Moléculas inflamatorias y marcadores de lesión endotelial en la isquemia cerebral: participación en el deterioro neurológico y la transformación hemorrágica

Los mecanismos implicados en el deterioro neurologico precoz (DNP) y en la transformacion hemorragica (TH) de la lesion isquemica cerebral no se conocen con exactitud. Estudios previos habian demostrado la asociacion de niveles elevados de TNF-a e IL-6 con el DNP en pacientes con isquemia cerebral independientemente del mecanismo ictal. Sin embargo, los mecanismos relacionados con el DNP en pacientes con infarto lacunar no se conocian con exactitud. Con el objetivo de determinar si los mecanismos inflamatorios participaban en la progresion y el pronostico funcional de estos pacientes se determinaron los niveles de TNF-a, IL-6 e ICAM-1 en el momento del ingreso en 113 pacientes con ictus lacunar de 14 pg/mL y de ICAM-1 > 208 pg/mL se asociaban de manera independiente tanto con el DNP como con el mal pronostico funcional evaluado a los 3 meses. En cuanto a la TH, se habia demostrado la asociacion de niveles elevados de MMP-9 y la aparicion de TH exclusivamente en pacientes con ictus de mecanismo cardioembolico por lo que se analizaron los niveles de esta molecula en 250 pacientes con ictus hemisferico de < 24 horas de evolucion con el objetivo de conocer la capacidad predictora de TH de esta molecula independientemente del mecanismo ictal. Los pacientes con TH presentaron niveles significativamente mas elevados de MMP-9. La regresion logistica demostro que niveles de MMP-9 = 140 ng/mL se asociaban de manera independiente con la aparicion de TH y predijeron la aparicion de sangrado con una sensibilidad del 87%, especificidad del 90%, valor predictivo positivo (VPP) del 61% y valor predictivo negativo (VPN) del 97%. Finalmente, se estudio la asociacion de los niveles de Fibronectina-celular (Fn-c) como molecula marcadora de dano endotelial y la aparicion de TH en 87 pacientes con ictus isquemico tratados con rt-PA. Tambien se analizaron los niveles de MMP-9 con el objetivo de comparar la capacidad predictora de ambas moleculas. Los niveles de Fn-c y MMP-9 previos a la administracion de rt-PA fueron significativamente mayores en pacientes con TH. Los niveles de Fn-c fueron ademas mas elevados en pacientes con TH sintomatica mientras que los niveles de MMP-9 fueron similares en pacientes con TH sintomatica y asintomatica. En el analisis de regresion, la Fn-c fue la unica variable asociada con la aparicion de TH independientemente de otros factores que aumentan el riesgo de TH en pacientes que reciben rt-PA. Niveles de Fn-c = 3.6 µg/mL predijeron la aparicion de infarto hemorragico tipo 2 y hemorragia parenquimatosa (tipos de TH cuya frecuencia aumenta por la administracion de rt-PA) con una sensibilidad del 100%, especificidad del 96%, VPP del 44% y VPN del 100%, mientras que los valores de los niveles de MMP-9 para los mismos tipos de TH fueron menores (81%, 88%, 41% y 98%, respectivamente). Los resultados de este estudio se demostraron en pacientes tratados tanto en las 6 como en las 3 primeras de evolucion. En conclusion, los resultados demuestran que la inflamacion participa en la progresion de pacientes con infarto lacunar y confirman que las concentraciones elevadas de MMP-9 son un factor predictor independiente de TH en pacientes con ictus isquemico agudo. Ademas, las concentraciones elevadas de Fn-c se asocian de manera independiente con la aparicion de TH en pacientes tratados con rt-PA con lo que la determinacion de Fn-c podria ser util en la clinica practica para mejorar el ratio riesgo/beneficio de la administracion de tratamiento trombolitico. The mechanisms related to early neurological deterioration (END) and hemorrhagic transformation (HT) in patients with acute cerebral ischemia are not completely understood. Previous studies have demostrated the association between high levels of TNF-a and IL-6 and END in patients with acute cerebral ischemia independently of the ischemic stroke mechanism. However, the mechanisms underlying neurological deterioration in patients with lacunar infarction have not been clearly established. The role of proinflammatory molecules (TNF-a, IL-6 and ICAM-1) in the early worsening and outcome of 113 consecutive patients with lacunar infarction within the first 24 hours of the onset of symptoms was investigated. Those patients with END as well as poor outcome had significantly higher levels at admission of the analyzed molecules. Logistic regression analysis showed that TNF-alfa > 14 pg/mL and ICAM-1 > 208 pg/mL were independently associated with both END and poor outcome at 3 months. On the other hand, the association between high levels of matrix metaloproteinase-9 (MMP-9) and secondary bleeding in patients with cardiembolic ischemic stroke had been already published. However, there were no data about the HT predictive capacity of MMP-9 in patients with other stroke subtypes. The association between high levels of MMP-9 and the development of HT was determined in 250 patients with hemispheric ischemic stroke within the first 24 hours of symptoms onset. The results demonstrated that those patients with HT had significantly higher levels of MMP-9 at admission compared to those without secondary bleeding. Logistic regression analysis showed that MMP-9 levels = 140 ng/mL were independently associated with HT after adjustment for potential confounders. Moreover, MMP-9 levels = 140 ng/mL predicted the development of HT with a sensitivity, especificity, negative predictive value (NPV) and positive predictive value (PPV) of 87%, 90%, 61% and 97%, respectively. Finally, the association between the levels of cellular-Fibronectin (c-Fn), taken as a more specific marker of endothelial damage, and the development of HT in 87 patients who received thrombolytic treatment with rt-PA was evaluated. In order to compare the predictive capacity of MMP-9 and c-Fn levels, the levels of MMP-9 were also analyzed in this group of patients. The results demonstrated that patients with HT had significantly higher c-Fn as well as MMP-9 levels before the administration of the treatment. The levels of c-Fn were also higher in patients with symptomatic HT whereas no differences were found in MMP-9 levels between symptomatic and asymptomatic HT. Logistic regression analysis showed that c-Fn levels was the only variable associated with HT development after adjustment of potential confounders, which included MMP-9 levels. Levels of c-Fn = 3.6 µg/mL predicted the development of hemorrhagic infarction type 2 and parenchymal hemorrhage (types of HT that has been reported to occur more often in patients treated with rt-PA) with a sensitivity of 100%, specificity of 96%, NPV of 44% and PPV of 100%, whereas the sensitivity, specificity, NPV and PPV of MMP-9 levels = 140 ng/mL were 81%, 88%, 41% and 98%, respectively. These results were observed both in patients treated within 6 hours and within 3 hours from symptoms onset. In conclusion, the results suggest that inflammation contributes to brain injury in patients with lacunar stroke and confirm that high plasma MMP-9 concentration is an independent predictor of HT in patients with acute ischemic stroke. Moreover, high plasma c-Fn levels are significantly associated with subsequent HT in stroke patients treated with rt-PA, so plasma c-Fn determinations might be useful in clinical practice to improve the risk/benefit ratio of thrombolytic treatment.