Adequacy of nutritional intake during the postoperative period, as measured by a change in weight-for-age z-scores from surgery to the time of discharge, was evaluated in infants (n = 58) diagnosed with a congenital heart defect and admitted for surgical intervention at Miami Children’s Hospital using a prospective observational study design. Parental consent was obtained for all infants who participated in the study. Forty patients had a weight available at hospital discharge. The mean preoperative weight-for-age z-score was -1.3 ±1.43 and the mean weight-for-age z-score at hospital discharge was -1.89 ±1.35 with a mean difference of 0.58 ±0.5 (P Nutritional intake during the postoperative period was inadequate based on a decrease in weight-for-age z-scores from the time of surgery until discharged home. Our findings suggested that limited fluid volume for nutrition likely contributes to suboptimal nutritional delivery during the postoperative period; however, inadequate nutrition prescription may also be an important contributing factor. Development of a nutrition protocol for initiation and advancement of nutrition support may reduce the delay in achieving patient’s nutritional goals and may attenuate the observed decrease in z-scores during the postoperative period.

Nkx2.5 is a cardiac transcription factor that plays a critical role in heart development. In humans, heterozygous mutations in the NKX2.5 gene result in congenital heart defects (CHDs), but the molecular mechanisms by which these mutations cause the defects are still unknown. NKX2.5 R142C is a mutation that is found to be associated with atrial septal defect and atrioventricular block in 13 patients from one family. The R142C mutation is located within both the DNA-binding domain and the nuclear localization sequence of NKX2.5 protein. The pathogenesis of CHDs in humans with R142C point mutation is not well understood. Also, a previous study in our laboratory has identified Mypt1/PP1 as a novel interacting partner of Nkx2.5 in stem cells during cardiomyogenesis. Nkx2.5 has a PP1-binding consensus sequence RVxF located in the N-terminus of the homeodomain. Notably, the PP1-binding sequence, RVxF, is mutated from arginine to cysteine in patients with the R142C heterozygous mutation. However, the ability of the R142C mutation to bind to the Mypt1/PP1 complex has not been investigated yet. The following thesis addresses the functional deficit associated with R142C by utilizing a combination of in vitro, and in vivo models. It also addresses the interaction of Mypt1/PP1 with the R142C mutation. We have generated a heterozygous mouse embryonic stem cell (mESC) line, harboring the murine homologue (R141C) of the human mutation R142C in Nkx2.5 gene. We show reduced cardiomyogenesis and impaired subcellular localization of Nkx2.5 protein in Nkx2.5R141C/+ mESCs. Gene expression profiling of Nkx2.5R141C/+ mESCs revealed a global misregulation of genes important for heart development and identified putative direct target genes of Nkx2.5 that are affected by the R141C heterozygous mutation. We also generated a mouse model harboring the human mutation R142C. We show that the Nkx2.5R141C/R141C homozygous embryos are developmentally arrested around E10.5 with delayed heart morphogenesis. Moreover, Nkx2.5R141C/+ newborn mice are grossly normal but show variable cardiac defects and downregulation of ion channel genes that later cause AV block in adult mice. Finally, we show that the R141C mutant binds to the Mypt1/PP1 complex but is not inhibited or translocated to the perinuclear region in the presence of Mypt1/PP1 as the WT Nkx2.5 is.

Cardiovascular diseases are the leading cause of death in humans throughout the world and “congenital heart defects” (CHDs) are the major cause of infant mortality and morbidity. GATA4 is one of the most critical and intensely studied cardiac transcription factor. It is important for proliferation of cardiomyocytes as well as their survival and adaptive response. The focus of the following thesis was to identify GATA4 mediators and cofactors in cardiac growth. The first part focused on cyclin D2 (CycD2), a growth inducible cell cycle protein. We identified Ccnd2 (gene encoding CycD2) as a direct transcriptional target of GATA4 in postnatal cardiomyocytes and Ccnd2 cardiomyocyte specific overexpression in Gata4 heterozygote mice was able to rescue their heart size and function. We further uncovered a novel regulatory loop between GATA4 and CycD2. CycD2 enhanced GATA4 activation of its target promoters. GATA4 was able to physically interact with CycD2 and its cyclin dependent kinase CDK4 suggesting that GATA4 recruits CycD2/CDK4 to its target promoters. Together, our data uncover a role of CycD2 in the developing and postnatal heart and provide novel insight for the potential of targeting the cell cycle in cardiac therapy. The second part of the project focused on KLF13, a cell specific cofactor of GATA4. KLF13 is a member of the Krϋppel-like transcription factors that are important regulators of cell proliferation and differentiation. Klf13 is highly enriched in the developing heart where it is found in both myocardial and endocardial cells. To determine its role in the mammalian heart, we deleted the Klf13 gene in transgenic mice. Klf13-/- mice were born at 50% reduced frequency and presented with variable cardiac phenotypes. Epithelial-mesenchymal transformation (EMT) was affected in these mice and reduced cell proliferation was evident in the AV cushion. These data uncover a role for a new class of transcription factors in heart formation and point to KLF13 as a regulator of endocardial cell proliferation and a potential CHD causing gene. Future discovery of more cardiac regulators and understanding the molecular basis of CHDs is essential for preventions of these defects and possible development of therapeutic approaches for myocardial repair.

No description available.

Background: The primary aim of this study was to examine selected maternal risk factors (i.e. maternal cigarette smoking prior to or during pregnancy, maternal age, and pre-pregnancy obesity) and the risk of congenital heart defects (CHD). We hypothesized that maternal cigarette smoking prior to or during pregnancy, increased maternal age, and obesity are maternal risk factors associated with an increased risk of CHD. The secondary aim was to examine the trend of CHD among residents of Philadelphia from 2003-2013. Methods: We examined de-identified PA birth certificate records from 2003-2013 and found 213 confirmed cases of CHD. A random sample of 5 controls per case were selected to produce a more balanced design given the small number of cases, resulting in a total number of 1293 subjects. Randomly selected controls reflected all pregnancies that did not result in a heart defect. We modeled the independent association between the selected risk factors and CHD using logistic regression. Results: Findings suggest a role of maternal race and age related to CHD risk. Black mothers were less likely than white mothers to experience a CHD (OR=0.692; 95% CI, 0.493-0.971). Young mothers (< 20) were more likely to experience a CHD compared to women over 20 years old (OR=1.536; 95% CI, 0.270-1.062). A link between CHD and obesity and smoking were not found. The trend analysis showed a small, positive linear association among race and CHD cases overall. Clinical Relevance: We provided further evidence that maternal age and race are risk factors for CHD. The prevalence of congenital heart defects is increasing among Philadelphia residents. These findings could be a result of better diagnosis and reporting, but the increase may also be due to other risk factors in the population. These findings may have implications for further and more aggressive counseling before and during pregnancy. / Public Health

A condição de hipertensão pulmonar é definida como a presença de pressão arterial pulmonar média acima de 25 mmHg em repouso. Esta é a resultante hemodinâmica de vários processos nosológicos que acometem a circulação nos pulmões, notadamente os pequenos vasos pré e intraacinares. A microcirculação pulmonar pode se alterar na presença de enfermidades cardíacas, pulmonares, tromboembólicas, infecto-parasitárias e do tecido conectivo, entre outras. Na ausência dessas condições, o diagnóstico de hipertensão arterial pulmonar idiopática se impõe. Com respeito especificamente à doença cardíaca levando a alterações vasculares pulmonares, temos as situações que acarretam aumento de fluxo sangüíneo pulmonar (cardiopatias congênitas que cursam com defeitos de septação das câmaras ou dos grandes vasos) ou dificuldade de drenagem venosa (disfunção sistólica ou diastólica do ventrículo esquerdo, valvopatia mitral e doenças do átrio esquerdo ou veias pulmonares). As alterações vasculares pulmonares que ocorrem nessas circunstâncias podem dificultar ou impedir o reparo cirúrgico de um defeito congênito de septação cardíaca, ou o encaminhamento de pacientes com doença miocárdica para o transplante. Por essas razões, a avaliação de pacientes com defeitos septais cardíacos ou miocardiopatia deve ser criteriosa. Na maioria das vezes a avaliação não invasiva é suficiente para o planejamento terapêutico. Entretanto, em pacientes com cardiopatia congênita e suspeita clínica de hipertensão pulmonar, assim como naqueles portadores de miocardiopatia candidatos ao transplante, a medida direta da resistência vascular pulmonar, através de procedimento invasivo, se faz necessária. Nas últimas décadas, tem havido interesse progressivo de se ampliar a indicação da avaliação não invasiva, omitindo-se a invasiva, sobretudo com o uso de parâmetros avaliados pela ecocardiografia com Doppler e pela ressonância magnética. O uso dessas medidas, na prática clínica, ainda é restrito, mas tende a ampliar-se. O presente estudo foi idealizado no sentido de se verificar, em portadores de defeitos septais cardíacos ou de miocardiopatia na faixa etária pediátrica, se dados ecocardiográficos poderiam ser preditivos de determinadas condições hemodinâmicas, a ponto de isentar certos pacientes da avaliação invasiva pré-operatória. Esta verificação foi feita nos dois grupos de indivíduos (cardiopatias congênitas ou miocardiopatia), com o exame ecocardiográfico realizado simultaneamente ao cateterismo cardíaco. Foram estudados 30 pacientes com defeitos septais cardíacos (idade entre 0,41 a 58,2 anos) e 23 pacientes com miocardiopatia candidatos a transplante (idade entre 0,40 a 15 anos). Para avaliação comparativa entre o ecocardiograma e o cateterismo foram utilizadas várias medidas. Do ponto de vista ecocardiográfico procurou-se analisar variáveis derivadas do fluxo pulmonar ao Doppler: tempo de aceleração (TAc), tempo de ejeção (TEj), período pré-ejetivo (PPE), integral velocidade-tempo do fluxo sistólico da via de saída do ventrículo direito (VTIVSVD) e índices envolvendo essas variáveis). Além disso, avaliou-se a integral velocidade-tempo do componente sistólico e diastólico da veia pulmonar superior direita (VTIVP) e a razão entre o fluxo pulmonar e o sistêmico (Qp/Qs). Do ponto de vista do cateterismo foram obtidas medidas de pressões, razão entre fluxos pulmonar e sistêmico (Qp/Qs) e razão entre a resistência vascular pulmonar e sistêmica (RVP/RVS). No grupo de indivíduos com cardiopatias congênitas, fundamentalmente foram observadas associações: entre a razão PPE/TEj e a pressão arterial pulmonar diastólica, assim como o índice RVP/RVS; entre a razão PPE/VTIVSVD e RVP/RVS; entre as razões Qp/Qs pelos dois métodos; entre a variável VTIVSVD e a razão das resistências; entre a variável VTIVP e a razão das resistências. No grupo de indivíduos com miocardiopatia foram observadas associações: entre a razão PPE/VTIVSVD e a pressão arterial pulmonar sistólica; entre a razão PPE/TEj e a pressão arterial pulmonar diastólica; entre a variável TAc e a pressão arterial pulmonar média e razão das resistências. Apesar de ter sido possível o desenvolvimento de modelos preditivos para dados hemodinâmicos a partir destas variáveis ecocardiográficas, a dispersão dos valores foi considerável, não permitindo recomendar a adoção dos modelos para a predição pontual na prática clínica. No entanto, os dados mostraram ser possível, a partir da avaliação não invasiva, estimar, com especificidade adequada, valores de Qp/Qs, ao cateterismo, acima de 3,0. Isto foi possível a partir, de valores de Qp/Qs igual ou superiores a 2,89 no exame ecocardiográfico. Alem disso, as variáveis VTIVSVD (igual ou superior a 22 cm) e VTIVP (igual ou superior a 20 cm), para o grupo de pacientes com cardiopatia congênita, mostraram-se capazes de predizer a ocorrência de RVP/RVS 0,1 (cateterismo), com especificidade superior a 0,80. No grupo dos pacientes com miocardiopatia, a variável TAc (igual ou superior a 95 ms) mostrou-se capaz de predizer a ocorrência de RVP/RVS 0,1 (cateterismo) com especificidade também acima de 0,80. Assim sendo, nesses pacientes, o ecocardiograma pôde ser útil na identificação de um subgrupo de indivíduos em situação mais favorável com respeito à hemodinâmica pulmonar, para os quais o cateterismo cardíaco poderia ser considerado desnecessário. Futuros estudos serão importantes para se avaliar os resultados tardios (notadamente pós-operatório) nos pacientes avaliados de forma não invasiva, reforçando, a adequação desse tipo de avaliação. / Pulmonary hypertension is defined as a mean pulmonary arterial pressure of > 25 mmHg registered at rest, during cardiac catheterization. A number of conditions have been demonstrated to cause pulmonary hypertension, including congenital (septal defects) and acquired heart diseases, chronic lung disease, connective-tissue disease, thromboembolic disorders, schistosomosiasis, HIV infection, use of anorexigens, etc. In the absence of all these conditions, a diagnosis of idiopathic pulmonary arterial hypertension is established. In the specific setting of the cardiac disorders, either increased pulmonary blood flow (congenital cardiac septal defects) or altered pulmonary venous drainage ( left ventricular systolic or diastolic dysfunction, mitral valve disease, abnormalities of the left atrium) can cause pulmonary vascular abnormalities leading to pulmonary hypertension. Moderate to severe pulmonary vascular abnormalities lead to increased risk of postoperative complications and/or poor long-term outcomes in patients with septal defects undergoing surgical repair or those with cardiomyopathy undergoing heart transplantation. Thus, for these patients, preoperative measurement of pulmonary vascular resistance by cardiac catheterization is mandatory. In general, those with a pulmonary vascular resistance index of > 6 Wood units·m2 (pulmonary to systemic vascular resistance ratio of > 0,3) are not assigned to operation. In the last decades, there has been growing interest on the development of noninvasive methods/parameters that could allow for decision about the therapeutic strategies without cardiac catheterization. In this way, several parameters derived from Doppler-echocardiographic analysis or magnetic resonance has been used to predict hemodynamic data. In the present study, we used echocardiographic parameters to determine which patients with congenital cardiac septal defects or cardiomyopathy could theoretically be assigned to surgical treatments without catheterization. In order to correlate echocardiographic information with data derived from cardiac catheterization, both procedures were carried out simultaneously. Catheterization was performed as part of the routine evaluation, not specifically for research purposes. Thirty consecutive patients with congenital septal defects (aged 0,41 to 58,2 years) and 23 consecutive patients with cardiomyopathy (aged 0,40 to 15 years) were enrolled Doppler-echocardiographic evaluation consisted of flow analysis at the right and left ventricular outflow tract and pulmonary vein. The following parameters were recorded: right ventricular ejection time (RVET), acceleration time (AcT); right ventricular pre-ejection period (RVPEP); velocity time integral of the right ventricular systolic flow (VTIRVOT); velocity time integral of pulmonary venous flow (VTIPV); indexes involving these variables (AcT/RVET, RVPEP/RVET, RVPEP/VTIRVOT); pulmonary to systemic blood flow ratio (Qp/Qs). The parameters derived from cardiac catheterization included pulmonary and systemic pressures, blood flow and vascular resistance. Blood flow and vascular resistance were expressed as ratios Qp/Qs and PVR/SVR, respectively pulmonary to systemic blood flow and vascular resistance ratios). In patients with congenital septal defects, a Qp/Qs of 2,89 by Doppler-echocardiographic analysis was predictive of Qp/Qs > 3,0 by cardiac catheterization, with specificity > 0.78. For values of 4.0 (echocardiography), the specificity was > 0.91. A VTIRVOT of 22 cm or VTIPV 20 cm could predict PVR/SVR ratios 0.1 with specificity > 0.81. For values of 27 cm and 24 cm respectively, the specificity was > 0.93. In patients with cardiomyopathy, a AcT of 95 msec was predictive of PVR/SVR 0.1 with specificity > 0.85. Doppler-echocardiographic parameters could not predict absolute values of hemodynamic variables with acceptable accuracy. Based on these results we conclude that Doppler-echocardiographic analysis can be used to identify patients with low levels of pulmonary vascular resistance (those with septal defects or cardiomyopathy) and increased pulmonary blood flow (septal defects).These patients could be safely assigned surgical treatments with no need for invasive evaluation. In view of the relatively low levels of sensitivity that we observed (< 0.65), some patients with favourable pulmonary hemodynamics would still be assigned to catheterization in case of adoption of the cut-off levels used in the study. Prediction of absolute values of hemodynamic parameters was not considered sufficiently accurate for decision making. Further studies are obviously necessary to evaluate long-term outcomes in patients treated on the basis of noninvasive evaluation only.

A condição de hipertensão pulmonar é definida como a presença de pressão arterial pulmonar média acima de 25 mmHg em repouso. Esta é a resultante hemodinâmica de vários processos nosológicos que acometem a circulação nos pulmões, notadamente os pequenos vasos pré e intraacinares. A microcirculação pulmonar pode se alterar na presença de enfermidades cardíacas, pulmonares, tromboembólicas, infecto-parasitárias e do tecido conectivo, entre outras. Na ausência dessas condições, o diagnóstico de hipertensão arterial pulmonar idiopática se impõe. Com respeito especificamente à doença cardíaca levando a alterações vasculares pulmonares, temos as situações que acarretam aumento de fluxo sangüíneo pulmonar (cardiopatias congênitas que cursam com defeitos de septação das câmaras ou dos grandes vasos) ou dificuldade de drenagem venosa (disfunção sistólica ou diastólica do ventrículo esquerdo, valvopatia mitral e doenças do átrio esquerdo ou veias pulmonares). As alterações vasculares pulmonares que ocorrem nessas circunstâncias podem dificultar ou impedir o reparo cirúrgico de um defeito congênito de septação cardíaca, ou o encaminhamento de pacientes com doença miocárdica para o transplante. Por essas razões, a avaliação de pacientes com defeitos septais cardíacos ou miocardiopatia deve ser criteriosa. Na maioria das vezes a avaliação não invasiva é suficiente para o planejamento terapêutico. Entretanto, em pacientes com cardiopatia congênita e suspeita clínica de hipertensão pulmonar, assim como naqueles portadores de miocardiopatia candidatos ao transplante, a medida direta da resistência vascular pulmonar, através de procedimento invasivo, se faz necessária. Nas últimas décadas, tem havido interesse progressivo de se ampliar a indicação da avaliação não invasiva, omitindo-se a invasiva, sobretudo com o uso de parâmetros avaliados pela ecocardiografia com Doppler e pela ressonância magnética. O uso dessas medidas, na prática clínica, ainda é restrito, mas tende a ampliar-se. O presente estudo foi idealizado no sentido de se verificar, em portadores de defeitos septais cardíacos ou de miocardiopatia na faixa etária pediátrica, se dados ecocardiográficos poderiam ser preditivos de determinadas condições hemodinâmicas, a ponto de isentar certos pacientes da avaliação invasiva pré-operatória. Esta verificação foi feita nos dois grupos de indivíduos (cardiopatias congênitas ou miocardiopatia), com o exame ecocardiográfico realizado simultaneamente ao cateterismo cardíaco. Foram estudados 30 pacientes com defeitos septais cardíacos (idade entre 0,41 a 58,2 anos) e 23 pacientes com miocardiopatia candidatos a transplante (idade entre 0,40 a 15 anos). Para avaliação comparativa entre o ecocardiograma e o cateterismo foram utilizadas várias medidas. Do ponto de vista ecocardiográfico procurou-se analisar variáveis derivadas do fluxo pulmonar ao Doppler: tempo de aceleração (TAc), tempo de ejeção (TEj), período pré-ejetivo (PPE), integral velocidade-tempo do fluxo sistólico da via de saída do ventrículo direito (VTIVSVD) e índices envolvendo essas variáveis). Além disso, avaliou-se a integral velocidade-tempo do componente sistólico e diastólico da veia pulmonar superior direita (VTIVP) e a razão entre o fluxo pulmonar e o sistêmico (Qp/Qs). Do ponto de vista do cateterismo foram obtidas medidas de pressões, razão entre fluxos pulmonar e sistêmico (Qp/Qs) e razão entre a resistência vascular pulmonar e sistêmica (RVP/RVS). No grupo de indivíduos com cardiopatias congênitas, fundamentalmente foram observadas associações: entre a razão PPE/TEj e a pressão arterial pulmonar diastólica, assim como o índice RVP/RVS; entre a razão PPE/VTIVSVD e RVP/RVS; entre as razões Qp/Qs pelos dois métodos; entre a variável VTIVSVD e a razão das resistências; entre a variável VTIVP e a razão das resistências. No grupo de indivíduos com miocardiopatia foram observadas associações: entre a razão PPE/VTIVSVD e a pressão arterial pulmonar sistólica; entre a razão PPE/TEj e a pressão arterial pulmonar diastólica; entre a variável TAc e a pressão arterial pulmonar média e razão das resistências. Apesar de ter sido possível o desenvolvimento de modelos preditivos para dados hemodinâmicos a partir destas variáveis ecocardiográficas, a dispersão dos valores foi considerável, não permitindo recomendar a adoção dos modelos para a predição pontual na prática clínica. No entanto, os dados mostraram ser possível, a partir da avaliação não invasiva, estimar, com especificidade adequada, valores de Qp/Qs, ao cateterismo, acima de 3,0. Isto foi possível a partir, de valores de Qp/Qs igual ou superiores a 2,89 no exame ecocardiográfico. Alem disso, as variáveis VTIVSVD (igual ou superior a 22 cm) e VTIVP (igual ou superior a 20 cm), para o grupo de pacientes com cardiopatia congênita, mostraram-se capazes de predizer a ocorrência de RVP/RVS 0,1 (cateterismo), com especificidade superior a 0,80. No grupo dos pacientes com miocardiopatia, a variável TAc (igual ou superior a 95 ms) mostrou-se capaz de predizer a ocorrência de RVP/RVS 0,1 (cateterismo) com especificidade também acima de 0,80. Assim sendo, nesses pacientes, o ecocardiograma pôde ser útil na identificação de um subgrupo de indivíduos em situação mais favorável com respeito à hemodinâmica pulmonar, para os quais o cateterismo cardíaco poderia ser considerado desnecessário. Futuros estudos serão importantes para se avaliar os resultados tardios (notadamente pós-operatório) nos pacientes avaliados de forma não invasiva, reforçando, a adequação desse tipo de avaliação. / Pulmonary hypertension is defined as a mean pulmonary arterial pressure of > 25 mmHg registered at rest, during cardiac catheterization. A number of conditions have been demonstrated to cause pulmonary hypertension, including congenital (septal defects) and acquired heart diseases, chronic lung disease, connective-tissue disease, thromboembolic disorders, schistosomosiasis, HIV infection, use of anorexigens, etc. In the absence of all these conditions, a diagnosis of idiopathic pulmonary arterial hypertension is established. In the specific setting of the cardiac disorders, either increased pulmonary blood flow (congenital cardiac septal defects) or altered pulmonary venous drainage ( left ventricular systolic or diastolic dysfunction, mitral valve disease, abnormalities of the left atrium) can cause pulmonary vascular abnormalities leading to pulmonary hypertension. Moderate to severe pulmonary vascular abnormalities lead to increased risk of postoperative complications and/or poor long-term outcomes in patients with septal defects undergoing surgical repair or those with cardiomyopathy undergoing heart transplantation. Thus, for these patients, preoperative measurement of pulmonary vascular resistance by cardiac catheterization is mandatory. In general, those with a pulmonary vascular resistance index of > 6 Wood units·m2 (pulmonary to systemic vascular resistance ratio of > 0,3) are not assigned to operation. In the last decades, there has been growing interest on the development of noninvasive methods/parameters that could allow for decision about the therapeutic strategies without cardiac catheterization. In this way, several parameters derived from Doppler-echocardiographic analysis or magnetic resonance has been used to predict hemodynamic data. In the present study, we used echocardiographic parameters to determine which patients with congenital cardiac septal defects or cardiomyopathy could theoretically be assigned to surgical treatments without catheterization. In order to correlate echocardiographic information with data derived from cardiac catheterization, both procedures were carried out simultaneously. Catheterization was performed as part of the routine evaluation, not specifically for research purposes. Thirty consecutive patients with congenital septal defects (aged 0,41 to 58,2 years) and 23 consecutive patients with cardiomyopathy (aged 0,40 to 15 years) were enrolled Doppler-echocardiographic evaluation consisted of flow analysis at the right and left ventricular outflow tract and pulmonary vein. The following parameters were recorded: right ventricular ejection time (RVET), acceleration time (AcT); right ventricular pre-ejection period (RVPEP); velocity time integral of the right ventricular systolic flow (VTIRVOT); velocity time integral of pulmonary venous flow (VTIPV); indexes involving these variables (AcT/RVET, RVPEP/RVET, RVPEP/VTIRVOT); pulmonary to systemic blood flow ratio (Qp/Qs). The parameters derived from cardiac catheterization included pulmonary and systemic pressures, blood flow and vascular resistance. Blood flow and vascular resistance were expressed as ratios Qp/Qs and PVR/SVR, respectively pulmonary to systemic blood flow and vascular resistance ratios). In patients with congenital septal defects, a Qp/Qs of 2,89 by Doppler-echocardiographic analysis was predictive of Qp/Qs > 3,0 by cardiac catheterization, with specificity > 0.78. For values of 4.0 (echocardiography), the specificity was > 0.91. A VTIRVOT of 22 cm or VTIPV 20 cm could predict PVR/SVR ratios 0.1 with specificity > 0.81. For values of 27 cm and 24 cm respectively, the specificity was > 0.93. In patients with cardiomyopathy, a AcT of 95 msec was predictive of PVR/SVR 0.1 with specificity > 0.85. Doppler-echocardiographic parameters could not predict absolute values of hemodynamic variables with acceptable accuracy. Based on these results we conclude that Doppler-echocardiographic analysis can be used to identify patients with low levels of pulmonary vascular resistance (those with septal defects or cardiomyopathy) and increased pulmonary blood flow (septal defects).These patients could be safely assigned surgical treatments with no need for invasive evaluation. In view of the relatively low levels of sensitivity that we observed (< 0.65), some patients with favourable pulmonary hemodynamics would still be assigned to catheterization in case of adoption of the cut-off levels used in the study. Prediction of absolute values of hemodynamic parameters was not considered sufficiently accurate for decision making. Further studies are obviously necessary to evaluate long-term outcomes in patients treated on the basis of noninvasive evaluation only.

Medfödda hjärtfel är globalt en av de vanligaste defekterna vid födsel, trots det är den underliggande mekanismen och dess sjukdomsförlopp fortfarande inte välkända. Flera hundra sjukdomsgener har identifierats vilket gör sjukdomen inte bara komplex, men också heterogen. För att kunna avancera i förebyggande syfte, i patient-diagnostik och behandling behövs en djupare förståelse av dess etiologi. Noterbart är att många patienter med medfödda hjärtfel också upplever samsjuklighet som utvecklingsneurologiska störningar, neurodegenerativa sjukdomar samt psykiska hälsoproblem. I den här studien undersöktes tre potentiella sjukdomsgener: ANK3, COPZ1 och DCTN1 för deras roll i både hjärtat och hjärnans utveckling i zebrafisk som experimentell modell. Detta gjordes genom att göra gen-knockouts på generna individuellt med hjälp av F0 Crispant CRISPR/Cas9 tekniken i följd av in-situ hybridisering, för att undersöka potentiella laterala defekter i hjärtat samt bildanalys för att mäta storleken på hjärnan. Alla tre gener verkade orsaka en signifikant ökning av hjärtfel genom att laterala defekter observerades, där två av generna också visade en signifikant minskad hjärtfrekvens. Angående hjärnan så verkade två av generna orsaka en mindre hjärna medan en av generna orsakade en förstorad hjärna. Dessa resultat ger en preliminär inblick i deras medverkan i hjärtat och hjärnans utveckling, dock behövs vidare studier inte bara för att stärka resultaten men också för att kunna grundligt säkerställa korrelationen till samsjukligheten med utvecklingsneurologiska störningar, neurodegenerativa sjukdomar samt psykiska hälsoproblem. / Congenital heart defects (CHD) are amongst the most common birth defects globally, yet the underlying mechanism and the disease trajectory of it is still poorly understood. Several hundred disease genes have been discovered, making it not only complex but also heterogeneous. In order to advance in prevention, patient diagnosis and treatment, a deeper understanding of its etiology is needed. Notably, many patients with CHD experience comorbidities such as neurodevelopmental- and neurodegenerative disorders as well as mental health issues. In this project, three candidate disease genes: ANK3, COPZ1 and DCTN1 were chosen to further investigate their role in both heart- and brain development in zebrafish as the experimental model. This was done by knocking out the genes individually using the F0 Crispant CRISPR/Cas9 method followed by whole mount in situ hybridization (WISH), to assess potential defective lateral phenotypes of the heart and image analysis to measure the size of the brain. All three genes seemed to cause a significant increase in overall heart defects by showing laterality defects whereas two of them also showed significantly slower heart rate. As for the brain, two of the genes seemed to cause a smaller brain, whereas one gene seemed to cause an enlarged brain. These findings give a preliminary insight into their involvement in the heart- and brain development, however, further research is necessary to not only strengthen the findings but to also more thoroughly establish the correlation to the comorbidity of the neurodevelopmental, neurodegenerative disorders and mental health issues.

La fermeture percutanée est le traitement de référence des communications interatriales (CIA). Après son implantation, une cicatrisation du dispositif est classiquement attendue après quelques mois ; il semble cependant qu’un recouvrement incomplet ou partiel puisse être observé dans de rares cas, sans que l’on en connaisse les mécanismes impliqués. Cette cicatrisation imparfaite du dispositif est associée à la survenue de complications retardées. Dans le cadre de cette thèse nous avons étudié la cicatrisation de ces prothèses de CIA, en nous focalisant sur les processus de recouvrement et d’endothélialisation des dispositifs, à travers une approche translationnelle incluant expérimentations in vitro, modèle animal chronique et étude clinique. A la fin de ce travail, il est possible de conclure que : 1) il existe des cas de complications au long cours après fermeture de CIA, liées à un défaut de recouvrement du dispositif, 2) sur une large cohorte pédiatrique avec un suivi allant jusqu’à 18 ans après l’implantation, l’incidence de ces complications est faible 3) les modèles animaux, utilisés seuls, ne peuvent suffire à expliquer ni à avancer dans la compréhension de ce phénomène, 4) il n’existe pas de différences significatives concernant le processus de recouvrement entre les 3 prothèses analysées au cours de ce travail, 5) une évaluation non invasive et individualisée du recouvrement prothétique , grâce aux techniques d’imagerie, est une perspective prometteuse. Ces données montrent qu’une meilleure compréhension du processus de recouvrement prothétique passe par la réalisation conjointe d’études fondamentales et cliniques. Cependant, le développement d’outils permettant une évaluation individualisée du recouvrement doit être poursuivi, du fait de leur fort potentiel de translation clinique et de leur capacité à optimiser la prise en charge du patient. / The percutaneous device closure is the gold treatment of atrial septal defect (ASD). After implantation, device healing is classically expected following several months; however, an incomplete or partial covering of the device may be observed without a full knowledge of the underlying mechanisms. In this thesis we studied the healing of these intracardiac prostheses, focusing on the covering and endothelialization processes of devices, approach through a translational approach including in vitro experiments, chronic animal model and clinical study. At the end of this work, it is possible to conclude that 1) there are cases of long-term complications after closure of CIA, related to a lack of recovery of the device, 2) in a large cohort of pediatric with a follow up of up to at 18 years after implantation, the incidence of these complications is low 3) animal models, used alone, can not suffice to explain or improve the understanding of this complex process, 4) there is no significant differences in the covering process between the 3 prostheses analyzed during this work, 5) a non-invasive and individualized assessment of prosthetic recovery, using imaging techniques, is a promising perspective with significant potential for clinical translation . These data show that a better understanding of device healing process needs the joint undertake of basic and clinical studies. Moreover, the development of tools for individualized assessment of device covering should be pursued in parallel, due to their high translational potential, in order to optimize patient management.

nÃo hà / A PolÃtica Nacional de AtenÃÃo Cardiovascular de Alta Complexidade com foco na Cirurgia Cardiovascular PediÃtrica, formalizada em 15 de junho de 2004, por meio das Portarias NÂ1169/GM e N 210 SAS/MS, à gestada por intervenÃÃo da SBCCV e DCCVPed junto ao MinistÃrio da SaÃde e se propÃe atender a demanda em cirurgia cardiovascular pediÃtrica. à Ãpoca da formulaÃÃo, os deficits em cirurgias eram expressivos, sendo mais crÃticos nas regiÃes Norte e Nordeste. A pesquisa objetiva avaliar a polÃtica quanto ao desenho, implementaÃÃo e resultados. Foram empregados mÃtodos quantitativos para anÃlise de dados primÃrios dos questionÃrios, aplicados aos cirurgiÃes e secundÃrios coletados no MS/DATASUS e IBGE. O recorte temporal foi de 1999 a 2008 para os procedimentos em cardiopatias congÃnitas e de 2001 a 2008 para os valvares. Os qualitativos foram empregados para anÃlise das portarias e discursos de diretores de sociedades e gestores do MS. As anÃlises foram balizadas nas premissas do Sistema Ãnico de SaÃde, equidade, integralidade e regionalizaÃÃo, à luz de alguns autores. Os resultados demonstram ser a polÃtica um marco, pelo fato de reconhecer caracterÃsticas e necessidades particulares na Ãrea. Carece porÃm, de medidas que visem otimizar a frequÃncia de procedimentos ainda com deficits significativos - 62% para o Brasil e 91%, 76%, 55%, 36% e 47% para as regiÃes Norte, Nordeste, Sudeste, Sul e Centro-Oeste, respectivamente, e resolver iniquidades regionais. A polÃtica Ã, à anÃlise empregada, ineficaz e ineficiente. Como estratÃgias que visam a subsidiar aÃÃes de governanÃa, encontraram-se: realinhar valores de pagamento por procedimento; implementar banco de dados em parceria com o DCCVPed; compatibilizar tabelas de diagnÃstico, procedimentos e Ãrteses e prÃteses; identificar centros de excelÃncia em cardiopatias complexas e defini-los como de referÃncia regional; patrocinar centros para treinamento profissional; valorizar honorÃrios; subsidiar reestruturaÃÃo das instituiÃÃes habilitadas e estruturaÃÃo daquelas que entrarem no sistema; estabelecer polÃtica de equidade regional; criar Programa de PrevenÃÃo e Controle da Febre ReumÃtica. Em suma, entende-se a polÃtica como desencadeadora de um processo de estruturaÃÃo e que a avaliaÃÃo continuada poderà trazer subsÃdios fundamentados e ser ferramenta de persuasÃo junto ao poder constituÃdo. / The National Cardiovascular Care High Complexity Policy, focusing on Pediatric Cardiovascular Surgery, formalized on June 15, 2004, through Ordinance NÂ. 1169/GM N and 210 SAS / MS is fomented by the intervention from the SBCCV and DCCVPed together with the Ministry Health and aims to meet the demand in pediatric cardiovascular surgery. At the time of the formulation the deficits in surgeries were expressive, being more critical in the North and Northeast. The research aims to evaluate the policy on its design, implementation and results. We used quantitative methods for analysis of primary data from questionnaires administered to surgeons and secondary collected from the MS / DATASUS and IBGE. The time frame was 1999 to 2008 for procedures in congenital heart disease and from 2001 to 2008 for the valve procedures. The qualitative analyses were used for the entrances and speeches by corporate directors and managers of MS. Analyses were buoyed on the premises of the National Health System, as fairness, integrity and regionalization in the light of some authors. The results have proved to be a landmark policy by recognizing the characteristics and particular needs in the area. However, there is lack of measures to improve the frequency of the procedures, still with significant deficits, 62% for Brazil and 91%, 76%, 55%, 36% and 47% for the north, northeast, southeast, south and central west respectively, and resolve regional inequities. Politics is, according to the the analysis employed, ineffective and inefficient. As strategies to support governance actions met: realign payment amounts per procedure; implement database in partnership with DCCVPed; tables reconcile the diagnostic procedures with the orthesis and prosthesis, identify centers of excellence in complex heart and set them as reference regional centers to sponsor professional training value fees, subsidize the restructuring of the institutions empowered and structuring those who enter the system, establish policy for regional equity, create Program Prevention and Control of Rheumatic Fever. In sum, it means the policy as a trigger of a process of structuring and continuous evaluation that will provide input and be a tool to persuade the powers that be.