Michael E. Kelly

Background: Despite advances in cardiac tissue engineering, generating constructs that simultaneously achieve vascularization and organized cardiomyocyte function remains a major challenge. Methods: In this study, three-dimensional (3D) bioprinting was used to fabricate human umbilical vein endothelial cell (HUVEC)-laden alginate/gelatin constructs with defined architectures designed to mimic myocardial alignment. Constructs were cultured with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) under static conditions followed by short-term dynamic stimulation in a bioreactor. Cardiomyocytes - H9c2 cells, neonatal rat ventricular myocytes (NRVMs), or human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) - were subsequently seeded onto the constructs. Vascularization and the distribution of cells were assessed using immunofluorescence, and functional activity of cardiomyocytes was evaluated by calcium transient imaging. Results: Bioprinted constructs developed interconnected CD31-positive endothelial networks in response to growth factor supplementation and dynamic culture, whereas control constructs cultured without growth factors or bioreactor exposure showed limited vascular organization. Cardiomyocytes seeded onto vascularized constructs exhibited improved structural organization, including increased alignment and integration with endothelial networks. Functional assessment revealed more synchronized and rhythmic calcium transients compared to non-vascularized constructs. Conclusion: This study demonstrates that combining 3D bioprinting with controlled architectural design and endothelial network formation enhances cardiomyocyte organization and function. These findings highlight the critical role of vascular-like networks in improving the performance of engineered cardiac tissues.

This boy in mid childhood presented with a sudden, excruciating occipital headache following a week of progressive gait unsteadiness and neck-accentuated meningeal pain. CT demonstrated tetraventricular haemorrhage with early obstructive hydrocephalus and perimesencephalic subarachnoid blood. CT angiography/magnetic resonance angiography (MRA) and digital subtraction angiography revealed a cervicomedullary perimedullary arteriovenous fistula (PMAVF) supplied by the anterior and posterior spinal arteries with a single venous pouch aneurysm at C3–4. Emergency external ventricular drain (EVD) placement was performed. Definitive endovascular cure was achieved 72 hours later using simultaneous bilateral micro-catheterisation of the venous pouch and 'parallel' coiling under multimodality neuromonitoring, completely occluding the shunt while preserving spinal arterial flow. The patient recovered without any neurological deficit, the EVD was gradually weaned over the first 5 postoperative days and removed without clinical or radiological difficulty, and the 12-week MRI/MRA confirmed complete occlusion; at that time, he had returned fully to school and sports including football. This case highlights the importance of cervicomedullary vascular imaging in atraumatic paediatric Subarachnoid Hemorrhage (SAH)/intraventricular haemorrhage and illustrates that complex type III/C PMAVFs can be safely cured in a single session using a dual-pedicle coiling strategy in select cases.

Lower gray matter volume, and cortical thinning in heart failure are regionally dependent, and independent of age. Patients living with heart failure had higher cortical curvature, but older adults did not. Lower gray matter volume, cortical thinning, and cognitive impairment were associated with markers of cardiac dysfunction, with ejection fraction, and end systolic volume index being better predictors among the older and heart failure cohort than cardiac index.

Background: Most people do not recognize symptoms of neurological and cardiac emergencies in a timely manner. This leads to delays in hospital arrival and reduced access to therapies that can open arteries. We created a smartphone app to help patients and families evaluate if symptoms may be high risk for stroke or heart attack (myocardial infarction, MI). The ECHAS (Emergency Call for Heart Attack and Stroke) app guides users to assess their risk through evidence-based questions and a test of weakness in one arm by evaluating finger-tapping on the smartphone. Objective: This study is an initial step in the accuracy evaluation of the app focused on sensitivity. We evaluated whether the app provides appropriate triage advice for patients with known stroke or MI symptoms in the Emergency Department. We designed this study to evaluate the sensitivity of the app, since the most dangerous output of the app would be failure to recognize the need for emergency evaluation. Specificity is also important, but the consequences of low specificity are less dangerous than those of low sensitivity. Methods: In this single-center cross-sectional study, we enrolled patients presenting with symptoms of possible stroke or MI. The ECHAS app assessment consisted of a series of evidence-based questions regarding symptoms and a test of finger-tapping speed and accuracy on the phone’s screen to detect unilateral arm weakness. The primary outcome was the sensitivity of the ECHAS app in detecting the need for ED evaluation. The secondary outcome was the sensitivity of the ECHAS app in detecting the need for hospital admission. Two independent and blinded board-certified physicians reviewed the medical record and adjudicated the appropriateness of the ED visit based on a 5-point score (ground truth). Finally, we asked patients semistructured questions about the app’s ease of use, drawbacks, and benefits. Results: We enrolled 202 patients (57 with stroke and 145 with MI). The ECHAS score was strongly correlated with the ground truth appropriateness score (Spearman correlation 0.41, P<.001). The ECHAS app had a sensitivity of 0.98 for identifying patients in whom ED evaluation was appropriate. The app had a sensitivity of 1.0 for identifying patients who were admitted to the hospital because of their ED evaluation. Patients completed an app session in an average of 111 (SD 60) seconds for the stroke pathway and 60 (SD 33) seconds for the MI pathway. Patients reported that the app was easy to use and valuable for personal emergency situations at home. Conclusions: The ECHAS app demonstrated a high sensitivity for the detection of patients who required emergency evaluation for symptoms of stroke or MI. This study supports the need for a study of specificity of the app, and then a prospective trial of the app in patients at increased risk of MI and stroke.

The brain is a privileged organ with regards to its trace element composition and maintains a robust barrier system to sequester this specialized environment from the rest of the body and the vascular system. Stroke is caused by loss of adequate blood flow to a region of the brain. Without adequate blood flow ischemic changes begin almost immediately, triggering an ischemic cascade, characterized by ion dysregulation, loss of function, oxidative damage, cellular degradation, and break down of the barrier that helps maintain this environment. Ion dysregulation is a hallmark of stroke pathophysiology and we observe that most elements in the brain are dysregulated after stroke. X-ray fluorescence-based detection of physiological changes in the neurometallome after stroke reveals profound ion dysregulation within the lesion and surrounding tissue. Not only are most elements significantly dysregulated after stroke, but the level of dysregulation cannot be predicted from a cell-level description of dysregulation. X-ray fluorescence imaging reveals that the stroke lesion retains < 25% of essential K⁺ after stroke, but this element is not concomitantly elevated elsewhere in the organ. Moreover, elements like Na⁺, Ca²⁺, and Cl⁻ are vastly elevated above levels available in normal brain tissue (>400%, >200%, and > 150%, respectively). We hypothesize that weakening of the blood-brain-barrier after stroke allows elements to freely diffuse down their concentration gradient so that the stroke lesion is in equilibrium with blood (and the compartments containing brain interstitial fluid and cerebrospinal fluid). The changes observed for the neurometallome likely has consequences for the potential to rescue infarcted tissue, but also presents specific targets for treatment.

BACKGROUND: Interhospital transfer for patients with stroke due to large vessel occlusion for endovascular thrombectomy (EVT) has been associated with treatment delays. METHODS: We analyzed data from Optimizing Patient Treatment in Major Ischemic Stroke With EVT, a quality improvement registry to support EVT implementation in Canada. We assessed for unadjusted differences in baseline characteristics, time metrics, and procedural outcomes between patients with large vessel occlusion transferred for EVT and those directly admitted to an EVT-capable center. RESULTS: Between January 1, 2018, and December 31, 2021, a total of 6803 patients received EVT at 20 participating centers (median age, 73 years; 50% women; and 50% treated with intravenous thrombolysis). Patients transferred for EVT (n=3376) had lower rates of M2 occlusion (22% versus 27%) and higher rates of basilar occlusion (9% versus 5%) compared with those patients presenting directly at an EVT-capable center (n=3373). Door-to-needle times were shorter in patients receiving intravenous thrombolysis before transfer compared with those presenting directly to an EVT center (32 versus 36 minutes). Patients transferred for EVT had shorter door-to-arterial access times (37 versus 87 minutes) but longer last seen normal-to-arterial access times (322 versus 181 minutes) compared with those presenting directly to an EVT-capable center. No differences in arterial access-to-reperfusion times, successful reperfusion rates (85% versus 86%), or adverse periprocedural events were found between the 2 groups. Patients transferred to EVT centers had a similar likelihood for good functional outcome (modified Rankin Scale score, 0–2; 41% versus 43%; risk ratio, 0.95 [95% CI, 0.88–1.01]; adjusted risk ratio, 0.98 [95% CI, 0.91–1.05]) and a higher risk for all-cause mortality at 90 days (29% versus 25%; risk ratio, 1.15 [95% CI, 1.05–1.27]; adjusted risk ratio, 1.14 [95% CI, 1.03–1.28]) compared with patients presenting directly to an EVT center. CONCLUSIONS: Patients transferred for EVT experience significant delays from the time they were last seen normal to the initiation of EVT.

Element dysregulation is a pathophysiologic hallmark of ischemic stroke. Prior characterization of post-stroke element dysregulation in the photothrombotic model demonstrated significant element changes for ions that are essential for the function of the neurovascular unit. To characterize the dynamic changes during the early hyperacute phase (<6 h), we employed a temporary large-vessel occlusion stroke model. The middle cerebral artery was temporarily occluded for 30 min in male C57BL/6 mice, and coronal brain sections were prepared for histology and X-ray fluorescence microscopy from 5 to 120 min post-reperfusion. Ion dysregulation was already apparent by 5 min post-reperfusion, evidenced by reduced total potassium in the lesion. Later time points showed further dysregulation of phosphorus, calcium, copper, and zinc. By 60 min post-reperfusion, the central portion of the lesion showed pronounced element dysregulation and could be differentiated from a surrounding region of moderate dysregulation. Despite reperfusion, the lesion continued to expand dynamically with increasing severity of element dysregulation throughout the time course. Given that the earliest time point investigated already demonstrated signs of ion disruption, we anticipate such changes may be detectable even earlier. The profound ion dysregulation at the tissue level after reperfusion may contribute to hindering treatments aimed at functional recovery of the neurovascular unit.

BACKGROUND AND PURPOSE: Baseline CTP sometimes overestimates the size of the infarct core (“ghost core” phenomenon). We investigated how often CTP overestimates infarct core compared with 24-hour imaging, and aimed to characterize the patient subgroup in whom a ghost core is most likely to occur. MATERIALS AND METHODS: Data are from the randomized controlled ESCAPE-NA1 trial, in which patients with acute ischemic stroke undergoing endovascular treatment were randomized to intravenous nerinetide or placebo. Patients with available baseline CTP and 24-hour follow-up imaging were included in the analysis. Ghost infarct core was defined as CTP core volume minus 24-hour infarct volume > 10 mL). Clinical characteristics of patients with versus without ghost core were compared. Associations of ghost core and clinical characteristics were assessed by using multivariable logistic regression. RESULTS: A total of 421 of 1105 patients (38.1%) were included in the analysis. Forty-seven (11.2%) had a ghost core > 10 mL, with a median ghost infarct volume of 13.4 mL (interquartile range 7.6–26.8). Young patient age, complete recanalization, short last known well to CT times, and possibly male sex were associated with ghost infarct core. CONCLUSIONS: CTP ghost core occurred in ∼1 of 10 patients, indicating that CTP frequently overestimates the infarct core size at baseline, particularly in young patients with complete recanalization and short ischemia duration.

Background and Aim Endovascular treatment of acute stroke necessitates fast transport across large geographic distances which influences the time to treatment and ultimately patient outcomes. While probabilistic models have been developed to postulate the influence of distance and processing times in drip and ship models,¹ real life data on actual transport times and its influence on outcomes has been under studied in real-world populations. We retrospectively examined and analysed the transport registry of EVT treated patients across the large province of Saskatchewan. Methods A linked registry based on medical records and Optimize database was used to capture the journey from home to hospital in patients who underwent EVT from Aug 2017 to Dec 2022 across Saskatchewan. Transport modality of the patients and whether they were directly presented to CSC, or first presented to a peripheral hospital PSC was determined and the patient’s geolocation was mapped using the google distance matrix API. Communities were classified as large urban, medium, and small population centers based on stats Canada classification. Association of functionally independent outcomes mRS 0-2 was examined for transport type, community size, and Kilometer distance from home to CSC, and some via PSC. Influence of each Km of distance during each transport was examined on the shift of outcome using ordinal logistic regression. Results 303 patient that underwent thrombectomy over a 5 year period were examined of which 55% presented directly via EMS, 36% Transferred from peripheral sites, and 9% were in-patient treated. Compared to the direct presentation, the transfer patients did not have a significantly worse outcomes OR 0.8 p=0.382 (CI 0.16 - 0.7) as the direct patient, while the inpatients did worse overall OR 0.38 p=0.042 (CI 0.16- 0.97). Size of community the patient presented from or transferred from did not influence outcomes. In an adjusted analysis number of Km of transport did not have an influence on outcomes OR 1.00 p=0.827 (CI .99- 1.00). Conclusions Real world geographic factors influence time to treatment, however patient specific factors play a great role in determining patient’s overall outcome during long transports. Factors such as collaterals, occlusion location, and initial aspects are more important than number of kilometers distance travelled or transfer from PSC alone. In an efficient transport system, centralized treatment at the CSC is a viable solution and does not preclude achieving functionally independent outcomes. Disclosures N. Kashani: None. A. Zhou: None. J. Ospel: None. N. Singh: None. A. Gardner: None. A. Persad: None. R. Otani: None. U. Ahmed: None. L. Peeling: None. M. Kelly: None.