RESUMO
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: 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
The bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA) procedure allows patients with severe aortic stenosis and anatomical challenges from aortic leaflet orientation, positioning of coronary ostia, and height of sinuses of Valsalva to undergo TAVR. We present a case of intraprocedural cardiac arrest secondary to iatrogenic left main coronary artery obstruction following a successful BASILICA procedure.
Assuntos
Estenose da Valva Aórtica , Parada Cardíaca , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Substituição da Valva Aórtica Transcateter/métodos , Estenose da Valva Aórtica/cirurgia , Parada Cardíaca/etiologia , Idoso de 80 Anos ou mais , Doença Iatrogênica/prevenção & controle , Masculino , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/prevenção & controle , Bioprótese/efeitos adversos , Feminino , Angiografia CoronáriaRESUMO
Background: Hyperthyroidism has a significant, well-established impact on the cardiovascular system on both a molecular and circulatory level. The cardiac consequences of thyrotoxicosis are not uncommon, indicated by a 1.2% prevalence of this disorder in the United States. However, our case describes the less widely observed association between thyrotoxicosis and valvulopathy. Case summary: A 69-year-old Hispanic male presented with a 3-week history of shortness of breath, intermittent chest pain, and lower extremity swelling. Transthoracic echocardiogram revealed a dilated left and right atrium with severe tricuspid regurgitation, moderate mitral regurgitation, malcoaptation of the tricuspid valve leaflets, and a myxomatous mitral valve. In addition, right ventricular systolic function was moderately reduced. A right and left heart catheterization was performed with findings of normal right heart pressures and normal coronary arteries, respectively. To further evaluate the aetiology of the patient's heart failure, thyroid studies were sent, revealing a thyroid-stimulating hormone value of <0.010â uIU/mL and a free T4 of 1.96â ng/dL. A 4.9â cm lesion was seen on thyroid ultrasound. We concluded that the patient's heart failure and notable valvular abnormalities were likely as a result of thyrotoxic heart disease. Furosemide and methimazole were initiated while inpatient, and the patient was discharged with close follow-up. Discussion: We demonstrate a unique case of the possible hemodynamic and cellular effects of thyroid hormone on the development of primary and secondary valve dysfunction. This association is important for clinicians to be aware of, as treatment of its underlying aetiology can lead to improvement in a patient's cardiac outcomes.
RESUMO
Cardiac allograft vasculopathy is a major cause of long-term graft failure following heart transplantation. Asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, has been mechanistically implicated in the development of cardiac allograft vasculopathy, but its impact on coronary physiology early after transplantation is unknown. Invasive indices of coronary physiology, namely, fractional flow reserve (FFR), the index of microcirculatory resistance, and coronary flow reserve, were measured with a coronary pressure wire in the left anterior descending artery within 8 weeks (baseline) and 1 year after transplant. Plasma levels of ADMA were concurrently assayed using high-performance liquid chromatography. In 46 heart transplant recipients, there was a statistically significant correlation between elevated ADMA levels and lower FFR values at baseline (r = -0.33; p = 0.024); this modest association persisted 1 year after transplant (r = -0.39; p = 0.0085). Patients with a baseline FFR <0.90 (a prognostically validated cutoff) had significantly higher baseline ADMA levels (0.63 ± 0.16 vs 0.54 ± 0.12 µM; p = 0.034). Baseline ADMA (odds ratio 1.80 per 0.1 µM; 95% confidence interval 1.07 to 3.03; p = 0.027) independently predicted a baseline FFR <0.90 after multivariable adjustment. Even after dichotomizing ADMA (≥0.60 µM, provides greatest diagnostic accuracy by receiver operating characteristic curve), this association remained significant (odds ratio 7.52, 95% confidence interval 1.74 to 32.49; p = 0.006). No significant relationship between ADMA and index of microcirculatory resistance or coronary flow reserve was detected. In conclusion, baseline ADMA was a strong independent predictor of FFR <0.90, suggesting that elevated ADMA levels are associated with abnormal epicardial function soon after heart transplantation.
Assuntos
Arginina/análogos & derivados , Doença da Artéria Coronariana/prevenção & controle , Vasos Coronários/fisiopatologia , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Transplante de Coração/efeitos adversos , Arginina/administração & dosagem , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Feminino , Seguimentos , Reserva Fracionada de Fluxo Miocárdico/efeitos dos fármacos , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Tempo , Resistência Vascular/efeitos dos fármacosRESUMO
Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.