Adult congenital heart disease : long-term survival, arrhytmias, and emerging therapy

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Cardiopulmonary bypass down-regulates NOD signaling and inflammatory response in children with congenital heart disease

In the present study, we aimed to examine the impact of cardiopulmonary bypass (CPB) on expression and function of NOD1 and NOD2 in children with congenital heart disease (CHD), in an attempt to clarify whether NOD1 and NOD2 signaling is involved in the modulation of host innate immunity against postoperative infection in pediatric CHD patients. Peripheral blood samples were collected from pediatric CHD patients at five different time points: before CPB, immediately after CPB, and 1, 3, and 7 days after CPB. Real-time PCR, Western blot, and ELISA were performed to measure the expression of NOD1 and NOD2, their downstream signaling pathways, and inflammatory cytokines at various time points. Proinflammatorycytokine IL-6 and TNF-α levels in response to stimulation with either the NOD1 agonist Tri-DAP or the NOD2 agonist MDP were significantly reduced after CPB compared with those before CPB, which is consistent with a suppressed inflammatory response postoperatively. The expression of phosphorylated RIP2 and activation of the downstream signaling pathways NF-κB p65 and MAPK p38 upon Tri-DAP or MDP stimulation in PBMCs were substantially inhibited after CPB. The mRNA level of NOD1 and protein levels of NOD1 and NOD2 were also markedly decreased after CPB. Our results demonstrated that NOD-mediated signaling pathways were substantially inhibited after CPB, which correlates with the suppressed inflammatory response and may account, at least in part, for the increased risk of postoperative infection in pediatric CHD patients.

Adult congenital heart disease : long-term survival, arrhytmias, and emerging therapy

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

Quality of life in children and adolescents with congenital heart disease. A new challenge for parents, professionals and community

The Quality of life is currently a major topic discussed in our society. The World Health Organization (WHO) has been developing a unifying and transcultural definition of QOL. They considered it as 'the individual's perception of his or her position in life, within the cultural context and value system he or she lives in, and in relation to his or her goals, expectations, parameters and social relations. It is a broad ranging concept affected in a complex way by the person's physical health, psychological state, level of independence, social relationships and their relationship to salient features of their environment (WHOQOL, 1997, p. 1). Congenital heart disease is the most prevalent congenital disease in Portugal. Despite the advances in cardiac treatment and an early correct diagnosis that could increase the survival of children with congenital heart disease, this condition influences the quality of life of children, adolescents and their parents. Knowing the perception of quality of life could help healthcare professionals, nurses in particular, providing suited care to the needs of these families, establishing priorities in their interventions, sensing predictors of a poor quality of life, promoting adherence to treatment and boosting compliance with treatment, and fostering greater satisfaction for these children, adolescents and their parents. Purpose As part of broader research and with the awareness that the chronic conditions could impact the quality of life and considering that all advances on treating congenital cardiac diseases we have defined this main objective: To determine the quality of life in children and adolescents with congenital heart disease (CHD) and the perception of their parents, as well as factors that influence it. Methods It is a quantitative, descriptive and correlational research. The data collection tool was a questionnaire, which consisted of four parts: socio-demographic and educational characteristics, clinical characteristics, and quality of life, obtained using the Pediatric Cardiac Quality of Life Inventory - PCQLI - (Marino, Tomlinson, Wernovsky, Drotar , Newburger, Mahony et al., 2010) translated into Portuguese. Data collection took place between February and July 2014, in compliance with ethical research guidelines. The sample comprised 59 children, 59 parents of children, 80 adolescents and 80 parents of adolescents. Results The results indicated that children, adolescents, and their parents have high level of perceived health. The results are similar in all groups: children and parents and adolescents and parents. In the group of children, we observed the classification of "Good" in 66.10%, followed by the "Very Good" at 18.65% and "fair" in 15.25% of cases. The parents of the children responded in about half the cases that the health of their children was "good" (50.85%), "very good" in 30.51% "fair" in 11.86% and "Excellent "in 6.78%. In turn, the group of adolescents can be seen that 46.25% rate their health as "good", 32.50% as "very good", 16.25% as "Average" and 5% as "Excellent". Parents of teenagers classify the health of their children mostly as "good" in 42.50%, 31.25% as "very good", 20% as "fair" and 6.25% as "excellent". To point out that none of the respondents pointed out the option of a health status "Bad". About the quality of life, in general the results indicated that children, adolescents and their parents have high levels of quality of life, and that perceptions of parents and children are similar. Only in the children's group (8 to 12 years old), was no influence of socio-demographic, school or clinical variables on quality of life observed. For adolescents (13 to 18 years old), school, special education, school retention, the age of diagnosis of congenital heart disease, cardiac catheterization and surgical intervention influenced their quality of life. Perception of quality of life of parents of children and of adolescents was influenced by socio-demographic and clinical variables. The results partly agree with the literature in this field. About the influence of some variables: - The perception of quality of life expressed by children and adolescents with congenital heart disease and parents are related, with statistical significance. - There were no statistically significant relationships between the quality of life of children and adolescents and their age, gender or socioeconomic status. - Adolescents differ statistically significant between their quality of life and their education, the frequency of special education and the existence of grade retention. The severity of heart disease, the number of cardiac catheterizations or surgery and the presence of other health disorders are unrelated to the quality of life of children and adolescents. - Adolescents revealed that the level of quality of life is influenced by the age of diagnosis of CHD by cardiac catheterization and surgery. - For parents of children and adolescents gender and their education don´t influence their perception of quality of life. Only the socioeconomic status of parents of teens has statistically significant difference to quality of life. - Parents of children and adolescents do not show statistically significant relationship between the perceived level of quality of life and severity of disease, age at diagnosis, the number of surgical interventions and the existence of other health disorders. - There is a relationship of statistical significance between cardiac catheterization and the perceived quality of life by parents of adolescents; between the number of cardiac catheterizations and the perception of quality of life of parents of children; and between performing surgery and the perception of parents of children and adolescents. Conclusion To analyze the quality of life of children and adolescents with CHD must be a key focus of attention in caring for this population, allowing the identification of individual differences, interests, preferences, and prevent potential problems. The knowledge acquired along with clinical experience contributes to improve the quality of life of children and families, facilitating their growth, psycho-emotional development and social integration. Nevertheless, the reading and interpretation of these results must be prudent and cautious, there are limitations to this research, including: the use of a range of specific quality of life for the Congenital heart disease in children, adolescents, and parents but whose validation process could not be completed in this study; the low prevalence of severe conditions in our sample; the absence of national studies to enable comparison with the results obtained. We intend to continue the process of validation of instrument and enlarge the research to Lisbon and Oporto, other major centers where the cardiac conditions can be treated

Quality of life in children and adolescents with congenital heart disease

Purpose: The Quality of life is currently a major topic discussed in our society. The World Health Organization (WHO) has been developing a unifying and transcultural definition of QOL. They considered it as 'the individual's perception of his or her position in life, within the cultural context and value system he or she lives in, and in relation to his or her goals, expectations, parameters and social relations. It is a broad ranging concept affected in a complex way by the person's physical health, psychological state, level of independence, social relationships and their relationship to salient features of their environment (WHOQOL, 1997, p. 1). Congenital heart disease is the most prevalent congenital disease in Portugal. Despite the advances in cardiac treatment and an early correct diagnosis that could increase the survival of children with congenital heart disease, this condition influences the quality of life of children, adolescents and their parents. Knowing the perception of quality of life could help healthcare professionals, nurses in particular, providing suited care to the needs of these families, establishing priorities in their interventions, sensing predictors of a poor quality of life, promoting adherence to treatment and boosting compliance with treatment, and fostering greater satisfaction for these children, adolescents and their parents. 'As part of broader research and with the awareness that the chronic conditions could impact the quality of life and considering that all advances on treating congenital cardiac diseases we have defined this main objective: To determine the quality of life in children and adolescents with congenital heart disease (CHD) and the perception of their parents, as well as factors that influence it. Methods: It is a quantitative, descriptive and correlational research. The data collection tool was a questionnaire, which consisted of four parts: socio-demographic and educational characteristics, clinical characteristics, and quality of life, obtained using the Pediatric Cardiac Quality of Life Inventory ? PCQLI - (Marino, Tomlinson, Wernovsky, Drotar , Newburger, Mahony et al., 2010) translated into Portuguese. Data collection took place between February and July 2014, in compliance with ethical research guidelines. The sample comprised 59 children, 59 parents of children, 80 adolescents and 80 parents of adolescents. Results: The results indicated that children, adolescents, and their parents have high level of perceived health. The results are similar in all groups: children and parents and adolescents and parents. In the group of children, we observed the classification of "Good" in 66.10%, followed by the "Very Good" at 18.65% and "fair" in 15.25% of cases. The parents of the children responded in about half the cases that the health of their children was "good" (50.85%), "very good" in 30.51% "fair" in 11.86% and "Excellent "in 6.78%. In turn, the group of adolescents can be seen that 46.25% rate their health as "good", 32.50% as "very good", 16.25% as "Average" and 5% as "Excellent". Parents of teenagers classify the health of their children mostly as "good" in 42.50%, 31.25% as "very good", 20% as "fair" and 6.25% as "excellent". To point out that none of the respondents pointed out the option of a health status "Bad". About the quality of life, in general the results indicated that children, adolescents and their parents have high levels of quality of life, and that perceptions of parents and children are similar. Only in the children?s group (8 to 12 years old), was no influence of socio-demographic, school or clinical variables on quality of life observed. For adolescents (13 to 18 years old), school, special education, school retention, the age of diagnosis of congenital heart disease, cardiac catheterization and surgical intervention influenced their quality of life. Perception of quality of life of parents of children and of adolescents was influenced by socio-demographic and clinical variables. The results partly agree with the literature in this field. About the influence of some variables: The perception of quality of life expressed by children and adolescents with congenital heart disease and parents are related, with statistical significance. There were no statistically significant relationships between the quality of life of children and adolescents and their age, gender or socioeconomic status. Adolescents differ statistically significant between their quality of life and their education, the frequency of special education and the existence of grade retention. The severity of heart disease, the number of cardiac catheterizations or surgery and the presence of other health disorders are unrelated to the quality of life of children and adolescents. Adolescents revealed that the level of quality of life is influenced by the age of diagnosis of CHD by cardiac catheterization and surgery. For parents of children and adolescents gender and their education don?t influence their perception of quality of life. Only the socioeconomic status of parents of teens has statistically significant difference to quality of life. Parents of children and adolescents do not show statistically significant relationship between the perceived level of quality of life and severity of disease, age at diagnosis, the number of surgical interventions and the existence of other health disorders. There is a relationship of statistical significance between cardiac catheterization and the perceived quality of life by parents of adolescents; between the number of cardiac catheterizations and the perception of quality of life of parents of children; and between performing surgery and the perception of parents of children and adolescents. Conclusion: To analyze the quality of life of children and adolescents with CHD must be a key focus of attention in caring for this population, allowing the identification of individual differences, interests, preferences, and prevent potential problems. The knowledge acquired along with clinical experience contributes to improve the quality of life of children and families, facilitating their growth, psycho-emotional development and social integration. Nevertheless, the reading and interpretation of these results must be prudent and cautious, there are limitations to this research, including: the use of a range of specific quality of life for the Congenital heart disease in children, adolescents, and parents but whose validation process could not be completed in this study; the low prevalence of severe conditions in our sample; the absence of national studies to enable comparison with the results obtained. We intend to continue the process of validation of instrument and enlarge the research to Lisbon and Oporto, other major centers where the cardiac conditions can be treated.

Investigation between the S377G3 GATA-4 polymorphism and migraine

Migraine is a common and painful neurological disorder, with genetic and environmental components. Several conditions have been shown to be comorbid with migraine, notably a cardiac malformation affecting the interatrial septum and leading to patent foramen ovale (PFO). Mutations in the development regulatory gene GATA-4, located on human chromosome 8p23.1-p22, have been found to be responsible for some cases of congenital heart defects including PFO. To determine whether the GATA-4 gene is involved in migraine, the present study performed an association analysis of a common GATA-4 variant that results in a change of amino acid (S377G), in a large case/control population (275 unrelated Caucasian migraineurs versus 275 control individuals). The results showed that there was no significant association for this polymorphism between migraine and controls (χ² = 0.84, P = 0.66). Thus it appears that the GATA-4 (S377G) mutation does not play a significant role in common migraine susceptibility.

Cardiac function before and after treatment for various types of loading conditions and in myocardial restriction : A prospective study on pediatric patients with two- and three-dimensional echocardiography and measurement of serum natriuretic peptides

Background: The incidence of all forms of congenital heart defects is 0.75%. For patients with congenital heart defects, life-expectancy has improved with new treatment modalities. Structural heart defects may require surgical or catheter treatment which may be corrective or palliative. Even those with corrective therapy need regular follow-up due to residual lesions, late sequelae, and possible complications after interventions. Aims: The aim of this thesis was to evaluate cardiac function before and after treatment for volume overload of the right ventricle (RV) caused by atrial septal defect (ASD), volume overload of the left ventricle (LV) caused by patent ductus arteriosus (PDA), and pressure overload of the LV caused by coarctation of the aorta (CoA), and to evaluate cardiac function in patients with Mulibrey nanism. Methods: In Study I, of the 24 children with ASD, 7 underwent surgical correction and 17 percutaneous occlusion of ASD. Study II had 33 patients with PDA undergoing percutaneous occlusion. In Study III, 28 patients with CoA underwent either surgical correction or percutaneous balloon dilatation of CoA. Study IV comprised 26 children with Mulibrey nanism. A total of 76 healthy voluntary children were examined as a control group. In each study, controls were matched to patients. All patients and controls underwent clinical cardiovascular examinations, two-dimensional (2D) and three-dimensional (3D) echocardiographic examinations, and blood sampling for measurement of natriuretic peptides prior to the intervention and twice or three times thereafter. Control children were examined once by 2D and 3D echocardiography. M-mode echocardiography was performed from the parasternal long axis view directed by 2D echocardiography. The left atrium-to-aorta (LA/Ao) ratio was calculated as an index of LA size. The end-diastolic and end-systolic dimensions of LV as well as the end-diastolic thicknesses of the interventricular septum and LV posterior wall were measured. LV volumes, and the fractional shortening (FS) and ejection fraction (EF) as indices of contractility were then calculated, and the z scores of LV dimensions determined. Diastolic function of LV was estimated from the mitral inflow signal obtained by Doppler echocardiography. In three-dimensional echocardiography, time-volume curves were used to determine end-diastolic and end-systolic volumes, stroke volume, and EF. Diastolic and systolic function of LV was estimated from the calculated first derivatives of these curves. Results: (I): In all children with ASD, during the one-year follow-up, the z score of the RV end-diastolic diameter decreased and that of LV increased. However, dilatation of RV did not resolve entirely during the follow-up in either treatment group. In addition, the size of LV increased more slowly in the surgical subgroup but reached control levels in both groups. Concentrations of natriuretic peptides in patients treated percutaneously increased during the first month after ASD closure and normalized thereafter, but in patients treated surgically, they remained higher than in controls. (II): In the PDA group, at baseline, the end-diastolic diameter of LV measured over 2SD in 5 of 33 patients. The median N-terminal pro-brain natriuretic peptide (proBNP) concentration before closure measured 72 ng/l in the control group and 141 ng/l in the PDA group (P = 0.001) and 6 months after closure measured 78.5 ng/l (P = NS). Patients differed from control subjects in indices of LV diastolic and systolic function at baseline, but by the end of follow-up, all these differences had disappeared. Even in the subgroup of patients with normal-sized LV at baseline, the LV end-diastolic volume decreased significantly during follow-up. (III): Before repair, the size and wall thickness of LV were higher in patients with CoA than in controls. Systolic blood pressure measured a median 123 mm Hg in patients before repair (P < 0.001) and 103 mm Hg one year thereafter, and 101 mm Hg in controls. The diameter of the coarctation segment measured a median 3.0 mm at baseline, and 7.9 at the 12-month (P = 0.006) follow-up. Thicknesses of the interventricular septum and posterior wall of the LV decreased after repair but increased to the initial level one year thereafter. The velocity time integrals of mitral inflow increased, but no changes were evident in LV dimensions or contractility. During follow-up, serum levels of natriuretic peptides decreased correlating with diastolic and systolic indices of LV function in 2D and 3D echocardiography. (IV): In 2D echocardiography, the interventricular septum and LV posterior wall were thicker, and velocity time integrals of mitral inflow shorter in patients with Mulibrey nanism than in controls. In 3D echocardiography, LV end-diastolic volume measured a median 51.9 (range 33.3 to 73.4) ml/m² in patients and 59.7 (range 37.6 to 87.6) ml/m² in controls (P = 0.040), and serum levels of ANPN and proBNP a median 0.54 (range 0.04 to 4.7) nmol/l and 289 (range 18 to 9170) ng/l, in patients and 0.28 (range 0.09 to 0.72) nmol/l (P < 0.001) and 54 (range 26 to 139) ng/l (P < 0.001) in controls. They correlated with several indices of diastolic LV function. Conclusions (I): During the one-year follow-up after the ASD closure, RV size decreased but did not normalize in all patients. The size of the LV normalized after ASD closure but the increase in LV size was slower in patients treated surgically than in those treated with the percutaneous technique. Serum levels of ANPN and proBNP were elevated prior to ASD closure but decreased thereafter to control levels in patients treated with the percutaneous technique but not in those treated surgically. (II): Changes in LV volume and function caused by PDA disappeared by 6 months after percutaneous closure. Even the children with normal-sized LV benefited from the procedure. (III): After repair of CoA, the RV size and the velocity time integrals of mitral inflow increased, and serum levels of natriuretic peptides decreased. Patients need close follow-up, despite cessation of LV pressure overload, since LV hypertrophy persisted even in normotensive patients with normal growth of the coarctation segment. (IV): In children with Mulibrey nanism, the LV wall was hypertrophied, with myocardial restriction and impairment of LV function. Significant correlations appeared between indices of LV function, size of the left atrium, and levels of natriuretic peptides, indicating that measurement of serum levels of natriuretic peptides can be used in the clinical follow-up of this patient group despite its dependence on loading conditions.

Late results after paediatric cardiac surgery

Background: Congenital heart defects include a wide range of inborn malformations. Depending on the defect, the life expectancy of a newborn with cardiac anomaly varies from a few days to a normal life span. In most instances surgery, is the only treatment available. The late results of surgery have not been comprehensively investigated. Aims: Mortality, morbidity and the life situation of all Finnish patients who had been operated on for congenital heart defect during childhood were investigated. Methods: Patient and surgical data were gathered from all hospitals that had performed heart surgeries on children. Late mortality and survival data were obtained from the population registry, and the causes of deaths from Statistics Finland. Morbidity of patients operated on during 1953-1989 was assessed by the usage of medicines. The pharmacotherapy data of patients and controls were obtained from the Social Insurance Institute. The life situation of patients was surveyed by mailed questionnaire. Survival, causes of deaths and life situation of patients were compared with those of the general population. Results: A total of 7240 cardiac operations were performed on 6461 children during the first 37 years of cardiac surgery (1953-1989). The number of procedures constantly rose during this period, and the increase continued in later years. The patient material varied over time, as more defects became surgically treatable. During 1953-1989 the operative mortality (death within 30 days of surgery) was 6.9%. In the 1990s a slight rise occurred in early mortality, as increasingly complicated patients were surgically treated. During 2000-2003 practically no defects were beyond the operative range. Thus, the operative mortality of 4.4% was excellent, decreasing even further to 2.0% in 2004-2007. The overall 45-year survival of patients operated on in 1953-1989 was 78%, and the corresponding figure for the general population was 93%. Survival depended on the defect, being worst among patients with univentricular heart. Late survival was also better during the 1990s and at the beginning of the 21st century. Of the 6028 early survivors, 592 died late (>30 days) after surgery. A total of 397 deaths (67%) were related and 185 (31%) unrelated to congenital heart defect. The cause of death was unknown in 10 cases. Of those 5774 patients who survived their first operation and had complete follow-up, 16% were operated on several times. Seventeen percent of patients used medicines for cardiac symptoms (heart failure, arrhythmia, hypertension and coronary disease). Patients risk of using cardiac medicines was 2.16 (Cl 1.97-2.37) times higher than that of controls. Patients also had more genetic syndromes and mental retardation and more often used medicines for asthma and epilepsy. Adult patients who had been operated on as children had coped surprisingly well with their defects. Their level of education was similar and their employment level even higher than expected, and they were living in a steady relationship as often as the general population. Conclusions: Cardiac surgery developed rapidly, and nowadays practically all defects can be treated. The overall survival of all operated patients was 78%, 16% less than that of the general population. However, it was significantly better than the anticipated natural survival. However, many patients had health problems; 16% needed reoperations and 17% cardiac medicines to maintain their condition. Most of the patients assessed their general health as good and lived a normal life.

Diversité fonctionnelle du facteur de transcription Tbx5 dans le coeur

Le cœur des vertébrés est un organe modulaire qui requiert le " patterning " complexe des champs morphogénétiques cardiogènes et la convergence coordonnée des diverses sous-populations de progéniteurs cardiogéniques. Au moins 7 facteurs de transcription de la famille T-box coopèrent au sein de ces nombreuses sous-populations de progéniteurs cardiogéniques afin de réguler la morphogenèse et l’agencement de multiples structures le long de l’ébauche cardiaque, ce qui explique que les mutations humaines de ces gènes engendrent diverses malformations congénitales cardiaques (MCCs). L’un de ces gènes T-box, Tbx5, dont l’haploinsuffisance génère le syndrome de Holt-Oram (SHO), intervient dans une grande variété de réseaux de régulation géniques (RRGs) qui orchestrent la morphogenèse des oreillettes, du ventricule gauche, de la valve mitrale, des septums inter-auriculaire et inter-ventriculaire, ainsi que du système de conduction cardiaque. La diversité des RRGs impliqués dans la formation de ces structures cardiaques suggère que Tbx5 détient une profusion de fonctions qui ne seront identifiables qu’en répertoriant ses activités moléculaires dans chaque lignée cardiaque examinée isolément. Afin d’aborder cette problématique, une ablation génétique de Tbx5 dans l’endocarde a été réalisée. Cette expérience a démontré le rôle crucial de Tbx5 dans la survie des cellules endocardiques bordant le septum primum et des cardiomyocytes au sein de cette structure embryonnaire qui contribuera à la morphogenèse du septum inter-auriculaire. En outre, cette étude a révélé l’existence d’une communication croisée entre la sous-population de cellules endocardiques Tbx5+ et le myocarde au niveau du septum primum, afin d’assurer la survie des cardiomyocytes, et ultimement de garantir la maturation du septum inter-auriculaire. Nos résultats confirment aussi l’importance de l’interdépendance génétique (Tbx5 et Gata4 ainsi que Tbx5 et Nos3) entre différents loci dans la morphogenèse de la cloison inter-auriculaire, et particulièrement de l’influence que peut avoir l’environnement sur la pénétrance et l’expressivité des communications inter-auriculaires (CIAs) dans le SHO. En outre, puisque les fonctions d’un gène dépendent ordinairement des différents isoformes qu’il peut générer, une deuxième étude a focalisé davantage sur l’aspect transcriptionnel de Tbx5. Cette approche a mené à la découverte de 6 transcrits alternatifs exhibant des fonctions à la fois communes et divergentes. La caractérisation de 2 de ces isoformes a révélé le rôle de l’isoforme long (Tbx5_v1) dans la régulation de la croissance des cardiomyocytes durant la cardiogénèse, tandis que l’isoforme court (Tbx5_v2), préférentiellement exprimé dans le cœur mature, réprime la croissance cellulaire. Il est donc entièrement concevable que les mutations de TBX5 entraînant une troncation de la région C-terminale accroissent la concentration d’une protéine mutée qui, à l’instar de Tbx5_v2, interfère avec la croissance de certaines structures cardiaques. En revanche, la divergence de fonctions de ces isoformes, caractérisée par les disparités de localisation subcellulaire et de d’interaction avec d’autres cofacteurs cardiaques, suggère que les mutations affectant davantage un isoforme favoriseraient l’émergence d’un type particulier de MCC. Finalement, un dernier objectif était d’identifier le ou les mécanisme(s) moléculaire(s) par le(s)quel(s) Tbx5 régule son principal gène cible, Nppa, et d’en extraire les indices qui éclairciraient sa fonction transcriptionnelle. Cet objectif nécessitait dans un premier lieu d’identifier les différents modules cis-régulateurs (MCRs) coordonnant la régulation transcriptionnelle de Nppa et Nppb, deux gènes natriurétiques dont l’organisation en tandem et le profil d’expression durant la cardiogénèse sont conservés dans la majorité des vertébrés. L’approche d’empreinte phylogénétique employée pour scanner le locus Nppb/Nppa a permis d’identifier trois MCRs conservés entre diverses espèces de mammifères, dont un (US3) est spécifique aux euthériens. Cette étude a corroboré que la régulation de l’expression du tandem génique Nppb/Nppa requérait l’activité transcriptionnelle d’enhancers en complément aux promoteurs de Nppa et Nppb. La concordance quasiment parfaite entre les profils d’expression de Tbx5 et de ces deux gènes natriurétiques chez les mammifères, suggère que le gradient d’expression ventriculaire de Tbx5 est interprété par le recrutement de ce facteur au niveau des différents enhancers identifiés. En somme, les études présentées dans cette thèse ont permis de clarifier la profusion de fonctions cardiaques que possède Tbx5. Certaines de ces fonctions émanent de l’épissage alternatif de Tbx5, qui favorise la synthèse d’isoformes dotés de propriétés spécifiques. Les diverses interactions combinatoires entre ces isoformes et d’autres facteurs cardiaques au sein des diverses sous-populations de progéniteurs cardiogènes contribuent à l’émergence de RRGs cardiaques divergents.

Valvuloplastia pulmonar con balón resultados a corto y largo plazo del complexo Hospitalario Universitario a Coruña

Evaluar los resultados a corto y largo plazo de la valvuloplastia pulmonar con balón en el Complexo Hospitalario Universitario A Coruña. Metodología: Revisión de las historias clínicas, datos hemodinámicos y seguimiento ecocardiográfico de los pacientes sometidos a valvuloplastia pulmonar en nuestra institución entre marzo de 1998 y marzo de 2011. Resultados: En 13 años, se han realizado 81 valvuloplastias pulmonares, de las cuales 67 fueron evaluadas. 56.7% fueron mujeres, con una mediana de edad de 2 meses y un peso de 4.7 kg. 25% de los casos tenían otras malformaciones cardiacas asociadas y en el 65% se encontró una válvula pulmonar en cúpula. El procedimiento fue exitoso en el 82% de los casos, con una morbilidad del 1.49% y sin mortalidad asociada en nuestra serie. Los resultados a largo plazo muestran una incidencia de reestenosis del 23%, la cual se asocio a un gradiente pico post valvuloplastia > 30 mmHg (p <0.001). La insuficiencia pulmonar fue observada en el 86.5% de los casos, siendo leve en la mayoría de ellos. La mortalidad global de nuestra seria fue del 4.5%. Discusión: La valvuloplastía pulmonar con balón, es para nuestra población, el tratamiento de elección en la estenosis pulmonar, con buenas tasas de éxito y baja morbilidad asociada al procedimiento. A largo plazo, la incidencia de lesiones residuales (estenosis y/o insuficiencia) así como los tiempos libres de reintervención, son comparables con los publicados en la literatura.

Caracterización de cardiopatías congénitas en pacientes con Síndrome de Down en una institución especializada de Bogotá

Las cardiopatías son el principal defecto congénito asociado al Síndrome de Down (SD), y su detección e intervención oportuna contribuye a reducir la morbimortalidad. El objetivo del presente estudio fue caracterizar las malformaciones cardiacas congénitas de la población pediátrica con SD que asiste a un centro de atención especializado en la ciudad de Bogotá (Colombia). Materiales y métodos: Se realizó un estudio descriptivo transversal con registros clínicos de pacientes con diagnostico cariotípico de SD, evaluando las cardiopatías congénitas documentadas en las valoraciones pediátricas institucionales; se estudió su posible relación con determinados factores como la edad de los padres y el género del hijo. Resultados: Se revisaron 157 historias clínicas que cumplieron con los criterios de calidad para estudio. El 57,2% eran hombres y el 42,8% mujeres. El cariotipo del 91,7% fue trisomía libre, 3.8% mosaicismos y un caso de translocación. El diagnóstico prenatal se realizó en el 12,1% de los evaluados. Se observó algún defecto cardiaco congénito en el 65,8% de los pacientes (n=103). Se identificaron defectos aislados en 53 pacientes (33,7%), siendo el ductus arterioso persistente el más frecuente con un 26,2%. El defecto múltiple más recurrente fue la comunicación interauricular asociada a comunicación interventricular con un 18,4%. No se identificó relación entre los factores de riesgo estudiados y algún tipo de cardiopatía. Conclusiones: Se identificó una prevalencia de cardiopatías congénitas similar a la reportada por la literatura, sin embargo se documentaron diferencias en cuanto a la frecuencia y tipos de defectos únicos y múltiples descritos en otros estudios. Palabras Clave: Síndrome Down, Cardiopatías congénitas, Colombia.

Efectos de la asociación vasopresina-noradrenalina en pacientes pediátricos con choque séptico refractario

Objetivo: Evaluar el efecto sobre presión arterial media (PAM), estancia hospitalaria, mortalidad y perfusión tisular con el uso de vasopresores en niños con choque séptico refractario en la Unidad de Cuidado Intensivo pediátrico de la Fundación CardioInfantil. Materiales y Métodos: Estudio observacional de cohorte retrospectiva en niños de 1 mes a 18 años con choque séptico refractario atendidos de enero 2008 a diciembre 2013 tratados con noradrenalina sola ó vasopresina-noradrenalina. Se excluyeron pacientes con choque de otra etiología, cardiopatías congénitas, diabetes insípida y muerte encefálica. Se estimaron, como medidas de asociación riesgos relativos con sus respectivos intervalos de confianza al 95%.Resultados: Se evaluaron 129 pacientes, de los cuales 51% eran niños, edad promedio 52 meses con una mortalidad global del 34.1%. La PAM inicial en ambos grupos mostró incremento significativo que se mantuvo en las siguientes 3 horas (p<0,005). La mortalidad en el grupo PRISM III de bajo riesgo fue menor con la noradrenalina sola (p<0,005 RR3,7 IC95% 1,16-12,2) pero igual en ambos grupos en los de riesgo moderado según esta escala(p=0,42 RR 0,88 IC95% 0,60-1,30). No se encontraron diferencias estadísticamente significativas en estancia en UCIP (p=0,79) ni hospitalaria total (p=0,96) pero sí mejoría en función hepática (p=0,004)y renal (p<0,005) del grupo de vasopresina-noradrenalina Conclusiones: La asociación vasopresina-noradrenalina mejora la PAM cuando no se han alcanzado metas con un solo vasopresor en pacientes con choque séptico refractario. Se necesitan estudios prospectivos que corroboren estos hallazgos. Palabras claves:Choque séptico refractario, noradrenalina, vasopresina, mortalidad.

Sobrevida y factores relacionados con reintervención en pacientes tratados con valvuloplastia aórtica con balón en la Fundación Cardioinfantil

Introducción: La valvuloplastía aórtica con balón (VAB) es el procedimiento de elección para el manejo de La estenosis valvular aórtica en pediatría. La mortalidad y la supervivencia libre de reintervenciones no han sido evaluadas en Colombia. Objetivo: Determinar la sobrevida global y los factores asociados de reintervención valvular aórtica (RVA) en los pacientes tratados con VAB en la Fundación Cardio infantil – Instituto de Cardiología entre febrero del 2005 y marzo del 2013. Métodos: estudio estudio analítico de cohorte Resultados: Se evaluaron 69 VAB. La edad promedio de realización fue de 74,89 meses. La relación hombre: mujer de 4:1. Un 30,5% de los pacientes tenían malformaciones cardiacas asociadas. Se presentaron complicaciones en 13% de las VAB. La presión sistólica del ventrículo izquierdo presento una reducción promedio de un 63,6%. Se siguieron el 81,2% de las VAB, encontrando a los 9 años de seguimiento, supervivencia de 89,2% y necesidad de RVA en 14,2% de las VAB, siendo más frecuentes en VAB con gradiente post-VAB mayor de 35 mmhg (p= 0.005), con un RR de 6.6. Los otros factores no mostraron relaciones estadísticamente significativas (edad, morfología valvular, malformaciones asociadas, insuficiencia aórtica post-VAB). Conclusiones: La VAB es eficaz en el manejo de la EVA congénita, con una mortalidad y supervivencia libre de RVA similares a las encontradas en estudios previamente publicados. El gradiente post VAB mayor de 35 mm hg fue el único factor de riesgo que se correlacionó con la supervivencia libre de RVA.