent implantation;furthermore, that improvement of insulin resistancemay contribute to prevent coronary restenosis after drugelutingstent implantation

Search for continuous gravitational wave emission from the Milky Way center in O3 LIGO--Virgo data

We present a directed search for continuous gravitational wave (CW) signals emitted by spinning neutron stars located in the inner parsecs of the Galactic Center (GC). Compelling evidence for the presence of a numerous population of neutron stars has been reported in the literature, turning this region into a very interesting place to look for CWs. In this search, data from the full O3 LIGO--Virgo run in the detector frequency band $[10,2000]\rm~Hz$ have been used. No significant detection was found and 95$\%$ confidence level upper limits on the signal strain amplitude were computed, over the full search band, with the deepest limit of about $7.6\times 10^{-26}$ at $\simeq 142\rm~Hz$. These results are significantly more constraining than those reported in previous searches. We use these limits to put constraints on the fiducial neutron star ellipticity and r-mode amplitude. These limits can be also translated into constraints in the black hole mass -- boson mass plane for a hypothetical population of boson clouds around spinning black holes located in the GC.Comment: 25 pages, 5 figure

Search for Eccentric Black Hole Coalescences during the Third Observing Run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass $M>70$ $M_\odot$) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities $0 < e \leq 0.3$ at $0.33$ Gpc$^{-3}$ yr$^{-1}$ at 90\% confidence level.Comment: 24 pages, 5 figure

All-sky search for continuous gravitational waves from isolated neutron stars using Advanced LIGO and Advanced Virgo O3 data

We present results of an all-sky search for continuous gravitational waves which can be produced by spinning neutron stars with an asymmetry around their rotation axis, using data from the third observing run of the Advanced LIGO and Advanced Virgo detectors. Four different analysis methods are used to search in a gravitational-wave frequency band from 10 to 2048 Hz and a first frequency derivative from $-10^{-8}$ to $10^{-9}$ Hz/s. No statistically-significant periodic gravitational-wave signal is observed by any of the four searches. As a result, upper limits on the gravitational-wave strain amplitude $h_0$ are calculated. The best upper limits are obtained in the frequency range of 100 to 200 Hz and they are ${\sim}1.1\times10^{-25}$ at 95\% confidence-level. The minimum upper limit of $1.10\times10^{-25}$ is achieved at a frequency 111.5 Hz. We also place constraints on the rates and abundances of nearby planetary- and asteroid-mass primordial black holes that could give rise to continuous gravitational-wave signals.Comment: 23 main text pages, 17 figure

All-sky search for continuous gravitational waves from isolated neutron stars using Advanced LIGO and Advanced Virgo O3 data

We present results of an all-sky search for continuous gravitational waves which can be produced by spinning neutron stars with an asymmetry around their rotation axis, using data from the third observing run of the Advanced LIGO and Advanced Virgo detectors. Four different analysis methods are used to search in a gravitational-wave frequency band from 10 to 2048 Hz and a first frequency derivative from $-10^{-8}$ to $10^{-9}$ Hz/s. No statistically-significant periodic gravitational-wave signal is observed by any of the four searches. As a result, upper limits on the gravitational-wave strain amplitude $h_0$ are calculated. The best upper limits are obtained in the frequency range of 100 to 200 Hz and they are ${\sim}1.1\times10^{-25}$ at 95\% confidence-level. The minimum upper limit of $1.10\times10^{-25}$ is achieved at a frequency 111.5 Hz. We also place constraints on the rates and abundances of nearby planetary- and asteroid-mass primordial black holes that could give rise to continuous gravitational-wave signals