Les lésions d’athérosclérose sont une des causes majeurs du développement de pathologies cardiovasculaires. Cette pathologie chronique à l’origine inflammatoire est caractérisée par des mécanismes moléculaires et cellulaires complexes. L’activité de minéralisation retrouvée au sein des lésions est un critère clé de l’avancée de la maladie. A l’aide d’un modèle murin d’athérosclérose accélérée et de travaux d’optimisation technique, nous avons exploré la faisabilité de l’exploitation de l’imagerie par tomographie à émission de positons au fluorure de sodium associée à l’imagerie à résonance magnétique de la pathologie dans un modèle murin d’athérosclérose accélérée. Dans ce travail nous avons mis en évidence une activité de minéralisation précoce et soutenue associée à un statut inflammatoire plus avancé chez les animaux insuffisants rénaux. Ajouté à cela, nous avons mis en place un nouveau modèle murin de rétrécissement aortique calcifié par irradiation localisée. / Atherosclerosis lesions are a leading cause of cardiovascular events. Atherosclerosis is a chronic inflammatory disease including complex molecular and cellular mechanisms. Mineralization process within the atherosclerosis lesions is a key feature of the disease development. Using a mouse model of accelerated atherosclerosis and imaging optimisation study, we showed the feasability of sodium fluoride positron emission tomography combined to magnetic resonance imaging to assess molecular activity in a mouse model of accelerated atherosclerosis. We showed that uremic animals had an early and sustained mineralization activity associated to an advanced inflammatory state. Furthermore, we developped a new mouse model of calcified aortic stenosis using targeted radiation exposure.

In der Literatur wird bei kleineren Patientenkohorten über eine erhöhte Prävalenz des linkskoronaren Versorgungstyps bei Patienten mit valvulärer Aortenklappenstenose berichet. Es wird auch postuliert, dass dies nur Patienten mit Aortenklappenstenose und bikuspider Aortenklappe betrifft. Die funktionelle Konsequenz der Kombination aus einem linksdominanten koronaren Versorgungstyp und valvulärer Aortenklappenstenose ist bisher nicht klar. Ziel der vorliegenden Arbeit war es, die Prävalenz des Linksversorgungstyps in einer großen Kohorte von Patienten mit diagnostizierter relevanter Aortenklappenstenose im Vergleich zu einer Kontrollkohorte ohne Aortenklappenstenose zu analysieren. Es galt ferner zu prüfen, ob sich eine etwaig höhere Prävalenz des koronaren Linksversorgungstyps auf Patienten mit bikuspider Aortenklappe beschränkt, ob der koronare Linksversorgungstyp ein unabhängiger Risikofaktor für die Progression einer Aortenklappenstenose ist und ob die koronare Linksdominanz Relevanz für das postoperative beziehungsweise postinterventionelle Outcome nach Aortenklappenersatz hat. Über eine Datenbankabfrage wurden alle Patienten identifiziert, die vom 01.01.2007 bis 31.12.2008 in der Klinik für Innere Medizin und Kardiologie im Herzzentrum der Universität Leipzig aufgenommen wurden. Zwei Subkohorten wurden extrahiert. Kohorte 1 umfasste alle Patienten mit einer bekannten oder neu diagnostizierten, symptomatischen und isolierten Stenose der nativen Aortenklappe. Kohorte 2 umfasste alle Patienten, welche einer invasiven Koronarangiographie unterzogen wurden und keine beginnende oder fortgeschrittene Aortenklappenstenose zeigten sowie ≥70 Jahre waren. Kohorte 1 umfasste 721, Kohorte 2 6990 Patienten. Der linkskoronare Versorgungstyp zeigte sich bei Patienten mit Aortenklappenstenose signifikant häufiger als bei Kontrollpatienten ohne Aortenklappenstenose (13.2% versus 10.2%, p=0.003). Eine signifikant niedrigere Prävalenz des rechtskoronaren Versorgungstypen fand sich bei Patienten mit einer Aortenklappenstenose (66.9% versus 71.6%, p=0.008). Beide Prävalenzen waren unabhängig vom Vorliegen einer bi- oder trikuspiden Klappenarchitektur. Es bestand lediglich ein geringer Trend zu einer höheren Prävalenz der linkskoronaren Dominanz bei Patienten mit bikuspider Klappe im Vergleich zu Patienten mit trikuspider Klappe (15 [20.8%] versus 60 [13.9%], p=0.12). Keine Unterschiede zeigten sich indessen für die intrahospitale Mortalität und Auftreten eines akuten Myokardinfarktes zwischen den koronaren Versorgungstypen. Die linkskoronare Dominanz ist kein Risikofaktor für eine Progression der Aortenklappenstenose.

Background: Once aortic stenosis (AS) is severe, patients develop symptoms at different stages. Indeed, symptom status may correlate poorly with the grade of valve narrowing. Multiple pathophysiological mechanisms, other than valvular load, may explain the link between AS and symptom severity. We aimed to describe the relationship between the severity of symptoms and the characteristics of a cohort of patients with severe AS already referred for aortic valve replacement (AVR). Methods: We analyzed 118 consecutive patients (70 ± 9 years, 55% men) with severe AS referred for AVR. We identified 84 patients with New York Heart Association (NYHA) I–II, and 34 with NYHA III–IV symptoms. Clinical and echocardiographic parameters were compared between these two groups. Left ventricular ejection fraction (LVEF), global longitudinal peak systolic strain (GLPS), NT-pro-B-type natriuretic peptide (BNP), and high-sensitive troponin T (hs-TNT) were determined at the time of admission. Results: AS severity was similar between groups. Compared with the NYHA I–II group, patients in NYHA III–IV group were older and more likely to have comorbidities, worse intracardiac hemodynamics and more LV damage. Variables independently associated with NYHA III–IV symptomatology were the absence of sinus rhythm, higher E/e0 ratio, and increased hs-TNT. GLPS showed a good correlation not only with hs-TNT as a marker of myocardial damage, but also with markers of increased afterload imposed on LV, being not directly related with advanced symptoms. Conclusions: Advanced symptoms in patients with severe AS referred for AVR are associated with worse intracardiac hemodynamics, absence of sinus rhythm, and more myocardial damage. It supports the concept of transition from adaptive LV remodeling to myocyte death as an important determinant of symptoms of heart failure. :Einführung................................................................................................3 Publikationsmanuskript...........................................................................12 Zusammenfassung..................................................................................19 Literaturverzeichnis..................................................................................24 Erklärung über die eigenständige Abfassung der Arbeit.........................28 Darstellung des eigenen Beitrags............................................................29 Curriculum vitae.......................................................................................30 Danksagung.............................................................................................36

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.

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23767号 / 医博第4813号 / 新制||医||1056(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 大鶴 繁, 教授 小西 靖彦, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Coarctation of the aorta (CoA) is a congenital heart disease which represents a narrowing of the proximal descending aorta, hence increasing pressure afterload to the left ventricle (LV). Conventional treatment of native CoA is surgical repair, however potential recurrence or other related complications e.g. aortic rupture, heart failure and cerebrovascular events are common. Thus, lifelong follow-up of these patients is required. Echocardiography is the most patient’s friendly method to evaluate CoA and in particular its effect on LV function. Moreover, the novel speckle tracking echocardiography (STE) is an important method to assess subclinical LV dysfunction, a technique that promises better evaluation of LV function in these patients. The aims of this thesis were to review the literature on LV function in children with CoA using myocardial deformation imaging technologies, hence, to better understand the current knowledge and vagueness of the scientific evidence. We also aimed to study the effect of early CoA repair on the structure and function of LV and ascending aorta. In addition, we wished to establish in a meta-analysis format normal values of speckle tracking derived strain and strain rate values. Methods: Study 1. We have systematically searched the PubMed, and studies that fulfilled the inclusion criteria were critically analyzed and presented on a narrative form. Study 2 and 3. In addition to conventional echocardiographic measures of LV and ascending aorta, we measured longitudinal strain and strain rate of the LV using a vendor independent software, TomTec. We have also measured the aorto-septal angle (AoSA). Data was compared with normal healthy controls. Study 4. Electronic databases were systematically searched and suitable studies were meta analyzed using Comprehensive meta-analysis version 3 software. Results: Study 1. In 7/4945 included articles, 123 and 76 patients with congenital aortic stenosis (CAS) and CoA were reported, respectively. Normal conventional LV function, with subclinical myocardial dysfunction were reported in all studies before intervention. After intervention, a consistent improvement of myocardial deformation parameters was documented, even though not reaching normal values. Study 2. In 21 patients with CoA, LV function significantly improved after intervention (p <0.001), however normal values were not reached even at medium-term follow-up (p = 0.002). Medium-term longitudinal strain correlated with pre intervention LV ejection faction (EF) (r = 0.58, p = 0.006). Medium-term subnormal values were more frequently associated with Bicuspid aortic valve (BAV) (33.3% vs. 66.6%; p <0.05). Study 3. AoSA was abnormally wide before intervention, in particular at peak ejection in the descending aorta (p <0.0001), and correlated with CoA pressure gradient. After intervention, AoSA normalized and significantly correlated with the increase of LV cavity function and overall LV deformation parameters. Study 4. In a meta-analysis of 28/282 studies including 1192 subjects, strain and strain rate values were established. Longitudinal strain normal mean values varied from -12.9 to -26.5 (mean, -20.5; 95 % CI, -20.0 to -21.0). Normal mean values of circumferential strain varied from -10.5 to -27.0 (mean, -22.06; 95 % CI, -21.5 to -22.5). Radial strain normal mean values varied from 24.9 to 62.1 (mean, 45.4; 95 % CI, 43.0 to 47.8). Meta-regression showed LV end-diastolic diameter as a significant determinant of variation of longitudinal strain. Longitudinal systolic strain rate was significantly determined by age and radial strain was influenced by the type of vendor used. Conclusion: The systematic review showed subclinical LV dysfunction in children with CoA before and after correction. However, since most of the patients were operated at an older age and had preserved LV EF, the effect of early intervention on LV function was only speculated. Our children with CoA who were operated at an earlier age showed LV subclinical dysfunction even at medium- term after intervention while the AoSA returned to normal shortly after intervention. Lower longitudinal strain values were found in patients with LV dysfunction (LV EF <50%) before intervention and BAV. Finally, normal range values for strain and strain rate have been established and seem to be influenced by patients’ age, LV end-diastolic diameter and vendor used.

Introduction: Transcatheter aortic valve implantation (TAVI) is an established procedure to treat severe aortic stenosis (AS). This study investigates the impact of ischemic heart disease (IHD) on survival in patients undergoing TAVI. Aim: Five-year all-cause mortality stratified according to the presence or absence of IHD. Methods: Retrospective register study including all patients that underwent a TAVI-procedure 2009 to 2018. Patients were stratified according to the presence or absence of IHD. Our primary end-point was five-year all-cause mortality. Survival was analyzed using Kaplan-Meier curve. Data were acquired through the SWENTRY registry and patient files. Results: A total of 264 patients were included in the study, with 139 (52.7 %) patients in the IHD group vs 125 (47.3 %) patients in the non-IHD group. Mean follow-up time was 40 ±30 months. At baseline, there was a higher proportion of males, patients with hypertension, peripheral arterial disease, left ventricular ejection fraction <50 % and, a higher EuroSCORE I in the IHD-group. Transfemoral approach was most common in both groups. No differences were noted in respect to peri- and postoperative complications. Five-year all-cause mortality was 17/38 (44.7 %) vs 18/30 (60.0 %), p = 0,232, in the IHD and non-IHD group respectively. Non-adjusted cumulative five-year survival was not significantly different between the groups (Log-Rank, p = 0,056). Conclusions: In patients with severe AS undergoing TAVI, the five-year all-cause mortality was not statistically different between patients with or without IHD.

Background:  The right ventricle (RV) is multi-compartmental in orientation with a complex structural geometry. However, assessment of this part of the heart has remained an elusive clinical challenge. As a matter of fact, its importance has been underestimated in the past, especially its role as a determinant of cardiac symptoms, exercise capacity in chronic heart failure and survival in patients with valvular disease of the left heart. Evidence also exists that pulmonary hypertension (PH) affects primarily the right ventricular function. On the other hand, previous literature suggested that severe aortic stenosis (AS) affects left ventricular (LV) structure and function which partially recover after aortic valve replacement (AVR). However, the impact of that on RV global and segmental function remains undetermined.  Objectives: We sought to gain more insight into the RV physiology using 3D technology, Speckle tracking as well as already applicable echocardiographic measures. Our first aim was to assess the normal differential function of the RV inflow tract (IT), apical and outflow tract (OT) compartments, also their interrelations and the response to pulmonary hypertension. We also investigated the extent of RV dysfunction in severe AS and its response to AVR. Lastly, we studied the extent of global and regional right ventricular dysfunction in patients with pulmonary hypertension of different aetiologies and normal LV function. Methods: The studies were performed on three different groups; (1) left sided heart failure with (Group 1) and without (Group 2) secondary pulmonary hypertension, (2) severe aortic stenosis and six months post AVR and (3) pulmonary hypertension of different aetiologies and normal left ventricular function. We used 3D, speckle tracking echocardiography and conventionally available Doppler echocardiographic transthoracic techniques including M-mode, 2D and myocardial tissue Doppler. All patients’ measurements were compared with healthy subjects (controls). Statistics were performed using a commercially available SPSS software. Results: 1-  Our RV 3D tripartite model was validated with 2D measures and eventually showed strong correlations between RV inflow diameter (2D) and end diastolic volume (3D) (r=0.69, p<0.001) and between tricuspid annular systolic excursion (TAPSE) and RV ejection fraction (3D) (r=0.71, p<0.001). In patients (group 1 & 2) we found that the apical ejection fraction (EF) was less than the inflow and outflow (controls:  p<0.01 & p<0.01, Group 1:  p<0.05 & p<0.01 and Group 2: p<0.05 & p<0.01, respectively). Ejection fraction (EF) was reduced in both patient groups (p<0.05 for all compartments). Whilst in controls, the inflow compartment reached the minimum volume 20 ms before the outflow and apex, in Group 2 it was virtually simultaneous. Both patient groups showed prolonged isovolumic contraction (IVC) and relaxation (IVR) times (p<0.05 for all). Also, in controls, the outflow tract was the only compartment where the rate of volume fall correlated with the time to peak RV ejection (r = 0.62, p = 0.03). In Group 1, this relationship was lost and became with the inflow compartment (r = 0.61, p = 0.01). In Group 2, the highest correlation was with the apex (r=0.60, p<0.05), but not with the outflow tract. 2- In patients with severe aortic stenosis, time to peak RV ejection correlated with the basal cavity segment (r = 0.72, p<0.001) but not with the RVOT. The same pattern of disturbance remained after 6 months of AVR (r = 0.71, p<0.001). In contrast to the pre-operative and post-operative patients, time to RV peak ejection correlated with the time to peak outflow tract strain rate (r = 0.7, p<0.001), but not with basal cavity function. Finally in patients, RVOT strain rate (SR) did not change after AVR but basal cavity SR fell  (p=0.04). 3- In patients with pulmonary hypertension of different aetiologies and normal LV function, RV inflow and outflow tracts were dilated (p<0.001 for both). Furthermore, TAPSE (p<0.001), inflow velocities (p<0.001), basal and mid-cavity strain rate (SR) and longitudinal displacement (p<0.001 for all) were all reduced. The time to peak systolic SR at basal, mid-cavity (p<0.001 for both) and RVOT (p=0.007) was short as was that to peak displacement (p<0.001 for all). The time to peak pulmonary ejection correlated with time to peak SR at RVOT (r=0.7, p<0.001) in controls, but with that of the mid cavity in patients (r=0.71, p<0.001). Finally, pulmonary ejection acceleration (PAc) was faster (p=0.001) and RV filling time shorter in patients (p=0.03) with respect to controls. Conclusion: RV has distinct features for the inflow, apical and outflow tract compartments, with different extent of contribution to the overall systolic function. In PH, RV becomes one dyssynchronous compartment which itself may have perpetual effect on overall cardiac dysfunction. In addition, critical aortic stenosis results in RV configuration changes with the inflow tract, rather than outflow tract, determining peak ejection. This pattern of disturbance remains six month after valve replacement, which confirms that once RV physiology is disturbed it does not fully recover. The findings of this study suggest an organised RV remodelling which might explain the known limited exercise capacity in such patients. Furthermore, in patients with PH of different aetiologies and normal LV function, there is a similar pattern of RV disturbance. Therefore, we can conclude that early identification of such changes might help in identifying patients who need more aggressive therapy early on in the disease process.