Apoptosis and Acute Cellular Rejection in Human Heart Transplants

Introduction and objectivesApoptosis has been implicated in the pathophysiology of various forms of heart disease. Acute cellular rejection leads to morbidity after heart transplantation and invasive techniques are needed for its diagnosis. We investigated the presence of cardiomyocyte apoptosis in transplanted hearts, its progression, its relationship with rejection, and the possibility that serological markers of apoptosis can be used to detect rejection noninvasively.MethodsOverall, 130 endomyocardial biopsies obtained sequentially from 14 consecutive patients during the first 6 months following heart transplantation underwent histochemical analysis. The degree of acute rejection was determined, myocyte apoptosis was assessed using the TUNEL method, and caspase-3 activity was measured. In the first 10 patients, soluble Fas, tumor necrosis factor-alpha (TNFα) and interleukin 6 levels were determined in serum collected at biopsy.ResultsApoptotic cells were detected in 81.5% of biopsies. No significant correlation was found between the apoptotic index and either the degree of rejection or the time from transplantation; there was only a trend to higher values during prolonged episodes of rejection, which did not reach statistical significance. An inverse correlation was observed between the degree of rejection and the TNFα level (rs=–0.33; P=.003). There was no correlation with any other variable.ConclusionsCardiomyocyte loss due to apoptosis was observed in transplanted hearts, but no correlation was observed with either acute rejection or the time from transplantation. Our findings suggest there could be an inverse correlation between rejection and the serum TNFα level. No serum parameter evaluated was regarded as suitable for the noninvasive diagnosis of acute rejection.

Introducción y objetivosLa apoptosis se ha implicado en la fisiopatología de diversas cardiopatías. El rechazo agudo celular causa morbilidad tras el trasplante cardiaco y su diagnóstico requiere técnicas invasivas. Hemos investigado la existencia de apoptosis de cardiomiocitos en el corazón trasplantado, su evolución temporal, su relación con el rechazo y la posibilidad de diagnosticar de forma no invasiva el rechazo mediante detección de marcadores séricos de apoptosis.MétodosAnálisis histoquímico de 130 biopsias endomiocárdicas obtenidas secuencialmente de 14 pacientes consecutivos en los primeros 6 meses tras el trasplante. Se determinaron: grado de rechazo agudo, apoptosis de cardiomiocitos mediante TUNEL y actividad de caspasa 3. En los primeros 10 pacientes, se analizaron en sueros extraídos simultáneamente a las biopsias: Fas soluble, factor de necrosis tumoral alfa e interleucina 6.ResultadosSe detectaron células apoptósicas en el 81,5% de las biopsias. No encontramos correlación del índice apoptósico con el grado de rechazo ni con el tiempo desde el trasplante, sólo una tendencia a valores mayores en casos de rechazo prolongado que no alcanza la significación estadística. Observamos correlación inversa entre grado de rechazo y factor de necrosis tumoral alfa (rs = –0,33; p = 0,003). No encontramos correlación del rechazo con el resto de las variables.ConclusionesDetectamos en el corazón trasplantado pérdida de cardiomiocitos por apoptosis. No hallamos correlación con el rechazo agudo ni con el tiempo desde el trasplante. Nuestros datos indican que podría haber correlación inversa entre rechazo y factor de necrosis tumoral alfa en suero. Consideramos que ninguno de los parámetros séricos valorados es óptimo para diagnóstico no invasivo de rechazo.