Acceleration of the Development of Microcirculation Embolism in the Brain due to Capillary Narrowing.

BACKGROUND: Cerebral microvascular obstruction is critically involved in recurrent stroke and decreased cerebral blood flow with age. The obstruction must occur in the capillary with a greater resistance to perfusion pressure through the microvascular networks. However, little is known about the relationship between capillary size and embolism formation. This study aimed to determine whether the capillary lumen space contributes to the development of microcirculation embolism. METHODS: To spatiotemporally manipulate capillary diameters in vivo, transgenic mice expressing the light-gated cation channel protein ChR2 (channelrhodopsin-2) in mural cells were used. The spatiotemporal changes in the regional cerebral blood flow in response to the photoactivation of ChR2 mural cells were first characterized using laser speckle flowgraphy. Capillary responses to optimized photostimulation were then examined in vivo using 2-photon microscopy. Finally, microcirculation embolism due to intravenously injected fluorescent microbeads was compared under conditions with or without photoactivation of ChR2 mural cells. RESULTS: Following transcranial photostimulation, the stimulation intensity-dependent decrease in cerebral blood flow centered at the irradiation was observed (14%-49% decreases relative to the baseline). The cerebrovascular response to photostimulation showed significant constriction of the cerebral arteries and capillaries but not of the veins. As a result of vasoconstriction, a temporal stall of red blood cell flow occurred in the capillaries of the venous sides. The 2-photon excitation of a single ChR2 pericyte demonstrated the partial shrinkage of capillaries (7% relative to the baseline) around the stimulated cell. With the intravenous injection of microbeads, the occurrence of microcirculation embolism was significantly enhanced (11% increases compared to the control) with photostimulation. CONCLUSIONS: Capillary narrowing increases the risk of developing microcirculation embolism in the venous sides of the cerebral capillaries.

A Rare Cause of Respiratory Insufficiency in a 30-Year-Old Transgender Woman.

CASE PRESENTATION: A 30-year-old transgender woman who was HIV positive presented to the ED with progressive severe dyspnea and hemoptysis that started 1 day earlier. The patient was undergoing antiretroviral therapy with emtricitabine-rilpivirine-tenofovir with good compliance and feminizing hormone therapy with cyproterone acetate. She was otherwise healthy and was not taking any other medications.

Neutrophil Extracellular Trap-Driven Occlusive Diseases.

The enlightenment of the formation of neutrophil extracellular traps (NETs) as a part of the innate immune system shed new insights into the pathologies of various diseases. The initial idea that NETs are a pivotal defense structure was gradually amended due to several deleterious effects in consecutive investigations. NETs formation is now considered a double-edged sword. The harmful effects are not limited to the induction of inflammation by NETs remnants but also include occlusions caused by aggregated NETs (aggNETs). The latter carries the risk of occluding tubular structures like vessels or ducts and appear to be associated with the pathologies of various diseases. In addition to life-threatening vascular clogging, other occlusions include painful stone formation in the biliary system, the kidneys, the prostate, and the appendix. AggNETs are also prone to occlude the ductal system of exocrine glands, as seen in ocular glands, salivary glands, and others. Last, but not least, they also clog the pancreatic ducts in a murine model of neutrophilia. In this regard, elucidating the mechanism of NETs-dependent occlusions is of crucial importance for the development of new therapeutic approaches. Therefore, the purpose of this review is to address the putative mechanisms of NETs-associated occlusions in the pathogenesis of disease, as well as prospective treatment modalities.

Statin treatment and outcomes after embolic stroke of undetermined source.

The association of low-density lipoprotein cholesterol lowering with outcomes in embolic stroke of undetermined source (ESUS) patients is unclear. In these patients we aimed to assess the effect of statin on stroke recurrence, major adverse cardiovascular events (MACE) and death rates. Consecutive ESUS patients in the Athens Stroke Registry were prospectively followed-up to 10 years for stroke recurrence, MACE, and death. The Nelson-Aalen estimator was used to estimate the cumulative probability by statin allocation at discharge and cox-regression analyses to investigate whether statin at discharge was a predictor of outcomes. Among 264 ESUS patients who were discharged and followed for 4 years, 89 (33.7%) were treated with statin at discharge. Patients who were discharged on statin had lower rates of stroke recurrence (3.58 vs. 7.23/100 patient-years, HR: 0.48; 95% CI 0.26-0.90), MACE (4.98 vs. 9.89/100 patient-years, HR: 0.49; 95% CI 0.29-0.85), and death (3.93 vs. 8.21/100 patient-years, HR: 0.50; 95% CI: 0.28-0.89). In the multivariate analysis, statin treatment at discharge was an independent predictor of stroke recurrence (adjusted HR: 0.48; 95% CI 0.26-0.91), MACE (adjusted HR: 0.48; 95% CI 0.28-0.82), and death (adjusted HR: 0.50; 95% CI 0.27-0.93). Patients with ESUS discharged on statins have lower rates of stroke recurrence, MACE, and death compared to those not receiving statin therapy.

Predictors of atrial fibrillation detection and features of recurrent strokes in patients after cryptogenic stroke.

BACKGROUND AND PURPOSE: Use of implantable cardiac monitors (ICMs) has increased diagnosis of atrial fibrillation (AF) in cryptogenic stroke (CS) patients. Identifying AF predictors may enhance the yield of AF detection. Recurrent strokes after CS are not well described. We aimed to assess the predictors for AF detection and the characteristics of recurrent strokes in patients after CS. METHODS: We reviewed electronic medical records of CS patients who were admitted between February 2014 and September 2017 and underwent ICM placement with minimum one-year follow-up. Patient demographics, stroke characteristics, pre-defined risk factors as well as recurrent strokes were compared between patients with and without AF detection. RESULTS: 389 patients with median follow-up of 548 days were studied. AF was detected in 102 patients (26.2%). Age (per decade increase, OR 2.10, CI 1.64-2.68, with vs. without AF) and left atrium diameter (per 5 mm increase, OR 1.91, CI 1.33-2.74) were identified as AF predictors. Intracranial large vessel stenosis >50% irrelevant to the index strokes was associated with AF detection within 30 days (OR 0.24, CI 0.09-0.69, >30 vs. <30 days). Recurrent strokes occurred in 14% patients with median follow-up about 2.5 years. Topography of these strokes resembled embolic pattern and was comparable between patients with and without AF. Among recurrent strokes in patients with AF, the median time to AF detection was much shorter (90 vs. 251 days), and the median time to first stroke recurrence was much longer (422 vs. 76 days) in patients whose strokes recurred after AF detection than those before AF detection. CONCLUSIONS: Older age and enlarged left atrium are predictors for AF detection in CS patients. Intracranial atherosclerosis is more prevalent in patients with early AF detection within 30 days. Recurrent strokes follow the embolic pattern, and early AF detection could delay the stroke recurrence.

Embolic Stroke of Undetermined Source and Sleep Disorders.

Background and Purpose- Compared with other causes of ischemic stroke, the mechanism of action of embolic stroke of undetermined source (ESUS) remains unclear, with previous literature suggesting that ESUS may be due to an undetected cardioembolic source. This study aimed to improve our understanding of the pathophysiology of ESUS through current knowledge of sleep disorders. Methods- Patients were included in this study if they sustained an ischemic stroke and completed either polysomnography or a home sleep apnea test. Strokes were classified into 1 of 6 mechanisms and were compared with the presence of sleep disorders (ie, obstructive sleep apnea, periodic limb movements, and abnormalities in sleep architecture). Results- There was a significant relationship between obstructive sleep apnea and cardioembolic stroke mechanism compared with the other stroke mechanisms (P=0.018). There was no significant relationship between obstructive sleep apnea and ESUS (P=0.585). Patients with ESUS were significantly more likely to have an elevated periodic limb movement index (P=0.037) and prolonged sleep onset latency (P=0.0166) compared with patients with other causes of stroke. Conclusions- ESUS was not associated with markers of cardioembolic stroke such as obstructive sleep apnea. There was a significant relationship between ESUS and elevated periodic limb movements and impaired sleep architecture, which suggests that ESUS may have a multifactorial underlying pathophysiology.

Increased Left Atrial Appendage Density on Computerized Tomography is Associated with Cardioembolic Stroke.

BACKGROUND AND PURPOSE: While studies have stratified cardioembolic (CE) stroke risk by qualitative left atrial appendage (LAA) morphology and biomarkers of atrial dysfunction, the quantitative properties that underlie these observations are not well established. Accordingly, we hypothesized that LAA volume and contrast density (attenuation) on computerized tomography (CT) may capture the structural and hemodynamic processes that underlie CE stroke risk. METHODS: Data were collected from a single center prospective ischemic stroke database over 18 months and included all patients with ischemic stroke who previously underwent routine, nongated, contrast enhanced thin-slice (≤2.5 mm) chest CT. Stroke subtype was determined based on the inpatient diagnostic evaluation. LAA volume and attenuation were determined from CT studies performed for various clinically appropriate indications. Univariate and multivariable analyses were performed to determine factors associated with ischemic stroke subtype, including known risk factors and biomarkers, as well as LAA density and morphologic measures. RESULTS: We identified 311 patients with a qualifying chest CT (119 CE subtype, 109 Embolic Stroke of Undetermined Source (ESUS), and 83 non-CE). In unadjusted models, there was an association between CE (versus non-CE) stroke subtype and LAA volume (OR per mL increase 1.15, 95% CI 1.07-1.24, P < .001) and LAA density (4th quartile versus 1st quartile; OR 2.95, 95% CI 1.28-6.80, P = .011), but not with ESUS (versus non-CE) subtype. In adjusted models, only the association between LAA density and CE stroke subtype persisted (adjusted OR 3.71, 95% CI 1.37-10.08, P = .010). CONCLUSION: The LAA volume and density values on chest CT are associated with CE stroke subtype but not ESUS subtype. Patients with ESUS and increased LAA volume or attenuation may be a subgroup where the mechanism is CE and anticoagulation can be tested for secondary stroke prevention.

Normal Systolic Blood Pressure at Presentation With Acute Ischemic Stroke Predicts Cardioembolic Etiology.

Background Early insight into the possible etiology of ischemic stroke allows for early initiation of mechanism-specific secondary stroke prevention. Initial systolic blood pressure during acute ischemic stroke may relate to stroke etiology. We sought to determine whether normotension at presentation with acute ischemic stroke predicts cardioembolic etiology. Methods and Results All patients presenting with acute ischemic stroke within 12 hours of symptom onset at a comprehensive stroke center from January 2015 to December 2017 were assessed. Normotension was defined as systolic blood pressure ≤130 mm Hg. The primary exposure was blood pressure on arrival at the hospital, and the primary outcome was cardioembolic etiology. Multivariable regression with stepwise selection was used to adjust for relevant covariates. We included 683 patients in our analysis, 303 (44%) of whom were diagnosed with cardioembolic etiology at 6 months. The probability of cardioembolic etiology was inversely associated with systolic blood pressure, and initial systolic blood pressure was significantly associated with cardioembolic etiology (odds ratio: 1.15; 95% CI, 1.05 to 1.26). Normotension was associated with 2.62-fold increased odds of cardioembolic etiology (95% CI, 1.46 to 4.72). Conclusions Normotension at presentation with acute ischemic stroke strongly predicts cardioembolic etiology. These patients may especially benefit from early and prolonged cardiac investigations.

Percutaneous Mechanical Thrombectomy for Acute Superior Mesenteric Artery Embolism: Preliminary Experience in Five Cases.

BACKGROUND: This study was performed to summarize our experience in treating acute superior mesenteric artery embolism (SMAE) by percutaneous mechanical thrombectomy (PMT). METHODS: The clinical data of five patients with acute SMAE treated by PMT in our center from October 2015 to May 2018 were retrospectively analyzed. PMT was performed under local anesthesia. Access was established via the femoral artery or brachial artery. Thrombectomy was performed on the superior mesenteric artery using a 6F Rotarex catheter (Straub Medical, Wangs, Switzerland). RESULTS: Technical success of PMT was achieved in all five patients; emboli were completely removed in three patients and partially removed in two patients. No PMT-related complications were noted after surgery. Four patients were smoothly discharged from the hospital after their symptoms were relieved. One patient still had symptoms of intestinal ischemia after the operation, and massive small intestinal necrosis was found by exploratory laparotomy. Intestinal resection was performed, and the patient died 4 months later. CONCLUSIONS: PMT by the Rotarex system is a minimally invasive, safe, and effective technique in removing SMAE. Early application of PMT can avoid intestinal necrosis.

Prevention of serious air embolism during cryoballoon ablation; risk assessment of air intrusion into the sheath by catheter selection and change in intrathoracic pressure: An ex vivo study.

INTRODUCTION: One cause of cerebral infarction during cryoballoon ablation is the entry of air into a sheath due to the use of inappropriate catheters. It is known that the left atrial pressure of patients with obstructive sleep apnea syndrome can be negative. However, the effects of catheter selection and negative pressure changes in the sheath on air intrusion are not yet well understood. The aim of this study was to evaluate how catheter selection and negative pressure changes affect air intrusion and to perform countermeasures for air intrusion. METHODS AND RESULTS: This experiment used siphon principle to create negative pressure in the sheath. Noncryoablation catheters (not designed exclusively for cryoballoon ablation) and cryoballoon catheters were investigated. Catheters were inserted into the sheath and then removed. Thereafter, the amount of air in the sheath was measured. For catheters producing significantly larger amounts of air intrusion, the catheters were inserted via a long sheath in the sheath (sheath-in-sheath technique) and the same procedures were repeated. We found that the amount of air intrusion through most of the noncryoablation catheters was significantly larger than that through cryoablation catheters. An increase in the magnitude of negative pressure in the sheath resulted in a proportional increase in air intrusion, but the sheath-in-sheath technique significantly reduced air intrusion. CONCLUSION: The amount of air intrusion increased when using catheters with complicated tip shapes and thin outer diameters and when the magnitude of negative pressure in the sheath increased. The sheath-in-sheath technique may be an effective countermeasure.

Embolus Transport Simulations with Fully Resolved Particle Surfaces.

PURPOSE: There has been interest in recent work in using computational fluid dynamics with Lagrangian analysis to calculate the trajectory of emboli-like particles in the vasculature. While previous studies have provided an understanding of the hemodynamic factors determining the fates of such particles and their relationship to risk of stroke, most analyses have relied on a particle equation of motion that assumes the particle is "small" e.g., much less than the diameter of the vessel. This work quantifies the limit when a particle can no longer be considered "small". METHODS: The motion of embolus-like particles are simulated using an overset mesh technique. This allows the fluid stresses on the particle surface to be fully resolved. Consequently, the particles can be of arbitrary size or shape. The trajectory of resolved particles and "small" particles are simulated through a patient-specific carotid artery bifurcation model with particles 500, 1000, and 2000 µm in diameter. The proportions of particles entering the internal carotid artery are treated as the outcome of the particle fate, and statistical comparisons are made to ascertain the importance of non-small particle effects. RESULTS: For the 2000 µm embolus, the proportion of particles traveling to the internal carotid artery is 74.7 ± 1.3% (mean ± 95% confidence margin) for the "small" particle model and is 85.7 ± 5.4% for a resolved particle model. The difference is statistically significant, [Formula: see text], based on the binomial test for the particle outcomes. No statistically discernible differences are found for the smaller diameter particles. CONCLUSIONS: Quantitative differences are observable for the 2000 µm trajectories between the "small" and resolved particle models which is a particle diameter 27% relative to the common carotid artery diameter. A fully resolved particle model ought to be considered for emboli trajectory simulations when the particle size ratio is ≳ 20%.

Investigation of the Hemodynamics Influencing Emboli Trajectories Through a Patient-Specific Aortic Arch Model.

Background and Purpose- Cardiogenic emboli account for 15% to 20% of acute ischemic stroke cases worldwide. However, the chance of such emboli, of varying sizes, causing a stroke under various flow types has not been evaluated. Methods- A patient-specific aortic arch model was fabricated from a medical image dataset of a 77-year-old male case, with atrial fibrillation and distal occlusion of the right M1 vessel. One hundred and eighty mammalian embolus analogs (EAs) were released one by one into the model under normal and atrial fibrillation flow conditions. A further 270 clots were fabricated using varying levels of thrombin (5-20 National Institutes of Health units thrombin). The effect of releasing several clots simultaneously was also examined by grouping EAs into 18 multiples of 5, 4, 3, and 2 clots, resulting in 504 EAs released. Results- EAs with a length of ≤10 mm were the most common geometry to travel through the common carotid arteries (44%); however, longer clots also traveled through these narrow vessels. Twenty two percent of EAs ranged from 10-20mm in length, 27% from 20-30mm and 7% were >30 mm in length. Higher density clots increased the propensity for clots to travel along the cerebral vessels ( P<0.05). Releasing more clots during each test, increased the probability of at least one clot traveling through an aortic arch branching vessel. Conclusions- Embolus trajectory through the branching vessels of the aortic arch is not exclusively dependent on embolus size. EAs tend to travel proportionally with outlet flow rates, with a greater chance of a stroke caused by multiple breakaway emboli.

Macrophage-targeted, enzyme-triggered fluorescence switch-on system for detection of embolism-vulnerable atherosclerotic plaques.

The development of atherosclerotic plaques is a critical step that can result in an arterial embolism. Therefore, detection of these vulnerable plaques is of clinical significance for the diagnosis of atherosclerosis. However, there are few imaging systems able to detect such plaques easily. In this study, we designed a new platform for near-infrared fluorescence (NIRF) imaging of macrophages in atherosclerotic plaques, one using both a liposomal DDS and an activatable fluorescent probe, and evaluated the utility of this imaging for the diagnosis of atherosclerosis. We first synthesized a fluorescent switch-on probe, Peptide-ICG2, which is optically silent under normal conditions but activated in the presence of the lysosomal enzyme, cathepsin B. To achieve macrophage-specific fluorescence activation, we encapsulated Peptide-ICG2 into phosphatidylserine-containing liposome (P-ICG2-PS-Lip), since the accumulation of phosphatidylserine receptor-bearing macrophages is characteristic of embolism-vulnerable plaques. The experiments using macrophage-like RAW264 cells in culture showed that P-ICG2-PS-Lip was selectively taken up into the cells and that significant fluorescence of the probe was observed. For NIRF imaging of the atherosclerotic plaques, P-ICG2-PS-Lip was intravenously injected into ApoE-knockout atherosclerotic model mice or WHHL rabbits, and the fluorescence at the aortae was imaged. The results indicated that ICG fluorescence could be successfully observed at the plaques on the artery walls. The results of the present study thus suggest that NIRF imaging using P-ICG2-PS-Lip would be useful for detecting embolism-vulnerable atherosclerotic plaques.

The Clinical Impact of Splanchnic Ischemia on Patients Affected by Thoracoabdominal Aortic Aneurysms Treated with Fenestrated and Branched Endografts.

BACKGROUND: Fenestrated/branched endografts for aortic repair (FB-EVAR) are valid options to treat thoracoabdominal aortic aneurysms (TAAAs). Successful repair requires manipulation of target visceral vessels (TVVs) with possible splanchnic ischemia. The aim of the study was to evaluate the clinical impact of splanchnic ischemia occurring in FB-EVAR for TAAA. METHODS: Between 2010 and 2015, patients with TAAAs undergoing FB-EVAR were prospectively enrolled. Clinical, morphological, procedural, and 30-day data were evaluated. Splanchnic ischemia was defined as the presence of splanchnic ischemic lesions (SILs) visible at perioperative computed tomography angiography. Preoperative, postoperative, and 30-day hepatic/pancreatic/renal laboratory functions were analyzed. End points were incidence of SILs, laboratory splanchnic functions worsening (≥25% of baseline), and presence of related clinical/morphological and procedural risk factors. RESULTS: Thirty-six patients (male: 78%; age: 73 ± 7 years) with 27 (75%) type I-III and 9 (25%) type IV TAAA who underwent FB-EVAR for a total of 127 TVV (branches: 47-60%; fenestrations: 53-67%). Fourteen SILs occurred in 12 (33%) patients: 4 (29%) in pancreas, 3 (21%) in spleen, 2 (14%) in bowel, 5 (36%) in kidney. The cause was embolic in 79% and thrombotic in 21%. No preoperative clinical/morphological data or procedural data were correlated with SIL. Pancreatic, hepatic, or renal function worsening occurred at 24 hr in 16 (44%), 16 (44%), and 9 (25%) cases, respectively. Overall, SILs were associated with increased values of C-reactive protein (CRP) (17.9 ± 0.4 vs. 9.9 ± 9.0 mg/dL; P = 0.03) and bilirubin (1.2 ± 2.3 vs. 1.0 ± 0.5 mg/dL; P = 0.02) at 24 hr. Specifically, SIL of the celiac trunk and superior mesenteric and renal arteries' parenchyma were associated with the significant laboratory function changes 24 hr. SIL of the superior mesenteric artery was associated with increased 30-day mortality (50% vs. 7 %; P = 0.002). Pancreatic, hepatic, or renal function worsening occurred at 30 days in 2 (6%), 0 (0%), and 4 (12%) cases, with similar laboratory tests in patients with and without SIL. CONCLUSIONS: SIL can be frequently detected after FB-EVAR for TAAA and appears mainly of embolic origin. No clinical, morphological, or procedural predictors could be identified in our series. Postoperative laboratory changes of CRP, bilirubin, activated partial thromboplastin time, and amylases are associated with SIL but disappear without clinical consequences within 30 days. However, SIL occurring in the superior mesenteric artery are associated with an increased 30-day mortality.

The combined use of stent retriever and neuro-aspiration as successful bail-out reperfusion strategy in a patient with embolic myocardial infarction.

Embolic myocardial infarction account for ≈3% of all ST-segment myocardial infarction and represents a challenge often left no-reperfused because current thrombectomy technologies are inefficient to grab thrombus wedged into distal coronary arteries. We present the case of a 34-year-old man who presented with anterior STEMI and a proximal left anterior descending coronary artery ulcerated plaque with a great thrombus burden, which led to distal embolization. Failure of several attempts of manual and rheolytic thrombectomy, led us to use the "Solumbra technique", the combined use of stent retriever and Penumbra catheter was successful in restoring patency and flow.

Safety of transfer, type of procedure, and factors predictive of limb salvage in a modern series of acute limb ischemia.

OBJECTIVE: The primary objective was to evaluate the safety of transfer, type of procedure, and factors associated with limb salvage in patients with acute limb ischemia (ALI) treated at a quaternary referral center. METHODS: A retrospective review of all patients with ALI secondary to thrombotic or embolic occlusion at a quaternary referral hospital from 2013 to 2016 was conducted. Patients were transferred from throughout Washington and Alaska by ambulance, helicopter, or fixed-wing modes of transportation. Demographics, transport and operative timing, Rutherford classification, level of occlusion, procedural information, and fasciotomy characteristics were reviewed. Outcomes measured included limb salvage rates, discharge disposition, and mortality. RESULTS: One hundred twelve patients with ALI were identified, with 82% due to thrombosis and 18% due to arterial embolization. Fifty-seven percent of patients were transferred from a referring hospital with low mean transfer times (1.9 hours for embolic, 2.7 hours for thrombotic). Although the initial operative strategy varied according to the etiology, with 50% of thrombotic occlusions treated with endovascular therapies and 80% of embolic occlusions treated with open thrombectomy, the rates of limb salvage did not vary based on operative approach (92% endovascular first, 90% open first). Further, limb salvage rates were identical between transferred and nontransferred patients (77%). Limb salvage was successful in 91% of patients with Rutherford class 1 and 2 disease, but only 8% in patients with Rutherford class 3 disease. In-hospital and 30-day mortality rates were not different based on ischemic etiology (5%), although patients with Rutherford class 3 disease had significantly higher mortality rates (15%) compared with patients with class 1 (6%), class 2a (6%), and class 2b (2%) disease. Fasciotomy was performed in 29% of patients, with 59% of fasciotomy wounds closed primarily. Predictors of amputation include multiple attempts at limb salvage, higher Rutherford class, multilevel occlusion, more proximal levels of occlusion, and nonviable muscle seen after fasciotomy, with ischemic times trending toward higher amputation rates without statistical significance. There was no difference in discharge disposition based on ischemic etiology. CONCLUSIONS: The modern treatment of patients with ALI is effective, with high rates of limb salvage and low mortality regardless of transfer status, etiology, or initial operation performed. In situations where compartment syndrome is unclear, fasciotomy should not be withheld because it provides valuable predictive information regarding limb salvage.