Valutazione angiografica e ruolo di endotelina-1 ed ossido nitrico nel no-reflow phenomenon in pazienti con ictus ischemico acuto da occlusione dei grossi vasi trattati con successo con trombectomia meccanica

Abstract

Background. Futile recanalization (FR), defined as a 90-day mRS 3-6 despite successful recanalization, account for 29% to 60% of large vessel occlusion (LVO) acute ischemic stroke (AIS) treated with mechanical thrombectomy (MT). Failure of early neurological improvement (fENI) describes patients successfully recanalized but not clinically improving at 24-hours or at 7-days. No-reflow phenomenon (NRP) is a possible cause of FR and fENI, described in animal models and myocardial infarction as deficient microvascular reperfusion. Evidence of NRP in AIS patients is scarce. Proposed determinants of NRP include vasoactive agents such as Endothelin-1 (ET-1) and Nitric oxide (NO), possibly involved in microvascular disfunction of NRP. Aim of our research was to define NRP in AIS from LVO of the anterior circulation treated with MT with successful recanalization. STUDY 1. Methods. We retrospectively analyzed 185 post-interventional digital subtraction angiographies (DSA) of anterior circulation LVO AIS patients treated with MT. We created a score, called modified capillary index score (mCIS), dividing middle cerebral artery territory in three segments. For each segment we gave 2 points if the capillary blush was present without any delay, 1 if delayed and 0 if absent. We used ROC curve to define mCIS≤3 as cut-off and marker of NRP. The primary endpoint was to identify a marker of NRP on post interventional DSA and to test whether this marker may predict FR and fENI. Secondary endpoint was to search a correlation between NRP, lesion volume and hemorrhagic transformation. Results. NRP was present in 35.1% of patients. NRP predicted fENI at 24h (aOR2.617, 95%CI1.192–5.745, p=0.016) and at 7 days (aOR4.601, 95%CI1.636–12.936, p=0.004), but not FR. Moreover, NRP predicted hemorrhagic transformation (aOR2.444, 95%CI 1.266–4.717, p=0.008). Discussion. NRP is poorly investigated in AIS. We identified an angiographic score able to identify NRP in AIS patients. Our angiographic marker was able to predict early outcome and hemorrhagic transformation of the ischemic lesion. STUDY 2. Methods. We prospectively enrolled 61 patients with AIS from LVO of the anterior circulation, successfully treated with MT. Patients were divided in groups according to the presence of NRP, as defined in study1. Peripheral venous blood samples were taken to dose ET-1 and NO at admission, after 24 and 48 hours. When technically possible, intracranial arterial blood samples, before and after recanalization, were taken. Primary endpoint was to test the association between ET-1 and NO levels and NRP. Secondary endpoint was to explore the association between ET-1 and NO levels and clinical outcome. Results. NRP Patients showed lower pre-MT intracranial levels of NO (9.60 µM ±2.80 vs 18.58 µM ±5.92, p=0.004) but the association was not confirmed at logistic regression (aOR0.561, 95%CI 0.297–1.061, p=0.075). Mean peripheral NO levels at 48 hours were 20.46 µM ±7.08 in the NRP group and 14.00 µM ± 8.06 in the no-NRP group (p=0.084). fENI at 24h was associated to lower serum NO levels at 24h (aOR1.19, 95%CI 1.014–1.213, p=0.023). Discussion. Our study tried to explore the role of ET-1 and NO in NRP. The trend to lower pre-MT levels of NO, might be the consequence of a reduced activity of the endothelial isoform of nitric oxide synthase (NOS). The increased values of NO at 24h in NRP patients might be due to the activation of the neuronal NOS. NO rather than ET-1 seems to have a major role in NRP. Conclusion. Reperfusion of main arteries in AIS from LVO is not always sufficient to ensure clinical improvement, a possible cause might be deficient microvascular reperfusion. We identified a marker of NRP in AIS patients, which could represent a useful tool to study this poorly recognized condition. Furthermore, we outlined a possible role of NO in NRP. Our data may contribute to future research studying NRP pathophysiology and possibly treatment.Background. Futile recanalization (FR), defined as a 90-day mRS 3-6 despite successful recanalization, account for 29% to 60% of large vessel occlusion (LVO) acute ischemic stroke (AIS) treated with mechanical thrombectomy (MT). Failure of early neurological improvement (fENI) describes patients successfully recanalized but not clinically improving at 24-hours or at 7-days. No-reflow phenomenon (NRP) is a possible cause of FR and fENI, described in animal models and myocardial infarction as deficient microvascular reperfusion. Evidence of NRP in AIS patients is scarce. Proposed determinants of NRP include vasoactive agents such as Endothelin-1 (ET-1) and Nitric oxide (NO), possibly involved in microvascular disfunction of NRP. Aim of our research was to define NRP in AIS from LVO of the anterior circulation treated with MT with successful recanalization. STUDY 1. Methods. We retrospectively analyzed 185 post-interventional digital subtraction angiographies (DSA) of anterior circulation LVO AIS patients treated with MT. We created a score, called modified capillary index score (mCIS), dividing middle cerebral artery territory in three segments. For each segment we gave 2 points if the capillary blush was present without any delay, 1 if delayed and 0 if absent. We used ROC curve to define mCIS≤3 as cut-off and marker of NRP. The primary endpoint was to identify a marker of NRP on post interventional DSA and to test whether this marker may predict FR and fENI. Secondary endpoint was to search a correlation between NRP, lesion volume and hemorrhagic transformation. Results. NRP was present in 35.1% of patients. NRP predicted fENI at 24h (aOR2.617, 95%CI1.192–5.745, p=0.016) and at 7 days (aOR4.601, 95%CI1.636–12.936, p=0.004), but not FR. Moreover, NRP predicted hemorrhagic transformation (aOR2.444, 95%CI 1.266–4.717, p=0.008). Discussion. NRP is poorly investigated in AIS. We identified an angiographic score able to identify NRP in AIS patients. Our angiographic marker was able to predict early outcome and hemorrhagic transformation of the ischemic lesion. STUDY 2. Methods. We prospectively enrolled 61 patients with AIS from LVO of the anterior circulation, successfully treated with MT. Patients were divided in groups according to the presence of NRP, as defined in study1. Peripheral venous blood samples were taken to dose ET-1 and NO at admission, after 24 and 48 hours. When technically possible, intracranial arterial blood samples, before and after recanalization, were taken. Primary endpoint was to test the association between ET-1 and NO levels and NRP. Secondary endpoint was to explore the association between ET-1 and NO levels and clinical outcome. Results. NRP Patients showed lower pre-MT intracranial levels of NO (9.60 µM ±2.80 vs 18.58 µM ±5.92, p=0.004) but the association was not confirmed at logistic regression (aOR0.561, 95%CI 0.297–1.061, p=0.075). Mean peripheral NO levels at 48 hours were 20.46 µM ±7.08 in the NRP group and 14.00 µM ± 8.06 in the no-NRP group (p=0.084). fENI at 24h was associated to lower serum NO levels at 24h (aOR1.19, 95%CI 1.014–1.213, p=0.023). Discussion. Our study tried to explore the role of ET-1 and NO in NRP. The trend to lower pre-MT levels of NO, might be the consequence of a reduced activity of the endothelial isoform of nitric oxide synthase (NOS). The increased values of NO at 24h in NRP patients might be due to the activation of the neuronal NOS. NO rather than ET-1 seems to have a major role in NRP. Conclusion. Reperfusion of main arteries in AIS from LVO is not always sufficient to ensure clinical improvement, a possible cause might be deficient microvascular reperfusion. We identified a marker of NRP in AIS patients, which could represent a useful tool to study this poorly recognized condition. Furthermore, we outlined a possible role of NO in NRP. Our data may contribute to future research studying NRP pathophysiology and possibly treatment