シン ハクドウカ オヨビ ジュッチュウ セイリ ショクエンスイ チュウニュウ シケンジ ニ オケル ソウボウベン - サシツ ケイタイ ノ ソウイ ニ カンスル ケンキュウ

京都大学0048新制・課程博士博士(医学)甲第14502号医博第3347号新制||医||974(附属図書館)UT51-2009-D214京都大学大学院医学研究科外科系専攻(主査)教授 伊達 洋至, 教授 渡邉 大, 教授 福田 和彦学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Chordal translocation for ischemic mitral regurgitation may ameliorate tethering of the posterior and anterior mitral leaflets

ObjectiveTreatment of ischemic mitral regurgitation accompanied by strong tethering remains a challenge. Undersized ring annuloplasty is frequently associated with residual/recurrent mitral regurgitation caused by mitral-leaflet tethering. Although chordal cutting is a simple procedure for repairing severe tethering of the anterior mitral leaflet, it often affects mitral valvular-ventricular continuity. In this study, using 3-dimensional echocardiography, we investigated the effects of “chordal translocation” on the geometry of the mitral components in a canine model of acute ischemic mitral regurgitation.MethodsIn 6 mongrel dogs, under cardiopulmonary bypass with cardiac arrest, artificial chordae were implanted to each papillary-muscle tip and passed through the midseptal annulus to an external tourniquet to control the tension of the stitch thereafter. Subsequently, secondary chordae were cut near their point of attachment to the anterior leaflet. After weaning from cardiopulmonary bypass, acute ischemic mitral regurgitation was induced by ligating the obtuse marginal branches. We obtained data in 2 states of the artificial chordae: relaxation (simulating chordal cutting) and gentle traction (simulating chordal translocation).ResultsIn the chordal translocation state versus the chordal cutting state, the left ventricle ejection fraction (42.6% ± 2.9% vs 33.2% ± 2.3%, P < .0001), preload recruitable stroke work (54.8 ± 2.7 mm Hg vs 34.1 ± 2.2 mm Hg, P = .0002), and end-systolic elastance (6.7 ± 0.5 mm Hg/mL vs 4.2 ± 0.2 mm Hg/mL, P = .0013) improved markedly. The mitral-valve tethering volume, defined as the volume enclosed by the mitral annulus and 2 leaflets, was smaller in the chordal translocation state than in the chordal cutting state (812 ± 88 mm3 vs 1213 ± 41 mm3, P = .03). In the chordal translocation state (CT-1 and CT-2) versus the chordal cutting state, the posterior mitral-leaflet tethering area (15.7 ± 0.7 mm2 vs 25.1 ± 1.2 mm2, P < .0001 for CT-1 and 15.0 ± 0.7 mm2 vs 25.1 ± 1.2 mm2, P < .0001 for CT-2) showed a greater improvement than the anterior mitral-leaflet tethering area (41.0 ± 0.7 mm2 vs 46.1 ± 1.3 mm2 for CT-1, P = .01 and 812 ± 88 mm2 vs 1213 ± 41 mm2 for CT-2, P = .03). The mitral annular geometry did not differ between the states.ConclusionCompared with chordal cutting alone, chordal translocation improved both the left ventricle function and mitral geometry in a canine model of acute ischemic mitral regurgitation. Chordal translocation may be beneficial because it ameliorates the tethering of both the anterior and posterior leaflets, which is aggravated by mitral annuloplasty alone

Dual Effect of Organogermanium Compound THGP on RIG-I-Mediated Viral Sensing and Viral Replication during Influenza a Virus Infection

The interaction of viral nucleic acid with protein factors is a crucial process for initiating viral polymerase-mediated viral genome replication while activating pattern recognition receptor (PRR)-mediated innate immune responses. It has previously been reported that a hydrolysate of Ge-132, 3-(trihydroxygermyl) propanoic acid (THGP), shows a modulatory effect on microbial infections, inflammation, and immune responses. However, the detailed mechanism by which THGP can modify these processes during viral infections remained unknown. Here, we show that THGP can specifically downregulate type I interferon (IFN) production in response to stimulation with a cytosolic RNA sensor RIG-I ligand 5 '-triphosphate RNA (3pRNA) but not double-stranded RNA, DNA, or lipopolysaccharide. Consistently, treatment with THGP resulted in the dose-dependent suppression of type I IFN induction upon infections with influenza virus (IAV) and vesicular stomatitis virus, which are known to be mainly sensed by RIG-I. Mechanistically, THGP directly binds to the 5 '-triphosphate moiety of viral RNA and competes with RIG-I-mediated recognition. Furthermore, we found that THGP can directly counteract the replication of IAV but not EMCV (encephalitismyocarditis virus), by inhibiting the interaction of viral polymerase with RNA genome. Finally, IAV RNA levels were significantly reduced in the lung tissues of THGP-treated mice when compared with untreated mice. These results suggest a possible therapeutic implication of THGP and show direct antiviral action, together with the suppressive activity of innate inflammation