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1.
Pediatr Crit Care Med ; 21(9): e827-e833, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32701748

RESUMO

OBJECTIVES: Neonatal cardiac surgery for congenital cardiac defects is associated with significant morbidity and mortality, and there is a need for early identification of patients at highest risk of adverse outcomes. Because vascular endothelial injury mediates damage across organ systems, we measured serum biomarkers of endothelial injury in neonates following cardiopulmonary bypass and examined their associations with short-term outcomes. DESIGN: Prospective cohort study. SETTING: Pediatric cardiac ICU. PATIENTS: Thirty neonates less than 2 weeks old undergoing repair of congenital cardiac defects with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Biomarkers of endothelial integrity, angiopoietin-1 and angiopoietin-2, were measured preoperatively and at 24 hours postoperatively. A composite adverse outcome was defined as any of the following: stroke, need for renal replacement therapy, extracorporeal membrane oxygenation support, cardiac arrest, or death. Associations of biomarkers with adverse outcomes were examined using Wilcoxon rank-sum test. There was an increase in angiopoietin-2 from preoperatively to 24 hours postoperatively (p < 0.0001) and a decrease in angiopoietin-1 from preoperatively to 24 hours postoperatively (p < 0.0001). Patients with greater rise in angiopoietin-2 from preoperatively to 24 hours postoperatively had greater risk of composite adverse outcome (p = 0.04). They had a trend toward higher Vasoactive-Inotropic Score (p = 0.06) and a higher prevalence of low cardiac output syndrome (p = 0.06). Twenty-four hour postoperative angiopoietin-2 level was associated with the composite adverse outcome (p = 0.03). The rise in angiopoietin-2 level from preoperatively to 24 hours postoperatively directly correlated with cardiopulmonary bypass duration (r = 0.47; p = 0.01). CONCLUSIONS: In neonatal cardiac surgery, longer duration of cardiopulmonary bypass is directly associated with greater endothelial injury as measured by increased serum levels of angiopoietin-2. Angiopoietin-2 levels 24 hours postoperatively were significantly associated with a composite adverse outcome. Postoperative angiopoietin-2 level may serve as an early indicator of patients in need of closer monitoring and protective intervention. Further research into endothelial protective strategies is warranted.

2.
J Immunol ; 205(1): 251-260, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32444389

RESUMO

Over the first days of polymicrobial sepsis, there is robust activation of the innate immune system, causing the appearance of proinflammatory cytokines and chemokines, along with the appearance of extracellular histones, which are highly proinflammatory and prothrombotic. In the current study, we studied different innate immune responses in mice with knockout (KO) of complement protein 6 (C6). Polymorphonuclear neutrophils (PMNs) from these KO mice had defective innate immune responses, including defective expression of surface adhesion molecules, generation of superoxide anion, and appearance of reactive oxygen species and histone release after activation of PMNs, along with defective phagocytosis. In addition, in C6-/- mice, the NLRP3 inflammasome was defective both in PMNs and in macrophages. When these KO mice were subjected to polymicrobial sepsis, their survival was improved, associated with reduced levels in the plasma of proinflammatory cytokines and chemokines and lower levels of histones in plasma. In addition, sepsis-induced cardiac dysfunction was attenuated in these KO mice. In a model of acute lung injury induced by LPS, C6-/- mice showed reduced PMN buildup and less lung epithelial/endothelial cell dysfunction (edema and hemorrhage). These data indicate that C6-/- mice have reduced innate immune responses that result in less organ injury and improved survival after polymicrobial sepsis.

3.
Circulation ; 142(3): 217-229, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32418493

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. METHODS: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285). RESULTS: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively). CONCLUSION: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.

4.
Circulation ; 141(8): 641-651, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31736357

RESUMO

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

5.
Data Brief ; 25: 104311, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31453292

RESUMO

The placenta is a highly vascular structure composed of both maternal and fetal elements. We have determined that damaging variants in genes responsible for the positive regulation of angiogenesis (PRA) (GO:0045766) that are inherited by the fetus impair fetal growth and placental function in pregnancies involving critical congenital cardiac defects (Russell et al., 2019). In this dataset, we present the specific genetic variants identified, describe the parental origin of each variant where possible and present the analyses regarding the potential effects of parental origin of the variant on placental function and fetal growth. The data presented are related to the research article "Damaging variants in pro-angiogenic genes impair growth in fetuses with cardiac defects" (Russell et al., 2019).

6.
Pediatr Cardiol ; 40(6): 1253-1257, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31263917

RESUMO

Obesity is associated with additional left ventricular hypertrophy (LVH) in adults with hypertrophic cardiomyopathy (HCM). It is not known whether obesity can lead to further LVH in children with HCM. Echocardiographic LV dimensions were determined in 504 children with HCM. Measurements of interventricular septal thickness (IVST) and posterior wall thickness (PWT), and patients' weight and height were recorded. Obesity was defined as a body mass index (BMI) ≥ 99th percentile for age and sex. IVST data was available for 498 and PWT data for 484 patients. Patient age ranged from 2 to 20 years (mean ± SD, 12.5 ± 3.9) and 340 (68%) were males. Overall, patient BMI ranged from 7 to 50 (22.7 ± 6.1). Obesity (BMI 18-50, mean 29.1) was present in 140 children aged 2-19.6 (11.3 ± 4.1). The overall mean IVST was 20.5 ± 9.6 mm and the overall mean PWT was 11.0 ± 8.4 mm. The mean IVST in the obese patients was 21.6 ± 10.0 mm and mean PWT was 13.3 ± 14.7 mm. The mean IVST in the non-obese patients was 20.1 ± 9.5 mm and mean PWT was 10.4 ± 4.3 mm. Obesity was not significantly associated with IVST (p = 0.12), but was associated with increased PWT (0.0011). Obesity is associated with increased PWT but not IVST in children with HCM. Whether obesity and its impact on LVH influences clinical outcomes in children with HCM needs to be studied.


Assuntos
Cardiomiopatia Hipertrófica/complicações , Ventrículos do Coração/patologia , Obesidade/complicações , Septo Interventricular/patologia , Adolescente , Índice de Massa Corporal , Cardiomiopatia Hipertrófica/fisiopatologia , Criança , Pré-Escolar , Ecocardiografia , Feminino , Humanos , Masculino , Adulto Jovem
8.
J Pediatr ; 213: 103-109, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31227283

RESUMO

OBJECTIVE: To determine the impact of damaging genetic variation in proangiogenic pathways on placental function, complications of pregnancy, fetal growth, and clinical outcomes in pregnancies with fetal congenital heart defect. STUDY DESIGN: Families delivering a baby with a congenital heart defect requiring surgical repair in infancy were recruited. The placenta and neonate were weighed and measured. Hemodynamic variables were recorded from a third trimester (36.4 ± 1.7 weeks) fetal echocardiogram. Exome sequencing was performed on the probands (N = 133) and consented parents (114 parent-child trios, and 15 parent-child duos) and the GeneVetter analysis tool used to identify damaging coding sequence variants in 163 genes associated with the positive regulation of angiogenesis (PRA) (GO:0045766). RESULTS: In total, 117 damaging variants were identified in PRA genes in 133 congenital heart defect probands with 73 subjects having at least 1 variant. Presence of a damaging PRA variant was associated with increased umbilical artery pulsatility index (mean 1.11 with variant vs 1.00 without; P = .01). The presence of a damaging PRA variant was also associated with lower neonatal length and head circumference for age z score at birth (mean -0.44 and -0.47 with variant vs 0.23 and -0.05 without; P = .01 and .04, respectively). During median 3.1 years (IQR 2.0-4.1 years) of follow-up, deaths occurred in 2 of 60 (3.3%) subjects with no PRA variant and in 9 of 73 (12.3%) subjects with 1 or more PRA variants (P = .06). CONCLUSIONS: Damaging variants in proangiogenic genes may impact placental function and are associated with impaired fetal growth in pregnancies involving a fetus with congenital heart defect.

9.
Heart Rhythm ; 16(10): 1462-1467, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31026510

RESUMO

BACKGROUND: Predictors of risk of lethal arrhythmic events (LAE) is poorly understood and may differ from adults in children with hypertrophic cardiomyopathy (HCM). OBJECTIVE: The purpose of this study was to determine predictors of LAE in children with HCM. METHODS: A retrospective data collection was performed on 446 children and teenagers 20 years and younger (290 [65%] male; mean age 10.1 ± 5.7 years) with idiopathic HCM from 35 centers. Patients were classified as group 1 (HCM with LAE) if having a secondary prevention implantable cardioverter-defibrillator (ICD) or primary prevention ICD with appropriate interventions or group 2 (HCM without LAE) if having a primary prevention ICD without appropriate interventions. RESULTS: There were 152 children (34%) in group 1 and 294 (66%) in group 2. Risk factors for group 1 by univariate analysis were septal thickness, posterior left ventricular (LV) wall thickness, lower LV outflow gradient, and Q wave > 3 mm in inferior electrocardiographic leads. Factors not associated with LAE were family history of SCD, abnormal blood pressure response to exercise, and ventricular tachycardia on ambulatory electrocardiographic monitoring. Risk factors for SCD by multivariate analysis were age at ICD placement (hazard ratio [HR] 0.9; P = .0025), LV posterior wall thickness z score (HR 1.02; P < .005), and LV outflow gradient < 30 mm Hg (HR 2.0; P < .006). LV posterior wall thickness z score ≥ 5 was associated with LAE. CONCLUSION: Risk factors for LAE appear different in children compared to adults. Conventional adult risk factors were not significant in children. Further prospective studies are needed to improve risk stratification for LAE in children with HCM.

10.
Radiology ; 290(3): 640-648, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30561279

RESUMO

Purpose To evaluate myocardial strain and circumferential transmural strain difference (cTSD; the difference between epicardial and endocardial circumferential strain) in a genotyped cohort with hypertrophic cardiomyopathy (HCM) and to explore correlations between cTSD and other anatomic and functional markers of disease status. Left ventricular (LV) dysfunction may indicate early disease in preclinical HCM (sarcomere mutation carriers without LV hypertrophy). Cardiac MRI feature tracking may be used to evaluate myocardial strain in carriers of HCM sarcomere mutation. Materials and Methods Participants with HCM and their family members participated in a prospective, multicenter, observational study (HCMNet). Genetic testing was performed in all participants. Study participants underwent cardiac MRI with temporal resolution at 40 msec or less. LV myocardial strain was analyzed by using feature-tracking software. Circumferential strain was measured at the epicardial and endocardial surfaces; their difference yielded the circumferential transmural strain difference (cTSD). Multivariable analysis to predict HCM status was performed by using multinomial logistic regression adjusting for age, sex, and LV parameters. Results Ninety-nine participants were evaluated (23 control participants, 34 participants with preclinical HCM [positive for sarcomere mutation and negative for LV hypertrophy], and 42 participants with overt HCM [positive for sarcomere mutation and negative for LV hypertrophy]). The average age was 25 years ± 11 and 44 participants (44%) were women. Maximal LV wall thickness was 9.5 mm ± 1.4, 9.8 mm ± 2.2, and 16.1 mm ± 5.3 in control participants, participants with preclinical HCM (P = .496 vs control participants), and participants with overt HCM (P < .001 vs control participants), respectively. cTSD for control participants, preclinical HCM, and overt HCM was 14% ± 4, 17% ± 4, and 22% ± 7, respectively (P < .01 for all comparisons). In multivariable models (controlling for septal thickness and log-transformed N-terminal brain-type natriuretic peptide), cTSD was predictive of preclinical and overt HCM disease status (P < .01). Conclusion Cardiac MRI feature tracking identifies myocardial dysfunction not only in participants with overt hypertrophic cardiomyopathy, but also in carriers of sarcomere mutation without left ventricular hypertrophy, suggesting that contractile abnormalities are present even when left ventricular wall thickness is normal. © RSNA, 2018 Online supplemental material is available for this article.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/genética , Imagem Cinética por Ressonância Magnética , Mutação/genética , Sarcômeros/genética , Disfunção Ventricular Esquerda/genética , Adulto , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos Transversais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Estudos Prospectivos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia
11.
Circulation ; 138(21): e653-e711, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30571578

RESUMO

This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.


Assuntos
Cardiopatias Congênitas/diagnóstico , American Heart Association , Aneuploidia , Variações do Número de Cópias de DNA , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Variação Genética , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia
12.
Biomed Res Int ; 2018: 4302726, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364002

RESUMO

We determined the roles of TLR3 and TLR9 in adverse events of polymicrobial sepsis, with a focus on development of septic cardiomyopathy, progression of which we have recently shown to be complement- and histones-dependent. So Wt, TLR3-knocked out (K.O.), and TLR9-K.O. mice were subjected to polymicrobial sepsis following cecal ligation and puncture (CLP). In the absence of either TLR3 or TLR9, the intensity of echocardiogram (Echo)-Doppler dysfunction during development of cardiomyopathy was substantially reduced in the K.O. mice. Based on our prior studies emphasizing the adverse effects of plasma C5a and histones in the cardiomyopathy of sepsis, in TLR3- and TLR9-K.O. mice, there were striking reductions in plasma levels of C5a and histones as well as reduced levels of cytokines in plasma and heart tissue after CLP. Since we know that histones cause cardiac dysfunction, rat cardiomyocytes (CMs) were exposed in vitro to the histones (purified from calf thymus), which caused bleb formation on the surfaces of CMs, suggesting histones may perturb the cell membrane of CMs. In vitro, exposure of CMs to the histones for 3 hours caused lactate dehydrogenase release from CMs. These data indicate that sepsis-induced cardiac dysfunction requires presence of TLR3 and TLR9 and may be linked to histone-induced damage of CMs.


Assuntos
Cardiomiopatias/imunologia , Histonas/imunologia , Miócitos Cardíacos/imunologia , Sepse/imunologia , Receptor 3 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia , Animais , Cardiomiopatias/sangue , Cardiomiopatias/genética , Histonas/sangue , Histonas/genética , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Sepse/sangue , Sepse/genética , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo
13.
Circ Genom Precis Med ; 11(6): e000046, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29844141

RESUMO

The completion of the Human Genome Project has unleashed a wealth of human genomics information, but it remains unclear how best to implement this information for the benefit of patients. The standard approach of biomedical research, with researchers pursuing advances in knowledge in the laboratory and, separately, clinicians translating research findings into the clinic as much as decades later, will need to give way to new interdisciplinary models for research in genomic medicine. These models should include scientists and clinicians actively working as teams to study patients and populations recruited in clinical settings and communities to make genomics discoveries-through the combined efforts of data scientists, clinical researchers, epidemiologists, and basic scientists-and to rapidly apply these discoveries in the clinic for the prediction, prevention, diagnosis, prognosis, and treatment of cardiovascular diseases and stroke. The highly publicized US Precision Medicine Initiative, also known as All of Us, is a large-scale program funded by the US National Institutes of Health that will energize these efforts, but several ongoing studies such as the UK Biobank Initiative; the Million Veteran Program; the Electronic Medical Records and Genomics Network; the Kaiser Permanente Research Program on Genes, Environment and Health; and the DiscovEHR collaboration are already providing exemplary models of this kind of interdisciplinary work. In this statement, we outline the opportunities and challenges in broadly implementing new interdisciplinary models in academic medical centers and community settings and bringing the promise of genomics to fruition.


Assuntos
Pesquisa Biomédica , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/terapia , Genômica/métodos , Estudos Interdisciplinares/normas , Medicina de Precisão/tendências , American Heart Association , Registros Eletrônicos de Saúde , Humanos , Estados Unidos
15.
Cardiol Young ; 28(1): 39-45, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28927471

RESUMO

BACKGROUND: We have previously shown that the minor alleles of vascular endothelial growth factor A (VEGFA) single-nucleotide polymorphism rs833069 and superoxide dismutase 2 (SOD2) single-nucleotide polymorphism rs2758331 are both associated with improved transplant-free survival after surgery for CHD in infants, but the underlying mechanisms are unknown. We hypothesised that one or both of these minor alleles are associated with better systemic ventricular function, resulting in improved survival. METHODS: This study is a follow-up analysis of 422 non-syndromic CHD patients who underwent neonatal cardiac surgery with cardiopulmonary bypass. Echocardiographic reports were reviewed. Systemic ventricular function was subjectively categorised as normal, or as mildly, moderately, or severely depressed. The change in function was calculated as the change from the preoperative study to the last available study. Stepwise linear regression, adjusting for covariates, was performed for the outcome of change in ventricular function. Model comparison was performed using Akaike's information criterion. Only variables that improved the model prediction of change in systemic ventricular function were retained in the final model. RESULTS: Genetic and echocardiographic data were available for 335/422 subjects (79%). Of them, 33 (9.9%) developed worse systemic ventricular function during a mean follow-up period of 13.5 years. After covariate adjustment, the presence of the VEGFA minor allele was associated with preserved ventricular function (p=0.011). CONCLUSIONS: These data support the hypothesis that the mechanism by which the VEGFA single-nucleotide polymorphism rs833069 minor allele improves survival may be the preservation of ventricular function. Further studies are needed to validate this genotype-phenotype association and to determine whether this mechanism is related to increased vascular endothelial growth factor production.


Assuntos
Cardiopatias Congênitas/genética , Cardiopatias Congênitas/cirurgia , Fator A de Crescimento do Endotélio Vascular/genética , Adolescente , Alelos , Procedimentos Cirúrgicos Cardíacos/estatística & dados numéricos , Criança , Pré-Escolar , Ecocardiografia , Feminino , Seguimentos , Transplante de Coração , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Masculino , Philadelphia , Polimorfismo de Nucleotídeo Único , Função Ventricular
16.
J Cardiovasc Magn Reson ; 19(1): 107, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29284499

RESUMO

BACKGROUND: Impaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH). METHOD: Seventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15). RESULTS: LA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 ± 8%) and overt HCM (59 ± 10%), compared with controls (70 ± 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 ± 11%) compared with controls (47 ± 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both). CONCLUSION: LA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non-distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis.


Assuntos
Função do Átrio Esquerdo , Cardiomiopatia Hipertrófica/genética , Átrios do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Mutação , Sarcômeros/genética , Adolescente , Adulto , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos de Casos e Controles , Estudos Transversais , Análise Mutacional de DNA , Feminino , Fibrose , Predisposição Genética para Doença , Átrios do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Função Ventricular Esquerda , Remodelação Ventricular , Adulto Jovem
17.
Open Heart ; 4(2): e000615, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29177058

RESUMO

Objective: Sarcomeric gene mutation carriers without overt left ventricular hypertrophy (G+/LVH-) can harbour subclinical changes in cardiovascular structure and function that precede the development of hypertrophic cardiomyopathy (HCM). We sought to investigate if circulating biomarkers of cardiovascular stress and collagen metabolism among G+/LVH- individuals, measured at rest and following exercise provocation, yield further insights into the underlying biology of HCM. Methods: We studied 76 individuals with overt HCM, 50 G+/LVH- individuals and 41 genotype-negative related controls enrolled in a cross-sectional, multicentre observational study (HCMNet). Biomarkers of cardiac stress (N-terminal pro-B-type natriuretic peptide, NT-proBNP; high-sensitivity troponin I, hsTnI; soluble ST2) and fibrosis (carboxy-terminal propeptide of procollagen type I; C-terminal telopeptide of type I collagen; galectin-3; periostin) were measured. Results: Individuals with overt HCM had elevated NT-proBNP and hsTnI compared with G+/LVH- subjects and controls at rest, along with an exaggerated increase in NT-proBNP and hsTnI in response to exercise. We found no detectable differences in resting or exercise-provoked biomarker profiles of cardiovascular stress and fibrosis among G+/LVH- individuals compared with healthy controls despite subtle echocardiographic differences in cardiac structure and function. Conclusion: Dynamic exercise testing exaggerated resting differences in natriuretic peptides and troponin elevations among individuals with overt HCM. In contrast, we found no differences in biomarker profiles of cardiovascular stress and fibrosis among G+/LVH- individuals compared with controls even after maximal exercise provocation. Our findings highlight the need for continued investigation into early phenotypes of sarcomeric gene mutations and the evolution of HCM.

18.
Nat Genet ; 49(11): 1593-1601, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28991257

RESUMO

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.


Assuntos
Transtorno Autístico/genética , Miosinas Cardíacas/genética , Predisposição Genética para Doença , Fator 1 de Diferenciação de Crescimento/genética , Cardiopatias Congênitas/genética , Cadeias Pesadas de Miosina/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Transtorno Autístico/patologia , Estudos de Casos e Controles , Criança , Exoma , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Cardiopatias Congênitas/patologia , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Risco
19.
J Thorac Cardiovasc Surg ; 154(5): 1703-1710.e3, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28734628

RESUMO

OBJECTIVES: Adrenergic receptor (ADR) genotypes have been associated with adverse outcomes in heart failure. Our objective was to evaluate the association of ADR genotypes with post-Norwood outcomes in infants with hypoplastic left heart syndrome (HLHS). METHODS: Infants with HLHS participating in the Pediatric Heart Network Single-Ventricle Reconstruction Trial underwent genotyping for 4 single-nucleotide polymorphisms in 3 ADR genes: ADRB1_231A/G, ADRB1_1165G/C, ADRB2_5318C/G, and ADRA2A_2790C/T. The association of genotype with freedom from serious adverse events (SAEs) (death, transplant, extracorporeal membrane oxygenation, cardiopulmonary resuscitation, acute shunt failure, unplanned reoperations, or necrotizing enterocolitis) during 14 months' follow-up was assessed with Cox regression and the association with post-Norwood complications was assessed with Poisson regression. Models were adjusted for clinical and surgical factors. RESULTS: The study included 351 eligible patients (62% male; 83% white). The mean age at Norwood procedure was 5.6 ± 3.6 days. A total of 152 patients had SAEs during 14-month follow-up including 84 deaths and 10 transplants. ADRA2A_2790CC genotype had lower SAE-free survival compared with CT/TT genotypes during follow-up (Log rank test, P = .02), and this association was independent of clinical and surgical risk factors (adjusted Cox regression, hazard ratio 1.54 [95% confidence interval 1.04, 2.30] P = .033). Post-Norwood complication rate did not differ by genotype. CONCLUSIONS: Infants with HLHS harboring ADR genotypes that are associated with greater catecholamine release or sensitivity had lower event-free survival after staged palliation. Excess catecholamine activation may adversely affect cardiovascular adaptation after the Norwood procedure. Future studies should explore whether targeting adrenergic activation in those harboring risk genotypes can improve outcomes. (ClinicalTrials.gov number NCT00115934).


Assuntos
Síndrome do Coração Esquerdo Hipoplásico , Procedimentos de Norwood/efeitos adversos , Complicações Pós-Operatórias , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Correlação de Dados , Feminino , Seguimentos , Humanos , Síndrome do Coração Esquerdo Hipoplásico/genética , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Recém-Nascido , Masculino , Procedimentos de Norwood/métodos , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/genética , Complicações Pós-Operatórias/terapia , Modelos de Riscos Proporcionais
20.
FASEB J ; 31(9): 4129-4139, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28572445

RESUMO

Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water-soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart.-Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huber-Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.


Assuntos
Complemento C5a/metabolismo , Regulação da Expressão Gênica/fisiologia , Cardiopatias/etiologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/metabolismo , Animais , Complemento C5a/genética , Cardiopatias/metabolismo , Interleucinas , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo
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