Rupal I. Mehta

Hydrophilic polymer emboli: an under-recognized iatrogenic cause of ischemia and infarct

With the increased use of percutaneous intravascular diagnostic and therapeutic devices, there is potential for embolization of materials introduced into the vasculature. We report nine cases of foreign body emboli in patients who underwent vascular procedures using hydrophilic-coated medical devices. The procedures performed included cardiac catheterization (four cases), diagnostic cerebral angiography (two cases), therapeutic cerebral angiography with coil embolization of intracerebral aneurysm (one case), lower extremity angiography (one case), and/or orthotopic cadaveric organ transplantation (three cases). Other procedures in these patients included hemodialysis and peripheral arterial or central venous catheterization. Clinical sequelae ranged from undetectable (no symptoms) to pulmonary infarction, stroke, ongoing gangrene, and/or death occurring within days to weeks of suspected embolization of foreign material. Microscopic findings in biopsy or autopsy tissue revealed aggregates of amorphous or lamellated, non-refractile, non-polarizable, predominantly basophilic foreign substances occluding intrapulmonary, intracerebral, or peripheral arteries. This is the largest series documenting embolization of polymer gel materials. Polymer gel is now widely used on several devices for interventional procedures worldwide, and we suspect that complications associated with iatrogenic embolization of this substance are under-recognized.

Hemorrhagic transformation of ischemic stroke in diabetics on sulfonylureas.

Disability or death occurs more frequently in patients with hemorrhagic transformation (HT) after ischemic stroke. In rat models of stroke, sulfonylurea (SU) drugs such as glibenclamide (adopted US name, glyburide) confer protection against swelling and HT through actions on the novel SUR1‐regulated NCCa‐ATP channel. Here, we sought to determine whether the use of SU drugs in patients with diabetes mellitus (DM) presenting with acute ischemic stroke might influence the incidence of HT.

Inhibition of the Sur1-Trpm4 Channel Reduces Neuroinflammation and Cognitive Impairment in Subarachnoid Hemorrhage

Background and Purpose— Subarachnoid hemorrhage (SAH) can leave patients with memory impairments that may not recover fully. Molecular mechanisms are poorly understood, and no treatment is available. The sulfonylurea receptor 1–transient receptor potential melastatin 4 (Sur1-Trpm4) channel plays an important role in acute central nervous system injury. We evaluated upregulation of Sur1-Trpm4 in humans with SAH and, in rat models of SAH, we examined Sur1-Trpm4 upregulation, its role in barrier dysfunction and neuroinflammation, and its consequences on spatial learning. Methods— We used Förster resonance energy transfer to detect coassociated Sur1 and Trpm4 in human autopsy brains with SAH. We studied rat models of SAH involving filament puncture of the internal carotid artery or injection of blood into the subarachnoid space of the entorhinal cortex. In rats, we used Förster resonance energy transfer and coimmunoprecipitation to detect coassociated Sur1 and Trpm4, we measured immunoglobulin G extravasation and tumor necrosis &agr; overexpression as measures of barrier dysfunction and neuroinflammation, and we assessed spatial learning and memory on days 7 to 19. Results— Sur1-Trpm4 channels were upregulated in humans and rats with SAH. In rats, inhibiting Sur1 using antisense or the selective Sur1 inhibitor glibenclamide reduced SAH-induced immunoglobulin G extravasation and tumor necrosis &agr; overexpression. In models with entorhinal SAH, rats treated with glibenclamide for 7 days after SAH exhibited better platform search strategies and better performance on incremental and rapid spatial learning than vehicle-treated controls. Conclusions— Sur1-Trpm4 channels are upregulated in humans and rats with SAH. Channel inhibition with glibenclamide may reduce neuroinflammation and the severity of cognitive deficits after SAH.

Intravascular polymer material after coil embolization of a giant cerebral aneurysm.

We report the case of an 87-year-old female who died after coil embolization of an intracerebral giant aneurysm. Guglielmi detachable (Boston Scientific Neurovascular, Fremont, CA) and Matrix2 coils (Boston Scientific Neurovascular, Fremont, CA) were used during the procedure to occlude the surgically untreatable left supraclinoid carotid artery aneurysm. Postprocedure imaging studies showed scattered areas of acute infarct involving multiple bilateral vascular territories. Autopsy confirmed widespread infarction due to embolized foreign material, morphologically consistent with hydrophilic polymer originating from the coated Matrix coil and Terumo glidewire (Terumo Medical, Somerset, NJ). Polymer gel is now widely used on several medical devices for interventional procedures worldwide, and we suspect that risks associated with iatrogenic embolization of this substance are underrecognized.

Pathology of explanted polytetrafluoroethylene vascular grafts

INTRODUCTION Graft occlusion is a well-documented etiology for arteriovenous fistulae failure. However, there is little morphologic information elucidating why synthetic vascular grafts fail. The purpose of this study was to examine the tissue responses occurring within and adjacent to explanted polytetrafluoroethylene grafts that were utilized during cardiovascular procedures and subsequently removed. METHODS Forty explanted polytetrafluoroethylene grafts (including 32 failed vascular grafts) originating from 18 females and 22 males who ranged in age from 6 to 82 years (mean age, 36 years) were evaluated. Duration of engraftment varied from 1 to 255 months (mean engraftment period, 64 months). RESULTS In addition to neointimal hyperplasia, foreign body reaction, and thrombosis, an unexpected finding was calcification involving the graft material, as well as luminal thrombus and adjacent soft tissues. Twenty-seven of forty cases (68%) showed evidence of calcification, either within or adjacent to polytetrafluoroethylene grafts. Histologic examination revealed variable degrees and patterns of calcification within and adjacent to explanted polytetrafluoroethylene membranes and conduits (arterial, arteriovenous, or cardiac grafts). A significantly longer duration of engraftment (P=.015) was identified in calcified versus noncalcified polytetrafluoroethylene materials. Patient age, serum calcium, creatinine level, and blood urea nitrogen level showed no statistically significant differences between patients with calcified grafts and patients without calcified grafts. CONCLUSIONS Interstitial calcification is frequently found within explanted polytetrafluoroethylene grafts and is associated with graft disruption. These findings suggest that calcification of polytetrafluoroethylene biomaterials may play a role in eventual graft failure. A better understanding of the process of polytetrafluoroethylene graft calcification may lead to novel therapies that aid in the prevention of polytetrafluoroethylene vascular graft failure.

Sulfonylurea receptor 1 expression in human cerebral infarcts.

Supplemental Digital Content is available in the article.

Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts

Abstract The nonselective monovalent cation channel transient receptor potential melastatin 4 (Trpm4) is transcriptionally upregulated in neural and vascular cells in animal models of brain infarction. It associates with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which have critical roles in cytotoxic edema, cell death, blood-brain barrier breakdown, and vasogenic edema. We examined Trpm4 expression in postmortem brain specimens from 15 patients who died within the first 31 days of the onset of focal cerebral ischemia. We found increased Trpm4 protein expression in all cases using immunohistochemistry; transcriptional upregulation was confirmed using in situ hybridization of Trpm4 messenger RNA. Transient receptor potential melastatin 4 colocalized and coassociated with Sur1 within ischemic endothelial cells and neurons. Coexpression of Sur1 and Trpm4 in necrotic endothelial cells was also associated with vasogenic edema indicated by upregulated perivascular tumor necrosis factor, extravasation of serum immunoglobulin G, and associated inflammation. Upregulated Trpm4 protein was present up to 1 month after the onset of cerebral ischemia. In a rat model of middle cerebral artery occlusion stroke, pharmacologic channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, mitigated perivascular tumor necrosis factor labeling. Thus, upregulated Sur1-Trpm4 channels and associated blood-brain barrier disruption and cerebral edema suggest that pharmacologic targeting of this channel may represent a promising therapeutic strategy for the clinical management of patients with cerebral ischemia.

Intrapulmonary Ectopic Liver After Orthotopic Heart Transplantation

We report a case of a 54-year-old woman who was found to have multiple intrapulmonary nodules detected on imaging 33 months after orthotopic heart transplantation. Needle biopsy of 2 discrete nodules showed benign hepatic tissue, consistent with intrapulmonary foci of ectopic liver. In this report, the clinical, radiologic, microscopic, and fluorescent in situ hybridization results of 2 biopsied nodules are described. A brief review of the published information on ectopic liver is also presented. To our knowledge, multiple ectopic foci of the liver have never been reported at any site. Furthermore, this is the first reported case that involves a transplant recipient, thereby introducing additional, unique ramifications to this rare but intriguing entity.

Perivascular spaces, glymphatic dysfunction, and small vessel disease

Cerebral small vessel diseases (SVDs) range broadly in etiology but share remarkably overlapping pathology. Features of SVD including enlarged perivascular spaces (EPVS) and formation of abluminal protein deposits cannot be completely explained by the putative pathophysiology. The recently discovered glymphatic system provides a new perspective to potentially address these gaps. This work provides a comprehensive review of the known factors that regulate glymphatic function and the disease mechanisms underlying glymphatic impairment emphasizing the role that aquaporin-4 (AQP4)-lined perivascular spaces (PVSs), cerebrovascular pulsatility, and metabolite clearance play in normal CNS physiology. This review also discusses the implications that glymphatic impairment may have on SVD inception and progression with the aim of exploring novel therapeutic targets and highlighting the key questions that remain to be answered.

Polymer-induced central nervous system complications following vascular procedures: spectrum of iatrogenic injuries and review of outcomes

Polymer substances are commonly applied as surface coatings on endovascular catheters and vascular devices. Adverse effects related to their use have been reported, although the overall clinical significance and appropriate methods of detection of these complications have been unclear. In this analysis, we systematically reviewed clinical and diagnostic features in 32 patients (age, 36-87years; mean, 59years) in whom intracranial polymer reactions were documented following vascular interventions. Associated neuroradiologic and neuropathologic findings were variable and included cerebral vasculitis or vasculopathy (63%), abscess or granuloma formation (38%), ischemic infarcts (28%), parenchymal hematomas (28%), white matter change (25%), and/or chemical meningitis (22%). Location(s) of polymer reactions varied and included sites adjacent to and/or downstream from instrument insertion or implantation. Presenting clinical signs included focal neurologic deficits (41%), headache (22%), constitutional symptoms (19%), meningitis (16%), seizure and/or involuntary movements (9%), coma (6%), and syncope (3%). Adverse outcomes included stroke (31%), death (28%), delayed communicating hydrocephalus (9%), steroid dependency (9%), steroid complications (6%), and cerebral volume loss (3%). In some cases, these complications necessitated increased cost and length of medical care. In this review, we highlight the diverse features of polymer-induced reactions involving the central nervous system and summarize distinct diagnostic patterns that may enable earlier premortem detection of these lesions in the postprocedural clinical setting. Further work in this area is necessary to identify additional etiologic, preventative and therapeutic strategies. These data have potentially broad implications pertaining to the safety, efficacy, standards of use, storage, manufacturing, and regulation of new and emerging vascular devices and polymer nanotechnologies.