RESUMO
There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence.
Assuntos
Antivirais/uso terapêutico , Sangue/virologia , Transplante de Coração , Imunossupressores/uso terapêutico , Transplante de Pulmão , Vírus/isolamento & purificação , Adulto , Antibioticoprofilaxia , Sangue/microbiologia , Criança , DNA/sangue , DNA/genética , Humanos , Vírus/classificaçãoRESUMO
BACKGROUND: Left ventricular dysfunction in potential donors meeting brain death criteria often results in nonuse of donor hearts for transplantation, yet little is known about its incidence or pathophysiology. Resolving these unknowns was a primary aim of the DHS (Donor Heart Study), a multisite prospective cohort study. METHODS: The DHS enrolled potential donors by neurologic determination of death (n=4333) at 8 organ procurement organizations across the United States between February 2015 and May 2020. Data included medications administered, serial diagnostic tests, and transthoracic echocardiograms (TTEs) performed: (1) within 48 hours after brain death was formally diagnosed; and (2) 24±6 hours later if left ventricular (LV) dysfunction was initially present. LV dysfunction was defined as an LV ejection fraction <50% and was considered reversible if LV ejection fraction was >50% on the second TTE. TTEs were also examined for presence of LV regional wall motion abnormalities and their reversibility. We assessed associations between LV dysfunction, donor heart acceptance for transplantation, and recipient 1-year survival. RESULTS: An initial TTE was interpreted for 3794 of the 4333 potential donors by neurologic determination of death. A total of 493 (13%) of these TTEs showed LV dysfunction. Among those donors with an initial TTE, LV dysfunction was associated with younger age, underweight, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and troponin levels. A second TTE was performed within 24±6 hours for a subset of donors (n=224) with initial LV dysfunction; within this subset, 130 (58%) demonstrated reversibility. Sixty percent of donor hearts with normal LV function were accepted for transplant compared with 56% of hearts with reversible LV dysfunction and 24% of hearts with nonreversible LV dysfunction. Donor LV dysfunction, whether reversible or not, was not associated with recipient 1-year survival. CONCLUSIONS: LV dysfunction associated with brain death occurs in many potential heart donors and is sometimes reversible. These findings can inform decisions made during donor evaluation and help guide donor heart acceptance for transplantation.
Assuntos
Transplante de Coração , Disfunção Ventricular Esquerda , Humanos , Doadores de Tecidos , Transplante de Coração/métodos , Estudos Prospectivos , Morte Encefálica , Função Ventricular EsquerdaRESUMO
Cardiac allograft vasculopathy (CAV) is a leading cause of death after heart transplantation (HT). We evaluated donor-derived cell-free DNA (dd-cfDNA) as a noninvasive biomarker of CAV development after HT. The INSPIRE registry at the Intermountain Medical Center was queried for stored plasma samples from HT patients with and without CAV. At Stanford University, HT patients with CAV (cases) and without CAV (controls) were enrolled prospectively, and blood samples were collected. All the samples were analyzed for dd-cfDNA using the AlloSure assay (CareDx, Inc.). CAV was defined per the ISHLT 2010 standardized classification system. Univariate associations between patient demographics and clinical characteristics and their CAV grade were tested using chi-square and Wilcoxon rank sum tests. Associations between their dd-cfDNA levels and CAV grades were examined using a nonparametric Kruskal-Wallis test. A total of 69 pts were included, and 101 samples were analyzed for dd-cfDNA. The mean age at sample collection was 58.6 ± 13.7 years; 66.7% of the patients were male, and 81% were White. CAV 0, 1, 2, and 3 were present in 37.6%, 22.8%, 22.8%, and 16.8% of included samples, respectively. The median dd-cfDNA level was 0.13% (0.06, 0.33). The median dd-cfDNA level was not significantly different between CAV (-) and CAV (+): 0.09% (0.05%-0.32%) and 0.15% (0.07%-0.33%), respectively, p = 0.25 and with similar results across all CAV grades. In our study, dd-cfDNA levels did not correlate with the presence of CAV and did not differ across CAV grades. As such, dd-cfDNA does not appear to be a reliable noninvasive biomarker for CAV surveillance.
Assuntos
Biomarcadores , Ácidos Nucleicos Livres , Transplante de Coração , Doadores de Tecidos , Humanos , Masculino , Feminino , Transplante de Coração/efeitos adversos , Ácidos Nucleicos Livres/sangue , Pessoa de Meia-Idade , Seguimentos , Estudos Prospectivos , Biomarcadores/sangue , Prognóstico , Fatores de Risco , Aloenxertos , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Estudos de Casos e Controles , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/sangue , Sobrevivência de Enxerto , Doenças Vasculares/etiologia , Doenças Vasculares/sangue , AdultoRESUMO
The development of donor-specific antibodies after lung transplantation is associated with downstream acute cellular rejection, antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), or death. It is unknown whether preemptive (early) treatment of de novo donor-specific antibodies (dnDSAs), in the absence of clinical signs and symptoms of allograft dysfunction, reduces the risk of subsequent CLAD or death. We performed a multicenter, retrospective cohort study to determine if early treatment of dnDSAs in lung transplant patients reduces the risk of the composite endpoint of CLAD or death. In the cohort of 445 patients, 145 patients developed dnDSAs posttransplant. Thirty patients received early targeted treatment for dnDSAs in the absence of clinical signs and symptoms of AMR. Early treatment of dnDSAs was associated with a decreased risk of CLAD or death (hazard ratio, 0.36; 95% confidence interval, 0.17-0.76; P < .01). Deferring treatment until the development of clinical AMR was associated with an increased risk of CLAD or death (hazard ratio, 3.00; 95% confidence interval, 1.46-6.18; P < .01). This study suggests that early, preemptive treatment of donor-specific antibodies in lung transplant patients may reduce the subsequent risk of CLAD or death.
Assuntos
Transplante de Pulmão , Pulmão , Humanos , Estudos Retrospectivos , Anticorpos , Transplante de Pulmão/efeitos adversos , Aloenxertos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/diagnósticoRESUMO
BACKGROUND: Donor-derived cell free DNA (dd-cfDNA) and gene expression profiling (GEP) offer noninvasive alternatives to rejection surveillance after heart transplantation; however, there is little evidence on the paired use of GEP and dd-cfDNA for rejection surveillance. METHODS: A single center, retrospective analysis of adult heart transplant recipients. A GEP cohort, transplanted from January 1, 2015 through December 31, 2017 and eligible for rejection surveillance with GEP was compared to a paired testing cohort, transplanted July 1, 2018 through June 30, 2020, with surveillance from both dd-cfDNA and GEP. The primary outcomes were survival and rejection-free survival at 1 year post-transplant. RESULTS: In total 159 patients were included, 95 in the GEP and 64 in the paired testing group. There were no differences in baseline characteristics, except for less use of induction in the paired testing group (65.6%) compared to the GEP group (98.9%), P < .01. At 1-year, there were no differences between the paired testing and GEP groups in survival (98.4% vs. 94.7%, P = .23) or rejection-free survival (81.3% vs. 73.7% P = .28). CONCLUSIONS: Compared to post-transplant rejection surveillance with GEP alone, pairing dd-cfDNA and GEP testing was associated with similar survival and rejection-free survival at 1 year while requiring significantly fewer biopsies.
Assuntos
Ácidos Nucleicos Livres , Transplante de Coração , Adulto , Humanos , Estudos Retrospectivos , Ácidos Nucleicos Livres/genética , Transplante de Coração/efeitos adversos , Perfilação da Expressão Gênica , Doadores de TecidosRESUMO
Solid organ transplantation continues to be constrained by a lack of suitable donor organs. Advances in donor management and evaluation are needed to address this shortage, but the performance of research studies in deceased donors is fraught with challenges. Here we discuss several of the major obstacles we faced in the conduct of the Donor Heart Study-a prospective, multi-site, observational study of donor management, evaluation, and acceptance for heart transplantation. These included recruitment and engagement of participating organ procurement organizations, ambiguities related to study oversight, obtaining authorization for donor research, logistical challenges encountered during donor management, sustaining study momentum, and challenges related to study data management. By highlighting these obstacles encountered, as well as the solutions implemented, we hope to stimulate further discussion and actions that will facilitate the design and execution of future donor research studies.
Assuntos
Transplante de Coração , Transplante de Órgãos , Obtenção de Tecidos e Órgãos , Humanos , Estudos Prospectivos , Doadores de TecidosRESUMO
Plasma donor-derived cell-free DNA (dd-cfDNA) is a sensitive biomarker for the diagnosis of acute rejection in lung transplant recipients; however, differences in dd-cfDNA levels between single and double lung transplant remains unknown. We performed an observational analysis that included 221 patients from two prospective cohort studies who had serial measurements of plasma dd-cfDNA at the time of bronchoscopy and pulmonary function testing, and compared dd-cfDNA between single and double lung transplant recipients across a range of disease states. Levels of dd-cfDNA were lower for single vs. double lung transplant in stable controls (median [IQR]: 0.15% [0.07, 0.44] vs. 0.46% [0.23, 0.74], p < .01) and acute rejection (1.06% [0.75, 2.32] vs. 1.78% [1.18, 5.73], p = .05). Doubling dd-cfDNA for single lung transplant to account for differences in lung mass eliminated this difference. The area under the receiver operating curve (AUC) for the detection of acute rejection was 0.89 and 0.86 for single and double lung transplant, respectively. The optimal dd-cfDNA threshold for the detection of acute rejection was 0.54% in single lung and 1.1% in double lung transplant. In conclusion, accounting for differences in dd-cfDNA in single versus double lung transplant is key for the interpretation of dd-cfDNA testing in research and clinical settings.
Assuntos
Ácidos Nucleicos Livres , Biomarcadores , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Humanos , Pulmão , Estudos Prospectivos , Doadores de Tecidos , TransplantadosRESUMO
AIMS: We evaluated the long-term prognostic value of invasively assessing coronary physiology after heart transplantation in a large multicentre registry. METHODS AND RESULTS: Comprehensive intracoronary physiology assessment measuring fractional flow reserve (FFR), the index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) was performed in 254 patients at baseline (a median of 7.2 weeks) and in 240 patients at 1 year after transplantation (199 patients had both baseline and 1-year measurement). Patients were classified into those with normal physiology, reduced FFR (FFR ≤ 0.80), and microvascular dysfunction (either IMR ≥ 25 or CFR ≤ 2.0 with FFR > 0.80). The primary outcome was the composite of death or re-transplantation at 10 years. At baseline, 5.5% had reduced FFR; 36.6% had microvascular dysfunction. Baseline reduced FFR [adjusted hazard ratio (aHR) 2.33, 95% confidence interval (CI) 0.88-6.15; P = 0.088] and microvascular dysfunction (aHR 0.88, 95% CI 0.44-1.79; P = 0.73) were not predictors of death and re-transplantation at 10 years. At 1 year, 5.0% had reduced FFR; 23.8% had microvascular dysfunction. One-year reduced FFR (aHR 2.98, 95% CI 1.13-7.87; P = 0.028) and microvascular dysfunction (aHR 2.33, 95% CI 1.19-4.59; P = 0.015) were associated with significantly increased risk of death or re-transplantation at 10 years. Invasive measures of coronary physiology improved the prognostic performance of clinical variables (χ2 improvement: 7.41, P = 0.006). However, intravascular ultrasound-derived changes in maximal intimal thickness were not predictive of outcomes. CONCLUSION: Abnormal coronary physiology 1 year after heart transplantation was common and was a significant predictor of death or re-transplantation at 10 years.
Assuntos
Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Transplante de Coração , Cateterismo Cardíaco , Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgia , Humanos , Microcirculação , Valor Preditivo dos Testes , PrognósticoRESUMO
BACKGROUND: The safety and efficacy of angiotensin converting enzyme inhibition (ACEI) after heart transplantation (HT) is unknown. This study examined long-term clinical outcomes after ACEI in HT recipients. METHODS: The ACEI after HT study was a prospective, randomized trial that tested the efficacy of ACEI with ramipril after HT. In this study, long-term clinical outcomes were assessed in 91 patients randomized to either ramipril or placebo (median, 5.8 years). The primary endpoint was a composite of death, retransplantation, hospitalization for rejection or heart failure, and coronary revascularization. RESULTS: The primary endpoint occurred in 10 of 45 patients (22.2%) in the ramipril group and in 14 of 46 patients (30.4%) in the placebo group (Hazard ratio (HR), 0.68; 95% CI, 0.29-1.51; Pâ¯=â¯.34). When the analysis was restricted to comparing patients who remained on a renin-angiotensin system inhibitor beyond 1 year with those who did not, there was a trend to improved outcomes (HR, 0.54; 95% CI, 0.22-1.28, Pâ¯=â¯.16). There was no significant difference in creatinine, blood urea nitrogen, and potassium at 3 years after randomization. The cumulative incidence of the primary endpoint was significantly higher in patients in whom the index of microcirculatory resistance increased from baseline to 1 year compared with those in whom it did not (39.1 vs 17.4%, HR: 3.36; 95% CI, 1.07-12.7; Pâ¯=â¯.037). CONCLUSION: The use of ramipril after HT safely lowers blood pressure and is associated with favorable long-term clinical outcomes. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT01078363.
Assuntos
Rejeição de Enxerto/prevenção & controle , Insuficiência Cardíaca/cirurgia , Transplante de Coração/efeitos adversos , Ramipril/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Seguimentos , Rejeição de Enxerto/fisiopatologia , Humanos , Masculino , Microcirculação/efeitos dos fármacos , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans. METHODS AND RESULTS: In 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; Pâ¯=â¯.007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; Pâ¯=â¯.01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; Pâ¯=â¯.003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; Pâ¯=â¯.44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (Pâ¯=â¯.047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; Pâ¯=â¯.02). CONCLUSIONS: Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.
Assuntos
Doença das Coronárias/sangue , Vasos Coronários/diagnóstico por imagem , Endotelina-1/sangue , Transplante de Coração/efeitos adversos , Complicações Pós-Operatórias/sangue , Aloenxertos , Biomarcadores/sangue , California/epidemiologia , Angiografia Coronária , Doença das Coronárias/diagnóstico , Doença das Coronárias/etiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/cirurgia , Transplante de Coração/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Curva ROC , Fatores de Risco , Taxa de Sobrevida/tendências , Ultrassonografia de IntervençãoRESUMO
The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.
Assuntos
DNA Viral/sangue , Rejeição de Enxerto/diagnóstico , Transplante de Pulmão/efeitos adversos , Cuidados Pós-Operatórios/métodos , Infecção da Ferida Cirúrgica/diagnóstico , Sequência de Bases , Citomegalovirus/genética , Humanos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Especificidade da Espécie , Infecção da Ferida Cirúrgica/virologiaRESUMO
BACKGROUND: The aim of this study is to determine the prognostic value of invasively assessing coronary physiology early after heart transplantation. METHODS AND RESULTS: Seventy-four cardiac transplant recipients had fractional flow reserve, coronary flow reserve, index of microcirculatory resistance (IMR), and intravascular ultrasound performed down the left anterior descending coronary artery soon after (baseline) and 1 year after heart transplantation. The primary end point was the cumulative survival free of death or retransplantation at a mean follow-up of 4.5±3.5 years. The cumulative event-free survival was significantly lower in patients with a fractional flow reserve <0.90 at baseline (42% versus 79%; P=0.01) or an IMR ≥20 measured 1 year after heart transplantation (39% versus 69%; P=0.03). Patients in whom IMR decreased or did not change from baseline to 1 year had higher event-free survival compared with patients with an increase in IMR (66% versus 36%; P=0.03). Fractional flow reserve <0.90 at baseline (hazard ratio, 0.13; 95% confidence interval, 0.02-0.81; P=0.03), IMR ≥20 at 1 year (hazard ratio, 3.93; 95% confidence interval, 1.08-14.27; P=0.04), and rejection during the first year (hazard ratio, 6.00; 95% confidence interval, 1.56-23.09; P=0.009) were independent predictors of death/retransplantation, whereas intravascular ultrasound parameters were not. CONCLUSIONS: Invasive measures of coronary physiology (fractional flow reserve and IMR) determined early after heart transplantation are significant predictors of late death or retransplantation.
Assuntos
Circulação Coronária/fisiologia , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Transplante de Coração/mortalidade , Microcirculação/fisiologia , Adulto , Feminino , Seguimentos , Transplante de Coração/tendências , Humanos , Masculino , Microvasos/fisiologia , Pessoa de Meia-Idade , Mortalidade/tendências , Valor Preditivo dos Testes , Estudos ProspectivosRESUMO
BACKGROUND: It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation. METHODS AND FINDINGS: In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient's net state of immunosuppression (correlation with tacrolimus level, r = -0.867, 95% CI -0.968 to -0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the availability of a large number of samples and the absence or presence of rejection events. CONCLUSIONS: If confirmed in larger, prospective studies, the method described here has potential applications in the tailored management of post-transplant immunosuppression and, more broadly, as a method for assessing the overall activity of the immune system.
Assuntos
Linfócitos B/imunologia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Transplante de Coração , Terapia de Imunossupressão/métodos , Imunossupressores/farmacologia , Monitorização Imunológica/métodos , Aloenxertos , Feminino , Humanos , Masculino , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
Many children who undergo heart transplantation will survive into adulthood. We sought to examine the QOL and capacity for achievement in long-term adult survivors of pediatric heart transplantation. Adults >18 yr of age who received transplants as children (≤18 yr old) and had survived for at least 10 yr post-transplant completed two self-report questionnaires: (i) Ferrans & Powers QLI, in which life satisfaction is reported as an overall score and in four subscale domains and is then indexed from 0 (very dissatisfied) to 1 (very satisfied); and (ii) a "Metrics of Life Achievement" questionnaire regarding income, education, relationships, housing status, and access to health care. A total of 20 subjects completed the survey. The overall mean QLI score was 0.77 ± 0.16. Subjects were most satisfied in the family domain (0.84 ± 0.21) and least satisfied in the psychological/spiritual domain (0.7 ± 0.28). Satisfaction in the domains of health/functioning and socioeconomic were intermediate at 0.78 and 0.76, respectively. Most respondents had graduated from high school, reported a median annual income >$50 000/yr, and lived independently. Adult survivors of pediatric heart transplant report a good QOL and demonstrate the ability to obtain an education, work, and live independently.
Assuntos
Logro , Transplante de Coração , Qualidade de Vida , Sobreviventes , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: Patients of advanced age are often considered to be poor candidates for heart transplant (HT). As the U.S. population continues to age, it is important for clinicians to understand how best to select patients for advanced therapies. METHODS: This was a retrospective analysis of the U.S. Scientific Registry of Transplant Recipients data from 2006 to August 2022 in adult recipients. Patients were excluded if they were multiorgan transplant, re-do transplants, or less than 1 year post transplant. RESULTS: Recipients ≥70 had a 1-year survival of 87.5%, compared to 91.1% for <60%, and 88.4% for 60-69 years (p < 0.001). Survival improved numerically, but not significantly, as transplant eras progressed for those ≥70 years. Survival by Kaplan-Meier analysis was greatest at 5 years for <60 years (80.6%), compared to 60-69 years (78.2%) and ≥70 years (77.1%). When comparing 60-69 years to ≥70 years by this same metric, there was significant difference (p = 0.12). One year survival for those ≥70 years has improved from 2000-2009 (80.7%) to 88.5% since October 2018 (p < 0.001). As recipients increased in age, they were more likely to be male, and less likely to be Black or Hispanic/Latino (p < 0.001). CONCLUSION: Overall, HT outcomes are excellent for carefully selected patients ≥70 years, and transplanting patients in this age cohort can be considered.
RESUMO
BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the leading cause of long-term graft failure and mortality after heart transplantation. Effective preventive and treatment options are not available to date, largely because underlying mechanisms remain poorly understood. We studied the potential role of leukotriene B4 (LTB4), an inflammatory lipid mediator, in the development of CAV. METHODS: We used an established preclinical rat CAV model to study the role of LTB4 in CAV. We performed syngeneic and allogeneic orthotopic aortic transplantation, after which neointimal proliferation was quantified. Animals were then treated with Bestatin, an inhibitor of LTB4 synthesis, or vehicle control for 30 days post-transplant, and evidence of graft CAV was determined by histology. We also measured serial LTB4 levels in a cohort of 28 human heart transplant recipients with CAV, 17 matched transplant controls without CAV, and 20 healthy nontransplant controls. RESULTS: We showed that infiltration of the arterial wall with macrophages leads to neointimal thickening and a rise in serum LTB4 levels in our rat model of CAV. Inhibition of LTB4 production with the drug Bestatin prevents development of neointimal hyperplasia, suggesting that Bestatin may be effective therapy for CAV prevention. In a parallel study of heart transplant recipients, we found nonsignificantly elevated plasma LTB4 levels in patients with CAV, compared to patients without CAV and healthy, nontransplant controls. CONCLUSIONS: This study provides key evidence supporting the role of the inflammatory cytokine LTB4 as an important mediator of CAV development and provides preliminary data suggesting the clinical benefit of Bestatin for CAV prevention.
Assuntos
Biomarcadores , Transplante de Coração , Leucotrieno B4 , Animais , Transplante de Coração/efeitos adversos , Leucotrieno B4/sangue , Leucotrieno B4/metabolismo , Ratos , Masculino , Biomarcadores/metabolismo , Biomarcadores/sangue , Humanos , Modelos Animais de Doenças , Aloenxertos , Pessoa de Meia-Idade , Ratos Endogâmicos Lew , Feminino , Neointima/patologiaRESUMO
Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HT). We sought to determine the association between pretransplant human leukocyte antigen (HLA) sensitization, as measured using the calculated panel reactive antibody (cPRA) value, and the risk of PGD. METHODS: Consecutive adult HT recipients (n = 596) from 1/2015 to 12/2019 at 2 US centers were included. Severity of PGD was based on the 2014 International Society for Heart and Lung Transplantation consensus statement. For each recipient, unacceptable HLA antigens were obtained and locus-specific cPRA (cPRA-LS) and pre-HT donor-specific antibodies (DSA) were assessed. RESULTS: Univariable logistic modeling showed that peak cPRA-LS for all loci and HLA-A was associated with increased severity of PGD as an ordinal variable (all loci: OR 1.78, 95% CI: 1.01-1.14, p = 0.025, HLA-A: OR 1.14, 95% CI: 1.03-1.26, p = 0.011). Multivariable analysis showed peak cPRA-LS for HLA-A, recipient beta-blocker use, total ischemic time, donor age, prior cardiac surgery, and United Network for Organ Sharing status 1 or 2 were associated with increased severity of PGD. The presence of DSA to HLA-B was associated with trend toward increased risk of mild-to-moderate PGD (OR 2.56, 95% CI: 0.99-6.63, p = 0.053), but DSA to other HLA loci was not associated with PGD. CONCLUSIONS: Sensitization for all HLA loci, and specifically HLA-A, is associated with an increased severity of PGD. These factors should be included in pre-HT risk stratification to minimize the risk of PGD.
Assuntos
Transplante de Coração , Disfunção Primária do Enxerto , Adulto , Humanos , Disfunção Primária do Enxerto/epidemiologia , Disfunção Primária do Enxerto/etiologia , Transplante de Coração/efeitos adversos , Antígenos HLA , Doadores de Tecidos , Anticorpos , Antígenos HLA-A , Estudos RetrospectivosRESUMO
BACKGROUND: Despite a shortage of potential donors for heart transplant in the United States, most potential donor hearts are discarded. We evaluated predictors of donor heart acceptance in the United States and applied machine learning methods to improve prediction. METHODS: We included a nationwide (2005-2020) cohort of potential heart donors in the United States (n=73â 948) from the Scientific Registry of Transplant Recipients and a more recent (2015-2020) rigorously phenotyped cohort of potential donors from DHS (Donor Heart Study; n=4130). We identified predictors of acceptance for heart transplant in both cohorts using multivariate logistic regression, incorporating time-interaction terms to characterize their varying effects over time. We fit models predicting acceptance for transplant in a 50% training subset of DHS using logistic regression, least absolute shrinkage and selection operator, and random forest algorithms and compared their performance in the remaining 50% (test) of the subset. RESULTS: Predictors of donor heart acceptance were similar in the nationwide and DHS cohorts. Among these, older age (P value for time interaction, 0.0001) has become increasingly predictive of discard over time while other factors, including those related to drug use, infection, and mild cardiac diagnostic abnormalities, have become less influential (P value for time interaction, <0.05 for all). A random forest model (area under the curve, 0.908; accuracy, 0.831) outperformed other prediction algorithms in the test subset and was used as the basis of a novel web-based prediction tool. CONCLUSIONS: Predictors of donor heart acceptance for transplantation have changed significantly over the last 2 decades, likely reflecting evolving evidence regarding their impact on posttransplant outcomes. Real-time prediction of donor heart acceptance, using our web-based tool, may improve efficiency during donor management and heart allocation.
Assuntos
Transplante de Coração , Doadores de Tecidos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doadores de Tecidos/provisão & distribuição , Adulto , Estados Unidos , Sistema de Registros , Aprendizado de Máquina , Seleção do Doador , Fatores de TempoRESUMO
Background: A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level. Methods: This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart. Results: BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; Pâ =â 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; Pâ =â 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; Pâ =â 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log10(donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: -0.0095 [0.0007] versus -0.0109 [0.0007]; Pâ =â 0.15). Conclusions: BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology.
RESUMO
The use of 50+ year-old donors for heart transplant (HT) is rare in the United States. We assessed reasons for this-and whether it reflects concern about age itself or associated risk factors-using a survey of US HT centers. The Donor Heart Study enrolled US adult potential heart donors from 2015 to 2020. A total of 6,814 surveys across 2,197 donors cited, on average, 2.4 reasons (per donor) for offer refusal. Age was cited often (by ≥50% of centers surveyed) for 715 donors (33%). In this subgroup, accompanying donor-related reasons for refusal were infrequent, with no cardiac abnormality cited in most cases. Donor age showed associations with (1) age as a reason for refusal and (2) discard. Both abruptly increased at age 50: 55% of 50 to 51-year-old donors were refused often due to age (vs 38% of 48-49-year-olds), and 72% were discarded (vs 55% of 48-49-year-olds), despite no evidence of a threshold effect of age on outcomes.