In this study, the incidence of AF in patients with AIS was 16.8%, which was in accordance with the incidence of 16.9% reported by Mehrpour et al [7]. The total rate of poor outcomes was 75.3%, including 22.5% of deaths; there was no significant difference between the two groups. The high morbidity and mortality of AF-AIS were consistent with other reports: Mehrpour et al. [7] studied 118 Iranian AIS received IV rt-PA (24 with AF, 94 no AF), the poor outcome of AF patients was significantly higher than that of non-AF patients (79.2% vs. 41.5%, P = 0.001) at 3 months. Findler et al. [6] studied 214 AIS patients who received IV rt-PA (63 with AF, 151 no AF) from 27 Israeli hospital, more patients had favorable outcome in non-AF group than in AF group (P = 0.058, OR = 2.217, 95% CI: 0.973 - 5.05). Alkhouli et al. [13] investigated a total of 930,010 AIS patients between 2003 and 2014 in the National Inpatient Samplein the United States, found that 18.2% of these patients had AF, the mortality rate was higher in patients with AF compared with patients without AF (9.9% vs. 6.1%; P < 0.001). Above results suggest that AF is a risk factor for poor outcome of AIS, and IV rt-PA could not improve the prognosis of AF-AIS.
Our data analysis also shown no significant difference in the outcome of the known AF and the newly discovered AF after stroke onset, it was consistent with the report by Hsich et al. [14].
The study of histological composition of clots retrieved from cerebral arteries in AIS patients confirmed that the clots from cardio-embolism, being formed in regions of stasis or slow flow in the atrium, had a significantly higher proportion of red blood cells and a lower proportion of fibrin, while thrombi occurring in atherosclerotic large arteries were mainly composed of fibrin and platelets [15]. The target of rt-PA is fibrin in thrombus, so the embolus of AF is more resistant to rt-PA, i.e. the so-called ''rt-PA resistance", it might partially explain why the IV rt-PA efficacy for AF-AIS is not ideal.
HT is an important complication of AIS, especially with the use of anticoagulants and thrombolytic agents. The rates of rt-PA-related symptomatic intracranial hemorrhage (sICH) in AIS patients were 3.8-22.6% [16, 17]; however, the rates in AF-AIS patients reached 22.0-33.0% [18, 19].
Jensen et al. [20] performed a multicenter, randomized, placebo-controlled trial, to study HT after IV rt-PA thrombolysis in patients with wake-up stroke. Of the 483 patients, HI and PH were 19.7% and 4.4%, respectively. Analyzing their data based on with and without AF, among 59 cases with AF, 47.5% developed HT and 8.5% had PH; by contrast,among 424 cases without AF, only 3.8% had PH. Multiple logistic regression analysis identified IV rt-PA (P = 0.003, OR = 2.08, 95% CI: 1.28-3.40), baseline NIHSS score (P < 0.001, OR = 1.11, 95% CI: 1.05-1.17), lesion volume (P = 0.005, OR = 1.03, 95% CI: 1.01-1.05), and AF (P < 0.001, OR = 3.02, 95% CI: 1.57-5.80) were associated with any HT.
Our data shown that the incidence of HT in group A was significantly higher than that in group B (40.0% vs. 21.4%, P = 0.010). According to HT classification analysis, the incidence of PH in group A was significantly higher than that in group B (22.2% vs. 5.5%, P = 0.001), but not HI. These results indicate that AF-AIS have a high incidence of HT, and rt-PA increases the risk of PH.
An earlier study [21] found that the majority of sICH occurred within the first 24 hours after the start of rt-PA therapy and 80% of fatal hemorrhage occurred within the first 12 hours. It suggests that sICH occurred after 36 hours could be considered unrelated to rt-PA treatment. Of our patients, the shortest time of PH after IV rt-PA in group A appeared at 2 hours, the median time was 12.5 (5.5, 22.5) hours, and the median time of PH in group B was 35.5 hours (11.0, 180.0), which supports that the earlier PH is related to IV rt-PA therapy.
The blood-brain barrier (BBB) forms the interface between cerebral vessels and nerve tissue to ensure the normal material exchange between blood and nerve tissue. The integrity of BBB depends on the tight junction between endothelial cells and basement membrane. Following AIS, there is the loss of BBB tight junction integrity, which leads to increased paracellular permeability and results in vasogenic edema and HT [22]. A study by Kidwel et al. [23] shown that after the use of rt-PA in AIS patients, abnormal high signals of fluid attenuated inversion recovery MRI sequence appeared in the sulcus containing cerebrospinal fluid in the area of occlusive vessels, suggesting that rt-PA have neurovascular toxic effect of BBB disruption and the development of ICH. It is known that rt-PA can induce activation of matrix metalloproteinase-9 (MMP-9), Montaner et al. [24] studied 41 patients with AIS involving the middle cerebral artery territory who received rt-PA within 3 hours after stroke onset, and found that the baseline levels of serum MMP-9 had a graded response with the degree of HT. The high activity of this enzyme further damages the matrix and leads to worse HT [25].
Mere HI may be understood as a marker of successful recanalization into partially ischemic damage area with no adverse clinical effect,while massive HT, especially PH2, is to be associated with poor outcome [20]. Another study by Nogueira et al. [26 found that both of HI (P < 0.0001, OR = 2.23, 95% CI: 1.53-3.25) and PH (P<0.0001, OR =6 .24, 95% CI: 3.06-12.75) were close related with functional outcome, however only PH was associated with a higher mortality (P < 0.0001, OR = 3.53, 95% CI: 2.19-5.68). In our study, we found that there was no correlation between HI and adverse prognosis in any groups, while the poor outcome rate of 10 patients with PH in each group was 100%, including 40% of deaths, it indicating that PH was associated with worse clinical outcome.
Baseline neurological severity was one of the risk factors independently associated with sICH in the NINDS trial (OR = 1.8, 95% CI: 1.2–2.9) [27]. In a multicenter t-PA Acute Stroke Survey, baseline NIHSS was a risk factor for all rt-PA related ICH and remained an independent predictor in each multivariate statistical model [28].
Size of infarction, or infarction volume, an important factor associated with prognosis, is correlated strongly with NIHSS score [29]. Our data analysis was consistent with it, the correlation coefficient between infarct size and NIHSS grade was 0.539 (P < 0.001), and for patients with lager size of infarction and NIHSS >10 score, the poor outcome was 94.5% and 94.3%, respectively. On multivariate Logistic regression analysis, both baseline infarction size (P = 0.013, OR = 4.558, 95% CI: 1.373-15.133) and NIHSS (P < 0.001, OR =1.348, 95% CI: 1.219-1.491) but not rt-PA entered into the final model as significant risk factors of poor prognosis. The result suggests that infarction size and NIHSS were risk factors of poor outcomes, and IV rt-PA could not improve the prognosis of patients with AF-AIS.
Researches indicate that different from the AIS patients with intracranial large artery stenosis or cerebral microvascular disease which has better collateral compensation, AF-AIS is a sudden vascular occlusion due to cardiogenic embolism, there is no time to establish adequate collateral compensation, therefore AF patients have greater infarct growth, larger infarcts, more frequent PH, worse functional outcome and higher mortality compared to patients with no AF [19, 30].
Our univariate analysis also showed that the outcome in anterior circulation infarction was significantly worse than that of posterior circulation (79.8%, vs. 50.0%, P < 0.001). It might be because patients with anterior circulation infarction have a higher proportion of large size of infarction and higher NIHSS score, in addition, all of 20 patients with PH occurred in anterior circulation.