胎盤増殖因子の可溶性Fms様チロシンキナーゼ-1に対する血中濃度比の上昇は安定冠動脈疾患患者における有害事象発症の予測因子である

OBJECTIVE: To investigate the predictive values of placental growth factor (PlGF) and its endogenous antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1), for the long-term prognosis of patients with stable coronary artery disease (CAD). Both PlGF and sFlt-1 play important roles in the pathological mechanisms of atherosclerosis. We recently demonstrated that the plasma levels of these molecules are correlated with the severity of coronary atherosclerosis. METHODS: We enrolled 464 patients with stable CAD who consecutively underwent coronary angiography. Baseline blood samples were collected from the femoral artery immediately before coronary angiography (after the administration of 20 units of heparin), and the plasma levels of PlGF and sFlt-1 were measured. A Cox proportional hazard regression analysis was performed to evaluate the relationship between these parameters and the occurrence of all-cause death (ACD) and total cardiovascular events (TCVE) during a median follow-up of 3.3 years. RESULTS: A total of 31 ACDs and 51 TCVEs occurred. Patients with higher PlGF/sFlt-1 ratios (>4.22×10(-2)) had a significantly higher risk of both ACD and TCVE than patients with lower ratios (<4.22×10(-2)) (hazard ratio [HR]: 3.32, 95% confidence interval [CI]: 1.43 to 7.72, p=0.005, and HR: 2.23, 95% CI: 1.23 to 4.03, p=0.008, respectively). A multivariate analysis showed the PlGF/sFlt-1 ratio to be an independent predictor for ACD, but not TCVE.博士（医学）・甲615号・平成26年3月17日発行元の規定により、本文の登録不可。本文は以下のURLを参照 "http://dx.doi.org/10.2169/internalmedicine.52.9073

高齢の非代償性心不全患者において、非心血管疾患、特に感染症は重要な死因である

BACKGROUND:Despite marked improvements in treatment strategies for heart failure (HF), the mortality rate of elderly patients with HF is still high. Detailed causes of death have not been fully understood.METHODS AND RESULTS:We studied 459 consecutive patients with acute decompensated HF (ADHF) emergently admitted to our hospital from 2007 to 2011. Patients were divided into 2 groups: <75 years old (younger group; n = 225) and ≥75 years old (elderly group; n = 234). All-cause death, cardiovascular death, and noncardiovascular death were assessed as adverse outcomes. Compared with the younger group, the elderly group was characterized by a higher proportion of women and hypertensive patients and higher left ventricular ejection fraction. During a mean follow-up of 20.7 months, a total of 174 patients (37.9%) died. All-cause death was significantly higher in the elderly group than in the younger group (46.6% vs 28.9%; P < .0001), and this difference was caused by an increase in noncardiovascular deaths (20.9% vs 9.3%; P < .001), especially deaths due to infection (10.7% vs 4.0%; P < .01). Cardiovascular deaths did not differ between the 2 groups.CONCLUSIONS:Noncardiovascular deaths, most of which were caused by infection, were frequent among elderly patients with ADHF.博士（医学）・甲第629号・平成27年3月16日Copyright © 2014 Elsevier Inc. All rights reserved

PHD2 regulates arteriogenic macrophages through TIE2 signalling

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可溶性Flt-1産生低下は、心筋リモデリングおよび心不全増悪に寄与する

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti–placental growth factor–neutralizing antibody prevented pressure overload–induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.博士（医学）・乙第1384号・平成28年11月24日© 2016 American Heart Association, Inc.The definitive version is available at " https://doi.org/10.1161/HYPERTENSIONAHA.116.07371

慢性腎臓病では血中可溶型fms様チロシンキナーゼ-1産生の減少が動脈硬化症を悪化させる

Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.博士（医学）・甲614号・平成26年3月17

Macrophage skewing by Phd2 haplodeficiency prevents ischemia by inducing arteriogenesis

The authors are thankful to Dr. P. Carmeliet for scientific discussion and support. VE-Cadherin:CreERT and PDGFRB:Cre transgenic mice were generated at the Cancer Research UK (London, UK) and kindly donated by Dr. R. Adams. The IKKβ floxed mice are a generous gift of Dr. M. Karin (UCSD, La Jolla, CA). The hydroxylase-deficient PHD2 construct was given by Dr. P. Ratcliffe (Oxford, UK).PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.This work was supported by grants from FWO (G.0726.10), Belgium, and from VIB. ED was granted by ARC, SC by FCT, RLO and VF by FWO, AH by DFG. CR was supported by COST action TD0901. MDP was supported by an ERC starting grant