京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13328号 / 論医博第2196号 / 新制||医||1044(附属図書館) / (主査)教授 柳田 素子, 教授 佐藤 俊哉, 教授 長船 健二 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Regelmäßige körperliche Aktivität verlangsamt die Progression arteriosklerotischer Läsionen, reduziert oxidativen Stress und erhöht die Bioverfügbarkeit von Stickstoffmonoxid. Von diesen Vorgängen erwartet man auch eine Verbesserung des Outcomes bei degenerativen Aortenklappenerkrankungen. Ziel der vorliegenden Arbeit war es den Effekt von körperlicher Aktivität im Sinne einer Primärprävention auf die Ausbildung einer Aortenklappensklerose, die ein frühes Stadium in der Entwicklung einer Aortenklappenstenose darstellt, mit ihrem zu Grunde liegendem Pathomechanismus zu untersuchen. Hierfür wurde das Tiermodell der LDL-Rezeptor-knockout-Maus gewählt, da bereits in Studien die regelhafte Induktion von Aortenklappensklerosen und hämodynamisch relevante Stenosen durch cholesterinreiche Nahrung gezeigt werden konnte. Für die vorliegende Studie wurden 4 Wochen alte LDL-Rezeptor-knockout-Mäuse in 4 Gruppen randomisiert: Eine Kontroll-Gruppe mit normaler Diät und bewegungsarmen Lebensstil, eine Cholesterin-Gruppe mit cholesterinreicher Ernährung und bewegungsarmen Lebensstil, eine regelmäßige Trainingsgruppe mit cholesterinreicher Ernährung und regelmäßiger körperlicher Aktivität (60 min/d, 5 Tage/Woche) und eine gelegentlichen Trainingsgruppe, mit cholesterinreicher Ernähung und körperlicher Aktivität (60 min/d, 1 Tag/Woche) für jeweils 16 Wochen. In der 20. Woche wurden histologische Untersuchungen vorgenommen, die Verdickungen der Aortenklappen in der Cholesterin-Gruppe verglichen zur Kontroll-Gruppe zeigten. Regelmäßige, jedoch keine gelegentliche körperliche Aktivität reduziert signifikant diese Verdickung der Aortenklappe. Die immunhistochemischen Untersuchungen zeigten, dass eine Cholesterin-Diät die Endothelintegrität der Aortenklappe zerstört, wohingegen sie durch regelmäßige körperliche Aktivität geschützt wird. Weiterhin zeigte sich eine Erhöhung der Serum-Myeloperoxidase, der oxidierten Low Density Lipoproteine, der in situ Superoxide, als Marker für oxidativen Stress. Es konnten erhöhte Spiegel für Mac3, als Marker für Makrophagenakkumulation, α-smooth muscle actin, als Marker für Klappenfibrose und der proosteogene Marker Alkalische Phosphatase sowie eine erhöhte Mineralisation in der Cholesterin-Gruppe nachgewiesen werden. Wohingegen die genannten Marker in der Gruppe mit regelmäßiger körperlicher Aktivität erniedrigt nachgewiesen werden konnten. Die Ergebnisse der Polymerase-Kettenreaktion ergaben eine erhöhte Expression der messenger-RNA für α-smooth muscle actin, bone morphogentic protein-2, runt- related transcription factor-2 und Alkalische Phosphatase, als Marker für Klappenfibrose und Proosteogenese in der Cholesterin-Gruppe, dagegen waren sie durch regelmäßige körperliche Aktivität erniedrigt. Darüber hinaus erhöht regelmäßige körperliche Aktivität signifikant die Spiegel von zirkulierendem Fetuin-A, als Hemmstoff der Kalzifizierung verglichen zur Cholesterin-Gruppe. Schlussfolgernd lässt sich sagen, dass regelmäßige, jedoch keine gelegentliche körperliche Aktivität einer Aortenklappensklerose im Sinne einer Primärprävention durch eine Anzahl von Mechanismen, wie dem Schutz der Endothelintegrität, der Reduktion von Inflammation und oxidativem Stress sowie der Hemmung des osteogenen Signalweges, vorbeugt.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Congenital heart disease (CHD) is a risk factor for premature cardiovascular complications. Great advances have occurred in the past years leading to the identification of several genes essential for proper cardiac formation such as GATA4/5/6 mutated in some individuals with CHD. GATA6 is a zinc finger transcription factor whose presence is crucial for early embryonic development. GATA6 is expressed in many cell types of the heart including myocardial, endocardial, neural crest, and vascular smooth muscle. In human, mutations in GATA6 result in variable cardiac phenotypes. The objective of this thesis was to determine the roles that GATA6 play in the different cell types of the heart and to elucidate the molecular basis of the cardiac defects associated with Gata6 haploinsufficiency. For this, a combination of cell and molecular techniques were used in vitro and in vivo. First, we show that Gata6 heterozygozity leads to RL-type bicuspid aortic valve (BAV)- the most common CHD affecting 2% of the population. GATA6-dependent BAV is the result of disruption of valve remodeling and extracellular matrix composition in Gata6 haploinsufficient mice. Cell-specific inactivation of one Gata6 allele from Isl-1 positive cells, but not from endothelial or neural crest cells, recapitulates the phenotype of Gata6 heterozygous mice revealing an essential role for GATA6 in secondary heart field myocytes during valvulogenesis. We further uncovered a role for GATA6 as an important regulator of the cardiac conduction system and revealed that GATA6 expression regulates the activity of the cardiac pacemaker. GATA6 exerts its role via regulation of the cross-talk among the different cell types of the SAN. Lastly, some CHDs are characterized by abnormalities of both the limbs and the heart such as the Holt Oram syndrome (caused by mutation in TBX5 transcription factor). The molecular basis for limb-heart defects remain poorly understood. In the course of this work, we discovered that Gata6 haploinsufficiency resulted in a partially penetrant polysyndactyly (extra digits fused together) phenotype. Together, the data provide novel molecular and cellular insight into GATA6 role in normal and pathologic heat development. Our results also suggest that GATA6 should be added to the list of genes whose mutations are potentially associated with heart and limb abnormalities. Better knowledge of the molecular basis of CHD is a prerequisite for the development of diagnostic and therapeutic strategies to improve care of individuals with congenital heart disease.

Transcatheter aortic valve replacement in the setting of failed surgical bioprosthesis (valve-in-valve) is a valuable option for patients with bioprosthetic aortic stenosis or regurgitation who are deemed high risk for repeat open heart surgery. Although the procedure is successful with proper preprocedural assessment, instances of left main (LM) coronary artery ostium obstruction have been documented. We present a case of LM coronary obstruction in the immediate postoperative period following implantation of a 20-mm Edwards Sapien 3 valve inside the degenerated 21-mm Mitroflow bioprosthesis stenosis, which was treated with double stenting alongside the Edwards Sapien 3 valve creating a channel (“neo left main”) that extended from mid-LM to the upper margin of the Edwards Sapien 3 valve. Although valve-in-valve in a Mitroflow degenerated bioprosthesis is a relatively safe procedure, 2 or more stents may be necessary to scaffold a channel to the coronary arteries between Edwards Sapien 3 prosthesis and aorta in the event of a coronary obstruction.

<div><div><div><p>The aorta has many complex features including valve and vessel wall geometry, blood flow, and wall composition. Diseases such as aortic aneurysms and aortic valve lesions affect vessel function and may even lead to rupture, which can be fatal. However, current clinical diagnoses of aortopathies mainly rely on simple parameters such as diameter and growth rate. To better understand aortopathies and ultimately improve patient diagnoses and treatments, it is important to investigate disease progression as well as the effect of vessel wall composition changes and hemodynamic forces on aortic biomechanics, such as strain and wall shear stress distribution. Preclinical research using small animals allows for disease progression to be studied while controlling outside factors. The next important step is to apply the methods used in the preclinical studies to human patient data. Both preclinical and clinical studies often focus on noninvasive, patient-specific methods for further characterizing the biomechanics of the aorta using advanced techniques such as 4D flow magnetic resonance imaging, 4D ultrasound, computational fluid dynamics (CFD), and fluid structure interaction (FSI) modeling. Yet the challenge of bridging these research techniques to a clinical setting remains. Factors such as financial costs, acquisition time, and ease of analysis must be considered. Therefore, the following document highlights two specific aims to extend our knowledge about the effects of aneurysms and aortic valve lesions. We will 1) characterize the regional effects of murine abdominal aortic aneurysms on strain over time, and 2) use CFD and FSI to simulate the hemodynamic effects on the thoracic aorta using both murine and human patient imaging data. Conducting research using clinically translatable methods of biomechanical characterization that consider the complexity of the aorta on a patient-specific basis will contribute to our understanding and lead to better patient outcomes.</p></div></div></div>

Objective: Studies have shown that iodinated radiocontrast use is associated with acute renal failure especially in the presence of chronic kidney disease and multiple factors modulate this risk. The purpose of this meta-analysis is to compare the incidence of renal failure requiring hemodialysis between transfemoral (TF) and transapical (TA) transcatheter aortic valve replacement using the Edwards valve. Methods: The PubMed database was searched from January 2000 through December 2014. A total of 10 studies (n = 2,459) comparing TF (n = 1,268) and TA (n = 1,191) TAVR procedures using the Edwards valve were included. Variables of interest were baseline logistic EuroSCORE, prevalence of diabetes mellitus, hypertension, peripheral arterial disease, chronic kidney disease and amount of contrast used. The primary endpoint was incidence of renal failure requiring hemodialysis. The odds ratio and 95% CI were computed and P < 0.05 was considered as the level of significance. Results: The logistic EuroSCORE was significantly higher in TA compared to TF (P = 0.001) TAVR. The amount of contrast (mL) used was significantly higher in the TF group compared to the TA group (mean difference: 36.9, CI: 25.7-48.1, P < 0.001). The incidence of hemodialysis following the procedure was significantly higher in the TA group compared to TF group (odds ratio = 4.3, CI: 2.4-7.8, P < 0.00001). Conclusions: This meta-analysis suggests that despite the lower amount of contrast used in TA-TAVR, the incidence of renal failure requiring hemodialysis was higher with the Edwards valve. This suggests that the incidence of renal failure requiring hemodialysis after TAVR is associated with baseline comorbidities in the TA-TAVR group rather than the volume of contrast used.

Objectives: In patients with severe aortic stenosis who are at high risk for surgery, transcatheter aortic valve replacement (TAVR) has emerged as an alternative procedure using EV or CV. The objective of this meta-analysis is to compare 1-year mortality and major adverse cardiovascular and cerebrovascular events (MACCE) between Edwards valve (EV) and Medtronic CoreValve (CV). Methods: PubMed and the Cochrane Center Register of Controlled Trials were searched through December 2014. Twenty seven studies (n = 12,249) comparing TAVR procedure that used EV (n = 5745) and CV (n = 6504) were included. End points were procedural success rates, post-procedural mortality, myocardial infarction (MI), stroke, major bleeding, major vascular complications, incidence of new permanent pacemaker (PPM) placement and new left bundle branch block (LBBB). The odds ratio (OR) with 95% confidence interval (CI) was computed and p < 0.05 was considered for significance. Results: There were no significant differences between EV and CV for post-procedural in-hospital, 30-day and 1-year all-cause mortality rates (p = 0.53, 0.33 and 0.94 respectively), cardiovascular mortality (p = 0.61), stroke (p = 0.54), major bleeding (p = 0.25) and major vascular complications (p = 0.27). MI was significantly lower with EV compared to CV (OR: 0.56, CI: 0.35-0.89, p = 0.01). Placement of new PPM and new onset LBBB were significantly higher in CV compared to EV (OR: 3.35, CI: 2.96-3.79, p < 0.00001 and OR: 6.55, CI: 4.76-9.03, p < 0.00001 respectively). Conclusions: The results of our meta-analysis suggest that TAVR procedure using CV may be associated with a higher incidence of MI, new PPM placement, and new onset LBBB compared to EV. However, the type of valve placed does not affect mortality.

No description available.

PhD Thesis / Cardiac surgeons rely on simulation training to improve their surgical skills. The focus of this research was on creating a 3D aortic valve model for cardiac surgical skills training. The research was divided into four different stages including CAD model development, tissue testing using surgical tools, aortic valve model manufacturing and model evaluation. First, the development of a patient-specific aortic valve model was carried out. The process involved heavily processing CT scanned data of the aortic valve to extract the geometric information via segmentation. Patient-specific models are critical for pre-operative planning and training. However, those models are not ideal for large volume quantities due to the high production costs and the extensive manual labour required to process the models. Therefore, another approach was chosen to produce a generic model that was more suitable for large volume quantities. The generic aortic valve model was developed using data obtained from the literature. The contribution in this stage was developing the methodology to reverse engineer patient-specific cardiac tissues. Additionally, a generic CAD model of the aortic valve was developed. Second, to select suitable materials for the model, samples from biological tissues and polymers were tested using a surgical tool. The contribution in this stage was documenting the forces and displacements obtained from puncturing and cutting the samples using suturing needles and scalpel blades. Third, the aortic valve model was manufactured using two approaches including AM and casting. The contribution in this stage revolved around the development of several moulds for casting. Finally, evaluation of the model was done via an initial assessment session with surgical residents. Although the model was not evaluated in extensive training sessions, a plan highlighting the important elements to do that was included in this research. Thus, the contribution in this stage was developing the model testing plan. / Thesis / Doctor of Philosophy (PhD) / Typically, surgeons use post-mortem human tissues (cadavers) and animal tissues for surgical skills training. However, those methods can be both expensive and limited in availability. Therefore, other non-biological methods are introduced constantly to provide viable alternatives. Those methods include producing models using 3D printing, virtual reality (VR) simulation and even using household items to create training models. However, to date, there is a lack of highly accurate representation of real tissues (fidelity) of most models for cardiac surgical training. The purpose of this research was to develop and manufacture surgical skill training tools for cardiac surgeons focusing on the aortic valve cardiac tissues. The research was divided into several parts including developing computer models using patient-specific medical imaging, developing a general training model and training models manufacturing. Also, the research included manufacturing materials selection process as well as plans for testing the training models in training sessions.