Human-robot collaboration (HRC) occurs when people and robots work together in a shared environment. Current robots often use rigid programs unsuitable for HRC. Multimodal robot programming offers an easier way to control robots using inputs like voice and gestures. In this scenario, human commands from different sensors trigger the robot’s actions. However, this data-driven approach has challenges: accurately understanding power dynamics, integrating inputs, and precisely controlling the robot. To address this, we introduce EEG signals to improve robot control, requiring reliable signal processing, feature extraction, and accurate classification using machine learning and deep learning. Existing deep learning models struggle to balance accuracy and efficiency. This thesis focuses on whether dilated convolutional neural networks can improve accuracy and reduce training and reaction times compared to the baseline. After using the Morlet wavelet for EEG feature extraction, in the thesis, an existing convolutional neural network as a benchmark is employed and uses the dilated convolution algorithm for comparison. Accuracy, precision, recall, and time are used to assess the comparison algorithm’s performance. The conclusion is that the dilated convolutional neural network performs better than the baseline in accuracy and time parameters. / Samarbete mellan människa och robot (HRC) inträffar när människor och robotar arbetar tillsammans i en delad miljö. Nuvarande robotar använder ofta rigida program som inte är lämpliga för HRC. Multimodal robotprogrammering erbjuder ett enklare sätt att styra robotar med hjälp av röst och gester. I detta scenario utlöser mänskliga kommandon från olika sensorer robotens handlingar. Dock har denna datadrivna ansats utmaningar: att noggrant förstå kraftdynamik, integrera inmatning och exakt styra roboten. För att hantera detta introducerar vi EEG-signaler för att förbättra robotstyrningen, vilket kräver pålitlig signalbehandling, funktionsextraktion och noggrann klassificering med maskininlärning och djupinlärning. Nuvarande djupinlärningsmodeller har svårt att balansera noggrannhet och effektivitet. Den här artikeln fokuserar på om dilaterade konvolutionella neurala nätverk kan förbättra noggrannheten och minska träningstider och reaktionstider jämfört med baslinjen. Efter att ha använt Morlet-våg för EEG-funktionsutvinning använder artikeln en befintlig konvolutionell neural modell som referens och jämför med dilaterad konvolution för att bedöma prestandan. Noggrannhet, precision, recall och tidsparametrar bedömer jämförelsealgoritmens prestanda. Slutsatsen är att det dilaterade konvolutionella neurala nätverket presterar bättre än baslinjen vad gäller noggrannhet och tidsparametrar.

L'évaluation de l'asynchronisme mécanique ventriculaire sous stress a soulevé une attention importante en tant que facteur prédictif de la réponse au traitement de resynchronisation cardiaque (CRT). De plus, il semble exister une relation significative entre le devenir du patient et la présence d’asynchronisme au repos. Plusieurs méthodes échocardiographiques peuvent être utilisées pour évaluer l’asynchronisme. Cependant, parmi toutes les différentes méthodologies ou index existant dans ce domaine, aucun critère ne fait l’unanimité. Cette thèse étudie l'importance des techniques d'imagerie nucléaire dans le cadre de l’évaluation de l’asynchronisme cardiaque induit par le stress en utilisant trois différents modèles canins expérimentaux. Le premier chapitre vise à examiner les effets du stress sur le synchronisme de la contraction du ventricule gauche (VG) en utilisant l'imagerie synchronisée de perfusion myocardique dans une cohorte canine normale. Le stress a été induit par différents niveaux d’infusion de dobutamine sur six sujets sains. Les paramètres hémodynamiques et l’asynchronisme ont été évalués par des mesures de pressions ventriculaires. L'analyse de phase sur l’imagerie s’est effectuée en utilisant un logiciel commercialement disponible (QGS) et un logiciel interne (MHI4MPI), basée sur le déplacement et l’épaississement des parois ventriculaires. L’augmentation de la concentration de dobutamine a démontré une amélioration de la capacité fonctionnelle et une réduction de l’asynchronisme ventriculaire. L’analyse de l’asynchronisme calculée à partir de l’épaississement de la paroi semble plus robuste et plus sensible que l’utilisation du déplacement des parois. (Salimian et. al., J Nucl Cardiol., 2014) Le second chapitre étudie les différents paramètres d’asynchronisme au repos et à différents niveaux de stress dans un modèle de cardiomyopathie dilatée et à QRS étroit. Ce modèle a été créé sur dix chiens par tachycardie via stimulation de l'apex du ventricule droit pendant 3-4 semaines, permettant d’atteindre une fraction d'éjection cible de 35% ou moins. Le stress a ensuite été induit par une perfusion de dobutamine jusqu'à un maximum de 20 μg/kg/min. Les données hémodynamiques et l’asynchronisme ont été analysés par des mesures de pression ventriculaire et l’analyse de l’imagerie dynamique du compartiment sanguin. L’importante variabilité individuelle des sujets inclus dans notre cohorte empêche toute conclusion définitive sur la mesure de l’asynchronisme interventriculaire. Cependant, les différents niveaux de stress, même dans des intervalles rapprochés, ont démontré un effet significatif sur les paramètres hémodynamiques et l’asynchronisme. (Salimian et. al., J Nucl Cardiol., 2015) La troisième section vise à déterminer si l’estimation du mode de stimulation optimal effectuée au repos demeure le choix optimal lorsque le niveau d’activité cardiaque s’intensifie pour des sujets avec bloc auriculo-ventriculaire (AV) et fonction ventriculaire normale. Cinq chiens ont été soumis à une ablation du nœud AV et des sondes de stimulation ont été insérées dans l'oreillette droite pour la détection, l’apex du ventricule droit (VD) et une veine postérolatérale du VG pour la stimulation. Cinq modes de stimulation ont été utilisés : LV pur, biventriculaire (BiV) avec pré-activation de 20 ms du LV (LVRV20), BiV pur, BiV avec pré-activation de 20 ms du VD (RVLV20), VD pur. Des niveaux jusqu’à 20 μg/kg/min de dobutamine ont été atteints. Le stress a modifié l’étendue de l’asynchronisme de base et ce, pour tous les modes de stimulation. De plus, les effets physiologiques intrinsèques du stress permettent une évaluation plus précise de l’asynchronisme ventriculaire, diminuant la variabilité inter-sujet. Le mode de stimulation LVRV20 semble le mode optimal dans ce modèle, supportant l’utilisation de la stimulation bi-ventriculaire. / Assessment of ventricular mechanical dyssynchrony (MD) under stress has attracted a large amount of attention as a stronger predictor of response to cardiac resynchronization therapy (CRT) and as a parameter whose variation bears a greater relationship to clinical outcomes than resting-MD either in CRT candidates or another subset of patients. Several echocardiographic methods can be used to assess stress-MD. However, no standardized approach is currently used to explore stress-induced variations in inter- and intraventricular MD. This dissertation studies the importance of nuclear imaging techniques in assessing stress-induced MD variations by providing three different experimental canine models. The first chapter sought to examine the impacts of stress on the left ventricular (LV) synchrony with phase analysis of gated SPECT myocardial perfusion imaging (GMPS) within a normal canine cohort. Stress was induced by different levels of dobutamine infusion in six healthy subjects. Hemodynamic and LV MD parameters were assessed by LV pressure measurements and phase analysis of GMPS using commercially available QGS software and in-house MHI4MPI software with thickening- and displacement-based methodology. The increase of dobutamine level was shown to be in accordance with the improvement of LV functional capacity and reduction of MD parameters. MD analysis based on wall thickening was more robust and sensitive than the global wall displacement. (Salimian et. al., J Nucl Cardiol., 2014) The second chapter investigated the range of difference in inter- and intraventricular MD parameters from rest to various levels of stress in a dilated cardiomyopathy (DCM) and narrow QRS complex model. Ten large dogs were submitted to tachycardia-induced DCM by pacing the right ventricular apex for 3-4 weeks to reach a target ejection fraction of 35% or less. Stress was then induced by infusion of dobutamine up to a maximum of 20 μg/kg/min. Hemodynamic and MD data were analyzed by LV pressure measurements and gated-blood pool SPECT (GBPS) imaging. Individual differences in the magnitude and pattern of change in the various levels of stress precluded any definitive conclusion about interventricular MD. However, different levels of stress, even in close intervals, showed a significant positive impact on hemodynamic and intraventricular MD parameters. (Salimian et. al., J Nucl Cardiol., 2015) The third chapter sought to examine if the optimal pacing mode at rest could be the best one during the maximum stress level in terms of MD parameters in subjects with an atrioventricular (AV) block and normal function. Five dogs were submitted to AV node ablation and pacing leads were placed in the right atrium for sensing, in right ventricular (RV) apex, and in posterolateral LV vein for pacing in five modes of LV, biventricular (BiV) with 20 ms of LV pre-activation (LVRV20), BiV, BiV with 20 ms of RV pre-activation (RVLV20) and RV pacing. Stress was induced by dobutamine infusion up to a maximum of 20 μg/kg/min. Data analyses were the same as chapter one. Dobutamine stress changed the extent of resting-LV MD at all pacing modes. Intrinsic physiologic effects of stress resulted in more accurate MD assessment with lesser variability in subjects who underwent pacing. LVRV20 was the preferred site of stimulation in this model rather than single-site pacing.

As miocardiopatias dilatadas representam 87% das miocardiopatias e apresentam evolução adversa com grande morbi-mortalidade. Vários marcadores de prognóstico são bem definidos, entretanto, um marcador estrutural se faz necessário. Estudamos através da realização da biópsia endomiocárdica e exame ecocardiográfico, 9 indivíduos sem doença estrutural miocárdica (controle) e 45 pacientes com miocardiopatia dilatada grave de etiologia idiopática (MCDI) e chagásica (MCDC). Observamos se havia relação entre a quantidade de colágeno miocárdico intersticial (FVCI) e a sobrevida destes pacientes, se a FVCI diferia entre as etiologias, e se a fibrose interferia na função e geometria do miocárdio. Observamos que a FVCI foi 15x maior nos miocardiopatas em relação ao grupo controle, mas não diferiu em relação às MCDI e MCDC (FVCI % MCDC = 6,83 ± 5,47; MCDI = 5,75 ± 4,45; controle = 0,42 ± 0,14*; p<0,001). Não houve relação da FCVI com a sobrevida dos pacientes com miocardiopatias (MCDI-FVCI £5,53 (20,0%) ou >5,53 (0,0%) (p=0,249), e na MCDC-FVCI £5,53 (0,0%) ou >5,53 (7,7%) (p=0,587) e apenas na MCDI a fração de ejeção do ventrículo esquerdo (FEVE) teve relação com a FVCI. O diâmetro diastólico final do ventrículo esquerdo não se correlacionou com a FCVI nas duas etiologias. Conclusão: a fibrose miocárdica não diferiu entre as duas etiologias, não se correlacionou com o prognóstico das MCDC e MCDI e apenas na MCDI ela se correlacionou com a FEVE. / Dilated cardiomyopathies represent 87% of all cardiomyopathies and they have adverse prognosis with high morbidity and mortality. There are several prognostic markers, however, a structural one has not been described yet. Seems to be very important to find out whether morphological changes upon myocardial structure would affect the prognosis. We studied, using endomyocardial biopsy and 2D-echocardiogram, 9 patients with no structural myocardial changes (control) and 45 patients with severe dilated cardiomyopathies. They were divided according the etiology of cardiomyopathy into idiopathic group (IDCM) or Chagas group (CDCM). We analyzed the correlation between interstitial myocardial collagen (ICVF) and survival rates. We also evaluated the difference of ICVF between these groups and whether it correlates with geometric and functional changes of the heart. We observed that ICVF was 15 times higher in cardiomyopathies patients than in control group, but it did not differ between CDCM and IDCM (ICVF% CDCM = 6.83 ± 5.47; IDCM = 5.75 ± 4.45; control = 0.42 ± 0.14*; p<0.001). The ICVF did not correlate to survival rate in cardiomyopathies patients (IDCM-ICVF £5.53 (20.0%) or >5.53 (0.0%) (p=0.249), and CDCM-ICVF £5.53 (0.0%) or >5.53 (7.7%) (p=0.587). We observed a significant correlation between ICVF and left ventricular ejection fraction (LVEF) only on DMC, the ICVF did not correlate to left ventricular diastolic diameter in either etiology. Conclusion: the myocardial fibrosis did not differ between these two etiologies, it did not correlate to prognosis either in the IDCM or CDCM and only in the IDCM the ICVF correlated to the LVEF.

INTRODUÇÃO: O conhecimento anatômico desempenha importante papel no desenvolvimento de técnicas diagnósticas e cirúrgicas. Com esse objetivo, na área cardiológica, se mostra fundamental para o entendimento do processo de remodelamento cardíaco que acompanha as cardiomiopatias dilatadas (CMD) tanto isquêmicas (CMDIsq) como idiopáticas (CMDId), de modo particular do ventrículo esquerdo (VE) e sua correlação com alterações do anel atrioventricular esquerdo, levando a graus variáveis de insuficiência cardíaca (IC). OBJETIVOS: Os objetivos desta pesquisa são: 1) Obter medidas do anel atrioventricular esquerdo (mitral) e do ventrículo esquerdo em corações normais, com CMDIsq ou CMDId, comparando-as entre si; 2) Analisar a proporcionalidade entre segmentos da câmara ventricular esquerda dos corações com CMDIsq ou CMDId em relação ao normal; 3) Determinar a esfericidade ou não da câmara ventricular esquerda nos corações com CMDIsq ou CMDId. MÉTODO: Foram analisados 43 corações humanos, divididos em três grupos: NORMAL (n=10), CMDIsq (n=15) e CMDId (n=18). De posse da medida da distância do sulco atrioventricular posterior até o ápice do VE, foram realizados cortes transversais baso-apicais seqüenciais e, após digitalização dos mesmos, por meio de método computadorizado, foram obtidas medidas perimetrais e espessura das paredes. Empregando-se o mesmo método, mensurou-se o perímetro do anel mitral. Foram criados índices de proporção porcentual entre os perímetros dos segmentos provenientes dos cortes do VE, comparando-os intergrupos. Nos dilatados os perímetros segmentares mensurados foram comparados com os perímetros esperados se considerássemos a câmara ventricular como uma esfera perfeita. Realizou-se a análise estatística dessas medidas e índices. RESULTADOS: O perímetro do anel mitral teve o seguinte resultado: somente o grupo CMDIsq teve média significativamente maior que o grupo NORMAL e houve baixo coeficiente de correlação com os perímetros ventriculares segmentares nos corações dilatados. Distância do sulco atrioventricular até o ápice do VE: CMDId = CMDIsq > NORMAL. Perímetros segmentares ventriculares basais (PerB), equatoriais (PerE) e apicais (PerA): grupo NORMAL-> PerE = PerB > PerA; grupos CMDId e CMDIsq- > PerE > PerB > PerA, sendo que o grupo CMDId teve essas 3 medidas maiores que o grupo CMDIsq e ambos tiveram essas 3 medidas maiores que o grupo NORMAL. Nos 3 grupos as medidas de espessura das paredes ventriculares foram iguais estatisticamente. O índice de proporção perimetral PerB/PerE foi igual nos 3 grupos, enquanto o índice PerA/PerE foi igual entre os corações dilatados, mas em ambos foi menor que no grupo NORMAL. Todos perímetros segmentares ventriculares dos corações dilatados foram menores do que os calculados segundo a fórmula da esfera. CONCLUSÕES: 1) O anel atrioventricular esquerdo dilata-se na CMDIsq, sendo essa alteração independente da dilatação dos três segmentos do VE; 2) Os corações com CMDId e CMDIsq desenvolvem uma similar dilatação longitudinal do VE; 3) Ocorre uma dilatação trans versal do VE nessas afecções, sendo essa maior nos corações com CMDId; 4) A espessura das paredes ventriculares esquerdas dos corações com CMDIsq ou CMDId não se altera quando comparada aos corações normais; 5) A dilatação transversal da câmara ventricular esquerda nos corações com CMD não se dá de forma proporcional ao longo do seu eixo longitudinal, sendo mais acentuada nas regiões basal e equatorial; 6) A câmara ventricular esquerda nos corações com CMD de origem isquêmica ou idiopática não apresenta formato esférico. / BACKGROUND: Anatomic knowledge is the cornerstone for the development of surgical and diagnostic image techniques and for understanding pathological entities. Understanding cardiac anatomy is essential for understanding cardiac remodeling in both ischemic and idiopathic dilated cardiomyopathies. Dysfunction in the physiological relationship between the morphology of left ventricle and its mitral ring plays an important role in the cardiac insufficiency etiopathogenesis. OBJECTIVES: 1) To compare morphology of left ventricle and its mitral ring among normal, ischemic and idiopathic dilated cardiomyophatic anatomic specimens; 2) To compare intra specimen ventricular segmental perimeters relationships between normal and dilated specimens; 3) To verify the presence of the spheroid shape of left ventricular chamber in dilated specimens. METHODS: It was analyzed 43 specimens of human hearts, classified in three groups: normal (n=10), dilated due to ischemic (n=15) or idiopathic cardiomyopathies (n=18). Several lengths were measured: the length from the posterior atrioventricular sulcus to the ventricular apex in the intact specimen; followed by three sequential transversal ventricular slicing in the basal, equatorial and apical level. Digital pictures were taken from these slices, in order to be analyzed in a computer assisted fashion. Internal perimeter and ventricular walls width of each slice were measured, as well the mitral ring perimeter. The three intra group perimeters were compared and correlated between themselves. Basal, equatorial and apical perimeter of each group was compared to their correspondent pairs inter groups. Regarding intra group relationships, for a given group, each slice perimeter was measured and considered as a percentage of the equatorial slice (index). This percentage was compared inter groups. Three perimeters were evaluated in both dilated groups, each one was compared to its expected value when considering left ventricular chamber as a perfect sphere (hypothesis). Measurements and index statistical analysis was performed. RESULTS: Mitral ring perimeter was longer than the NORMAL group only in ischemic group. There was a low correlation coefficient between mitral ring perimeter and ventricular segmental perimeters in both dilated groups. Longitudinal length from the left atrioventricular sulcus until the apex was similar in dilated specimens and higher compared to the normal group. Regarding sequential perimeters of ventricular slices in the normal specimens, the equatorial perimeter was as long as the basal ones, but both of them longer than the apical one. In the other hand, for dilated specimens, equatorial diameter was the longest one and apic al the smallest one. Comparing ventricular slices perimeters between dilated groups, all the perimeters lengths were longer in the idiopathic group than in the ischemic one. All the ventricular slices perimeters were longer for both dilated groups than for the normal group. There was no difference of ventricular wall width between groups. The proposed index of proportional perimeter: considering the proportion between basal and equatorial perimeter, there was no difference between any groups; but considering the proportion between apical and equatorial perimeter, dilated specimens displayed a lower index when compared to normal specimens. All the observed ventricular slice perimeters were smaller than the hypothetical (sphere) expected ones in both dilated groups. CONCLUSIONS: 1) Left atrioventricular ring dilatation occurs in ischemic dilated cardiomyopathy and it is independent of the dilatation of segments (apical, basal and equatorial) ventricular; 2) Longitudinal left ventricular dilatation is similar between dilated groups; 3) A transversal ventricular chamber dilatation was observed in dilated diseases and it is greater in the idiopathic disease; 4) The left ventricular wall widths in both dilated cardiomyopathies were similar to normal hearts; 5) Transversal dilatation of left ventricular chamber in both dilated cardiomyopathies is not proporcional along their longitudinal axis because it is more accentuated in equatorial and basal regions; 6) Left ventricular chamber in both dilated cardiomyopathies does not keep spherical shape.

As miocardiopatias dilatadas representam 87% das miocardiopatias e apresentam evolução adversa com grande morbi-mortalidade. Vários marcadores de prognóstico são bem definidos, entretanto, um marcador estrutural se faz necessário. Estudamos através da realização da biópsia endomiocárdica e exame ecocardiográfico, 9 indivíduos sem doença estrutural miocárdica (controle) e 45 pacientes com miocardiopatia dilatada grave de etiologia idiopática (MCDI) e chagásica (MCDC). Observamos se havia relação entre a quantidade de colágeno miocárdico intersticial (FVCI) e a sobrevida destes pacientes, se a FVCI diferia entre as etiologias, e se a fibrose interferia na função e geometria do miocárdio. Observamos que a FVCI foi 15x maior nos miocardiopatas em relação ao grupo controle, mas não diferiu em relação às MCDI e MCDC (FVCI % MCDC = 6,83 ± 5,47; MCDI = 5,75 ± 4,45; controle = 0,42 ± 0,14*; p<0,001). Não houve relação da FCVI com a sobrevida dos pacientes com miocardiopatias (MCDI-FVCI £5,53 (20,0%) ou >5,53 (0,0%) (p=0,249), e na MCDC-FVCI £5,53 (0,0%) ou >5,53 (7,7%) (p=0,587) e apenas na MCDI a fração de ejeção do ventrículo esquerdo (FEVE) teve relação com a FVCI. O diâmetro diastólico final do ventrículo esquerdo não se correlacionou com a FCVI nas duas etiologias. Conclusão: a fibrose miocárdica não diferiu entre as duas etiologias, não se correlacionou com o prognóstico das MCDC e MCDI e apenas na MCDI ela se correlacionou com a FEVE. / Dilated cardiomyopathies represent 87% of all cardiomyopathies and they have adverse prognosis with high morbidity and mortality. There are several prognostic markers, however, a structural one has not been described yet. Seems to be very important to find out whether morphological changes upon myocardial structure would affect the prognosis. We studied, using endomyocardial biopsy and 2D-echocardiogram, 9 patients with no structural myocardial changes (control) and 45 patients with severe dilated cardiomyopathies. They were divided according the etiology of cardiomyopathy into idiopathic group (IDCM) or Chagas group (CDCM). We analyzed the correlation between interstitial myocardial collagen (ICVF) and survival rates. We also evaluated the difference of ICVF between these groups and whether it correlates with geometric and functional changes of the heart. We observed that ICVF was 15 times higher in cardiomyopathies patients than in control group, but it did not differ between CDCM and IDCM (ICVF% CDCM = 6.83 ± 5.47; IDCM = 5.75 ± 4.45; control = 0.42 ± 0.14*; p<0.001). The ICVF did not correlate to survival rate in cardiomyopathies patients (IDCM-ICVF £5.53 (20.0%) or >5.53 (0.0%) (p=0.249), and CDCM-ICVF £5.53 (0.0%) or >5.53 (7.7%) (p=0.587). We observed a significant correlation between ICVF and left ventricular ejection fraction (LVEF) only on DMC, the ICVF did not correlate to left ventricular diastolic diameter in either etiology. Conclusion: the myocardial fibrosis did not differ between these two etiologies, it did not correlate to prognosis either in the IDCM or CDCM and only in the IDCM the ICVF correlated to the LVEF.

INTRODUÇÃO: O conhecimento anatômico desempenha importante papel no desenvolvimento de técnicas diagnósticas e cirúrgicas. Com esse objetivo, na área cardiológica, se mostra fundamental para o entendimento do processo de remodelamento cardíaco que acompanha as cardiomiopatias dilatadas (CMD) tanto isquêmicas (CMDIsq) como idiopáticas (CMDId), de modo particular do ventrículo esquerdo (VE) e sua correlação com alterações do anel atrioventricular esquerdo, levando a graus variáveis de insuficiência cardíaca (IC). OBJETIVOS: Os objetivos desta pesquisa são: 1) Obter medidas do anel atrioventricular esquerdo (mitral) e do ventrículo esquerdo em corações normais, com CMDIsq ou CMDId, comparando-as entre si; 2) Analisar a proporcionalidade entre segmentos da câmara ventricular esquerda dos corações com CMDIsq ou CMDId em relação ao normal; 3) Determinar a esfericidade ou não da câmara ventricular esquerda nos corações com CMDIsq ou CMDId. MÉTODO: Foram analisados 43 corações humanos, divididos em três grupos: NORMAL (n=10), CMDIsq (n=15) e CMDId (n=18). De posse da medida da distância do sulco atrioventricular posterior até o ápice do VE, foram realizados cortes transversais baso-apicais seqüenciais e, após digitalização dos mesmos, por meio de método computadorizado, foram obtidas medidas perimetrais e espessura das paredes. Empregando-se o mesmo método, mensurou-se o perímetro do anel mitral. Foram criados índices de proporção porcentual entre os perímetros dos segmentos provenientes dos cortes do VE, comparando-os intergrupos. Nos dilatados os perímetros segmentares mensurados foram comparados com os perímetros esperados se considerássemos a câmara ventricular como uma esfera perfeita. Realizou-se a análise estatística dessas medidas e índices. RESULTADOS: O perímetro do anel mitral teve o seguinte resultado: somente o grupo CMDIsq teve média significativamente maior que o grupo NORMAL e houve baixo coeficiente de correlação com os perímetros ventriculares segmentares nos corações dilatados. Distância do sulco atrioventricular até o ápice do VE: CMDId = CMDIsq > NORMAL. Perímetros segmentares ventriculares basais (PerB), equatoriais (PerE) e apicais (PerA): grupo NORMAL-> PerE = PerB > PerA; grupos CMDId e CMDIsq- > PerE > PerB > PerA, sendo que o grupo CMDId teve essas 3 medidas maiores que o grupo CMDIsq e ambos tiveram essas 3 medidas maiores que o grupo NORMAL. Nos 3 grupos as medidas de espessura das paredes ventriculares foram iguais estatisticamente. O índice de proporção perimetral PerB/PerE foi igual nos 3 grupos, enquanto o índice PerA/PerE foi igual entre os corações dilatados, mas em ambos foi menor que no grupo NORMAL. Todos perímetros segmentares ventriculares dos corações dilatados foram menores do que os calculados segundo a fórmula da esfera. CONCLUSÕES: 1) O anel atrioventricular esquerdo dilata-se na CMDIsq, sendo essa alteração independente da dilatação dos três segmentos do VE; 2) Os corações com CMDId e CMDIsq desenvolvem uma similar dilatação longitudinal do VE; 3) Ocorre uma dilatação trans versal do VE nessas afecções, sendo essa maior nos corações com CMDId; 4) A espessura das paredes ventriculares esquerdas dos corações com CMDIsq ou CMDId não se altera quando comparada aos corações normais; 5) A dilatação transversal da câmara ventricular esquerda nos corações com CMD não se dá de forma proporcional ao longo do seu eixo longitudinal, sendo mais acentuada nas regiões basal e equatorial; 6) A câmara ventricular esquerda nos corações com CMD de origem isquêmica ou idiopática não apresenta formato esférico. / BACKGROUND: Anatomic knowledge is the cornerstone for the development of surgical and diagnostic image techniques and for understanding pathological entities. Understanding cardiac anatomy is essential for understanding cardiac remodeling in both ischemic and idiopathic dilated cardiomyopathies. Dysfunction in the physiological relationship between the morphology of left ventricle and its mitral ring plays an important role in the cardiac insufficiency etiopathogenesis. OBJECTIVES: 1) To compare morphology of left ventricle and its mitral ring among normal, ischemic and idiopathic dilated cardiomyophatic anatomic specimens; 2) To compare intra specimen ventricular segmental perimeters relationships between normal and dilated specimens; 3) To verify the presence of the spheroid shape of left ventricular chamber in dilated specimens. METHODS: It was analyzed 43 specimens of human hearts, classified in three groups: normal (n=10), dilated due to ischemic (n=15) or idiopathic cardiomyopathies (n=18). Several lengths were measured: the length from the posterior atrioventricular sulcus to the ventricular apex in the intact specimen; followed by three sequential transversal ventricular slicing in the basal, equatorial and apical level. Digital pictures were taken from these slices, in order to be analyzed in a computer assisted fashion. Internal perimeter and ventricular walls width of each slice were measured, as well the mitral ring perimeter. The three intra group perimeters were compared and correlated between themselves. Basal, equatorial and apical perimeter of each group was compared to their correspondent pairs inter groups. Regarding intra group relationships, for a given group, each slice perimeter was measured and considered as a percentage of the equatorial slice (index). This percentage was compared inter groups. Three perimeters were evaluated in both dilated groups, each one was compared to its expected value when considering left ventricular chamber as a perfect sphere (hypothesis). Measurements and index statistical analysis was performed. RESULTS: Mitral ring perimeter was longer than the NORMAL group only in ischemic group. There was a low correlation coefficient between mitral ring perimeter and ventricular segmental perimeters in both dilated groups. Longitudinal length from the left atrioventricular sulcus until the apex was similar in dilated specimens and higher compared to the normal group. Regarding sequential perimeters of ventricular slices in the normal specimens, the equatorial perimeter was as long as the basal ones, but both of them longer than the apical one. In the other hand, for dilated specimens, equatorial diameter was the longest one and apic al the smallest one. Comparing ventricular slices perimeters between dilated groups, all the perimeters lengths were longer in the idiopathic group than in the ischemic one. All the ventricular slices perimeters were longer for both dilated groups than for the normal group. There was no difference of ventricular wall width between groups. The proposed index of proportional perimeter: considering the proportion between basal and equatorial perimeter, there was no difference between any groups; but considering the proportion between apical and equatorial perimeter, dilated specimens displayed a lower index when compared to normal specimens. All the observed ventricular slice perimeters were smaller than the hypothetical (sphere) expected ones in both dilated groups. CONCLUSIONS: 1) Left atrioventricular ring dilatation occurs in ischemic dilated cardiomyopathy and it is independent of the dilatation of segments (apical, basal and equatorial) ventricular; 2) Longitudinal left ventricular dilatation is similar between dilated groups; 3) A transversal ventricular chamber dilatation was observed in dilated diseases and it is greater in the idiopathic disease; 4) The left ventricular wall widths in both dilated cardiomyopathies were similar to normal hearts; 5) Transversal dilatation of left ventricular chamber in both dilated cardiomyopathies is not proporcional along their longitudinal axis because it is more accentuated in equatorial and basal regions; 6) Left ventricular chamber in both dilated cardiomyopathies does not keep spherical shape.

Kürzlich wurde mithilfe von Ribo-seq Experimenten die Translation hunderter Mikroproteine in menschlichen Herzen entdeckt. Diese blieben zuvor aufgrund ihrer geringen Größe (< 100 Aminosäuren) unentdeckt, und ihre physiologische Rolle ist noch weitgehend unbekannt. Ziel dieser Promotionsarbeit ist es, potentielle Funktionen dieser neuartigen Mikroproteine zu entschlüsseln. Dabei sollen insbesondere die Aufklärung ihrer evolutionären Konservierungssignatur, subzellulären Lokalisierung und ihres Proteininteraktoms helfen. Die Konservierungsanalyse ergab, dass fast 90% der Mikroproteine nur in Primaten konserviert ist. Weiterhin konnte ich die Produktion von Mikroproteine in vitro und in vivo nachweisen, die subzelluläre Lokalisierung von 92 Mikroproteinen definieren, und Interaktionspartner für 60 Mikroproteine identifizieren. Dutzende dieser Mikroproteine lokalisieren in Mitochondrien. Dazu gehörte ein im Herzen angereichertes Mikroprotein, das aufgrund der Interaktions- und Lokalisationsdaten einen neuartigen Modulator der mitochondrialen Proteintranslation darstellen könnte. Der Interaktom-Screen zeigte außerdem, dass evolutionär junge Mikroproteine ähnliche Interaktionsfähigkeiten wie konservierte Kandidaten haben. Schließlich wurden kurze Sequenzmotive identifiziert, die Mikroprotein-Protein-Wechselwirkungen vermitteln, wodurch junge Mikroproteine mit zellulären Prozessen – wie z.B. Endozytose und Spleißen – in Verbindung gebracht werden konnten. Zusammenfassend wurde die Produktion vieler kleiner Proteine im menschlichen Herzen bestätigt, von denen die meisten lediglich in Primaten konserviert sind. Zusätzlich verknüpften umfangreiche Lokalisierungs- und Interaktionsdaten mehrere Mikroproteine mit Prozessen wie Spleißen, Endozytose und mitochondrialer Translation. Weitere Untersuchungen dieses zuvor verborgenen Teils des Herzproteoms werden zu einem besseren Verständnis von evolutionär jungen Proteinen und kardiologischen Prozessen beitragen. / Recently, the active translation of hundreds of previously unknown microproteins was detected using ribosome profiling on tissues of human hearts. They had remained undetected due to their small size (< 100 amino acids), and their physiological roles are still largely unknown. This dissertation aims to investigate these novel microproteins and validate their translation by independent methods. Particularly, elucidating their conservation signature, subcellular localization, and protein interactome shall aid in deciphering their potential biological role. Conservation analysis revealed that sequence conservation of almost 90% of microproteins was restricted to primates. I next confirmed microprotein production in vitro and in vivo by in vitro translation assays and mass spectrometry-based approaches, defined the subcellular localization of 92 microproteins, and identified significant interaction partners for 60 candidates. Dozens of these microproteins localized to the mitochondrion. These included a novel cardiac-enriched microprotein that may present a novel modulator of mitochondrial protein translation based on its interaction profile and subcellular localization. The interactome screen further revealed that evolutionarily young microproteins have similar interaction capacities to conserved candidates. Finally, it allowed identifying short linear motifs that may mediate microprotein-protein interactions and implicated several young microproteins in distinct cellular processes such as endocytosis and splicing. I conclude that many novel small proteins are produced in the human heart, most of which exhibit poor sequence conservation. I provide a substantial resource of microprotein localization and interaction data that links several to cellular processes such as splicing, endocytosis, and mitochondrial translation. Further investigation into this hidden part of the cardiac proteome will contribute to our understanding of recently evolved proteins and heart biology.

Cardiotrophin-1 ist ein Zytokin der Familie Interleukin-6-Familie, zu der auch IL-11, CNTF, OSM und LIF gehören. Diese Substanzen wirken über die gemeinsame Rezeptoruntereinheit gp130. CT-1 induziert die Hypertrophie von Kardiomyozyten und inhibiert die Apoptose kardialer und Zellen. In verschiedenen Tiermodellen der Herzinsuffizienz konnte eine gesteigerte myokardiale CT-1 Expression beobachtet werden. Kardiomyopathien sind wiederum kardiale Erkrankungen, die mit einer Hypertrophie und Apoptose einhergehen und zu einer Herzinsuffizienz führen können. Man geht davon aus, dass 25-50 Prozent der familiär sind. Hierbei handelt es sich um eine monogenetische Erkrankung, die überwiegend autosomal-dominant vererbt werden. Daneben konnten aber auch modifizierende Polymorphismen in neurohumoralen Faktoren identifiziert werden. Basierend auf diesen Ergebnissen war das Ziel dieser Arbeit die Analyse der möglichen Beteiligung genetischer Varianten der kodierenden sowie der regulatorischen Region an der Pathogenese der Hypertrophen bzw. Dilatativen Kardiomyopathie. Zusätzlich sollte die mRNA-Expression von CT-1 in Myokardbiopsien von Patienten mit Herzinsuffizienz quantifiziert werden. Hierfür musste zunächst die Sequenzen der 5´-flankierenden Region identifiziert und bezüglich ihrer regulatorischen Eigenschaften analysiert werden. Es konnten 1,1 kb der 5´-flankierenden Region sequenziert werden. Die anschließende Luciferase-Reportergen-Analyse wies regulatorische Aktivitäten für den gesamten Bereich nach. Diese Region enthält zahlreiche cis-aktive DANN-Sequenzen aber keine TATA-Box. Für die Mutationssuche wurden 64 Patienten mit DCM, 53 Patienten mit HCM sowie 100 Kontrollpersonen mittels PCR-SSCP-Analyse untersucht. Es konnte eine kodierende Variante A92T bei jeweils einem DCM- bzw. HCM-Patienten identifiziert werden. Diese Substitution liegt in einem Bereich, der zwischen verschiedenen Spezies (Ratte, Maus, Mensch) konserviert ist. Diese Mutation könnte eine Veränderung der Sekundärstruktur bewirken und liegt in einem möglichen funktionellen Bereich. Die Promotorregion wies eine Basenpaarsubstitution bei -130 (G/T) sowie eine Deletion der Basen CTTT zwischen -992 und -995 auf. Der Polymorphismus an Position -130 fand sich tendenziell häufiger bei Patienten mit Dilatativer Kardiomyopathie. Die CTTT-Deletion konnte nur bei einer Patientin mit HCM nachgewiesen werden. Für die Quantifizierung der CT-1 mRNA wurden rechtsventrikuläre Endomyokardbiopsien von 6 Patienten mit eingeschränkter LVEF (CHI), 5 Patienten nach Herztransplantation (TX) sowie 3 Kontrollpatienten (KO) eingesetzt. Es konnte ein relativer Anstieg der CT-1 Expression um 82% bei den Patienten mit eingeschränkter LVEF festgestellt werden. Interessanterweise besteht eine enge Korrelation zur Schwere der eingeschränkten Herzfunktion sowie zur Zunahme der Hypertrophie. / Cardiotrophin-1 is a cytokine, which belongs to the interleukin-6 family, which includes IL-11, CNTF, OSM and LIF. These factors act via the receptor subunit gp130. CT-1 induces the hypertrophy of cardiomyocytes and inhibits the apoptosis of cardiac cells. Studies in animal models of congestive heart failure showed an enhanced expression of CT-1 in the myocardium. Cardiomyopathies are cardiac diesorders, which are charakterized by hypertrophy and apoptosis and which can terminate with congestive heart failure. About 25-50 percent of all cases are familial. It is a monogenetic mendelian disorder with an autosomal-dominant inheritance in most cases. Beside this, modifying polymorphisms in neurohunoral factors could be identified. Based on these facts, the aim of this study was to identify genetic variants within the coding and regulatory region of the CT-1 gene, which could influence the pathogenesis of hypertrophic or dilated cardiomyopathy. Additionally, the mRNA-expression of CT-1 in myocardial biopsies of heart failure patients should be quantified. First, it was necessary to sequence the 5´-untranslated region and to analyse its regulatory function. We could sequence 1.1 kb of the 5´-UTR. The luciferase reportergene assay showed a significant promoter activity for the whole region. The region contains various cis-active DNA sequences but no TATA-box.The TRANSFAC-analysis identified different binding sites for transcription factors but no TATA-box. The genetic material of 64 DCM and 53 HCM patients and 100 controls was screened for mutaions by using a PCR-based SSCP-analysis. A coding variant A92T could be identified for a patient with DCM and for an HCM patient. This mutation lies within a region which is conserved between different species (rat, mouse, human). This variant could disturb the secondary structure and lies in a probable functional region. Within the promoter we could identify a basepair substitution at position -130 (G/T) and a 4-basepair deletion between -992 and -995 (CTTTdel). The polymorphism at -130 showed a tendency for a higher occurrence in DCM patients. One HCM patient was heterozygous for the CTTT-deletion. To quantify the CT-1 mRNA we used endomyocardial biopsies of 6 patients with reduced LVEF (CHI), 5 patients after heart transplantation (TX) and 3 controls (KO). We performed a semiquantitative analysis by using HPLC and an external standard (PDH mRNA). We found an increased expression of CT-1 by 82% for patients with heart failure. Interestingly, we saw a tight correlation with to the reduction in LV function and to the degree of hypertrophy.