脂質メディエータースフィンゴシン1リン酸は,S1P[1]-Gi-Ras-MAPKに依存してKruppel-like Factor5を誘導することにより血小板由来成長因子を強力に刺激する

取得学位 : 博士（医学）, 学位授与番号 : 医博乙第1597号, 学位授与年月日 : 平成16年9月1日, 学位授与大学 : 金沢大

Adipose-derived regenerative cells exert beneficial effects on systemic responses following myocardial ischemia/reperfusion

Background: Acute coronary syndrome leads to systemic responses, including activation of the sympathetic nervous system, inflammation of atherosclerotic lesions, changes in metabolism and gene expressions of remote organs such as the spleen, bone marrow, and liver. Clinical trials and experimental studies have demonstrated that therapy with adipose-derived regenerative cells (ADRCs) attenuates myocardial ischemia/reperfusion (I/R) injury. The aim of this study is to investigate the role of ADRCs in regulating systemic reactions following I/R.Methods: Isolated ADRCs were obtained from green fluorescent protein transgenic male mice. Flow cytometry revealed that freshly isolated ADRCs expressed stem cell markers CD90 and Sca-1, and mesenchymal lineage marker. These cells exhibited multilineage differentiation into adipogenic, osteogenic, and chondrogenic lineages. Wild-type mice were subjected to 30 min of left ascending coronary ischemia and 24 h reperfusion. Freshly isolated ADRCs (105 cells) or vehicle (VEH), were administered intravenously through the tail at the time of reperfusion.Results: Compared to VEH, administration of ADRCs significantly reduced circulating troponin levels 24 h after I/R. Using quantitative real-time polymerase chain reaction analysis, the present study confirms that I/R-induced increase of factor X mRNA expression in the liver and was significantly inhibited by ADRCs compared to VEH. Administration of ADRCs significantly reduced the I/R-induced increase in serum levels of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-18 seen in mice receiving VEH.Conclusions: These results suggest that administration of ADRCs could have an important role in reducing myocardial injury and regulating the hepatic gene expression profile following I/R

Separated right and left ventricular excitation during right ventricular septal pacing in a patient with narrow QRS wave: A case report

Introduction. Right ventricular septal pacing is thought to be better than right ventricular apical pacing for shortening the QRS duration and for preserving left ventricular function. However, right ventricular septal pacing may not be effective in all cases. In this case report, we present a rare case in which right ventricular septal pacing induced thoroughly separated right and left ventricular excitation despite the presence of a relatively narrow QRS wave during atrium-only pacing. Case presentation. We report a case of 63-year-old Japanese man with cardiomyopathy with an implantable cardioverter defibrillator placement for ventricular tachycardia. Three years after implantation, he developed second-degree atrio-ventricular block. Therefore, atrio-ventricular sequential pacing was started; then his heart failure was much worsened. His electrocardiogram showed a dissociated biphasic QRS wave during right ventricular high-septal pacing, despite the presence of a non-fragmented QRS morphology during atrium-only pacing. An activation map during right ventricular high-septal pacing showed that right ventricular conduction started at the pacing site and ended at the right ventricular basal inferior site. Subsequently after a 10ms interval, left ventricular conduction started at the left ventricular posteroseptum and ended at the left ventricular lateral wall. These data indicate that during right ventricular high-septal pacing, the first component of the QRS wave supposedly reflects only right ventricular excitation and the second component only left ventricular excitation. Also due to the intracardiac electrograms, it was assumed that this phenomenon was caused by transversely limited severe transseptal conduction disturbance. Conclusion: It should be noted that even ventricular septal pacing could evoke harmful interventricular dyssynchrony due to transversely limited severe septal conduction disturbance, despite the presence of a relatively narrow QRS wave. © 2014 Yaegashi et al.; licensee BioMed Central Ltd

Autophagy Plays an Essential Role in Mediating Regression of Hypertrophy during Unloading of the Heart

Autophagy is a bulk degradation mechanism for cytosolic proteins and organelles. The heart undergoes hypertrophy in response to mechanical load but hypertrophy can regress upon unloading. We hypothesize that autophagy plays an important role in mediating regression of cardiac hypertrophy during unloading. Mice were subjected to transverse aortic constriction (TAC) for 1 week, after which the constriction was removed (DeTAC). Regression of cardiac hypertrophy was observed after DeTAC, as indicated by reduction of LVW/BW and cardiomyocyte cross-sectional area. Indicators of autophagy, including LC3-II expression, p62 degradation and GFP-LC3 dots/cell, were significantly increased after DeTAC, suggesting that autophagy is induced. Stimulation of autophagy during DeTAC was accompanied by upregulation of FoxO1. Upregulation of FoxO1 and autophagy was also observed in vitro when cultured cardiomyocytes were subjected to mechanical stretch followed by incubation without stretch (de-stretch). Transgenic mice with cardiac-specific overexpression of FoxO1 exhibited smaller hearts and upregulation of autophagy. Overexpression of FoxO1 in cultured cardiomyocytes significantly reduced cell size, an effect which was attenuated when autophagy was inhibited. To further examine the role of autophagy and FoxO1 in mediating the regression of cardiac hypertrophy, beclin1+/2 mice and cultured cardiomyocytes transduced with adenoviruses harboring shRNA-beclin1 or shRNA-FoxO1 were subjected to TAC/ stretch followed by DeTAC/de-stretch. Regression of cardiac hypertrophy achieved after DeTAC/de-stretch was significantly attenuated when autophagy was suppressed through downregulation of beclin1 or FoxO1. These results suggest that autophagy and FoxO1 play an essential role in mediating regression of cardiac hypertrophy during mechanical unloading

Cable externalization at the proximal portion of the superior vena cava coil in Riata implantable cardioverter defibrillator leads

Many Riata (St. Jude Medical, St. Paul, MN, USA) implantable cardioverter defibrillator (ICD) leads have reportedly developed cable externalization. The most likely cause of cable externalization is insulation abrasion, which often occurs at the can or between the right ventricular coil and superior vena cava (SVC) coil. We report a rare case of an adult male whose ICD lead cable was externalized at the proximal portion of the SVC coil. This lead became fixed to the wall at the subclavian vein and SVC and became bent between these adhesions. Furthermore, the motion of this lead was affected by pulsation of the aortic arch. The ICD lead might develop inside-out abrasion due to mechanical stress evoked by pulsation of the aortic arch at this site.. © 2016 Japanese College of Cardiology.Embargo Period 12 month

Intestinal angina in a patient with hypertrophic obstructive cardiomyopathy: a case report

Background: Intestinal angina is characterized by recurrent postprandial abdominal pain and anorexia. Commonly, these symptoms are caused by severe stenosis of at least two vessels among the celiac and mesenteric arteries. However, intestinal perfusion is affected not only by the degree of arterial stenosis but also by systemic perfusion. We experienced a unique case of intestinal angina caused by relatively mild stenosis of the abdominal arteries complicated with hypertrophic obstructive cardiomyopathy. Case presentation: We report an 86-year old Japanese man with hypertrophic obstructive cardiomyopathy and advanced atrioventricular block who was diagnosed with intestinal angina. Computed tomography showed mild stenosis of the celiac artery and severe stenosis of the inferior mesenteric artery, and these lesions were relatively mild compared with other reports. A dual-chamber pacemaker with right ventricular apical pacing was implanted to improve the obstruction of the left ventricular outflow tract. After implantation, the patient\u27s abdominal symptoms diminished markedly, and improvement of the left ventricular outflow tract obstruction was observed. Conclusions: Although intestinal angina is generally defined by severe stenosis of at least two vessels among the celiac and mesenteric arteries, the present case suggests that hemodynamic changes can greatly affect intestinal perfusion and induce intestinal angina in the presence of mild stenosis of the celiac and mesenteric arteries. © 2016 The Author(s)

Augmented single-unit muscle sympathetic nerve activity in heart failure with chronic atrial fibrillation

Atrial fibrillation (AF) is a common complication in heart failure (HF) patients. However, it remains unclear whether irregular ventricular response patterns induced by AF increase sympathetic nerve activity. We measured resting multi- and single-unit muscle sympathetic nerve activity (MSNA) in 21 age-matched HF patients with chronic AF (n= 11) rhythm or sinus rhythm (SR, n= 10). The multi-unit MSNA, which was expressed as total activity, was similar between HF + AF patients and HF + SR patients. However, the single-unit MSNA in HF + AF patients was significantly greater than that in HF + SR patients (62 ± 9 spikes min -1vs. 42 ± 4 spikes min -1, P < 0.05). Moreover, the incidence of multiple firing of single-unit MSNA within a given burst was augmented in HF + AF patients as compared with HF + SR patients (48 ± 8%vs. 26 ± 3%, P < 0.01). A significant negative relationship was observed between the reduced diastolic pressure induced by a prolonged cardiac interval in AF subjects and single-unit MSNA frequency within one cardiac interval in each HF + AF subject. The firing characteristics of single-unit MSNA were different between HF patients with AF and HF patients with SR; particularly, those with a prolonged long RR interval showed multiple firings of single-unit MSNA. These findings suggest that AF per se leads to the instantaneous augmentation of single-unit MSNA induced by decreased diastolic pressure, which might partially contribute to disease progression in HF patients. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society

Altered gene expression in T-cell receptor signalling in peripheral blood leucocytes in acute coronary syndrome predicts secondary coronary events

Objective: Comprehensive profiling of gene expression in peripheral blood leucocytes (PBLs) in patients with acute coronary syndrome (ACS) as a prognosticator is needed. We explored the specific profile of gene expression in PBLs in ACS for long-term risk stratification. Methods: 30 patients with ACS who underwent primary percutaneous coronary intervention (PCI) and 15 age-matched adults who participated in medical check-ups were enrolled from three centres. Peripheral blood samples were collected to extract RNA for microarray analyses. Results: During the 5-year follow-up, 36% of this cohort developed the expected non-fatal coronary events (NFEs) of target lesion revascularisation (TLR) and PCI for a de novo lesion. Class comparison analysis (p<0.005) demonstrated that 83 genes among 7785 prefiltered genes (41 upregulated vs 42 downregulated genes) were extracted to classify the patients according to the occurrence of NFE. Pathway analysis based on gene ontology revealed that the NFEs were associated with altered gene expression regarding the T-cell receptor signalling pathway in ACS. Univariate t test showed that the expression level of death-associated protein kinase1 (DAPK1), known to regulate inflammation, was the most significantly negatively regulated gene in the event group (0.61-fold, p<0.0005). Kaplan-Meier curve analysis and multivariate analysis adjusted for baseline characteristics or clinical biomarkers demonstrated that lower DAPK1 expression in PBL emerged as an independent risk factor for the NFEs (HR: 8.73; CI 1.05 to 72.8, p=0.045). Conclusions: Altered gene expression in T-cell receptor signalling in PBL in ACS could be a prognosticator for secondary coronary events. © Published by the BMJ Publishing Group Limited