In the present study, we showed that the plasma levels of CRP, IL-6 and TNF-α were significantly increased in acute TAAD patients (before T6) compared to those in uncontrolled hypertension and healthy volunteers. The expression levels of these inflammatory cytokines peaked at the acute phase of TAAD and gradually declined at different stages of TAAD progression. More importantly, the time-dependent changes of CRP level, particularly the CRP pattern provided more information in terms of prediction of TAAD-related inflammatory complications. Our data strongly suggested a critical role of inflammatory responses in the development of TAAD and resultant systemic complications.
CRP, a circulating and nonspecific inflammatory biomarker, has been shown to be elevated and varied with different stages of aortic dissection [7,11-13]. Peak plasma level of CRP at admission is regarded as a predictor of adverse short- and long-term events in patients with TAAD . Consistent with previous studies, we demonstrated a time-dependent change of CRP, which peaked in patients admitted on the 4th day (T5) after symptoms onset and declined thereafter. Secondly, because CRP is a non-specific inflammatory marker, it reflects not only the TAAD itself but also systemic inflammatory responses, leadig to pulmonary or renal injury [14,15]. More importantly, in the complication group, the time to peak CRP was earlier and the duration of peak CRP was longer than in the complication-free group. These findings indicated a contributory role of inflammation in the progression of dissection, and further suggested that TAAD patients with persistently high CRP levels during the first 7 days from symptoms onset might be of great risk for major adverse events.
Significant elevation of IL-6 and TNF-α levels were also detected in patients admitted at the acute phase of TAAD (before T7) when compared with other 2 control groups. However, in patients with chronic TAAD (T7-T9), no significant difference between the chronic TAAD subgroup and the uHT group was observed. In addition, the changing patterns of these two inflammatory cytokines were slightly different. Nevertheless, the plasma levels of IL-6 and TNF-α both peaked during the 12 hrs to 24 hrs period, which was much earlier than CRP. Current evidence demonstrated a significant infiltration of macrophages and neutrophils in the dissected aortic wall . These recruited leukocytes could release a series of pro-inflammatory cytokines, which would further accelerate the progression of dissection and lead to systemic complications. Since CRP is produced mainly in liver by the stimulation of many inflammatory cytokines , it is understandable that the plasma levels of leukocytes-derived cytokines like IL-6.and TNF-α peaked earlier than CRP.
In the current study, the average values of CRP, IL-6 and TNF-α in patients with chronic TAAD and hypertension tended to be higher than those in the healthy controls (Chronic TAAD vs. Healthy, P = 0.06; uHT vs. Healthy, P = 0.09). As the mechanism of TAAD remained large unknown , our findings accordingly confirmed that inflammation was closely involved into the pathogenesis of hypertension-induced aortic wall injury and the development of aortic dissection. Thus it is also important to follow up the plasma levels of inflammatory cytokines in patients with uncontrolled hypertension. If these biomarkers do not decrease after stringent control of blood pressure, there could be a potential risk of aneurysmal dilatation of the aorta that might lead to future dissection, and therefore, additional anti-inflammatory medications like statins for such patients might be a reasonable choice.
There are several limitations in the present study. Firstly, because of the absence of serial blood samples spanning the first few hours period of TAAD progression, it is difficult for us to fully elucidate the changing patterns of CRP, IL-6.and TNF-α and their clinical values for diagnosis and prophylactic treatment of complications. Secondly, in order to avoid significant influences of several known drugs on the expression levels of inflammatory biomarkers, we recruited TAAD patients without optimal medical management. However, the rationality of the inclusion criteria remains to be fully discussed. Nevertheless, to the best of our knowledge, the present study firstly provided information on the changes of the inflammatory biomarkers, which were less affected by anti-hypertensive and anti-inflammatory medications. In addition, we observed such a surprisingly high percentage of inappropriately treated patients from rural areas (78/92, 84.7%), indicating the urgent necessity and importance of the primary prevention for hypertension-related disease in the rural areas of China. Although this study was strengthened by its prospective design, the patient population is relatively small, and we cannot exclude the possibility that other confounders such as genetic factors (Marfan syndrome etc.), smoking, diabetes and use of β-blockers and missed medication history may have influenced our results.