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The management of the asymptomatic patients with severe aortic stenosis (AS) is challenging; clinicians have to balance the risks of early surgery against the risk that irreversible myocardial damage may occur with a conservative management strategy. It has become increasingly apparent that prognosis in asymptomatic AS depends not only on the degree of valvular stenosis, but also on the myocardial response to pressure overload and understanding the mechanisms of myocardial decompensation may help to guide management in the future. The degree of myocardial fibrosis, microvascular dysfunction, hypertrophy and left ventricular (LV) geometry may all play important roles. However, current guidelines for management of asymptomatic AS limit assessment of the myocardium to the measurement of ejection fraction with echocardiography. More advanced techniques may provide greater information that could be clinically useful. This thesis seeks to further our understanding of the mechanisms of the myocardial response to AS, using Cardiac Magnetic Resonance (CMR) in patients with moderate and severe AS. Myocardial perfusion in AS is examined in chapter 3. The results show that CMR first pass perfusion can be carried out safely and is well tolerated by AS patients. Microvascular dysfunction in these patients was associated with age, exercise time and markers of diastolic dysfunction. Myocardial strain is examined in chapter 4, utilizing a new software tool to look at strain throughout the left ventricle, and also to explore the relationship between strain and myocardial fibrosis. The results show that there are significant variations in circumferential strain measurements, depending on slice position in the LV, and also that there was no relationship found between strain and the degree of LV fibrosis. In chapter 5, the potential of CMR T1 mapping to identify fibrosis is examined using a new shortened non-contrast sequence (ShMOLLI - Shortened Modified Look-Locker Inversion) developed in our unit. CMR T1 values were validated against histological quantification of myocardial fibrosis in a large group of moderate and asymptomatic AS. A good correlation was found between ShMOLLI derived T1 values, with T1 values increasing with the severity of AS. The clinical value of measuring myocardial perfusion and LV global strain is examined in chapter 6 by linking these to prognosis. Measurement of circumferential strain could predict prognosis in asymptomatic AS, but myocardial perfusion showed poor ability to predict events. In conclusion, this thesis offers further insights into the changes that occur in the myocardium of patients with asymptomatic moderate and severe AS, using established and new CMR techniques. The clinical value of measuring these CMR parameters to aid risk stratification is shown, and the future potential for monitoring new therapies in these patients is discussed in the final chapter.

We report our experience with asymptomatic valvar aortic stenosis diagnosed during infancy. During the period between November 1, 1986 and October 31, 1992 a total of 13 infants were diagnosed with asymptomatic aortic stenosis, 5 of whom showed rapid progression over the first 2 years of life. Two of these asymptomatic infants had severe aortic stenosis by 2 months of age, requiring intervention. We agree that aortic stenosis is a progressive lesion even in mild cases, but we emphasize the need for close clinical and echocardiographic follow-up of these asymptomatic children during infancy to prevent congestive heart failure and sudden death.

UA Open Access Publishing Fund / Background: The use of intra-aortic balloon pump (IABP) via the trans-femoral approach has been established for hemodynamic support in patients undergoing high-risk percutaneous coronary intervention (PCI). However, there are various challenges associated with its use, especially in patients with aortoiliac occlusive arterial disease. Case presentation: We describe a case of high-risk PCI with IABP support complicated by intra-procedural detection of severe abdominal aortic stenosis that was successfully overcome with angioplasty of the stenotic lesion. Conclusions: Our report highlights distal abdominal aortic stenosis as a potential barrier to successful PCI with IABP support, and angioplasty as an effective means to overcome it.

Introduction. Aortic stenosis is characterised both by progressive narrowing of the valve and the hypertrophic response of the left ventricle. The purpose of this thesis was to study the contribution of inflammation and calcification to valve narrowing using Positron Emission and Computed Tomography (PET/CT) and to investigate the hypertrophic response using cardiovascular magnetic resonance (CMR). Methods. PET/CT studies. Patients with aortic sclerosis and mild, moderate and severe stenosis were prospectively compared to matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve and coronary arteries were assessed by sodium 18-­‐fluoride (18F-­‐NaF) and 18-­‐fluorodeoxyglucose (18F-­‐FDG) uptake using PET. CMR studies. Consecutive patients with moderate or severe aortic stenosis undergoing CMR were enrolled into a registry. Patients who received gadolinium contrast were categorised into absent, mid-­‐ wall or infarct patterns of late gadolinium enhancement (LGE) by blinded independent observers. Patients follow-­‐up was completed using patient questionnaires, source record data and the National Strategic Tracing Scheme. After excluding those patients with concomitant triggers to LV remodeling, the extent and patterns of hypertrophy were investigated based upon measurements of indexed LV mass, indexed LV volume and the relative wall mass. Results. PET/CT studies. 121 subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate and 23 severe aortic stenosis) were studied. Quantification of tracer uptake within the valve demonstrated excellent inter-­‐observer reproducibility with no biases and limits of agreement of ±0.21 (18F-­‐NaF) and ±0.13 (18F-­‐FDG) for maximum tissue-­‐to-­‐background ratios (TBR). Activity of both tracers was higher in patients with aortic stenosis than control subjects (18F-­‐NaF: 2.87±0.82 vs 1.55±0.17; 18F-­‐ FDG: 1.58±0.21 vs 1.30±0.13; both P<0.001). 18F-­‐NaF uptake displayed a progressive rise with valve severity (r2=0.540, P<0.001) with a more modest increase observed for 18F-­‐FDG (r2=0.218; P<0.001). Amongst patients with aortic stenosis, 91% had increased 18F-­‐NaF (>1.97) and 35% increased 18F-­‐ FDG (>1.63) uptake. Increased 18F-­‐NaF uptake was also observed in the coronary arteries in a subset of patients with atherosclerosis. These patients (n=40) had higher rates of prior cardiovascular events (p=0.016) and angina (p=0.023), and higher Framingham risk scores (p=0.011). CMR studies. 143 patients (aged 68±14 years; 97 male) were followed up for 2.0±1.4 years and 27 died. Compared to those with no LGE (n=49), univariate analysis revealed that patients with mid-­‐wall fibrosis (n=54) had an eight-­‐fold increase in all-­‐cause mortality despite similar aortic stenosis severity and coronary artery disease burden. Patients with an infarct pattern (n=40) had a six-­‐fold increase. Mid-­‐wall fibrosis (HR 5.35 [95% CI 1.16-­‐24.56]; P=0.03) emerged as an independent predictor of all cause mortality by multivariate analysis. The pattern of LV remodelling was studied in 91 patients (61±21 years; 57 male) and displayed wide variation comprising normal ventricular geometry (n=11), concentric remodelling (n=11), asymmetric remodelling (n=11), concentric hypertrophy (n=34), asymmetric hypertrophy (n=14) and LV decompensation (n=10). The magnitude of the hypertrophic response was unrelated to the severity of aortic valve narrowing. Conclusions. Modern imaging techniques have provided important insights in to the pathology underlying aortic stenosis and suggest that valvular calcification and myocardial fibrosis have a key role. Both represent important potential targets for future therapeutic interventions.

Transcatheter aortic valve implantation (TAVI) is an effective alternative treatment option for patients with severe aortic stenosis, who are at a high risk for conventional surgical aortic valve replacement or considered inoperable. Despite the short- and mid-term survival benefits of TAVI, adverse clinical events, such as paravalvular leak, aortic rupture, and coronary occlusion, have been reported extensively. Many of these adverse events can be explained from the biomechanics perspective. Therefore, an in-depth understanding of biomechanical interaction between the device and native tissue is critical to the success of TAVI. The objective of this thesis was to investigate the biomechanics involved in the TAVI procedure using patient-specific finite element (FE) simulations. Patient-specific FE models of the aortic roots were reconstructed using pre-procedural multi-slice computed tomography images. The models incorporated aged human aortic material properties with material failure criteria obtained from mechanical tests, and realistic stent expansion methods. TAV deployment and tissue-device interaction were simulated; and the simulation results were compared to the clinical observations. Additionally, parametric studies were conducted to examine the influence of the model input on TAVI simulation results and subsequently the potential clinical complications such as paravalvular leak, annular rupture, and coronary artery occlusion. The methodology presented in this thesis could be potentially utilized to develop valuable pre-procedural planning tools to evaluate device performance for TAVI and eventually improve clinical outcomes.

This diploma work is focused on using economic analysis methods to compare cost-effectivness of an innovative technology for treating aortic stenosis that is transcatheter implantation of an artificial valve CoreValve by Medtronic with traditional treatments. During the analyses we utilized only publicly available data which are often too general while more specific data might not be available because they do not exist or are not publicly available. This work sets up a theoretical foundation for the analyses, performs the analyse sof the product, PEST analyses and cost analyses. Since pacient's willigness to pay index (WTP) in the Czech republic has not yet been measured for this treatment, it is not posible to confirm the cost-effectivness of CoreValve, even though it has been confirmed in several countries based on the literature search related to this topic.

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 Aortic stenosis affects not only the valve but also the myocardium. In response to the increased afterload, left ventricular hypertrophy initially occurs as a compensatory response to maintain wall stress and cardiac output but ultimately, decompensation and heart failure ensues. The transition from adaptation to decompensation is driven by myocyte death and myocardial fibrosis. The aims of the thesis are to investigate cardiovascular magnetic resonance assessment of disease severity and myocardial fibrosis, and explore its relationship with other biomarkers of disease activity and clinical outcome in patients with aortic stenosis. METHODS AND RESULTS The conventional assessment of aortic stenosis relies heavily on two-dimensional and Doppler echocardiography but there are inherent limitations in echocardiography that can affect the severity classification. I demonstrated that cardiovascular magnetic resonance offered a more accurate estimation of left ventricular volumes and mass, and excellent myocardial characterization. Indeed, inaccurate stroke volume estimation by Doppler echocardiography and inconsistent thresholds in current guidelines accounted for more than 40% of patients with discordant small-area, lowgradient aortic stenosis. These data may explain the variable prognosis reported in this unique group of patients, and argue for more accurate assessment of borderline cases with cardiovascular magnetic resonance. Late gadolinium enhancement imaging detects focal areas of established myocardial fibrosis. In many conditions, including aortic stenosis, a more diffuse form of fibrosis predominates, which is potentially reversible and not readily identified by late gadolinium enhancement. Recently several myocardial T1 mapping approaches have been developed to quantify diffuse fibrosis. Using a standardized and systematic approach, I compared several commonly used T1 mapping techniques and identified that extracellular volume had the best profile (reproducibility and discriminatory potential) for the identification of diffuse fibrosis in patients with aortic stenosis. Cardiac troponin is a structural protein present in the cardiac myocytes. Recent advances in assay technology have substantially improved sensitivity, allowing quantification of troponin concentrations with a high degree of precision in everyone. In more than 250 patients with aortic stenosis, I demonstrated that cardiac troponin I concentrations were independently associated with markers of left ventricular decompensation (hypertrophy and fibrosis) and predicted clinical outcome in patients with aortic stenosis. This suggests that myocardial fibrosis detected by cardiovascular magnetic resonance is consequent on myocardial injury secondary to left ventricular decompensation. Left ventricular hypertrophy with strain pattern on a 12-lead electrocardiogram is associated with poor outcome in patients with aortic stenosis, but the mechanism of this electrocardiographic pattern has not been described. In more than 300 patients with aortic stenosis, I demonstrated that these characteristic repolarization abnormalities were a highly specific marker of focal mid-wall myocardial fibrosis (specificity of 99% and sensitivity of 54%). Moreover, the prognostic value of this electrocardiographic pattern was again confirmed with markedly worse long-term outcomes in these patients. CONCLUSION I have demonstrated that cardiovascular magnetic resonance can assist in the assessment of disease severity in patients with aortic stenosis and discordant echocardiographic findings. Moreover, I have validated the assessment of diffuse myocardial fibrosis, as well as, demonstrated the close association between myocardial fibrosis and biomarkers of myocardial injury and electrocardiographic strain pattern that predicted an adverse outcome in patients with aortic stenosis.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13421号 / 論医博第2229号 / 新制||医||1052(附属図書館) / (主査)教授 伊達 洋至, 教授 大鶴 繁, 教授 中山 健夫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM