Abstract
BackgroundMatrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in vascular remodeling, (neuro)inflammation, blood-brain barrier breakdown and neuronal apoptosis. Proinflammatory mechanisms are suggested to play an important role during early brain injury and cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This study aimed to analyze MMP-3, MMP-9, TIMP-1 and TIMP-3 in patients with SAH and their respective association with cerebral vasospasm (CVS).MethodsBlood samples were collected in 20 SAH patients on days 1 to 7, 9, 11, 13 and 15 and 20 healthy age and gender matched volunteers. Serum MMPs and TIMPs were analyzed using enzyme-linked immunosorbent assay. Doppler sonographic CVS was defined as a mean blood flow velocity above 120 cm/sec in the middle cerebral artery. When discharged from hospital and at 6 month follow-up neurological outcome was evaluated using the Glasgow Outcome Score and the modified Rankin Scale.ResultsMMP-9 was higher in SAH patients compared to healthy controls (p<0.001). Patients with CVS (n = 11) had elevated MMP-9 serum levels compared to patients without CVS (n = 9, p<0.05). Higher MMP-9 was observed in the presence of cerebral ischemia associated with cerebral vasospasm (p<0.05). TIMP-1 was increased in patients with SAH on day 4 (p<0.05). There was an imbalance of the MMP-9/TIMP-1 ratio in favor of MMP-9 in SAH patients, in particular those with CVS (p<0.001). MMP-3 and TIMP-3 were significantly lower in SAH patients throughout day 4 and day 7, respectively (p<0.05). We did not find an association between MMP-, TIMP levels and neurological outcome after 6 months.ConclusionsMMP-3 and -9 are differentially regulated in SAH patients with both enzymes showing peak levels correlating with the development of CVS. The inhibitors TIMP-1 and -3 were low during the acute phase after SAH and increased later on which might suggest a preponderance of pro-inflammatory mechanisms.
Highlights
Subarachnoid hemorrhage (SAH) accounts for 2–5% of all new strokes and is associated with high morbidity and mortality [1,2]
The aim of this study was to analyze the temporal profile of Matrix metalloproteinases (MMPs)-3, MMP-9, TIMP-1 and TIMP-3 serum levels in subarachnoid hemorrhage (SAH) patients and their association with cerebral vasospasm
To test the association between cerebral vasospasm or cerebral ischemia and the levels of MMP-9, MMP-3, TIMP-1 and TIMP-3 corrected for important covariates (age, sex, white blood cell count (WBC), C-reactive protein (CRP) and body temperature), generalized estimating equations were calculated with day post SAH and presence of Doppler sonographic cerebral vasospasm (dCVS) or cerebral ischemia as factors, respectively
Summary
Subarachnoid hemorrhage (SAH) accounts for 2–5% of all new strokes and is associated with high morbidity and mortality [1,2]. Cerebral vasospasm (CVS), an important complication after aneurysmal SAH, may be associated with delayed cerebral ischemia contributing to poor functional outcome and death [3,4,5]. It has been suggested that early brain injury contributes to the (later) development of cerebral vasospasm [6,8,9]. TIMP-1 is regarded as an inhibitor for both, MMP-3 and -9, playing an important role in inflammation [21,22]. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in vascular remodeling, (neuro)inflammation, blood-brain barrier breakdown and neuronal apoptosis. Proinflammatory mechanisms are suggested to play an important role during early brain injury and cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This study aimed to analyze MMP-3, MMP-9, TIMP-1 and TIMP-3 in patients with SAH and their respective association with cerebral vasospasm (CVS)
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