Haptoglobin phenotype predicts the development of focal and global cerebral vasospasm and may influence outcomes after aneurysmal subarachnoid hemorrhage
- Proceedings of the National Academy of Sciences of the United States of America
- Published about 3 years ago
Cerebral vasospasm (CV) and the resulting delayed cerebral ischemia (DCI) significantly contribute to poor outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Free hemoglobin (Hb) within the subarachnoid space has been implicated in the pathogenesis of CV. Haptoglobin (Hp) binds free pro-oxidant Hb, thereby modulating its harmful effects. Humans can be of three Hp phenotypes: Hp1-1, Hp2-1, or Hp2-2. In several disease states, the Hp2-2 protein has been associated with reduced ability to protect against toxic free Hb. We hypothesized that individuals with the Hp2-2 phenotype would have more CV, DCI, mortality, and worse functional outcomes after aSAH. In a sample of 74 aSAH patients, Hp2-2 phenotype was significantly associated with increased focal moderate (P = 0.014) and severe (P = 0.008) CV and more global CV (P = 0.014) after controlling for covariates. Strong trends toward increased mortality (P = 0.079) and worse functional outcomes were seen for the Hp2-2 patients with modified Rankin scale at 6 wk (P = 0.076) and at 1 y (P = 0.051) and with Glasgow Outcome Scale Extended at discharge (P = 0.091) and at 1 y (P = 0.055). In conclusion, Hp2-2 phenotype is an independent risk factor for the development of both focal and global CV and also predicts poor functional outcomes and mortality after aSAH. Hp phenotyping may serve as a clinically useful tool in the critical care management of aSAH patients by allowing for early prediction of those patients who require increased vigilance due to their inherent genetic risk for the development of CV and resulting DCI and poor outcomes.
The present study was conducted to examine the feasibility of nimodipine loaded PLGA microparticles suspended in Tisseel(™) fibrin sealant as an in situ forming depot system. This device locally placed can be used for the treatment of vasospasm after a subarachnoid hemorrhage. Microparticles were prepared via spray drying by using the vibration mesh spray technology of Nano Spray Dryer B-90. Spherically shaped microparticles with different loadings and high encapsulation efficiencies of 93.3% to 97.8% were obtained. Depending on nimodipine loading (10% - 40%) the particle diameter ranged from 1.9 ± 1.2 μm to 2.4 ± 1.3μm. Thermal analyses using DSC revealed that Nimodipine is dissolved in the PLGA matrix. Also fluorescent dye loaded microparticles were encapsulated in Tisseel(™) to examine the homogeneity of particles. 3D-pictures of the in situ forming devices displayed uniform particle homogeneity in the sealant matrix. Drug release was examined by fluorescence spectrophotometry which demonstrated a drug release proportional to the square root of time. A prolonged drug release of 19.5 h was demonstrated under in vitro conditions. Overall, the Nimodipine in situ forming device could be a promising candidate for the local treatment of vasospasm after a subarachnoid hemorrhage.
The goal of this study was to demonstrate the importance of intracoronary nitroglycerin (IC NTG) administration during diagnostic coronary angiography and prior to percutaneous coronary intervention (PCI).
Cerebral vasospasm and sodium and fluid imbalances are common sequelae of aneurysmal subarachnoid hemorrhage (SAH) and cause of significant morbidity and mortality. Studies have shown the benefit of corticosteroids in the management of these sequelae. We have reviewed the literature and analyzed the available data for corticosteroid use after SAH.
The aim of the present study was to assess the therapeutic effects of atorvastatin on cerebral vessel autoregulation and to explore the underlying mechanisms in a rabbit model of subarachnoid hemorrhage (SAH). A total of 48 healthy male New Zealand rabbits (weight, 2‑2.5 kg) were randomly allocated into SAH, Sham or SAH + atorvastatin groups (n=16/group). The Sham group received 20 mg/kg/d saline solution, whereas 20 mg/kg/d atorvastatin was administered to rabbits in the SAH + atorvastatin group following SAH induction. Changes in diameter, perimeter and basilar artery (BA) area were assessed and expression levels of the vasoactive molecules endothelin‑1 (ET‑1), von Willebrand factor (vWF) and thrombomodulin ™ were measured. Neuronal apoptosis was analyzed 72 h following SAH by terminal deoxynucleotidyl-transferase‑mediated dUTP nick‑end labeling (TUNEL) staining. The mortality rate in the SAH group was 18.75, 25% in the SAH + atorvastatin treated group and 0% in the Sham group (n=16/group). The neurological score in the SAH + atorvastatin group was 1.75±0.68, which was significantly higher compared with the Sham group (0.38±0.49; P<0.05). The BA area in the SAH + atorvastatin group (89.6±9.11) was significantly lower compared with the SAH group (115.4±11.0; P<0.01). The present study demonstrated that SAH induction resulted in a significant increase in the diameter, perimeter and cross‑sectional area of the BA in the SAH + atorvastatin group. Administration of atorvastatin may significantly downregulate the expression levels of ET‑1, vWF and TM (all P<0.01) vs. sham and SAH groups. TUNEL staining demonstrated that neuronal apoptosis was remarkably reduced in the hippocampus of SAH rabbits following treatment with atorvastatin (P<0.05). Atorvastatin treatment may alleviate cerebral vasospasm and mediate structural and functional remodeling of vascular endothelial cells, in addition to promoting anti‑apoptotic signaling. These results provided supporting evidence for the use of atorvastatin as an effective and well‑tolerated treatment for SAH in various clinical settings and may protect the autoregulation of cerebral vessels.
Subarachnoid hemorrhage (SAH) induces widespread inflammation leading to cellular injury, vasospasm and ischemia. Evidence suggests that progesterone (PROG) can improve functional recovery in acute brain injury due to its anti-inflammatory and neuroprotective properties, which could also be beneficial in SAH. We hypothesized that PROG treatment attenuates inflammation mediated cerebral vasospasm and microglial activation, improves synaptic connectivity, and ameliorates functional recovery after SAH.
Delayed cerebral ischemia (DCI) is common after subarachnoid hemorrhage (SAH) and represents a significant cause of poor functional outcome. DCI was mainly thought to be caused by cerebral vasospasm; however, recent clinical trials have been unable to confirm this hypothesis. Studies in humans and animal models have since supported the notion of a multifactorial pathophysiology of DCI. This review summarizes some of the main mechanisms under investigation including cerebral vascular dysregulation, microthrombosis, cortical spreading depolarizations, and neuroinflammation.
Although endovascular therapy has been widely adopted for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH), its effect on clinical outcomes remains incompletely understood. The aims of this retrospective cohort study are to evaluate the outcomes of endovascular intervention for post-aSAH vasospasm and identify predictors of functional independence at discharge and repeat endovascular vasospasm treatment.
Cerebral vasospasm (CVS) is a major determinant of prognosis in patients with subarachnoid hemorrhage (SAH). Alteration in the vascular phenotype contributes to development of CVS. However, little is known about the role of microRNAs (miRNAs) in the phenotypic alteration after SAH. We investigated the expression profile of miRNAs and the chronological changes in the expression of microRNA-15a (miR-15a) and Kruppel-like factor 4 (KLF4), a potent regulator of vascular phenotype modulation that modulates the expression of miR-15a, in the plasma and cerebrospinal fluid (CSF) of SAH patients.
One of the most serious complications following subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI) secondary to symptomatic vasospasm. An animal model mimicking post SAH vasospasm is essential for enabling the translation of newer technologies from the conceptual phase to animal studies, and eventually to clinical trials. Various animal models of DCI following SAH have been reported, with canine models being the most common. Due to the similarity of the swine cardiovascular system and its dimensions to the human’s system, the main objective of this study was to establish a consistent and quantitatively representative model of SAH-induced vasospasm in swine.