京都大学 / 新制・論文博士 / 博士(医学) / 乙第13585号 / 論医博第2305号 / 新制||医||1070(附属図書館) / (主査)教授 石見 拓, 教授 古川 壽亮, 教授 近藤 尚己 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

The general purpose of this thesis is to establish capability and accuracy of speckle tracking echocardiography (STE) in assessing left atrial (LA), left ventricular (LV) and right ventricular (RV) function and their correlation with myocardial fibrosis, filling pressure and clinical outcomes in advanced heart failure (HF) patients before and after heart transplantation (HT). I demonstrated that HT recipients had impaired LV twist dynamics in the form of reduced rotation twist angle and untwist rate but time to peak twist was not different from the age matched controls and other cardiac surgical patients. With a longitudinal study conducted on patients with refractory HF, the best prognostic power has been shown by RV strain analysis. Among the indexes of LV function, the LV ejection fraction (LVEF) demonstrated the lowest diagnostic accuracy; instead LV global circumferential strain (GCS) showed a better sensitivity and specificity than LV global longitudinal strain (GLS). When analyzing the relationship between different severity of myocardial fibrosis and LV cavity function, the strongest function parameter that correlated with severity of myocardial fibrosis was GLS. In contrast, none of diastolic LV function or even measures of exercise capacity correlated with myocardial fibrosis. In patients with end-stage HF, global peak atrial longitudinal strain (PALS), an index of atrial reservoir function was dependent by pulmonary capillary wedge pressure (PCWP) and LV fibrosis, but not influenced by LV systolic function. Results from this study confirm previous evidence of correlation between impaired global PALS and increased PCWP.

Left ventricular (LV) volumes and ejection fraction (EF) are important predictors of cardiac morbidity and mortality. LV volumes provide valuable prognostic information which isparticularly useful in the selection of therapy or determination of the optimal time for surgery. Two-dimensional (2D) echocardiography is the most widely used non-invasive method forassessment of cardiac function, 2D echocardiography has however several limitations inmeasuring LV volumes and EF since the formulas for quantifications are based on geometricalassumptions. Three-dimensional (3D) echocardiography has been available for almost twodecades, although the use of this modality has not gained wide spread acceptance. 3D echocardiography can overcome the above mentioned limitation in LV volume and EF evaluation since it is not based on geometrical assumption. 3D echocardiography has been shownin several studies to be more accurate and reproducible with low inter- and intraobservervariability in comparison to 2D echocardiography regarding the measurements of LV volumesand EF. The overall aim of the thesis was to evaluate the feasibility and accuracy of 3D echocardiography based-methods in the clinical context. In Study I the feasibility of 3D echocardiography was investigated for determination of LV volumes and EF using parasternal, apical and subcostal approaches. The study demonstrated that the apical 3D echocardiography view offers superior visualization. Study II tested the possibility of creating flow-volume loops to differentiate patients with valvular abnormalities from normal subjects. There were significant differences in the pattern from flow-volume loops clearly separating the groups. In Study III the visual estimation, “eyeballing” of EF was evaluated with two- and tri-plane echocardiography in comparison to quantitative 3D echocardiography. The study confirmed that an experienced echocardiographer can, with a high level of agreement estimate EF both with two- and tri-plane echocardiography. Study IV exposed the high accuracy of stroke volume and cardiac output determination using a3D biplane technique by planimetrically tracing the left ventricular outflow tract and indicating that an assumption of circular left ventricular outflow tract is not reliable. In Study V, two 3D echocardiography modalities, single-beat and four-beat ECG-gated 3D echocardiography were evaluated in patients having sinus rhythm and atrial fibrillation. Thesingle-beat technique showed significantly lower inter-and intraobserver variability in LV volumes and EF measurements in patients having atrial fibrillation in comparison to four-beat ECG-gated acquisition due to absence of stitching artifact. All studies demonstrated good results suggesting 3D echocardiography to be a feasible andaccurate method in daily clinical settings. / degree of Medical DoctorQC 20100629

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction and paravalvular leak (PVL) are relatively uncommon, but are serious complications of prosthetic valve replacement. CASE PRESENTATION: We present a case that displays the unique therapeutic challenges of treating a patient who developed both LVOT obstruction and mitral PVL after undergoing surgical aortic and mitral valve replacement (MVR). We also describe the use of alcohol septal ablation and albumin-glutaraldehyde (BioGlue) for septal ablation to percutaneously treat the patient's LVOT obstruction, followed by use of an Amplatzer vascular plug for percutaneous closure of an antero-medial mitral PVL associated with severe regurgitation. CONCLUSION: Percutaneous interventional management of these entities may be considered as an initial therapeutic option, especially in high-risk patients with significant morbidity and mortality of repeat surgical operations.

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) is a strong independent predictor of cardiovascular morbidity and mortality, while its regression is associated with an improved clinical prognosis. It is, therefore, vital to elucidate and fully comprehend the mechanisms that contribute to LVH development and to identify markers that indicate a strong predisposition to the development of severe cardiac hypertrophy, before its occurrence. Hypertrophic cardiomyopathy (HCM) serves as a model to investigate LVH development. This primary cardiac disease is characterised by LVH in the absence of increased external loading conditions and is caused by defective sarcomeric proteins, as a result of mutations within the genes encoding these proteins. However, the hypertrophic phenotype of HCM is largely complex, as we see strong variability in the extent and distribution of LVH in HCM, even in individuals with the same disease-causing mutation from the same family; this points toward the involvement of additional genetic and environmental modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) influence LVH indirectly, through their key role in blood pressure regulation, but also directly, due to the direct cellular hypertrophic effects of some RAAS components. Previous genetic association studies aimed at investigating the contribution of RAAS variants to LVH were largely centred on a subset of polymorphisms within the genes encoding the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor genes, while the renin section and RAAS components downstream from ACE remained largely neglected. In addition, most previous studies have reported relatively small individual effects for a small subset of RAAS variants on LVH. In the present study we, therefore, employ a family-based genetic association analysis approach to investigate the contribution of the entire RAAS to this complex hypertrophic phenotype by exploring both the individual as well as the compound effects of 84 variants within 22 RAAS genes, in a cohort of 388 individuals from 27 HCM families, in which either of three HCM-founder mutations segregate. During the course of this explorative study, we identified a number of RAAS variants that had significant effects on hypertrophy in HCM, whether alone or within the context of a multi-variant haplotype. Through single variant association analyses, we identified variants within the genes encoding angiotensinogen, renin-binding protein, the mannose-6-phosphate receptor, ACE, ACE2, angiotensin receptors 1 and 2, the mineralocorticoid receptor, as well as the epithelial sodium channel and the Na+/K+-ATPase β-subunits, that contribute to hypertrophy in HCM. Using haplotype-based association analyses, we were able to identify haplotypes within the genes encoding for renin, the mannose-6-phosphate receptor, angiotensin receptor 1, the mineralocorticoid receptor, epithelial sodium channel and Na+/K+-ATPase α- and β subunits, as well as the CYP11B1/B2 locus, that contribute significantly to LVH. In addition, we found that some RAAS variants and haplotypes had statistically significantly different effects in the three HCM founder mutation groups. Finally, we used stepwise selection to identify a set of nine risk-alleles that together predicted a 127.80 g increase in left ventricular mass, as well as a 13.97 mm increase in maximum interventricular septal thickness and a 14.67 mm increase in maximum left ventricular wall thickness in the present cohort. In contrast, we show that a set of previously identified “pro-LVH” polymorphisms rather poorly predicted LVH in the present South African cohort. This is the first RAAS investigation, to our knowledge, to provide clear quantitative effects for a subset of RAAS variants indicative of a risk for LVH development that are representative of the entire pathway. Our findings suggest that the eventual hypertrophic phenotype of HCM is modulated by the compound effect of a number of RAAS modifier loci, where each polymorphism makes a modest contribution towards the eventual phenotype. Research such as that presented here provides a basis on which future studies can build improved risk profiles for LVH development within the context of HCM, and ultimately in all patients with a risk of cardiac hypertrophy. / AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) is 'n sterk onafhanklike voorspeller van kardiovaskulêre morbiditeit en mortaliteit, terwyl LVH regressie verband hou met ‘n verbeterde kliniese voorspelling. Dit is dus noodsaaklik om die meganismes wat bydra to LVH ontwikkeling ten volle te verstaan en merkers wat 'n sterk geneigdheid tot die ontwikkeling van ernstige kardiale hipertrofie te identifiseer, voordat dit voorkom. Hipertrofiese kardiomiopatie (HKM) dien as 'n model om LVH ontwikkeling te ondersoek. Hierdie primêre hartsiekte word gekenmerk deur LVH en word meestal veroorsaak deur foutiewe sarkomeer proteïene as gevolg van mutasies binne die gene wat kodeer vir hierdie proteïene. Die hipertrofiese fenotipe van HKM is egter grootliks kompleks; ons sien, by voorbeeld, sterk veranderlikheid in die omvang en die verspreiding van LVH in HKM, selfs in individue met dieselfde siekte-veroorsakende mutasie binne dieselfde gesin, wat dui op die betrokkenheid van addisionele genetiese en omgewing modifiseerders. Komponente van die renien-angiotensien-aldosteroon sisteem (RAAS) beïnvloed LVH indirek, deur middel van hul belangrike rol in bloeddruk regulasie, maar ook direk, as gevolg van die direkte sellulêre hipertrofiese gevolge van sommige RAAS komponente. Vorige genetiese assosiasie studies wat daarop gemik was om die bydrae van RAAS variante LVH te ondersoek, was hoofsaaklik gesentreer op 'n groepie polimorfismes binne die gene wat kodeer vir die “angiotensin converting enzyme” (ACE) en angiotensien II tipe 1-reseptor gene, terwyl die renien gedeelte en RAAS komponente stroomaf van ACE meestal nie ondersoek was nie. Daarbenewens het die meeste vorige studies relatief klein individuele gevolge gerapporteer vir 'n klein groepie RAAS variante op LVH. In die huidige studie het ons dus 'n familie-gebaseerde genetiese assosiasie-analise benadering gebruik om die bydrae van die hele RAAS tot hierdie komplekse hipertrofiese fenotipe te ondersoek deur 'n studie van die individuele-, sowel as die saamgestelde effekte van 84 variante binne 22 RAAS gene, in 'n groep van 388 individue vanaf 27 HKM families, waarin een van drie HCM-stigter mutasies seggregeer. Gedurende die loop van hierdie studie het ons 'n aantal RAAS variante wat ‘n beduidende uitwerking op HKM hipertrofie geïdentifiseer, hetsy alleen of binne die konteks van' n multi-variant haplotipe. Deur middel van enkele variant assosiasie toetsing het ons variante geïdentifiseer binne die gene wat kodeer vir angiotensinogen, renien-bindende proteïen, die mannose-6-fosfaat reseptor, ACE, ACE2, angiotensien reseptore 1 en 2, die mineralokortikoïd reseptor, sowel as die epiteel natrium kanaal en Na+/ K+-ATPase β-subeenhede, wat bydra tot HKM hipertrofie. Deur die gebruik van haplotipe-gebaseerde assosiasie ontleding was ons in staat om haplotipes te identifiseer binne die gene wat kodeer vir renien, die mannose-6-fosfaat reseptor angiotensien reseptor 1, die mineralokortikoïd reseptor, epiteel natrium kanaal en die Na+/ K+-ATPase α-en β subeenhede, sowel as die CYP11B1/B2 lokus, wat aansienlik bydra tot LVH. Verder het ons bevind dat sommige RAAS variante en haplotipes statisties beduidende verskillende effekte gehad het in die drie HKM stigter mutasie groepe. Laastens, het ons stapsgewyse seleksie gebruik om 'n stel van nege risiko-allele wat saam' n toename van 127.80 g in linker ventrikulêre massa, sowel as 'n 13.97 mm toename in maksimum ventrikulêre septale dikte, en' n 14.67 mm verhoging in maksimum linker ventrikulêre wanddikte voorspel, te identifiseer in die huidige kohort. In teenstelling hiermee wys ons dat 'n stel van voorheen geïdentifiseerde "pro-LVH" polimorfismes swakker gevaar het as LVH-voorspellers in die huidige Suid-Afrikaanse kohort. Hierdie is die eerste RAAS ondersoek, tot ons kennis, wat ‘n duidelike kwantitatiewe gevolge vir 'n stel RAAS variante wat ‘n verhoogde risiko tot LVH ontwikkeling aandui, wat verteenwoordigend is van die hele RAAS. Ons bevindinge dui daarop dat die uiteindelike hipertrofiese fenotipe van HKM gemoduleer word deur die saamgestelde effek van 'n aantal RAAS wysiger loki, waar elke polimorfisme ' n beskeie bydrae maak tot die uiteindelike fenotipe. Navorsing soos dié wat hier aangebied word dien as 'n basis waarop toekomstige studies kan bou vir ‘n verbeterde risiko-profiel vir LVH ontwikkeling binne die konteks van die HKM, en uiteindelik in alle pasiënte met' n verhoogde risiko vir kardiale hipertrofie.

MSc (Med), University of the Witwatersrand, Faculty of Health Sciences, School of Physiology / The role of metabolic remodelling in heart failure is not fully understood, significant evidence has accumulated to suggest that it may be central to the development of left ventricular (LV) remodelling and LV dysfunction. Heart failure is also characterized by sustained neurohumoral activation. We have previously demonstrated that chronic low dose administration of isoproterenol contributes to cardiac structural and functional changes, however, little is known about metabolic and mitochondrial changes that may accompany the development of isoproterenol-mediated heart failure. In the current study, we hypothesised that metabolic dysregulation and loss of mitochondrial integrity mediates left ventricular hypertrophy (LVH) and left ventricular (LV) systolic dysfunction in the isoproterenol model of heart failure. Furthermore, modulation of expression of key metabolic genes and mitochondrial transcription factors by fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, will preserve left ventricular function. To achieve this, male Sprague-Dawley rats weighing between 250-300g were injected with low dose isoproterenol (0.04 mg.kg-1.day-1) and/or administered with fenofibrate (100 mg.kg-1.day-1) for five weeks. Thereafter, metabolic substrates such as glucose, FFAs and TG concentrations were obtained. Left ventricular hypertrophy (LVH) and cardiac function were assessed using echocardiography. Expressions of metabolic and mitochondrial genes such as PPARα, AMP-activated protein kinase alpha 2 (AMPKα2), PPARγ coactivator-1 (PGC-1α), mitochondrial transcription factor (TFAM) and nuclear respiratory factor-1 (NRF-1) were determined using real-time polymerase chain reaction. Mitochondrial integrity was assessed using transmission electron microscopy. Administration of isoproterenol significantly increased left ventricular mass (LVM) and decreased endocardial fractional shortening (FSend); isoproterenol also induced myofibrillar iv derangement, mitochondrial derangement and cristae disruption. Fenofibrate prevented isoproterenol-induced increase in LVM and improved FSend. Fenofibrate co-administration prevented loss of mitochondrial integrity possibly via TFAM. Furthermore, fenofibrate may have induced metabolic remodelling via upregulation of AMPKα2 and downregulation of cardiac PPARα and PGC-1α. Therefore our data suggests that fenofibrate-mediated cardioprotection against isoproterenol-induced LVH and LV systolic dysfunction was accompanied by metabolic switching and preservation of mitochondrial integrity. While isoproterenol did not induce any changes in metabolic genes, fenofibrate-mediated cardioprotection could have been through changes in metabolic genes.

Biomedical image processing is a very important research area. Image analysis is one of the most important techniques in studies related to heart functions. The clinical assessment of LV function is very important to evaluate the heart function for patients or suspected heart disease sufferers. 2D echocardiography allows us to study the dynamic analysis of the heart which results in obtaining the quantitative and qualitative analysis of the LV. Cardiac function quantitative analysis depends on the heart’s shape characteristics like the enclosed area and heart wall thickness. The segmentation of medical images and obtaining the traces of the LV boundaries is an essential procedure to get the quantitative and qualitative analysis. Yet, in clinical procedure, this task depends on manual tracing which is slow, tedious and time consuming job. Hence, automating this clinical procedure during the cardiac cycle is of great importance. The aim of this thesis is to automate the manual process of detecting and tracking the LV boundaries of 2D echocardiographic image sequence. Instead of depending only on the imaging based techniques, the designed and implemented framework utilizes the LV mechanics beside the imaging based techniques. When it comes to information extraction from patterns which have been classified, it has been proved that the different contour detection methods complement each other. As a result, efficient combination of different contour detectors is expected to achieve better contour detection than if only one detector is used. This combination of contour detectors produces incremental gains in overall performance. In the first framework, the detection and tracking are accomplished by employing the extended Kalman filter framework to combine the contours estimated by the biomechanical model and the contours extracted using the deformable models. An alternative framework is used by employing averaging fusion followed by level set method. A gold standard is created from three manual outlines and utilized in the experimental results to evaluate the automated results. The tracking and segmentation of LV during the cardiac cycle was accomplished successfully in all cases. The results showed limits of agreement for an average perpendicular distance of 1.277 ±0.252 mm versus the created gold standard. This proved that this framework achieved better performance in tracking and segmenting the LV through the cardiac cycle.

Implantation of a left ventricular assist device (LVAD) is a potential treatment in terminal heart failure. Right ventricular (RV) failure is a severe complication in these patients and sometimes requires additional placement of a right ventricular assist device (RVAD). RVAD implantation, however, is an invasive treatment associated with both increased mortality and morbidity. The aim of this thesis was to study whether partial volume exclusion of the RV through a modified Glenn shunt or cavoaortic shunt could treat severe RV failure. The ultimate goal would be to use it as an alternative to a RVAD in RV failure during LVAD therapy. Swine were used as the model animal in all studies. In Study I, experimental RV failure was induced by ischemia, and verified by hemodynamic measurements and genetic expression. Treatment with a modified Glenn shunt reduced venous stasis and improved hemodynamics in general. In Study II, experimental RV failure was induced by the same method as in Study I. Treatment with a cavoaortic shunt in addition to LVAD therapy proved to reduce venous stasis and improved hemodynamics in general, which was feasible with preserved oxygen delivery despite cyanotic shunting. In Study III, experimental RV failure was induced by pulmonary banding, and verified by hemodynamic measurements and genetic expression. Treatment with a modified Glenn shunt reduced venous stasis but did not improve hemodynamics in general compared with a control group. In Study IV, the effects of LVAD therapy and subsequent treatment with a modified Glenn shunt on the normal RV function were studied. It demonstrated that LVAD therapy can put strain on the RV by increasing stroke work and end-diastolic volume, and that these effects can be reversed by treatment with a modified Glenn shunt during LVAD therapy. In conclusion, partial volume exclusion through a modified Glenn shunt or cavoaortic shunt is a feasible treatment of experimental RV failure. Thus, it could potentially be used as an alternative treatment to a RVAD in severe RV failure during LVAD therapy.

The Ornate Tinamou (Nothoprocta ornata), an ancient bird, has adapted to life at high altitude (>2.400 m.a.s.l) for a longer period than the domestic chicken (Gallus domesticus), which came to South America with the Spanish conquerors. Ornate tinamous have a smaller heart in relation to body size than domestic chickens. This study was made to evaluate heart morphometric measurements comparing Ornate Tinamou and domestic chicken using echocardiography measurements to determine wall thickness and chamber size and to evaluate whether it can retrieve measurements consistent with previous results on dissected hearts. I was also interested in evaluating potential adaptations of the Ornate Tinamou to life in hypoxic environments by exposing the heart to positive inotropic stimulation. The results were compared with those previously obtained on dissected hearts. The results showed that the chamber size of the domestic chicken was significantly larger than in Ornate Tinamou, both in conscious and anesthetized birds. Injection of 1µg/kg isoproterenol caused domestic chickens’ systolic chamber size to decrease significantly and fractional shortening to increase significantly. The same changes were seen in the Ornate Tinamou but they were not significant. In conclusion, this study confirms that echocardiography is a valid method for retrieving cardiac measurements without euthanizing animals, opening for the possibility of taking several measurements at different ages.

The general purpose of this thesis was to investigate new cardiac resynchronization therapy (CRT) optimization techniques and to assess their reliability when compared to invasive measurements of left ventricular contractility (LV dP/dtmax).We first assessed whether cardiac output (CO) measured by trans-thoracic impedance cardiography could correctly identify the optimal interventricular (VV) pacing interval while using invasive measurements of LV dP/dtmax as reference. We did not find any significant statistical correlation between the two optimizing methods when their corresponding optimal VV intervals were compared. We also tested the hypothesis that measurements of right ventricular contractility (RV dP/dtmax) could be used to guide VV delay optimization in CRT. The comparison of optimal VV intervals obtained from the left and right ventricular dP/dtmax did not show a statistically significant correlation; however, a positive correlation was found when broader VV intervals were evaluated and we concluded that this finding deserves further investigation. An interesting alternative for CRT optimization is the use of device integrated algorithms or sensors capable to adapt the CRT settings to the current needs of the individual patient. In this respect we investigated the use of cardiogenic impedance (CI) measurements obtained through the CRT-D device as a method for CRT optimization with invasive measurements of LV dP/dtmax as a reference. Our results showed that CI could be measured through the device after implantation and that a patient-specific impedance-based prediction model was capable to accurately predict the optimal AV and VV delays. To follow up on these positive results we re-evaluated the patient-specific impedance-based prediction models 24 hours post implantation and investigated the possibility of calibrating them using parameters derived from non-invasive measurements of arterial pressure obtained by finger pelthysmography at implantation.The results showed that the patient-specific impedance-based prediction models did not perform as well on the follow-up data as they did on the data from implantation day and that they correlated poorly with plethysmographic parameters. Our studies suggest that novel methods for CRT optimization should be thoroughly evaluated and compared to established measures of left ventricular function prior to introduction into clinical practice.