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Objectives: To evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx ) of biopsy specimens in heart transplant (HT ) recipients with suspected rejection. Introduction: Histopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of "biopsy-negative" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection. Methods: Single-center prospective study of 418 consecutive for-cause endomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels. Results: We analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific antirejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017). Conclusions: In our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of antirejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.
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BACKGROUND: There are limited data evaluating the success of a structured transition plan specifically for pediatric heart transplant (HT) recipients following their transfer of care to an adult specialist. We sought to identify risk factors for poor adherence, graft failure, and mortality following the transfer of care to adult HT care teams. METHODS: We retrospectively reviewed all patients who underwent transition from the pediatric to adult HT program at our center between January 2011 and June 2021. Demographic characteristics, comorbid conditions, and psychosocial history were collected at the time of HT, the time of transition, and the most recent follow-up. Adverse events including mortality, graft rejection, infection, and renal function were also captured before and after the transition. RESULTS: Seventy-two patients were identified (54.1% male, 54.2% Caucasian). Mean age at the time of transition was 23 years after a median of 11.6 years in the pediatric program. The use of calcineurin inhibitors was associated with reduced mortality (HR .04, 95% CI .0-.6, p = .015), while prior psychiatric hospitalization (HR 45.3, 95% CI, 6.144-333.9, p = .0001) was associated with increased mortality following transition. Medication nonadherence and young age at the time of transition were markers for high-risk individuals prior to the transition of care. CONCLUSIONS: Transition of HT recipients from a pediatric program to an adult program occurs during a vulnerable time of emerging adulthood, and we have identified risk factors for mortality following transition. Development of a formalized transition plan with a large multidisciplinary team with focused attention on high-risk patients, including those with psychiatric comorbidities, may favorably influence outcomes.
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Transplante de Coração , Adesão à Medicação , Adulto , Humanos , Criança , Masculino , Feminino , Estudos Retrospectivos , Fatores de Risco , Rejeição de Enxerto/etiologia , Transplantados , Equipe de Assistência ao PacienteRESUMO
BACKGROUND: Among heart transplant (HT) recipients who develop advanced graft dysfunction, cardiac re-transplantation may be considered. A smaller subset of patients will experience failure of their second allograft and undergo repeat re-transplantation. Outcomes among these individuals are not well-described. METHODS: Adult and pediatric patients in the United Network for Organ Sharing (UNOS) registry who received HT between January 1, 1990 and December 31, 2020 were included. RESULTS: Between 1990 and 2020, 90 individuals received a third HT and three underwent a fourth HT. Recipients were younger than those undergoing primary HT (mean age 32 years). Third HT was associated with significantly higher unadjusted rates of 1-year mortality (18% for third HT vs. 13% for second HT vs. 9% for primary HT, p < .001) and 10-year mortality (59% for third HT vs. 42% for second HT vs. 37% for primary HT, p < .001). Mortality was highest amongst recipients aged >60 years and those re-transplanted for acute graft failure. Long-term rates of CAV, rejection, chronic dialysis, and hospitalization for infection were also higher. CONCLUSIONS: Third HT is associated with higher morbidity and mortality than primary HT. Further consensus is needed regarding appropriate organ stewardship for this unique subgroup.
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Transplante de Coração , Adulto , Humanos , Criança , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Rejeição de Enxerto/etiologia , Estudos RetrospectivosRESUMO
INTRODUCTION: Monitoring for graft rejection is a fundamental tenet of post-transplant follow-up. In heart transplantation (HT) in particular, rejection has been traditionally assessed with endomyocardial biopsy (EMB). EMB has potential complications and noted limitations, including interobserver variability in interpretation. Additional tests, such as basic cardiac biomarkers, cardiac imaging, gene expression profiling (GEP) scores, donor-derived cell-free DNA (dd-cfDNA) and the novel molecular microscope diagnostic system (MMDx) have become critical tools in rejection surveillance beyond standard EMB. METHODS: This paper describes an illustrative case followed by a review of MMDx within the context of other noninvasive screening modalities for rejection. CONCLUSIONS: We suggest MMDx be used to assist with early detection of rejection in cases of discordance between EMB and other noninvasive studies.
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Transplante de Coração , Miocárdio , Humanos , Miocárdio/patologia , Transplante de Coração/efeitos adversos , Biópsia , Perfilação da Expressão Gênica , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/epidemiologiaRESUMO
BACKGROUND: Leukopenia in the early period following heart transplantation (HT) is not well-studied. The aim of this study was to evaluate risk factors for the development of post-transplant leukopenia and its consequences for HT recipients. METHODS: Adult patients at a large-volume transplant center who received HT between January 1, 2010 and December 31, 2020 were included. The incidence of leukopenia (WBC ≤3 × 103 /µL) in the first 90-days following HT, individual risk factors, and its effect on 1-year outcomes were evaluated. RESULTS: Of 506 HT recipients, 184 (36%) developed leukopenia within 90-days. Median duration of the first leukopenia episode was 15.5 days (IQR 8-42.5 days). Individuals who developed leukopenia had lower pre-transplant WBC counts compared to those who did not (6.1 × 103 /µL vs. 6.9 × 103 /µL, p = .02). Initial immunosuppressive and infectious chemoprophylactic regimens were not significantly different between groups. Early leukopenia was associated with a higher mortality at 1-year (6.6% vs. 2.1%, p = .008; adjusted HR 3.0) and an increased risk of recurrent episodes. Rates of infection and rejection were not significantly different between the two groups. CONCLUSIONS: Leukopenia in the early period following HT is common and associated with an increased risk of mortality. Further study is needed to identify individuals at highest risk for leukopenia prior to transplant and optimize immunosuppressive and infectious chemoprophylactic regimens for this subgroup.
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Transplante de Coração , Transplante de Rim , Leucopenia , Adulto , Humanos , Transplante de Rim/efeitos adversos , Leucopenia/epidemiologia , Leucopenia/etiologia , Imunossupressores/efeitos adversos , Fatores de Risco , Transplante de Coração/efeitos adversos , Transplantados , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Estudos RetrospectivosRESUMO
Donor-specific antibodies (DSA) are associated with antibody-mediated rejection (AMR) and poor patient survival. In heart transplant, the efficacy of intermittent intravenous immunoglobulin (IVIg) in reducing de novo DSA levels and treating AMR has not been characterized. We retrospectively studied a cohort of 19 patients receiving intermittent IVIg for elevated DSA and examined changes in DSA levels and graft function. Intermittent IVIg infusions were generally safe and well tolerated. Overall, 23 of 62 total DSA (37%) were undetectable after treatment, 21 DSA (34%) had MFI decrease by more than 25%, and 18 (29%) had MFI decrease by less than 25% or increase. The average change in MFI was -51% ± 71% (P < .001). Despite reductions in DSA, among the six patients (32%) with biopsy-confirmed AMR, left ventricular ejection fraction (LVEF) decreased in five (83%) and cardiac index (CI) decreased in three (50%). Conversely, LVEF increased in 91% and CI increased in 70% of biopsy-negative patients. All six AMR patients were readmitted during treatment, four for confirmed or suspected rejection. IVIg infusions may stabilize the allograft in patients with elevated DSA and negative biopsies, but once AMR has developed does not appear to improve allograft function despite decreasing DSA levels.
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Transplante de Coração , Transplante de Rim , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Antígenos HLA , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Isoanticorpos , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Volume Sistólico , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
The Mustard procedure is a palliative surgical procedure used to repair complete transposition of the great arteries. Cardiac transplantation remains the only definitive therapy for patients who develop heart failure after a Mustard procedure. However, pulmonary hypertension represents a major hemodynamic contraindication. The use of a ventricular assist device as destination therapy has not yet been established after a Mustard procedure. Here, we present the case of a 41-year-old patient who presented with systemic right ventricular failure following Mustard procedure complicated by pulmonary hypertension. The patient received a HeartMate II (Thoratec, Pleasanton, CA) ventricular assist device as a bridge to decision.
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Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Complicações Pós-Operatórias/cirurgia , Disfunção Ventricular Direita/cirurgia , Adulto , Procedimentos Cirúrgicos Cardíacos/métodos , Insuficiência Cardíaca/complicações , Humanos , Hipertensão Pulmonar/complicações , Masculino , Transposição dos Grandes Vasos/cirurgia , Disfunção Ventricular Direita/complicaçõesRESUMO
BACKGROUND: Alternate waiting list strategies expand listing criteria for patients awaiting heart transplantation (HTx). We retrospectively analyzed clinical events and outcome of patients listed as high-risk recipients for HTx. METHODS AND RESULTS: We analyzed 822 adult patients who underwent HTx of whom 111 patients met high-risk criteria. Clinical data were collected from medical records and outcome factors calculated for 61 characteristics. Significant factors were summarized in a prognostic score. Age >65 years (67%) and amyloidosis (19%) were the most common reasons for alternate listing. High-risk recipients were older (63.2±10.2 versus 51.4±11.8 years; P<0.001), had more renal dysfunction, prior cancer, and smoking. Survival analysis revealed lower post-HTx survival in high-risk recipients (82.2% versus 87.4% at 1-year; 59.8% versus 76.3% at 5-year post-HTx; P=0.0005). Prior cerebral vascular accident, albumin <3.5 mg/dL, re-HTx, renal dysfunction (glomerular filtration rate <40 mL/min), and >2 prior sternotomies were associated with poor survival after HTx. A prognostic risk score (CARRS [CVA, albumin, re-HTx, renal dysfunction, and sternotomies]) derived from these factors stratified survival post-HTx in high-risk (3+ points) versus low-risk (0-2 points) patients (87.9% versus 52.9% at 1-year; 65.9% versus 28.4% at 5-year post-HTx; P<0.001). Low-risk alternate patients had survival comparable with regular patients (87.9% versus 87.0% at 1-year and 65.9% versus 74.5% at 5-year post-HTx; P=0.46). CONCLUSIONS: High-risk patients had reduced survival compared with regular patients post-HTx. Among patients previously accepted for alternate donor listing, application of the CARRS score identifies patients with unacceptably high mortality after HTx and those with a survival similar to regularly listed patients.
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Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/cirurgia , Transplante de Coração/mortalidade , Adulto , Amiloidose/complicações , Feminino , Insuficiência Cardíaca/complicações , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Período Pré-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND: Systemic amyloidosis complicated by heart failure is associated with high cardiovascular morbidity and mortality. Heart transplantation for patients with systemic amyloidosis is controversial due to recurrence of disease in the transplanted organ or progression of disease in other organs. METHODS: All patients with systemic amyloidosis and heart failure referred for heart transplant evaluation from 1997 to 2004 were included in this retrospective cohort analysis. An interdisciplinary protocol for cardiac transplantation using extended-donor criteria organs, followed in 6 months by either high-dose chemotherapy and stem cell transplantation for patients with primary (AL) or by orthotopic liver transplantation for familial (ATTR) amyloidosis, was developed. Survival of the transplanted amyloid cohort was compared to survival of those amyloid patients not transplanted and to patients transplanted for other indications. RESULTS: A total of 25 patients with systemic amyloidosis and heart failure were included in the study; 12 patients received heart transplants. Amyloid heart transplant recipients were more likely female (58% vs. 8%, P=0.02) and had lower serum creatinine (1.3+/-0.5 vs. 2.0+/-0.7 mg/dL, P=0.01) than nontransplanted amyloid patients. Survival at 1-year after heart transplant evaluation was higher among transplanted patients (75% vs. 23%) compared to patients not transplanted (P=0.001). Short-term survival posttransplant did not differ between transplanted amyloid patients and contemporaneous standard and extended-donor criteria heart transplant patients (P=0.65). CONCLUSIONS: Cardiac transplantation for amyloid patients with extended-donor criteria organs followed by either stem cell or liver transplantation is associated with improved survival compared to patients not transplanted. Short- to intermediate-term survival is similar to patients receiving heart transplantation for other indications. This clinical management strategy provides cardiac amyloid patients a novel therapeutic option.
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Amiloidose/cirurgia , Insuficiência Cardíaca/cirurgia , Transplante de Coração/métodos , Doadores de Tecidos , Amiloidose/complicações , Amiloidose Familiar/complicações , Amiloidose Familiar/cirurgia , Creatinina/sangue , Feminino , Insuficiência Cardíaca/etiologia , Transplante de Coração/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Transplante de Células-Tronco , Análise de Sobrevida , Resultado do TratamentoRESUMO
The phenylpropanoid pathway plays important roles in plants following exposure to environmental stresses, such as wounding and pathogen attack, which lead to the production of a variety of compounds, including lignin, flavonoids and phytoalexins. Ferulate 5-hydroxylase (F5H) is a cytochrome P450-dependent monooxygenase that catalyses the hydroxylation of ferulic acid, coniferaldehyde and coniferyl alcohol, leading to sinapic acid and syringyl lignin biosynthesis. We isolated F5H cDNA and genomic DNA from Camptotheca acuminata and investigated the expression pattern of the C. acuminata F5H (CaF5H1) gene in response to wounding. A search against the BLOCKS database of conserved protein motifs indicated that CaF5H1 retains features in common with F5Hs reported from other plants. 5'-flanking region analysis using the PLACE database showed that putative regulatory elements related to various abiotic and biotic stresses, such as drought, wounding, low temperature and pathogens, exist in the 5'-flanking region of CaF5H1. Based upon these analysis results, we investigated the expression pattern of CaF5H1 gene in response to wounding and stress-related molecules. Here, we show that CaF5H1 transcripts accumulated in the leaves in response to mechanical wounding or the application of molecules involved in the stress response, such as ethylene, ABA and hydrogen peroxide (H2O2). The application of salicylic acid and diphenylene iodonium (DPI) inhibited the wound-induced expression of CaF5H1. Taken together, we suggest that wound-induced expression of CaF5H1 may be mediated by MJ and H2O2 and enhanced phenylpropanoid contents via CaF5H1 maybe function in response to various stresses, including wounding, in plants.
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Camptotheca/enzimologia , Sistema Enzimático do Citocromo P-450/biossíntese , Oxigenases de Função Mista/biossíntese , Ácido Abscísico/farmacologia , Acroleína/análogos & derivados , Acroleína/farmacologia , Sequência de Aminoácidos , Sequência de Bases , Camptotheca/genética , Ácidos Cumáricos/farmacologia , Ciclopentanos/farmacologia , Etilenos/farmacologia , Peróxido de Hidrogênio/farmacologia , Dados de Sequência Molecular , Oniocompostos/farmacologia , Oxilipinas , Fenóis/farmacologia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/enzimologia , Raízes de Plantas/enzimologia , Caules de Planta/enzimologia , Caules de Planta/genética , Ácido Salicílico/farmacologia , Alinhamento de Sequência , Transcrição Gênica/efeitos dos fármacosRESUMO
The expression of CSDC9 encoding S-adenosylmethionine decarboxylase (SAMDC) is developmentally and spatially regulated in carnation. To examine the regulation of the SAMDC gene, we analyzed the spatial expression of CSDC9 with a 5'-flanking beta-glucuronidase fusion in transgenic tobacco plants. GUS was strongly expressed in flower, pollen, stem and vein of cotyledons. Expression in both anther and stigma was under developmental control; analysis of a series of mutants with deletions of the 5'-flanking region demonstrated differential activation in petal, anther, stigma and pollen grains. All the major cis-regulatory elements required for pollen-specific transcription were located in the upstream region between -273 and -158. This region contains four putative elements related to gibberellin induction (pyrimidine boxes, TTTTTTCC and CCTTTT) and pollen-specific expression (GTGA and AGAAA). In addition, the first 5'-leader intron was necessary for tissue-specific expression.
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Adenosilmetionina Descarboxilase/genética , Dianthus/genética , Regulação Enzimológica da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Íntrons , Pólen/genética , Regiões Promotoras Genéticas , Região 5'-Flanqueadora , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , DNA de Plantas/química , DNA de Plantas/genética , DNA de Plantas/isolamento & purificação , Dianthus/anatomia & histologia , Dianthus/química , Flores/genética , Flores/crescimento & desenvolvimento , Glucuronidase/metabolismo , Dados de Sequência Molecular , Fases de Leitura Aberta , Folhas de Planta/citologia , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Plantas Geneticamente Modificadas , Plantas Tóxicas , Plasmídeos , Pólen/citologia , RNA Mensageiro/genética , Proteínas Recombinantes de Fusão/metabolismo , Deleção de Sequência , TATA Box , Nicotiana/genéticaRESUMO
The regulation of ornithine decarboxylase (ODC) expression was studied in suspension-cultured tobacco (Nicotiana tabacum L.) BY2 cells. ODC activity increased rapidly 3 h after cells re-entered the cell cycle from the stationary phase, corresponding to the G1 phase, and continued to increase in the subsequent S phase, while the ODC transcript level increased only transiently. ODC activity was suppressed by sucrose-deficiency, while the ODC transcript level was not affected. U0126, a specific inhibitor of mammalian MAPK kinases (MEKs), significantly reduced ODC enzyme activity, but not the ODC transcript level. These results suggest that ODC activity is regulated independently of its transcript level in BY2 cells, and that sucrose and a U0126-sensitive protein kinase are required for the transcript-level-independent activation of ODC.