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1.
Pediatr Transplant ; 28(3): e14708, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38553812

RESUMO

BACKGROUND: The aims of the study were to assess the performance of a clinically available cell-free DNA (cfDNA) assay in a large cohort of pediatric and adult heart transplant recipients and to evaluate performance at specific cut points in detection of rejection. METHODS: Observational, non-interventional, prospective study enrolled pediatric and adult heart transplant recipients from seven centers. Biopsy-associated plasma samples were used for cfDNA measurements. Pre-determined cut points were tested for analytic performance. RESULTS: A total of 487 samples from 160 subjects were used for the analysis. There were significant differences for df-cfDNA values between rejection [0.21% (IQR 0.12-0.69)] and healthy samples [0.05% (IQR 0.01-0.14), p < .0001]. The pediatric rejection group had a median df-cfDNA value of 0.93% (IQR 0.28-2.84) compared to 0.09% (IQR 0.04-0.23) for healthy samples, p = .005. Overall negative predictive value was 0.94 while it was 0.99 for pediatric patients. Cut points of 0.13% and 0.15% were tested for various types of rejection profiles and were appropriate to rule out rejection. CONCLUSION: The study suggests that pediatric patients with rejection show higher levels of circulating df-cfDNA compared to adults and supports the specific cut points for clinical use in pediatric and adult patients with overall acceptable performance.


Assuntos
Ácidos Nucleicos Livres , Transplante de Coração , Adulto , Humanos , Criança , Estudos Prospectivos , Biomarcadores , Rejeição de Enxerto , Doadores de Tecidos
2.
Circulation ; 147(17): 1291-1303, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-36970983

RESUMO

BACKGROUND: During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure. METHODS: We performed an analysis beginning with an infant who presented with a rare case of iDCM. We derived induced pluripotent stem cells from the patient to model iDCM in vitro. We performed whole exome sequencing on the patient and his parents for causal gene analysis. CRISPR/Cas9-mediated gene knockout and correction in vitro were used to confirm whole exome sequencing results. Zebrafish and Drosophila models were used for in vivo validation of the causal gene. Matrigel mattress technology and single-cell RNA sequencing were used to characterize iDCM cardiomyocytes further. RESULTS: Whole exome sequencing and CRISPR/Cas9 gene knockout/correction identified RTTN, the gene encoding the centrosomal protein RTTN (rotatin), as the causal gene underlying the patient's condition, representing the first time a centrosome defect has been implicated in a nonsyndromic dilated cardiomyopathy. Genetic knockdowns in zebrafish and Drosophila confirmed an evolutionarily conserved requirement of RTTN for cardiac structure and function. Single-cell RNA sequencing of iDCM cardiomyocytes showed impaired maturation of iDCM cardiomyocytes, which underlie the observed cardiomyocyte structural and functional deficits. We also observed persistent localization of the centrosome at the centriole, contrasting with expected programmed perinuclear reorganization, which led to subsequent global microtubule network defects. In addition, we identified a small molecule that restored centrosome reorganization and improved the structure and contractility of iDCM cardiomyocytes. CONCLUSIONS: This study is the first to demonstrate a case of human disease caused by a defect in centrosome reduction. We also uncovered a novel role for RTTN in perinatal cardiac development and identified a potential therapeutic strategy for centrosome-related iDCM. Future study aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.


Assuntos
Cardiomiopatia Dilatada , Feminino , Gravidez , Animais , Humanos , Cardiomiopatia Dilatada/genética , Peixe-Zebra , Volume Sistólico , Função Ventricular Esquerda , Centrossomo/metabolismo , Miócitos Cardíacos
3.
J Thorac Cardiovasc Surg ; 165(2): 460-468.e2, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35643770

RESUMO

OBJECTIVES: Donor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients. METHODS: Pediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated. RESULTS: A total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively). CONCLUSIONS: Donor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value.


Assuntos
Ácidos Nucleicos Livres , Transplante de Coração , Humanos , Adulto , Criança , Transplante de Coração/efeitos adversos , Valor Preditivo dos Testes , Biópsia , Anticorpos , Rejeição de Enxerto , Aloenxertos
5.
JTCVS Open ; 16: 844-854, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38204728

RESUMO

Objective: To identify risk factors for aortopulmonary collateral (APC) development and assess the impact of severe APCs in children undergoing staged single ventricle palliation. Methods: Children undergoing a bidirectional Glenn operation between January 1, 2016, and March 31, 2021, at our center were included. All underwent angiography prior to Glenn and Fontan; APC flow was graded on a scale of 0 (no appreciable collateral flow) to 4 (severe burden). Demographic data, congenital diagnosis, clinical history, and outcomes were stratified by Glenn assessment; Fontan outcomes were stratified by pre-Fontan grade. Results: Sixty patients met the inclusion criteria, all of whom had angiographic evidence of APCs. There were 7 transplants and 9 deaths in the cohort. There were no significant differences in demographics among the patients. Right ventricular morphology was more common in patients with severe pre-Glenn collaterals (24 of 44 vs 2 of 6 vs 7 of 8; P = .014). Longer stage 1 aortic cross-clamp duration was associated with greater severity pre-Glenn (44 minutes vs 34 minutes vs 66 minutes; P = .023). Patients with grade 3 pre-Glenn collaterals more commonly required transplantation than those with grade 1 collaterals (P < .001) and had lower overall transplant-free survival than those with grade 1 (P = .005) or grade 2 (P = .04) collaterals. Conclusions: The ubiquity of APCs in this study demonstrates their prevalence in single ventricle disease. Right ventricular morphology and prolonged aortic cross-clamp duration are associated with higher burden. Greater severity was associated with decreased transplant-free survival. These data emphasize the negative long-term impact of these collaterals.

6.
Ann Thorac Surg ; 114(5): 1715-1722, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35430223

RESUMO

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) has many management strategies, with the emergence of anatomic repair increasing the available surgical options. Contemporary surgical practices have not been described in multicenter analyses. This study describes the distribution of heart surgery in patients with ccTGA and defines contemporary outcomes in a large multicenter cohort. METHODS: Index cardiovascular operations in patients with primary or fundamental diagnosis of ccTGA were identified in The Society of Thoracic Surgeons Congenital Heart Surgery Database from 2010 to 2019. Operations of interest were combined into mutually exclusive groups designating overall ccTGA management strategies. Outcomes were defined with standard Society of Thoracic Surgeons Congenital Heart Surgery Database definitions. Pearson χ2 and Kruskal-Wallis tests were used for statistical comparisons. RESULTS: One hundred one centers performed 985 index operations, with anatomic repair the most common approach. Twenty-six centers performed more than 10 operations. Atrial switch plus Rastelli operations had the highest rate of operative mortality (8.4%) and major complications (38.2%). Heart transplant operations had the longest postoperative length of stay among survivors (18 days [interquartile range, 13.5-26]). CONCLUSIONS: Patients with ccTGA remain a challenging cohort, with significant diversity in the operations used and a substantial burden of operative mortality and morbidity.


Assuntos
Transposição das Grandes Artérias , Procedimentos Cirúrgicos Cardíacos , Cirurgiões , Transposição dos Grandes Vasos , Humanos , Transposição das Grandes Artérias Corrigida Congenitamente , Transposição dos Grandes Vasos/complicações , Resultado do Tratamento
7.
Pediatr Transplant ; 26(4): e14264, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35258162

RESUMO

BACKGROUND: Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest. METHODS: Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA. RESULTS: A total of 835 samples from 269 subjects (57% pediatric) were included for this analysis, including 28 samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p < .0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p < .0001). CONCLUSION: DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients.


Assuntos
Ácidos Nucleicos Livres , Transplante de Coração , Biomarcadores , Criança , Rejeição de Enxerto , Humanos , Doadores de Tecidos
8.
Ann Thorac Surg ; 114(6): e447-e449, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35231436

RESUMO

Partial anomalous pulmonary venous return is a rare congenital heart defect that can escape detection until adulthood and can be misdiagnosed as pulmonary hypertension and managed with vasodilators before the anomaly is identified. This report describes the cases of 3 patients with pulmonary hypertension whose hemodynamics and symptoms improved after repair of anomalous veins. Anomalous pulmonary veins are difficult to identify on a transthoracic echocardiogram, so a high index of suspicion and early use of additional imaging modalities are important to avoid a delayed diagnosis and progression to irreversible disease.


Assuntos
Cardiopatias Congênitas , Hipertensão Pulmonar , Veias Pulmonares , Síndrome de Cimitarra , Humanos , Adulto , Síndrome de Cimitarra/complicações , Síndrome de Cimitarra/diagnóstico por imagem , Síndrome de Cimitarra/cirurgia , Hipertensão Pulmonar/diagnóstico , Veias Pulmonares/anormalidades , Cardiopatias Congênitas/diagnóstico , Hemodinâmica
9.
Cardiol Young ; 32(11): 1820-1825, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34986912

RESUMO

BACKGROUND: Obesity increases the risk of post-operative arrhythmias in adults undergoing cardiac surgery, but little is known regarding the impact of obesity on post-operative arrhythmias after CHD surgery. METHODS: Patients undergoing CHD surgery from 2007 to 2019 were prospectively enrolled in the parent study. Telemetry was assessed daily, with documentation of all arrhythmias. Patients aged 2-20 years were categorised by body mass index percentile for age and sex (underweight <5, normal 5-85, overweight 85-95, and obese >95). Patients aged >20 years were categorised using absolute body mass index. We investigated the impact of body mass index category on arrhythmias using univariate and multivariate analysis. RESULTS: There were 1250 operative cases: 12% underweight, 65% normal weight, 12% overweight, and 11% obese. Post-operative arrhythmias were observed in 38%. Body mass index was significantly higher in those with arrhythmias (18.8 versus 17.8, p = 0.003). There was a linear relationship between body mass index category and incidence of arrhythmias: underweight 33%, normal 38%, overweight 42%, and obese 45% (p = 0.017 for trend). In multivariate analysis, body mass index category was independently associated with post-operative arrhythmias (p = 0.021), with odds ratio 1.64 in obese patients as compared to normal-weight patients (p = 0.036). In addition, aortic cross-clamp time (OR 1.007, p = 0.002) and maximal vasoactive-inotropic score in the first 48 hours (OR 1.03, p = 0.04) were associated with post-operative arrhythmias. CONCLUSION: Body mass index is independently associated with incidence of post-operative arrhythmias in children after CHD surgery.


Assuntos
Cardiopatias Congênitas , Magreza , Criança , Humanos , Adulto Jovem , Magreza/complicações , Magreza/cirurgia , Sobrepeso/complicações , Fatores de Risco , Obesidade/complicações , Obesidade/epidemiologia , Índice de Massa Corporal , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/complicações , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/cirurgia , Estudos Retrospectivos
11.
Clin Transplant ; 36(1): e14509, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34649304

RESUMO

BACKGROUND: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. OBJECTIVE: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. METHODS: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints. RESULTS: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection. CONCLUSIONS: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant.


Assuntos
Ácidos Nucleicos Livres , Transplante de Coração , Adulto , Criança , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Transplante de Coração/efeitos adversos , Humanos , Estudos Prospectivos , Doadores de Tecidos , Transplantados
12.
JTCVS Tech ; 8: 124-125, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34401830
13.
World J Pediatr Congenit Heart Surg ; 12(4): 516-517, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34278869

RESUMO

Autograft root dilation is common after the unsupported Ross procedure. In the absence of valvar incompetence, and with the perception that dissection is exceedingly rare, expectant management of autograft aneurysm is common practice. Autograft dissection may not be as rare as thought though, as at this point 7 case reports have accrued that describe autograft dissection requiring urgent operative intervention. All had a bicuspid native aortic valve. Bicuspid aortic valve has been shown to be associated with an intrinsic, histologically demonstrated pulmonary arteriopathy, possibly contributing to autograft root dilation and dissection. Autograft root dilation can no longer be regarded as benign, especially in patients with bicuspid aortic valve. Mounting evidence further validates the practice of externally supporting the Ross autograft. For patients who have had an unsupported Ross procedure, mounting evidence may support earlier intervention for autograft root dilation and aneurysm.


Assuntos
Valva Aórtica , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Autoenxertos , Dilatação , Dilatação Patológica , Humanos , Estudos Retrospectivos , Transplante Autólogo
16.
Clin Transplant ; 35(5): e14266, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33615562

RESUMO

BACKGROUND: Adults with congenital heart disease (CHD) awaiting heart transplant (HT) have higher mortality and waitlist removal due to clinical deterioration than those without CHD. The selective use of non-lung donors (NLD) to recover donor pulmonary vasculature to assist in graft implantation may be a contributing factor and is supported by consensus statements despite the recent use of pericardium or graft material as an alternative in pulmonary vascular reconstruction. The impact of selecting NLD for CHD recipients on wait time and mortality has not been evaluated. METHODS/RESULTS: In the United Network for Organ Sharing (UNOS) Registry, 1271 HT recipients age ≥ 18 with CHD were identified between 1987 and 2016, 68% of which had NLDs. Prior to HT, NLD recipients were significantly less likely to be listed UNOS Status 1A, require mechanical ventilation, or intra-aortic balloon pump support. There was no difference in mean waitlist time (254 vs. 278 days, p = .31), 1-year mortality (82% vs. 80%, p = .81; adjusted odds ratio 1.32, 95% confidence interval [CI] 0.96-1.83, p = .08), or overall mortality (adjusted hazard ratio 1.08, 95% CI 0.86-1.36, p = .48) between recipients from NLD and concomitant lung donors. CONCLUSIONS: Adult CHD patients who are less critically ill or listed at a lower status are more likely to receive HT from NLD. There is no overall mortality benefit associated with this practice. While specific cases may necessitate waiting for NLD, programs need to re-evaluate whether this should remain a more widespread practice among CHD patients.


Assuntos
Cardiopatias Congênitas , Transplante de Coração , Adulto , Humanos , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida , Doadores de Tecidos , Estados Unidos , Listas de Espera
18.
J Mol Cell Cardiol ; 154: 6-20, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33516683

RESUMO

Congenital aortic valve stenosis (AS) progresses as an obstructive narrowing of the aortic orifice due to deregulated extracellular matrix (ECM) production by aortic valve (AV) leaflets and leads to heart failure with no effective therapies. Changes in glycoprotein and proteoglycan distribution are a hallmark of AS, yet valvular carbohydrate content remains virtually uncharacterized at the molecular level. While almost all glycoproteins clinically linked to stenotic valvular modeling contain multiple sites for N-glycosylation, there are very few reports aimed at understanding how N-glycosylation contributes to the valve structure in disease. Here, we tested for spatial localization of N-glycan structures within pediatric congenital aortic valve stenosis. The study was done on valvular tissues 0-17 years of age with de-identified clinical data reporting pre-operative valve function spanning normal development, aortic valve insufficiency (AVI), and pediatric endstage AS. High mass accuracy imaging mass spectrometry (IMS) was used to localize N-glycan profiles in the AV structure. RNA-Seq was used to identify regulation of N-glycan related enzymes. The N-glycome was found to be spatially localized in the normal aortic valve, aligning with fibrosa, spongiosa or ventricularis. In AVI diagnosed tissue, N-glycans localized to hypertrophic commissures with increases in pauci-mannose structures. In all valve types, sialic acid (N-acetylneuraminic acid) N-glycans were the most abundant N-glycan group. Three sialylated N-glycans showed common elevation in AS independent of age. On-tissue chemical methods optimized for valvular tissue determined that aortic valve tissue sialylation shows both α2,6 and α2,3 linkages. Specialized enzymatic strategies demonstrated that core fucosylation is the primary fucose configuration and localizes to the normal fibrosa with disparate patterning in AS. This study identifies that the human aortic valve structure is spatially defined by N-glycomic signaling and may generate new research directions for the treatment of human aortic valve disease.


Assuntos
Estenose da Valva Aórtica/metabolismo , Valva Aórtica/metabolismo , Glicômica , Glicoproteínas/metabolismo , Estenose da Valva Aórtica/congênito , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/fisiopatologia , Biomarcadores , Criança , Matriz Extracelular/metabolismo , Predisposição Genética para Doença , Glicômica/métodos , Glicosilação , Humanos , Imagem Molecular , Polissacarídeos/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
19.
Ann Thorac Surg ; 112(3): e169-e171, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33497668

RESUMO

We report the case of an 18-year-old male patient with a history of bicuspid aortic valve with severe aortic insufficiency who had undergone a Ross procedure 1 year prior but subsequently developed stenosis of the pulmonary homograft necessitating conduit replacement. His postoperative course was complicated by acute respiratory distress syndrome. Bronchoscopy revealed significant mucus plugging without identification of contributing pathogen. Further evaluation revealed a history of electronic cigarette use not identified preoperatively and thought to be largely contributory to his postoperative complications. This case highlights the importance of screening preoperatively for electronic cigarette use and counseling on cessation before surgical procedures.


Assuntos
Complicações Pós-Operatórias/etiologia , Síndrome do Desconforto Respiratório/etiologia , Vaping/efeitos adversos , Adolescente , Humanos , Masculino
20.
JTCVS Open ; 6: 220-221, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36003586
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