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2.
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
3.
J Pediatr ; 213: 103-109, 2019 Oct.
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.

4.
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.

5.
Radiology ; 290(3): 640-648, 2019 Mar.
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.

6.
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
7.
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.

8.
Circ Genom Precis Med ; 11(6): e000046, 2018 Jun.
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.

10.
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
11.
J Cardiovasc Magn Reson ; 19(1): 107, 2017 Dec 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.

12.
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.

13.
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
14.
J Thorac Cardiovasc Surg ; 154(5): 1703-1710.e3, 2017 Nov.
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).

15.
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
16.
Pediatrics ; 139(3)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28228502

RESUMO

Knowledge gaps persist about the incidence of and risk factors for sudden death in the young (SDY). The SDY Case Registry is a collaborative effort between the National Institutes of Health, the Centers for Disease Control and Prevention, and the Michigan Public Health Institute. Its goals are to: (1) describe the incidence of SDY in the United States by using population-based surveillance; (2) compile data from SDY cases to create a resource of information and DNA samples for research; (3) encourage standardized approaches to investigation, autopsy, and categorization of SDY cases; (4) develop partnerships between local, state, and federal stakeholders toward a common goal of understanding and preventing SDY; and (5) support families who have lost loved ones to SDY by providing resources on bereavement and medical evaluation of surviving family members. Built on existing Child Death Review programs and as an expansion of the Sudden Unexpected Infant Death Case Registry, the SDY Case Registry achieves its goals by identifying SDY cases, providing guidance to medical examiners/coroners in conducting comprehensive autopsies, evaluating cases through child death review and an advanced review by clinical specialists, and classifying cases according to a standardized algorithm. The SDY Case Registry also includes a process to obtain informed consent from next-of-kin to save DNA for research, banking, and, in some cases, diagnostic genetic testing. The SDY Case Registry will provide valuable incidence data and will enhance understanding of the characteristics of SDY cases to inform the development of targeted prevention efforts.


Assuntos
Morte Súbita/epidemiologia , Sistema de Registros , Autopsia , Médicos Legistas , DNA/genética , Bases de Dados de Ácidos Nucleicos , Morte Súbita/etiologia , Testes Genéticos , Humanos , Consentimento Livre e Esclarecido , Estados Unidos/epidemiologia
17.
Prehosp Disaster Med ; 32(3): 269-272, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28215188

RESUMO

Introduction Sudden cardiac death (SCD) is responsible for 5%-10% of all deaths among children 5-19 years-of-age. The incidence of SCD in youth in Michigan (USA) and nationwide is higher in racial/ethnic minorities and in certain geographic areas. School cardiac emergency response plans (CERPs) increase survival after cardiac arrest. However, school cardiac emergency preparedness remains variable. Studying population-level factors associated with school cardiac emergency preparedness and incidence of SCD in the young may improve understanding of disparities in the incidence of SCD. Hypothesis/Problem The objective of this pilot study was to determine the association of elements of high school cardiac emergency preparedness, including Automated External Defibrillator (AED) distribution and the presence of CERPs with county sociodemographic characteristics and county incidence of SCD in the young. METHODS: Surveys were sent to representatives from all public high schools in 30 randomly selected Michigan counties. Counties with greater than 50% response rate were included (n=19). Association of county-level sociodemographic characteristics with incidence of SCD in the young and existence of CERPs were evaluated using Spearman correlation coefficient. RESULTS: Factors related to the presence of AEDs were similar across counties. Schools in counties of lower socioeconomic status (SES; lower-median income, lower per capita income, and higher population below poverty level) were less likely to have a CERP than those with higher SES (all P<.01). Lack of a CERP was associated with a higher incidence of SCD in youth (r=-0.71; P=.001). Overall incidence of SCD in youth was higher in lower SES counties (r=-0.62 in median income and r=0.51 in population below poverty level; both P<.05). CONCLUSION: County SES is associated with the presence of CERPs in schools, suggesting a link between school cardiac emergency preparedness and county financial resources. Additionally, counties of lower SES demonstrated higher incidence of SCD in the young. Statewide and national studies are required to further explore the factors relating to geographic and socioeconomic differences in cardiac emergency preparedness and the incidence of SCD in the young. White MJ , Loccoh EC , Goble MM , Yu S , Odetola FO , Russell MW . High school cardiac emergency response plans and sudden cardiac death in the young. Prehosp Disaster Med. 2017;32(3):269-272.


Assuntos
Defesa Civil , Morte Súbita Cardíaca/epidemiologia , Parada Cardíaca/terapia , Adolescente , Criança , Serviços de Saúde da Criança , Pré-Escolar , Desfibriladores , Feminino , Humanos , Masculino , Michigan/epidemiologia , Projetos Piloto , Serviços de Saúde Escolar , Instituições Acadêmicas , Inquéritos e Questionários , Adulto Jovem
18.
JAMA Cardiol ; 2(4): 419-428, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28241245

RESUMO

Importance: Sarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression. Objectives: (1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers. Design, Setting, and Participants: This investigation was a cross-sectional, multicenter observational study in the setting of the HCMNet network of HCM clinical centers. Mutation carriers with LVH (G+/LVH+), mutation carriers without LVH (G+/LVH-), and healthy related control individuals (G-/LVH-) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Participants were enrolled between April 9, 2010, and January 30, 2012. Study analysis was performed between June 2015 and May 2016. Exposures: The primary stratifying variables were the presence of a sarcomere mutation and measures of LVWT. Main Outcomes and Measures: Variables from standardized exercise testing, echocardiography, cardiac magnetic resonance imaging, serum biomarker measurement, and electrocardiography were compared across study cohorts. Results: Analyses were performed in 178 participants, including 81 G+/LVH+ (mean [SD] age at baseline, 27 [14] years), 55 G+/LVH- (20 [10] years), and 42 G-/LVH- (18 [8] years). All mutation carriers had smaller LV cavity, higher ratio of LVWT to diastolic diameter, and higher echocardiographic LV ejection fraction than controls. A phenotypic burden score was evaluated as the cumulative number of 7 traits (changes on electrocardiography; decreased LV systolic, diastolic diameter, or septal E' velocity; higher ratio of LVWT to diastolic diameter; serum troponin level; and natriuretic peptide level) in each individual. The mean (SE) phenotypic burden was 4.9 (0.2) phenotypes per individual in G+/LVH+, 2.4 (0.2) in G+/LVH-, and 1.3 (0.2) in controls (P < .001). Classification and regression tree analysis identified an LV end-diastolic dimension z score less than -1.85 or the combination of an LV end-diastolic dimension z score of -1.85 or higher and a septal E' velocity z score less than -0.52 as having 74% accuracy in discriminating G+/LVH- participants from controls. In mutation carriers, clinical variables demonstrated a continuous correlation with LVWT, generally without a clear cutoff signifying pathologic transition. Conclusions and Relevance: G+/LVH- individuals demonstrated altered cardiac dimensions and function and a higher burden of early phenotypes than healthy G- controls. Two methods discriminated phenotypic subgroups, namely, a sum across 7 traits and a regression tree-based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear, manner. A single value of LVWT could not dichotomize the presence or absence of disease.

19.
Circulation ; 134(22): 1738-1748, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27688314

RESUMO

BACKGROUND: Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. METHODS: We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). RESULTS: Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban, calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM samples compared with controls. CaMKII protein abundance was increased only in sarcomere-mutation HCM (P<0.001). The CaMKII target pT17-phospholamban was 5.5-fold increased only in sarcomere-mutation HCM (P=0.01), as was autophosphorylated CaMKII (P<0.01), suggestive of constitutive activation. Calcineurin (PPP3CB) mRNA was not increased, nor was RCAN1 mRNA level, indicating a lack of calcineurin activation. Furthermore, myocyte enhancer factor 2 and nuclear factor of activated T cell transcription factor activity was not increased in HCM, suggesting that calcineurin pathway activation is not an upstream cause of increased CAMKII protein abundance or activation. SERCA2A mRNA transcript levels were reduced in HCM regardless of genotype, as was sarcoplasmic endoplasmic reticular calcium ATPase 2/phospholamban protein ratio (45% reduced; P=0.03). 45Ca sarcoplasmic endoplasmic reticular calcium ATPaseuptake assay showed reduced uptake velocity in HCM regardless of genotype (P=0.01). The cardiac ryanodine receptor was not altered in transcript, protein, or phosphorylated (pS2808, pS2814) protein abundance, and [3H]ryanodine binding was not different in HCM, consistent with no major modification of the ryanodine receptor. CONCLUSIONS: Human HCM demonstrates calcium mishandling through both genotype-specific and common pathways. Posttranslational activation of the CaMKII pathway is specific to sarcomere mutation-positive HCM, whereas sarcoplasmic endoplasmic reticular calcium ATPase 2 abundance and sarcoplasmic reticulum Ca uptake are depressed in both sarcomere mutation-positive and -negative HCM.


Assuntos
Sinalização do Cálcio/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Regulação para Baixo , Expressão Gênica , Genótipo , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Sarcômeros/genética , Sarcômeros/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/biossíntese , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
20.
Circ Cardiovasc Genet ; 9(5): 448-467, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27672144

RESUMO

Advances in genomics are enhancing our understanding of the genetic basis of cardiovascular diseases, both congenital and acquired, and stroke. These advances include finding genes that cause or increase the risk for childhood and adult-onset diseases, finding genes that influence how patients respond to medications, and the development of genetics-guided therapies for diseases. However, the ability of cardiovascular and stroke clinicians to fully understand and apply this knowledge to the care of their patients has lagged. This statement addresses what the specialist caring for patients with cardiovascular diseases and stroke should know about genetics; how they can gain this knowledge; how they can keep up-to-date with advances in genetics, genomics, and pharmacogenetics; and how they can apply this knowledge to improve the care of patients and families with cardiovascular diseases and stroke.


Assuntos
American Heart Association , Doenças Cardiovasculares/genética , Competência Clínica/normas , Educação Médica Continuada/normas , Testes Genéticos/normas , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Prestação Integrada de Cuidados de Saúde/normas , Difusão de Inovações , Predisposição Genética para Doença , Genômica/educação , Genômica/normas , Humanos , Farmacogenética/educação , Farmacogenética/normas , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Melhoria de Qualidade/normas , Indicadores de Qualidade em Assistência à Saúde/normas , Medição de Risco , Fatores de Risco , Estados Unidos
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