Chez l’humain, les maladies congénitales cardiaques (MCC) sont présentes chez 3-4% des nouveaux nés et sont une cause importante de mortalité infantile et de morbidité dans le monde. La majorité des MCCs implique les valves et les septums, qui proviennent des cellules endocardiques. Les valves aortiques bicuspides (VAB) sont la MCC la plus fréquente chez l’humain, avec un taux estimé de 1-2% dans la population. Cependant, les gènes et les mécanismes moléculaires qui causent cette malformation demeurent obscures. Le facteur de transcription GATA5 est exprimé dans les cellules et les coussins endocardiques de façon transitoire durant la septation et la formation des compartiments cardiaques. Chez le poisson zèbre, des mutations dans le gène Gata5 causent des malformations cardiaques sévères incluant l’absence de cellules endocardiques. In vitro, l’inhibition de Gata5 bloque la différentiation endocardique. Ces études suggéraient donc un rôle important de GATA5 dans la formation du cœur. Dans le cadre de ce projet de doctorat, nous avons analysé le rôle de GATA5 dans le développement du cœur en produisant des lignées de souris chez lesquelles le gène Gata5 était inactif soit dans toutes les cellules ou uniquement dans les cellules endocardiques. Les souris possédant 2 allèles mutées du gène Gata5 étaient viables mais plus de 26% des souris Gata5-/- ont développé des VABs. Par ailleurs, une incidence similaire de VABs a été obtenue chez les souris ayant une délétion spécifique de Gata5 des cellules endocardiques, obtenue en croisant les souris Gata5WT/Flox avec les souris transgéniques Tie2-Cre. Sur le plan mécanistique, une réduction significative de JAG1, un corécepteur pour Notch1, ainsi qu’une augmentation marquée de Rbj un répresseur de cette voie, ont été détectés chez les souris Gata5-/- et Tie2- cre+;Gata5Flox/Flox, suggérant qu’une dérégulation de la voie Notch dans les cellules endocardiques puisse être la cause des VABs. Ces résultats démontrent l’importance de GATA5 pour le développement endocardique et la formation de la valve aortique. De plus, ils identifient GATA5 comme gène candidat de MCCs chez l’humain. Environ 12-14% des MCCs sont causés par le développement anormal de la voie de chasse, menant aux malformations telles que la transposition des grandes artères, la tétralogie de Fallot ou le syndrome du ventricule droit à double issue. Des mutations dans Gata4 et Gata6 sont associés à des défauts de la voie de chasse, dans plusieurs espèces incluant l’humain. Nous avons examiné si GATA5 interagit avec GATA4 ou GATA6 dans le développement de la voie de chasse. Alors que les souris hétérozygotes pour Gata5, Gata4 ou Gata6 ont des défauts cardiaques subtiles et sont viables, les embryons Gata4+/-Gata5+/- et Gata5+/-Gata6+/- démontrent une létalité embryonnaire et périnatale due à des défauts cardiaques, tel qu’un ventricule droit à double issue et des défauts de septation ventriculaire. Ces résultats indiquent l'importance des interactions génétiques entre GATA5 et les autres facteurs GATA pour la rotation et l’alignement de la voie de chasse au cours du développement cardiaque et soulèvent la possibilité que des changements subtiles de l'activité de 2 facteurs GATA puissent mener à des MCCs chez l'humain. / Congenital heart defect (CHD) in humans occur in 3-4% of live birth and is a major cause of infant mortality and morbidity in the world. The majority of CHD involves the valves and septa, which originate from endocardial cells. Bicuspid aortic valve (BAV) is the most common CHD in humans with an estimated rate of 1-2% in the population. However, very few genes have been linked to this defect and the mechanisms underlying BAV formation remain undefined. GATA5, a member of the GATA family of transcription factors, is expressed in a spatial and temporal manner in the developing heart where it is predominantly found in endocardial cells and endocardial cushions (ECs) of the outflow tract (OFT) and atrioventricular canal between E9.5-E12.5 in the mouse. Mutations in the Gata5 gene in zebrafish (faust mutants) cause cardia bifida and lead to endocardial cell depletion. In vitro studies using antisense mRNA against Gata5 revealed a critical role for this gene in differentiation of endocardial cells. In the context of the present doctoral research project, we investigated the role of GATA5 in mammalian heart development by generating a mouse line with a null Gata5 allele. Gata5 null mice are viable but over 26% of them developed BAVs. Endocardial specific deletion of Gata5 obtained by crossing mice with floxed (Flox) Gata5 alleles with Tie2-cre transgenic mice resulted in a similar incidence of BAVs. RNA profiling revealed that Jag-1, a co-receptor for Notch1, is significantly downregulated in both Gata5 null and Tie2-cre+;Gata5Flox/Flox mice, suggesting that disruption of Notch signaling in endocardial cells may be the underlying mechanism of disease. These findings reveal an important function for GATA5 in endocardial cell development and aortic valve formation and identify GATA5 as an important candidate CHD causing gene. Abnormal development of the OFT accounts for about 12-14% of all CHDs, leading to malformations such as persistent truncus arteriosus (PTA), tetralogy of Fallot (TOF), double outlet right ventricle (DORV) and transposition of the great arteries (TGA). Both GATA4 and GATA6 play important role in OFT development. We tested whether GATA5 might interact genetically with GATA4 and GATA6 for proper heart morphogenesis. We found that, whereas mice lacking a single copy of Gata5, Gata4 or Gata6 have subtle cardiac defects, the Gata4+/-Gata5+/- and Gata5+/-Gata6+/- mutant embryos show embryonic and perinatal lethality due to severe heart defects, including double outlet right ventricle and ventricular septal defects. These findings reveal the importance of genetic interactions between GATA5 and the other cardiac GATA factors in the normal rotation and patterning of the OFT during heart development in vivo. The results raise the possibility that subtle alterations in the level or activity of 2 cardiac GATA factors might lead to congenital heart disease in human. / réalisé en cotutelle avec le Dr. Marie Kmita et Dr. Marco Horb

Cardiovascular disease varies by ethnicity in the UK. South Asians (SA) have higher coronary heart disease (CHD) and diabetes prevalence, while African-Caribbeans (AfC) have greater stroke, but intriguingly lower CHD rates despite higher blood pressures and diabetes risk than Europeans. Conventional risk factors do not fully explain such differences. This cross-sectional study tested the hypothesis that the hormones, vitamin D measured as 25(OH)D and aldosterone, would be independently associated with intermediate cardiovascular outcome markers in these ethnic groups. Community-dwelling men 40-80 years old (AfC: n=67, 55±10yr; SA: n=68, 55±10yr; European: n=63, 57±8yr) were sampled from Greater Manchester’s multi-ethnic population. The intermediate markers examined were aortic pulse wave velocity (aPWV), left ventricular (LV) mass and function, and carotid intima media thickness (CIMT), measured non-invasively by ultrasound, and hemodynamic profiling methods (the Arteriograph) in the total sample and by magnetic resonance imaging (MRI) in a subsample of 50. Adjusted for age, systolic blood pressure and diabetes, mean(SE) aPWV by the Arteriograph, was 0.5(0.2) m/s higher in SA than AfC and Europeans (p=0.01), which paralleled known cross-ethnic CHD risk differences in the UK. By MRI, aPWV along the descending aorta in SA was 0.7(0.3) and 0.8(0.3) m/s higher than that in AfC and Europeans, but aPWV along the aortic arch was not significantly different. Unlike aldosterone, 25(OH)D was independently and inversely correlated with aPWV (unstandardised B(SE)=-0.013[0.004] m/s, p<0.001), and partly explained the ethnic variation in aPWV. Similar inverse correlations were found between 25(OH)D and LV concentricity measured by echocardiography and MRI. Compared to Europeans, SA and AfC, had 21(3) and 14(3) nmol/L lower mean(SE) 25(OH)D, respectively (p<0.01). Mean(SE) of relative wall thickness, an index of LV concentricity by echocardiography, was 0.05(0.01) higher in SA and AfC than Europeans. Lower 25(OH)D levels were also associated with higher myocardial deformation rates measured by MRI myocardial tagging (n=50), supporting previous animal experimental evidence. A one standard deviation (SD) decrease in 25(OH)D was associated with a 0.38 SD increase in absolute systolic strain rate (p=0.003) and 0.22 SD rise in diastolic strain rate (p=0.04). Right and left CIMT showed different relations with 25(OH)D and aldosterone. Left-right CIMT differences varied by ethnicity and were related to SA ethnicity and aldosterone levels. Two related technical studies investigated the relatively new method of hemodynamic profiling, the Arteriograph, used here. The results suggested a standardisation method of aortic length estimation for purely central aPWV, which significantly improved aPWV agreement between the Arteriograph and MRI (reference method here), and was used for calibrating the Arteriograph aPWV in the above-mentioned results for the total sample. Future well-designed trials are necessary to investigate any cause-effect relationship between vitamin D deficiency and the unfavourable cardiovascular intermediate outcomes found here in a cross-sectional design and multi-ethnic background.

Indiana University-Purdue University Indianapolis (IUPUI) / Recent advancements in the management of systemic glucose regulation in obesity/T2DM include drug therapies designed to utilize components of the incretin system specifically related to glucagon-like peptide 1 (GLP-1). More recently, GLP-1 has been investigated for potential cardioprotective effects. Several investigations have revealed that acute/sub-acute intravenous administration of GLP-1 significantly reduces myocardial infarct size following ischemia/reperfusion injury and improves cardiac contractile function in the settings of coronary artery disease, myocardial ischemia/reperfusion injury, and heart failure. Despite an abundance of data indicating that intravenous infusion of GLP-1 is cardioprotective, information has been lacking on the cardiac effects of iv GLP-1 in the MetS or T2DM population. Some important questions this study aimed to address are 1) what are the direct, dose-dependent cardiac effects of GLP-1 in-vivo 2) are the cardiac effects influenced by cardiac demand (MVO2) and/or ischemia, 3) does GLP-1 effect myocardial blood flow, glucose uptake or total oxidative metabolism in human subjects, and 4) are the cardiac effects of GLP-1 treatment impaired in the settings of obesity/MetS and T2DM. Initial studies conducted in canines demonstrated that GLP-1 had no direct effect on coronary blood flow in-vivo or vasomotor tone in-vitro, but preferentially increased myocardial glucose uptake in ischemic myocardium independent of effects on cardiac contractile function or coronary blood flow. Parallel translational studies conducted in the humans and Ossabaw swine demonstrate that iv GLP-1 significantly increases myocardial glucose uptake at rest and in response to increases in cardiac demand (MVO2) in lean subjects, but not in the settings of obesity/MetS and T2DM. Further investigation in isolated cardiac tissue from lean and obese/MetS swine indicate that this impairment in GLP-1 responsiveness is related to attenuated activation of p38-MAPK, independent of alterations in GLP-1 receptor expression or PKA-dependent signaling. Our results indicate that the affects of GLP-1 to reduce cardiac damage and increase left ventricular performance may be impaired by obesity/MetS and T2DM.

No / PURPOSE: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius (AoS) in chronic cerebrospinal venous insufficiency (CCSVI)-positive and -negative healthy individuals using cine phase contrast imaging. MATERIALS AND METHODS: Fifty-one healthy individuals (32 CCSVI-negative and 19 age-matched CCSVI-positive subjects) were examined using Doppler sonography (DS). Diagnosis of CCSVI was established if subjects fulfilled >/=2 venous hemodynamic criteria on DS. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and routine 3T MRI outcomes. RESULTS: CCSVI was associated with increased CSF pulsatility in the AoS. Net positive CSF flow was 32% greater in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.008). This was accompanied by a 28% increase in the mean aqueductal characteristic signal (ie, the AoS cross-sectional area over the cardiac cycle) in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.021). CONCLUSION: CSF dynamics are altered in CCSVI-positive healthy individuals, as demonstrated by increased pulsatility. This is accompanied by enlargement of the AoS, suggesting that structural changes may be occurring in the brain parenchyma of CCSVI-positive healthy individuals.

Introdução: O bloqueio atrioventricular congênito isolado (BAVCi) é raro e tem múltiplas apresentações clínicas. O implante de marca-passo cardíaco permanente (MP) é o tratamento de escolha, resultando em evolução clínica satisfatória para a maioria dos casos, porém, aproximadamente 10% deles apresentam remodelamento ventricular e insuficiência cardíaca grave. Objetivos: Estudar a evolução tardia de crianças e adultos jovens com BAVCi e estimulação crônica do ventrículo direito (VD), visando determinar: a prevalência de sinais clínicos e laboratoriais de insuficiência cardíaca e de remodelamento ventricular; a capacidade funcional; a qualidade de vida e fatores preditores de alterações clínicas, funcionais ou ecocardiográficas. Métodos: Estudo transversal realizado em coorte de portadores de BAVCi e MP implantado antes de 21 anos de idade com estimulação no VD há mais de um ano. Todos os indivíduos foram submetidos a avaliação clínica e laboratorial, da capacidade funcional, da qualidade de vida e a ecocardiograma. Mães e sujeitos da pesquisa foram investigados para doenças reumatológicas. Os dados foram armazenados no sistema REDCap (Research Electronic Data Capture) e analisados pelos programas SAS (Statistical Analysis System), SPSS (Statistical Package for the Social Sciences) e R Studio. A análise dos dados incluiu: análise univariada para pesquisa de associações entre variáveis preditoras e desfechos, coeficiente de correlação de Pearson e modelo de regressão linear multivariado. Resultados: De março/2010 a dezembro/2013, foram avaliados 63 indivíduos, 68% do sexo feminino, com idade de 1 a 40 anos, com MP por 13,4 ± 6,5 anos e estimulação do VD por 10,0 ± 5,4 anos. O modo de estimulação era atrioventricular em 55,6%, o percentual de estimulação de VD de 97,9 ± 4,2% e a duração do complexo QRS estimulado de 152,4 ± 20,1 ms. A maioria (88,9%) era assintomática e não utilizava medicamentos de ação cardiovascular. Maior tempo de MP (P= 0,013), maior tempo de estimulação do VD (P= 0,005), maior idade na inclusão no estudo (P= 0,032) ou menor fração de ejeção do ventrículo (FEVE) (P= 0,013) associaram-se com a presença de classe funcional II (NYHA) e/ou uso medicamentos. Os valores do peptídeo natriurético tipo B foram normais em todos os exames laboratoriais, mas houve alteração da proteína C reativa ultrassensível, fator de necrose tumoral alfa e interleucina-6 em 66%, 34% e 13% exames, respectivamente. A distância média percorrida no teste de caminha de seis minutos foi de 546,9 ± 76,2 metros (91,0 ± 12,5% do valor predito). Os escores médios da qualidade de vida foram 78,1 ± 17,7 para o \"Sumário Físico\" e 76,6 ± 17,1 para o \"Sumário Mental\" do questionário Short Form 36 (SF-36) e de 77,4 ± 18,5, para o \"Sumário Físico\" e de 77,7 ± 21,6 para o \"Sumário Psicossocial\", do Child Health Questionnaire - Parent Form 50 (CHQ-PF50). Diminuição da FEVE foi detectada em 39,7% e aumento do diâmetro diastólico do ventrículo esquerdo (DDVE) em 22,2% dos indivíduos. A idade mais avançada no primeiro implante de MP se correlacionou negativamente com menor FEVE (r= -0,302; P= 0,016); a duração do complexo QRS estimulado (r= 0,447; P= 0,002) e maior tempo sob estimulação do VD (r= 0,416; P= 0,007) se correlacionaram positivamente ao aumento do DDVE. Foi detectada dissincronia ventricular em 60,3% dos indivíduos. O retardo da ativação eletromecânica intraventricular esquerda foi de 86,5 ± 56,9 ms e interventricular, de 141,9 ± 88 ms. Contudo, não houve correlação com os fatores estudados. Autoanticorpos anti-Ro/SSA foram detectados em 18 (32,1%) mães, com associação entre idade no momento do implante do MP (P= 0,032) e uso de MP ventricular no momento do estudo (P= 0,022). A regressão linear multivariada confirmou a correlação entre a idade no momento do implante do MP com a FEVE (P= 0,016), da duração do complexo QRS estimulado (P= 0,004) e do tempo sob estimulação do VD (P= 0,014) com o DDVE. Conclusões: A prevalência de manifestações clínicas e laboratoriais de insuficiência cardíaca foi baixa; por outro lado, a de remodelamento ventricular esquerdo foi elevada. A capacidade funcional foi satisfatória, assim como a qualidade de vida, nos aspectos físicos e emocionais. Idade mais avançada no primeiro implante de MP, maior tempo sob estimulação cardíaca e complexo QRS estimulado mais alargado foram fatores independentes de remodelamento ventricular e/ou de manifestação de insuficiência cardíaca / Introduction: Isolated congenital atrioventricular block (iCAVB) is a rare condition with multiple clinical presentations. Permanent cardiac pacing is the most effective therapy for this population resulting in satisfactory long-term outcomes. However, approximately 10% of patients may have ventricular remodeling and severe heart failure. Objectives: To study the long-term effects of chronic right ventricular (RV) pacing in children and young adults with iCAVB in order to determine: prevalence of clinical and laboratory signs of heart failure and ventricular remodeling, functional capacity, quality of life and predictors of clinical, functional or echocardiographic abnormalities. Methods: Cross-sectional study of a cohort of iCAVB patients with <= 21 years old at initial pacemaker (PM) implantation and single or dual-chamber pacing in a unique RV site for a minimum of one year. All subjects underwent clinical and laboratory assessment, functional capacity, quality of life and echocardiogram. Mothers and research subjects were investigated for rheumatic diseases. Data were stored in REDCap (Research Electronic Data Capture) system and analyzed by SAS (Statistical Analysis System), SPSS (Statistical Package for the Social Sciences) and R Studio programs. Data analysis included: univariate analysis for associations between predictor variables and outcomes, Pearson correlation coefficient and linear regression multivariate model. Results: Between March/2010 and December/2013, we evaluated 63 subjects aged 1-40 years old, 68% female, under PM for 13.4 ± 6.5 years and under RV pacing for 10.0 ± 5.4 years. Pacing mode was atrioventricular in 55.6%, percentage of RV pacing was 97.9 ± 4.2% and paced QRS duration was 152.4 ± 20.1 ms. Overall, the majority (88.9%) were asymptomatic and did not use cardiovascular drugs. Longer time under PM (P= 0.013), or even under RV pacing (P= 0.005), higher age at study inclusion (P= 0.032) and lower left ventricular ejection fraction (LVEF) (P= 0.013) were associated with functional class II (NYHA) and / or drug use. B-natriuretic peptide values were normal in all tests. C reactive protein ultrasensitive, tumor necrosis factor alfa and interleukin-6 were increased in 66%, 34% and 13% tests, respectively. The mean walked distance in the sex minute walk test was 546.9 ± 76.2 meters (91.0 ± 12.5% of the predicted value). Mean scores of quality of life were 78.1 ± 17.7 for \"Physical Summary\" and 76.6 ± 17.1 for \"Mental Summary\" in the Short Form 36 (SF-36) and 77.4 ± 18.5 for \"Physical Summary\" and 77.7 ± 21.6 for \"Psychosocial Summary\", of Child Health Questionnaire - Parent Form 50 (CHQ-PF50). Decreased LVEF was detected in 39.7% and increased left ventricular end-diastolic diameter (LVDD) in 22.2% of subjects. Higher age at the first PM implant was negatively correlated with lower LVEF (r= -0.302; P= 0.016); paced QRS duration (r= 0.447; P= 0.002) and time under RV pacing (r= 0.416; P= 0.007) were positively correlated with LVDD. Ventricular dyssynchrony was detected in 60.3 % of individuals. Intra-left ventricular electromechanical delay was 86.5 ± 56.9 ms and interventricular was 141.9 ± 88 ms. However, ventricular dyssynchrony was not correlated with the studied variables. Autoantibodies anti-SSA/Ro were detected in 18 (32.1%) mothers. There was association between age at PM implant (P= 0.032) and use of ventricular PM at the time of the study (P= 0.022) and presence of anti-SSA/Ro. Multivariate linear regression showed significant correlation between age at PM implant with LVEF (P= 0.016); and paced QRS duration (P= 0.005) and time under RV pacing (P= 0.014) with LVDD. Conclusions: Clinical and laboratorial manifestations of heart failure presented low prevalence in this population. On the other hand, the prevalence of left ventricular remodeling was high. Functional capacity was adequate, as well as quality of life, in both physical and emotional aspects. Higher age at first PM implant, longer time under pacing and wider paced QRS duration were independent factors of ventricular remodeling and/or manifestation of heart failure

Introdução: O bloqueio atrioventricular congênito isolado (BAVCi) é raro e tem múltiplas apresentações clínicas. O implante de marca-passo cardíaco permanente (MP) é o tratamento de escolha, resultando em evolução clínica satisfatória para a maioria dos casos, porém, aproximadamente 10% deles apresentam remodelamento ventricular e insuficiência cardíaca grave. Objetivos: Estudar a evolução tardia de crianças e adultos jovens com BAVCi e estimulação crônica do ventrículo direito (VD), visando determinar: a prevalência de sinais clínicos e laboratoriais de insuficiência cardíaca e de remodelamento ventricular; a capacidade funcional; a qualidade de vida e fatores preditores de alterações clínicas, funcionais ou ecocardiográficas. Métodos: Estudo transversal realizado em coorte de portadores de BAVCi e MP implantado antes de 21 anos de idade com estimulação no VD há mais de um ano. Todos os indivíduos foram submetidos a avaliação clínica e laboratorial, da capacidade funcional, da qualidade de vida e a ecocardiograma. Mães e sujeitos da pesquisa foram investigados para doenças reumatológicas. Os dados foram armazenados no sistema REDCap (Research Electronic Data Capture) e analisados pelos programas SAS (Statistical Analysis System), SPSS (Statistical Package for the Social Sciences) e R Studio. A análise dos dados incluiu: análise univariada para pesquisa de associações entre variáveis preditoras e desfechos, coeficiente de correlação de Pearson e modelo de regressão linear multivariado. Resultados: De março/2010 a dezembro/2013, foram avaliados 63 indivíduos, 68% do sexo feminino, com idade de 1 a 40 anos, com MP por 13,4 ± 6,5 anos e estimulação do VD por 10,0 ± 5,4 anos. O modo de estimulação era atrioventricular em 55,6%, o percentual de estimulação de VD de 97,9 ± 4,2% e a duração do complexo QRS estimulado de 152,4 ± 20,1 ms. A maioria (88,9%) era assintomática e não utilizava medicamentos de ação cardiovascular. Maior tempo de MP (P= 0,013), maior tempo de estimulação do VD (P= 0,005), maior idade na inclusão no estudo (P= 0,032) ou menor fração de ejeção do ventrículo (FEVE) (P= 0,013) associaram-se com a presença de classe funcional II (NYHA) e/ou uso medicamentos. Os valores do peptídeo natriurético tipo B foram normais em todos os exames laboratoriais, mas houve alteração da proteína C reativa ultrassensível, fator de necrose tumoral alfa e interleucina-6 em 66%, 34% e 13% exames, respectivamente. A distância média percorrida no teste de caminha de seis minutos foi de 546,9 ± 76,2 metros (91,0 ± 12,5% do valor predito). Os escores médios da qualidade de vida foram 78,1 ± 17,7 para o \"Sumário Físico\" e 76,6 ± 17,1 para o \"Sumário Mental\" do questionário Short Form 36 (SF-36) e de 77,4 ± 18,5, para o \"Sumário Físico\" e de 77,7 ± 21,6 para o \"Sumário Psicossocial\", do Child Health Questionnaire - Parent Form 50 (CHQ-PF50). Diminuição da FEVE foi detectada em 39,7% e aumento do diâmetro diastólico do ventrículo esquerdo (DDVE) em 22,2% dos indivíduos. A idade mais avançada no primeiro implante de MP se correlacionou negativamente com menor FEVE (r= -0,302; P= 0,016); a duração do complexo QRS estimulado (r= 0,447; P= 0,002) e maior tempo sob estimulação do VD (r= 0,416; P= 0,007) se correlacionaram positivamente ao aumento do DDVE. Foi detectada dissincronia ventricular em 60,3% dos indivíduos. O retardo da ativação eletromecânica intraventricular esquerda foi de 86,5 ± 56,9 ms e interventricular, de 141,9 ± 88 ms. Contudo, não houve correlação com os fatores estudados. Autoanticorpos anti-Ro/SSA foram detectados em 18 (32,1%) mães, com associação entre idade no momento do implante do MP (P= 0,032) e uso de MP ventricular no momento do estudo (P= 0,022). A regressão linear multivariada confirmou a correlação entre a idade no momento do implante do MP com a FEVE (P= 0,016), da duração do complexo QRS estimulado (P= 0,004) e do tempo sob estimulação do VD (P= 0,014) com o DDVE. Conclusões: A prevalência de manifestações clínicas e laboratoriais de insuficiência cardíaca foi baixa; por outro lado, a de remodelamento ventricular esquerdo foi elevada. A capacidade funcional foi satisfatória, assim como a qualidade de vida, nos aspectos físicos e emocionais. Idade mais avançada no primeiro implante de MP, maior tempo sob estimulação cardíaca e complexo QRS estimulado mais alargado foram fatores independentes de remodelamento ventricular e/ou de manifestação de insuficiência cardíaca / Introduction: Isolated congenital atrioventricular block (iCAVB) is a rare condition with multiple clinical presentations. Permanent cardiac pacing is the most effective therapy for this population resulting in satisfactory long-term outcomes. However, approximately 10% of patients may have ventricular remodeling and severe heart failure. Objectives: To study the long-term effects of chronic right ventricular (RV) pacing in children and young adults with iCAVB in order to determine: prevalence of clinical and laboratory signs of heart failure and ventricular remodeling, functional capacity, quality of life and predictors of clinical, functional or echocardiographic abnormalities. Methods: Cross-sectional study of a cohort of iCAVB patients with <= 21 years old at initial pacemaker (PM) implantation and single or dual-chamber pacing in a unique RV site for a minimum of one year. All subjects underwent clinical and laboratory assessment, functional capacity, quality of life and echocardiogram. Mothers and research subjects were investigated for rheumatic diseases. Data were stored in REDCap (Research Electronic Data Capture) system and analyzed by SAS (Statistical Analysis System), SPSS (Statistical Package for the Social Sciences) and R Studio programs. Data analysis included: univariate analysis for associations between predictor variables and outcomes, Pearson correlation coefficient and linear regression multivariate model. Results: Between March/2010 and December/2013, we evaluated 63 subjects aged 1-40 years old, 68% female, under PM for 13.4 ± 6.5 years and under RV pacing for 10.0 ± 5.4 years. Pacing mode was atrioventricular in 55.6%, percentage of RV pacing was 97.9 ± 4.2% and paced QRS duration was 152.4 ± 20.1 ms. Overall, the majority (88.9%) were asymptomatic and did not use cardiovascular drugs. Longer time under PM (P= 0.013), or even under RV pacing (P= 0.005), higher age at study inclusion (P= 0.032) and lower left ventricular ejection fraction (LVEF) (P= 0.013) were associated with functional class II (NYHA) and / or drug use. B-natriuretic peptide values were normal in all tests. C reactive protein ultrasensitive, tumor necrosis factor alfa and interleukin-6 were increased in 66%, 34% and 13% tests, respectively. The mean walked distance in the sex minute walk test was 546.9 ± 76.2 meters (91.0 ± 12.5% of the predicted value). Mean scores of quality of life were 78.1 ± 17.7 for \"Physical Summary\" and 76.6 ± 17.1 for \"Mental Summary\" in the Short Form 36 (SF-36) and 77.4 ± 18.5 for \"Physical Summary\" and 77.7 ± 21.6 for \"Psychosocial Summary\", of Child Health Questionnaire - Parent Form 50 (CHQ-PF50). Decreased LVEF was detected in 39.7% and increased left ventricular end-diastolic diameter (LVDD) in 22.2% of subjects. Higher age at the first PM implant was negatively correlated with lower LVEF (r= -0.302; P= 0.016); paced QRS duration (r= 0.447; P= 0.002) and time under RV pacing (r= 0.416; P= 0.007) were positively correlated with LVDD. Ventricular dyssynchrony was detected in 60.3 % of individuals. Intra-left ventricular electromechanical delay was 86.5 ± 56.9 ms and interventricular was 141.9 ± 88 ms. However, ventricular dyssynchrony was not correlated with the studied variables. Autoantibodies anti-SSA/Ro were detected in 18 (32.1%) mothers. There was association between age at PM implant (P= 0.032) and use of ventricular PM at the time of the study (P= 0.022) and presence of anti-SSA/Ro. Multivariate linear regression showed significant correlation between age at PM implant with LVEF (P= 0.016); and paced QRS duration (P= 0.005) and time under RV pacing (P= 0.014) with LVDD. Conclusions: Clinical and laboratorial manifestations of heart failure presented low prevalence in this population. On the other hand, the prevalence of left ventricular remodeling was high. Functional capacity was adequate, as well as quality of life, in both physical and emotional aspects. Higher age at first PM implant, longer time under pacing and wider paced QRS duration were independent factors of ventricular remodeling and/or manifestation of heart failure

Ce travail a été consacré à l’étude non invasive de la circulation pulmonaire normale par mise en œuvre de l’échocardiographie Doppler. <p>En intégrant les mesures obtenues dans une approche physiopathologique, et en exploitant les nouvelles possibilités d’échocardiographes portables, techniquement performants, nous avons analysé les effets d’un inhibiteur de la phosphodiestérase-5 et d’une prostacycline, pour tenter d’en identifier d’éventuels effets introtropes intrinsèques, nous avons exploré le concept de réserve vasculaire pulmonaire comme facteur limitant de l’aptitude aérobie et indice potentiel d’une atteinte vasculaire pulmonaire précoce, et obtenu des résultats préliminaires permettant d’identifier une hypertension artérielle pulmonaire (HTAP) latente. Nos principaux résultats peuvent être résumés comme suit :<p>1. Chez le sujet sain, en normoxie ou dans un modèle expérimental d’HTAP induite par l’inhalation d’un mélange gazeux hypoxique, le sildenafil per os ou l’epoprostenol par voie intraveineuse, à des doses utilisées en clinique pour le traitement de l’HTAP, améliorent les indices de la fonction ventriculaire droite en proportion de leurs effets vasodilatatoires pulmonaires, sans effets inotropes intrinsèques détectables.<p>2. La consommation d’oxygène maximale du sujet sain augmente en raison directe de son volume capillaire pulmonaire (calculé à partir de sa capacité de diffusion pour l’oxyde nitrique et le monoxyde de carbone) et en raison inverse de sa résistance vasculaire pulmonaire, non seulement en altitude, mais aussi au niveau de la mer. Ce résultat suggère qu’une plus grande réserve vasculaire pulmonaire est propice aux efforts aérobiques intenses, probablement par moindre postcharge ventriculaire droite.<p>3. Des mesures réalisées chez un petit nombre de sujets suggèrent que la distensibilité vasculaire pulmonaire, calculée à partir d’une relation débit-pression vasculaire pulmonaire, est typiquement réduite chez des porteurs asymptomatiques de la mutation BMPR2, qui est actuellement le facteur de risque le plus élevé connu de l’HTAP. La mutation BMPR2 pourrait aussi être associée à une réactivité vasculaire pulmonaire accrue à l’hypoxie. <p>Nos résultats suggèrent indirectement que l’échocardiographie Doppler, de repos ou de stress, pourrait être davantage développée dans la mise au point de patients à risque d’HTAP./<p><p>Novel advances in echocardiography offer the opportunity to reliably characterize pulmonary circulation in terms of pressure-flow relationship, and to better understand the coupling of right ventricular (RV) function with normal and abnormal pulmonary hemodynamics. Moreover, when combined with the measurement of pulmonary capillary blood volume, this renewed methodological approach may help to understand the concept of pulmonary vascular reserve as a limiting factor of exercise capacity and potential sensitive marker of early vascular disease.<p><p>In the present work we used a model of hypoxic pulmonary vasoconstriction to analyse the effects of two targeted therapies of pulmonary arterial hypertension (PAH) on the RV function. We showed that the beneficial effects of these drugs are mainly driven by a decrease in RV afterload and not an enhanced myocardial inotropic state. Whether this is transposable to abnormal RV-arterial coupling in PAH patients remains to be investigated.<p><p>Echocardiography may be useful to explore the pulmonary vascular reserve as an important limiting factor of exercise capacity. We showed that a higher pulmonary vascular reserve, defined by a decreased PVR and increased lung diffusing capacity, allows for an improved aerobic exercise capacity (as assessed by a higher peak oxygen consumption), at a lower ventilatory cost, at sea level and at high altitude. <p><p>Stress echocardiography may detect an abnormal pulmonary vasoreactivity. We showed that asymptomatic relatives of patients suffering from idiopathic pulmonary arterial hypertension, and who carry a bone morphogenetic protein receptor type 2 mutation (BMPR2) present with a decreased pulmonary vascular distensibility and an enhanced pulmonary vasoreactivity to hypoxia, which are identifiable by echocardiography examination. However, the predictive value of these findings is not known. <p><p>Thus echocardiography may represent, in experienced and dedicated hands, a noninvasive, safe, widely available, applicable at the bed-side as well as in extreme environment (e.g. high altitudes), less expensive alternative for the evaluation of the pulmonary circulation, either by the interrogation of pressure-flow relationship (stress echocardiography), by the investigation of the right ventricle global and regional function in relation to its afterload (standard and Tissue Doppler Imaging), or by a combined approach with the measurement of lung diffusing capacity (DLNO / DLCO) to assess the pulmonary vascular reserve.<p><p>The present data are encouraging for further development and implementation of echocardiography for the detection, but also the diagnosis and follow-up of patients with pulmonary hypertension.<p><p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

This biomedical engineering thesis explores the opportunities and challenges of 2D+t contrast echocardiography for left ventricle functional analysis, both clinically and within a computer vision atlas-based deformable template model framework. A database was created for the experiments in this thesis, with 21 studies of contrast Dobutamine Stress Echo, in all 4 principal planes. The database includes clinical variables, human expert hand-traced myocardial contours and visual scoring. First the problem is studied from a clinical perspective. Quantification of endocardial global and local function using standard measures shows expected values and agreement with human expert visual scoring, but the results are less reliable for myocardial thickening. Next, the problem of segmenting the endocardium with a computer is posed in a standard landmark and atlas-based deformable template model framework. The underlying assumption is that these models can emulate human experts in terms of integrating previous knowledge about the anatomy and physiology with three sources of information from the image: texture, geometry and kinetics. Probabilistic atlases of contrast echocardiography are computed, while noting from histograms at selected anatomical locations that modelling texture with just mean intensity values may be too naive. Intensity analysis together with the clinical results above suggest that lack of external boundary definition may preclude this imaging technique for appropriate measuring of myocardial thickening, while endocardial boundary definition is appropriate for evaluation of wall motion. Geometry is presented in a Principal Component Analysis (PCA) context, highlighting issues about Gaussianity, the correlation and covariance matrices with respect to physiology, and analysing different measures of dimensionality. A popular extension of deformable models ---Active Appearance Models (AAMs)--- is then studied in depth. Contrary to common wisdom, it is contended that using a PCA texture space instead of a fixed atlas is detrimental to segmentation, and that PCA models are not convenient for texture modelling. To integrate kinetics, a novel spatio-temporal model of cardiac contours is proposed. The new explicit model does not require frame interpolation, and it is compared to previous implicit models in terms of approximation error when the shape vector changes from frame to frame or remains constant throughout the cardiac cycle. Finally, the 2D+t atlas-based deformable model segmentation problem is formulated and solved with a gradient descent approach. Experiments using the similarity transformation suggest that segmentation of the whole cardiac volume outperforms segmentation of individual frames. A relatively new approach ---the inverse compositional algorithm--- is shown to decrease running times of the classic Lucas-Kanade algorithm by a factor of 20 to 25, to values that are within real-time processing reach.

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