Acute Ischemic Events Research Articles

Computed Tomography Perfusion Imaging in Acute Ischemic Stroke: Accurate Interpretation Matters.

Computed Tomography Perfusion Imaging in Acute Ischemic Stroke: Accurate Interpretation Matters.

Atherosclerotic carotid plaque characteristics vary with time from ischemic event: A multicenter, prospective magnetic resonance vessel wall imaging registry study

Recent studies report that the rate of recurrent stroke is highest in the stages immediately following cerebral infarction and decreases over time in patients with atherosclerotic carotid stenosis. The purpose of this study was to identify temporal differences in early stage carotid plaque components from acute cerebrovascular ischemic events using carotid MRI. Carotid plaque images were obtained on 3 T MRI from 128 patients enrolled in MR-CAS. Among the 128 subjects, 53 were symptomatic and 75 asymptomatic. The symptomatic patients were classified into three groups based on interval from onset of symptoms to the date of the carotid MRI (Group <14 days; 15-30 days; and > 30 days). The volume of each plaque component was identified and quantified from MR images. The presence of juxtaluminal loose matrix/inflammation (LM/I) was identified as a possible indicator of inflammation on the luminal side. Plaque components were compared between groups using the Wilcoxon rank-sum or the Chi-square test. Patient characteristics and carotid plaque morphology were similar among all four groups. The median volume of LM/I in Group >30 days was significantly lower than in other groups (0 mm3 vs 12.3 mm3 and 18.1 mm3; p = 0.003). In addition, the prevalence of juxtaluminal LM/I decreased over time (ptrend = 0.002). There were no statistically significant differences in other plaque components between the symptomatic groups. The volume of LM/I was significantly smaller in Group >30 days and prevalence of juxtaluminal LM/I in the atherosclerotic carotid plaque was high in the early stages after events. This suggests that carotid plaques undergo rapid evolution after an acute cerebrovascular ischemic event.

MTHFR C677T polymorphism, homocysteine, burden, and location of AMI and ACI.

We aimed to investigate the relationship between homocysteine levels and MTHFR C677T polymorphisms and acute ischemic vascular events and focused on the differential effects of the MTHFR C677T polymorphisms on the burden and location of AMI and ACI. 102 acute cerebral infarction (ACI) and acute myocardial infarction (AMI) patients who were admitted to the First Hospital of Jilin University in northeast China as the patient group, 83 healthy people who were hospitalized during the same period served as a control group. MTHFR C677T genotypes were identified via Polymerase Chain Reaction (PCR)-Fluorescent Probe Method. Patient group had higher serum homocysteine levels (p=0.013), lower serum folic acid (p<0.001), and Vit B12 levels (p=0.004) compared to the control group. Homocysteine levels in the patient group with the TT genotypes of the MTHFR C677T polymorphisms were higher than those with the CC and CT genotypes (p<0.05). Folic acid levels in the patients with TT genotypes were lower than those with the CC genotypes (p<0.05), but not in the control group (p>0.05). There were negative and significant associations between serum homocysteine levels and serum vitamin B12 levels in the control group (r=-0.234, p=0.033), but not between serum homocysteine levels and serum folic acid levels (r=-0.103, p=0.355). Conversely, there was a negative and significant association between serum homocysteine levels and serum folic acid levels in the patients' group (r=-0.257, p=0.01), but not between serum homocysteine levels and serum vitamin B12 levels (r=-0.185, p=0.64). No statistically significant differences in MTHFR C677T genotype and C/T alleles distribution were investigated between the patient and control group (p>0.05). The MTHFR C677T polymorphism did not differentially affect the burden and location of AMI and ACI. Homocysteine played a common role in atherosclerosis-related acute ischemic vascular events. These correlations were modified by MTHFR C677T polymorphisms and influenced by folic acid levels. The MTHFR C677T polymorphisms were not directly related to acute ischemic vascular events, nor did they differentially affect the burden and location of AMI and ACI.

Abstract WP184: Identifying Optimal Cut Points Of National Institutes Of Health Stroke Scale To Predict Mortality: A Population-based Assessment

Background: Ischemic stroke is the 5 th leading cause of death in the US. As a measure of stroke severity, initial NIHSS has been used to predict clinical outcome. We sought to identify the optimal cut-points of NIHSS at initial presentation that are associated with higher 30-day mortality. Methods: In 2005, 2010, and 2015 all hospitalized, first acute ischemic stroke events occurring within the Greater Cincinnati area were ascertained. Potential ischemic stroke cases underwent chart abstraction and physician adjudication, including retrospective NIHSS score (range 0 - 42) based on clinical findings at initial presentation. Descriptive statistics for NIHSS were estimated by study year, demographics, and medical history. Data regarding mortality was obtained from the National Death Index. The Contal and O’Quigley method based on a modified log-rank test statistic was used to determine cut-points of the NIHSS score associated with 30-day mortality, and hazard ratios were obtained from Cox models with adjustment for sex, race, and age. Results: In 2005, 2010, and 2015 there were 1704, 1818 and 1852 ischemic stroke events with 30-day mortality rates of 10.5%, 9.6% and 9.0%, respectively. Optimal cut-points of NIHSS &lt;9, 9-16 and &gt;16 were identified. Across all 3 periods, 3431 (84.5%) cases had NIHSS 0-8, 352 (8.7%) had NIHSS 9-16 and 274 (6.8%) &gt;16. Kaplan Meier Survival Curves for the 3 NIHSS groups are shown in the Figure. Strokes with NIHSS &gt;16 at initial presentation were associated with a 15-fold (HR with 95% CI: 13, 19) increase in the risk of death at 30-days compared to those with NIHSS &lt;9. Discussion: NIH Stroke Scale scores are a reliable predictor of mortality, with higher NIHSS scores having higher risk of death. The cut points reported identify subgroups of stroke patients with dramatically different prognoses. Future studies should assess if this excess mortality risk among severe strokes persists after the more widespread implementation of thrombectomy beyond 2015.

Protocolised reduction of non-resuscitation fluids versus usual care in patients with septic shock (REDUSE): a protocol for a multicentre feasibility trial

IntroductionAdministration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care...

Abstract 43: Is Dual Antiplatelet Therapy Underutilized Following TIA And Minor Stroke?

Background: Initiation of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel plays a significant role in the secondary prevention of recurrent acute ischemic events following high risk transient ischemic attack (TIA) and minor acute ischemic stroke (AIS). However, some patients do not receive the same targeted therapy on discharge and are only maintained on single antiplatelet therapy. Our aim was to identify the variations in single vs dual antiplatelet prescribing practices at the time of discharge within a Stroke Clinical Network consisting of nine stroke centers located in rural, suburban, and urban geographical regions. Methods: The GWTG registry was queried for all patients &gt;18 years old with a TIA or a minor AIS (admission NIHSS ≤5), who were admitted to a single hospital network between January 2018 and December 2021. Demographics collected including age, race, gender, and BMI. Patients on concurrent anticoagulation were excluded. We evaluated antiplatelet discharge practices at the tertiary stroke center vs the entire network, among men vs. women, African Americans (AA) vs whites, age 18-70 vs &gt;70 years, and across BMI. Chi squared and generalized linear models were used to test significant relationships between subgroups. Results: Among 2953 patients with a TIA or minor AIS, the mean age was 67.3 (SD +/- 13.8 years), with 42% &gt;70 years of age. 47.8% were women; 37% were AA and 60% were white. DAPT was prescribed at the time of discharge to 40% of patients overall. Gender was a significant factor with men (43%) more likely to get prescribed DAPT than females (37%) (p=.002). While BMI did not have a lone effect on number of antiplatelets (AP) prescribed, when it was included as a covariate, there was a significant effect on the number of AP prescribed; with the higher the BMI, the less likely patients were to receive DAPT. Differences according to age, race, and effect of whether the patient was discharged from a tertiary center were not significant. Conclusion: We identified underutilization of DAPT following TIA and minor stroke across a health system, especially in women. Targeted intervention to increase DAPT use could lead to reduced rate of short-term stroke recurrence.

Absence of High Lipoprotein(a) Levels Is an Independent Predictor of Acute Myocardial Infarction without Coronary Lesions.

The pathophysiological mechanisms underlying Myocardial Infarction with Non-Obstructive Coronary Artery Disease (MINOCA) are still under debate. Lipoprotein (a) [Lp(a)] has proinflammatory and prothrombotic actions and has been involved in the pathogenesis of atherosclerosis. However, no previous studies have linked Lp(a) levels with the probability of developing MINOCA. Moreover, the relationship between MINOCA and the plasma levels of other proatherogenic and proinflammatory molecules such as Interleukin-18 (IL18) and proprotein convertase subtilisin/kexin type 9 (PCSK9) has not been studied. We conducted a prospective, multicenter study involving 1042 patients with acute myocardial infarction (AMI). Seventy-six patients had no significant coronary lesions. All patients underwent plasma analysis on admission. MINOCA patients were younger (57 (47-68) vs. 61 (52-72) years; p = 0.010), more frequently female (44.7% vs. 21.0%; p < 0.001), and had lower rates of diabetes and of Lp(a) > 60 mg/dL (9.2% vs. 19.8%; p = 0.037) than those with coronary lesions; moreover, High Density Lipoprotein cholesterol (HDL-c) levels were higher in MINOCA patients. The absence of Lp(a) > 60 mg/dL and of diabetes were independent predictors of MINOCA, as well as female sex, high HDL-c levels, and younger age. IL-18 and PCSK9 levels were not predictors of MINOCA. During a follow-up of 5.23 (2.89, 7.37) years, the independent predictors of the primary outcome (acute ischemic events or death) in the whole sample were Lp(a) > 60 mg/dL, older age, low estimated Glomerular Filtration rate (eGFR), hypertension, previous heart failure (HF), coronary artery bypass graft, use of insulin, and no therapy with acetylsalicylic acid. In conclusion, in AMI patients, the absence of high Lp(a) levels, as well high HDL-c levels, were independent predictors of the inexistence of coronary artery disease. High Lp (a) levels were also an independent predictor of ischemic events or death.

Comparison of adhesive single-lead cardiac ECG patch device with Holter monitoring for detecting atrial fibrillation after an acute cerebral ischemic event: An interim analysis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health Malaysia Background Stroke secondary to atrial fibrillation (AF) is common and often associated with higher risk of stroke recurrence. Detection of AF is challenging due to brief unpredictable episodes of AF runs, especially in patients whose admission electrocardiogram (ECG) demonstrates a sinus rhythm. Probability of AF detection may be higher with early initiation of prolonged ECG monitoring. Purpose To compare diagnostic yield of 7-day cardiac ECG patch versus 24-hour Holter monitoring for detecting AF≥30 seconds; to identify predictors of AF in stroke patients; to determine if 7-day cardiac ECG patch results in a change in clinical practice. Methods In this investigator-initiated prospective study with pairwise comparison of 24-hour Holter and 7-day cardiac ECG patch monitoring, 150 patients who were admitted to a tertiary referral centre with acute ischemic stroke (AIS) or transient ischemic attack (TIA) within 1 week, without known AF, and had sinus rhythm in the admission 12-lead ECG were enrolled. Each patient underwent simultaneous 24-hour Holter and 7-day cardiac ECG patch monitoring. Routine transthoracic echocardiography was performed on each patient to assess cardiac function and exclude intracardiac thrombus. Results There were 102 (68.0%) male patients. 12 (8.0%) patients had underlying history of coronary artery disease; 26 (17.3%) had recurrent stroke or TIA. On admission, median NIH Stroke scale was 4; 18 (12.0%) patients had thrombolysis with alteplase. On transthoracic echocardiography, none had intracardiac thrombus. Both Holter and cardiac ECG patch monitoring were initiated simultaneously at median 2 days after index stroke event. Of 150 patients, 17 (11.3%) detected AF ≥30 seconds. Of these 17 patients, 7 (4.7%) had AF detected within the first 24 hours on both Holter and cardiac ECG patch; 10 (6.7%) were detected after 24 hours on cardiac ECG patch only. Number needed to screen to detect one AF was 6. Compliance to 7-day cardiac ECG patch monitoring was 81.3%. There was no significant difference in age among patients with and without AF. Although left atrium (LA) was not found to be dilated in patients with AF, LA volume index was significantly higher (28.3±15.9 vs 21.8±8.5, p=0.018) and LA emptying fraction (LAEF) was significantly lower (38.0%±30.2 vs 52.6%±16.7, p=0.007). The prolonged 7-day cardiac ECG monitoring patch resulted in 1.5-fold increase in prescription of anticoagulation therapy. Conclusions A 7-day cardiac ECG patch monitoring detected more patients with AF ≥30 seconds than 24-hour Holter monitoring and resulted in increase in prescription of anticoagulation therapy. Higher LA volume index and lower LA emptying fraction were predictors of AF in patients with a recent stroke.

CRP as a potential predictor of outcome in acute ischemic stroke.

Ischemic stroke is one of the major causes of death and long-term disability worldwide. C-reactive protein (CRP) as a potential biomarker for functional outcome after acute ischemic stroke remains controversial. The aim of the present study was to examine the association between the level of CRP and functional outcome of stroke. A total of 218 consecutive patients with acute ischemic stroke within 24 h after onset were recruited for the study. Poor functional outcome was defined as a modified Rankin scale score of >2 at 3 months after stroke. The retrospective analysis was performed to investigate whether CRP within 24 h after stroke is associated with poor functional outcome at 3 months. Multivariate logistic regression analysis indicated that the CRP level (odds ratio=1.146, 95%CI: 1.012-1.297, P=0.031) was an independent risk factor for poor outcome. The receiver operating characteristics curve analysis revealed that the optimal cut-off value of CRP to distinguish favorable from poor outcome was 6.34 (area under the curve=0.829, 95%CI: 0.772-0.887, P<0.001), with 68.2% sensitivity and 85.7% specificity. Spearman correlation analysis indicated that the CRP level was positively related to the baseline National Institutes of Health Stroke Scale (NIHSS) score (r=0.551, P<0.001), fasting glucose (r=0.301, P<0.001) and age (r=0.252, P<0.001). In conclusion, a high level of CRP within 24 h after onset was associated with a poor functional outcome after the acute ischemic event. The elevation of CRP may be correlated with the baseline NIHSS score, fasting glucose and age.

Intake of marine and plant-derived n-3 fatty acids and development of atherosclerotic cardiovascular disease in the Danish Diet, Cancer and Health cohort.

The objective of this study was to investigate the association between intake of seafood and plant-derived n-3 polyunsaturated fatty acids (PUFA) and development of total atherosclerotic cardiovascular disease (ASCVD) and acute major ischemic events. A total of 53,909 men and women were enrolled between 1993 and 1997 into the Danish Diet, Cancer and Health cohort and followed through nationwide Danish registries for development of total ASCVD defined as a first registration of myocardial infarction, peripheral artery disease, or ischemic stroke due to large artery atherosclerosis or small-vessel occlusion. At recruitment, the intake of the major marine n-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the plant-derived n-3 PUFA, alpha-linolenic acid (ALA), was assessed using a validated food frequency questionnaire. Statistical analyses were conducted using sex-stratified multivariable Cox proportional hazard regression models. During a median of 13.5years of follow-up, 3958 participants developed ASCVD including 3270 patients with an acute major ischemic event. In multivariable analyses including adjustment for established risk factors, we found no associations for intake of ALA, but indications of inverse associations between intake of EPA, DHA and EPA + DHA and the rate of total ASCVD and acute major ischemic events. A high intake of marine n-3 PUFA was associated with a lower risk of total ASCVD and acute major ischemic events, whereas no association could be demonstrated for the plant-derived ALA.

Factors associated with development of an acute ischemic event during hospitalization for COVID-19 in cancer and non-cancer patients.

COVID-19 and solid cancer are both associated with an increased risk of thromboembolism. Assess whether solid cancer is a risk factor for acute ischemic event development among patients with COVID-19. Retrospective cohort SETTING: A tertiary training and research hospital PATIENTS AND METHODS: Patients who were hospitalized for COVID-19 for ≥3 days between 15 March 2020 and 30 March 2021 at Antalya Training and Research Hospital, Antalya, Turkiye. were included in the study. Independent predictors of the development of acute ischemic events during hospitalization were determined using multivariable logistic regression analysis. Risk factors for acute ischemic event development. 538 patients. Patients diagnosed with solid cancer comprised 11.3% of the cohort (n=61). Forty-one (7.6%) developed an acute ischemic event at a median of 3 (range, 1-15) days after hospitalization. The presence of a solid cancer (OR 3.80, 95% CI 1.20-12.03, P=.023) along with length of hospital stay (OR 1.05 per day, 95% CI 1.01-1.09, P=.025) were independent predictors of acute ischemic event development during the course of COVID-19. Mortality was reported in 200 (37%) patients at a median of 5 (range, 3-10) days after hospitalization. The presence of solid tumor increased mortality 5.83 times (95% CI 3.19-10.63, P<.001) while this ratio was 4.59 (95% CI 2.29-9.23, P<.001) for patients who experienced an acute ischemic event. Patients with active cancer carry a significant risk for acute ischemic event development during the course of COVID-19 and such patients may require particular attention in terms of anticoagulation therapy. Retrospective design and small sample size. None.

Protective Role of Chronic Exercise Training in Modulating the Impact of Hyperglycemia on Vascular Sensitivity to Ischemia-Reperfusion

Hyperglycemia (HG) is associated with increased mortality and morbidity in acute ischemic events. Regardless of the tissue or organs involved, the vascular endothelium is a key target of ischemia-reperfusion (I/R) injury severity. Among endothelium-protective strategies, exercise has been widely described as useful. However, whether this strategy is able to impact the deleterious effect of HG on endothelial function during I/R has never been challenged. For this, 48 male Wistar rats were randomized into 4 groups: sedentary (Sed) or exercised (Ex, 45 min/day, 5 days/week for 5 weeks) rats, treated (hyperglycemic, HG) or not (normoglycemic, NG) with streptozotocin (40 mg/kg, 48 h before procedure). Vascular I/R (120/15 min) was performed by clamping the femoral artery. Arterial and downstream muscular perfusions were assessed using laser speckle contrast imaging. Vascular endothelial function was assessed in vivo 15 min after reperfusion. HG was responsible for impairment of reperfusion blood flow as well as endothelial function. Interestingly exercise was able to prevent those impairments in the HG group. In agreement with the previous results, HG increased reactive oxygen species production and decreased nitric oxide bioavailability whereas exercise training normalized these parameters. It, therefore, appears that exercise may be an effective prevention strategy against the exacerbation of vascular and muscular damage by hyperglycemia during I/R.

Hypoxia Primes Human ISCs for Interleukin-Dependent Rescue of Stem Cell Activity

Hypoxia in the intestinal epithelium can be caused by acute ischemic events or chronic inflammation in which immune cell infiltration produces inflammatory hypoxia starving the mucosa of oxygen. The epithelium has the capacity to regenerate after some ischemic and inflammatory conditions suggesting that intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of hypoxia on human ISC (hISC) function has not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs from healthy donors and test the hypothesis that prolonged hypoxia modulates how hISCs respond to inflammation-associated interleukins (ILs). hISCs were exposed to <1.0% oxygen in the MPS for 6, 24, 48, and 72 hours. Viability, hypoxia-inducible factor 1a (HIF1a) response, transcriptomics, cell cycle dynamics, and response to cytokines were evaluated in hISCs under hypoxia. HIF stabilizers and inhibitors were screened to evaluate HIF-dependent responses. The MPS enables precise, real-time control and monitoring of oxygen levels at the cell surface. Under hypoxia, hISCs maintain viability until 72 hours and exhibit peak HIF1a at 24 hours. hISC activity was reduced at 24 hours but recovered at 48 hours. Hypoxia induced increases in the proportion of hISCs in G1 and expression changes in 16 IL receptors. Prolyl hydroxylase inhibition failed to reproduce hypoxia-dependent IL-receptor expression patterns. hISC activity increased when treated IL1β, IL2, IL4, IL6, IL10, IL13, and IL25 and rescued hISC activity caused by 24 hours of hypoxia. Hypoxia pushes hISCs into a dormant but reversible proliferative state and primes hISCs to respond to a subset of ILs that preserves hISC activity. These findings have important implications for understanding intestinal epithelial regeneration mechanisms caused by inflammatory hypoxia.

Thromboembolic phenomenon to bilateral lower limbs is a catastrophic complication of blood culture-negative infective endocarditis

Background: Blood culture-negative infective endocarditis (BCNIE) refers to infective endocarditis (IE) with negative microorganism growth using usual blood culture method. It poses dilemma in terms of diagnosis, associated complication, and treatment. The study aims to highlight the occurrence of acute bilateral lower limb ischemia in BCNIE and its management approach. Case presentation: We present a BCNIE patient who developed acute bilateral lower limb ischemia, Rutherford stage 2b despite on course of antibiotic treatment. Patient underwent emergency bilateral open femoral embolectomy and right profundaplasty. A full six-weeks course of antibiotics and short-term anticoagulant successfully reverse the acute ischemic event. Conclusion: This case highlighted that despite the rarity of BCNIE causing limb ischemia, it can still occur due to significant risk factors. The early recognition of acute limb ischemia and prompt treatment are deemed important in saving the threatened limb from being amputated.

Sonodynamic therapy suppresses matrix collagen degradation in vulnerable atherosclerotic plaque by modulating caspase 3 - PEDF/HIF-1α - MMP-2/MMP-9 signaling in macrophages.

The rupture of vulnerable atherosclerotic plaque is the main cause of acute ischemic vascular events, and is characterized by pathological degradation of matrix collagen in the fibrous cap. In a previous study, we reported that 5-aminolevulinic acid-mediated sonodynamic therapy suppressed collagen degradation in rabbit plaque. However, the underlying molecular mechanism has yet to be fully elucidated. We applied sinoporphyrin sodium-mediated sonodynamic therapy (DVDMS-SDT) to balloon-denuded rabbit and apolipoprotein E-deficient (ApoE-/-) mouse models to observe collagen content in plaque. Cultured human THP-1 and mouse peritoneal macrophage-derived foam cells were used for in vitro mechanistic studies. We observed that DVDMS-SDT decreased plaque area and increased the percentages of collagen and smooth muscle cells and reduced the percentage of macrophages in rabbit and ApoE-/- mouse advanced plaques. In vitro, DVDMS-SDT modulated the caspase 3-pigment epithelium-derived factor/hypoxia-inducible factor-1α (PEDF/HIF-1α)-matrix metalloprotease-2/9 (MMP-2/MMP-9) signaling in macrophage foam cells. Our findings show that DVDMS-SDT effectively inhibits matrix collagen degradation in advanced atherosclerotic plaque by modulating caspase 3-PEDF/HIF-1α-MMP-2/MMP-9 signaling in macrophage foam cells and therefore represents a suitable and promising clinical regimen to stabilize vulnerable plaques.

INVESTIGATING THE PHYSIOLOGICAL RELATIONSHIP BETWEEN ISCHEMIC HEART DISEASE AND HYPOTHYROIDISM

Both hypothyroidism and hyperthyroidism, which are thyroid conditions that are extremely prevalent throughout the world, predispose to CVD in general and CAD in particular. This is especially important for people who have hypothyroidism. Heart failure progression risk and the frequency of coronary events are both raised by overt and subclinical hypothyroidism. Thyroid hormone abnormalities are a common complication of heart disease, especially ischemic heart disease, and should be taken into consideration. In actuality, it is necessary to consider low thyroid hormone levels as a cardiovascular risk factor. Regarding ischemic heart disease, thyroid hormones impact left ventricular structure, function, and geometry in the late post-myocardial infarction stage. Cardio-protection is the new goal of therapies to reduce infarct size and stop the development of heart failure following an acute ischemic event in order to enhance cardiovascular outcomes. Through TR1 binding, TH replacement therapy administered soon after myocardial infarction (or even when delayed) may enhance cardiac function. In this review we will look at the relationship between hypothyroidism and ischemic heart disease.

Canadian Stroke Best Practice Recommendations: Acute Stroke Management, 7th Edition Practice Guidelines Update, 2022.

The 2022 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management, 7th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by an interdisciplinary team of healthcare providers and system planners caring for persons with an acute stroke or transient ischemic attack. These recommendations are a timely opportunity to reassess current processes to ensure efficient access to acute stroke diagnostics, treatments, and management strategies, proven to reduce mortality and morbidity. The topics covered include prehospital care, emergency department care, intravenous thrombolysis and endovascular thrombectomy (EVT), prevention and management of inhospital complications, vascular risk factor reduction, early rehabilitation, and end-of-life care. These recommendations pertain primarily to an acute ischemic vascular event. Notable changes in the 7th edition include recommendations pertaining the use of tenecteplase, thrombolysis as a bridging therapy prior to mechanical thrombectomy, dual antiplatelet therapy for stroke prevention, the management of symptomatic intracerebral hemorrhage following thrombolysis, acute stroke imaging, care of patients undergoing EVT, medical assistance in dying, and virtual stroke care. An explicit effort was made to address sex and gender differences wherever possible. The theme of the 7th edition of the CSBPR is building connections to optimize individual outcomes, recognizing that many people who present with acute stroke often also have multiple comorbid conditions, are medically more complex, and require a coordinated interdisciplinary approach for optimal recovery. Additional materials to support timely implementation and quality monitoring of these recommendations are available at www.strokebestpractices.ca.

Electrophysiological Changes of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes during Acute Hypoxia and Reoxygenation.

Ischemic heart disease is the most common cardiovascular disease and a major burden for healthcare worldwide. However, its pathophysiology is still not fully understood, and human-based models for disease mechanisms and treatments are needed. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model acute ischemia-reperfusion in our novel cell culture assembly. The assembly enables exchange of oxygen partial pressure for the cells within minutes, mimicking acute ischemic event. In this study, hypoxia was induced using 0% O2 gas for three hours and reoxygenation with 19% O2 gas for 24 hours in serum- and glucose-free medium. According to electrophysiological recordings, hypoxia decreased the hiPSC-CM-beating frequency and field potential (FP) amplitude. Furthermore, FP depolarization time and propagation slowed down. Most of the electrophysiological changes reverted during reoxygenation. However, immunocytochemical staining of the hypoxic and reoxygenation samples showed that morphological changes and changes in the sarcomere structure did not revert during reoxygenation but further deteriorated. qPCR results showed no significant differences in apoptosis or stress-related genes or in the expression of glycolytic genes. In conclusion, the hiPSC-CMs reproduced many characteristic changes of adult CMs during ischemia and reperfusion, indicating their usefulness as a human-based model of acute cardiac ischemia-reperfusion.

Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Acute Venous and Arterial Thromboembolic Events in Patients with Monoclonal Gammopathy of Undetermined Significance: A Nation Wide Analysis

Introduction: Monoclonal Gammopathy of Undetermined Significance (MGUS) is a premalignant plasma cell disorder. It is found in over 3% of patients who are 50 years of age or older (Kyle et al., 2006). MGUS is usually asymptomatic; however, it carries an increased risk of certain comorbidities. Some literature suggests an increased risk of venous and arterial thromboembolism in MGUS patients. We sought to examine this relationship using data from the National Inpatient Sample (NIS). Methods: We conducted a cross-sectional study using data from the NIS from the year 2016. We evaluated the frequencies of composite venous and composite arterial thromboembolism outcomes in adult patients with MGUS compared with those who had no history of the disease. IBM SPSS 26.0 was used for analysis. We constructed several logistic regression models to adjust for common confounding variables, including age, sex, race, and expected primary payer. Adjusted odds ratios and confidence intervals were calculated for each composite and component variable. Chi-square tests were used for comparing categorical variables. Results: We identified a total of 8500 patients with the diagnosis of MGUS. Among patients with MGUS, 135 patients (1.6%) had the primary diagnosis of a venous thromboembolic event. These included 55 patients (0.65%) who had acute deep vein thromboembolic events and 80 patients (0.94%) who had pulmonary embolism. Also, 374 patients (4.4%) had the primary diagnosis of an arterial thromboembolic event. These arterial events were divided into 3 categories as follows: 171 discharges (2.01%) were acute thrombo-embolic cardiac events, 190 discharges (2.24%) were acute cerebrovascular ischemic events, and 13 discharges (0.15%) with other arterial thromboembolic events. Patients with MGUS had an increased risk of the composite venous thromboembolism outcome (adjusted odds ratio [OR] 1.271, 95% CI 1.069-1.512). Analysis of the individual components showed a significant increase in the risk of acute deep vein thrombosis (adjusted OR 1.366, 95% CI 1.047-1.782) but failed to show a significant association with the risk of pulmonary embolism (adjusted OR 1.207, 95% CI 0.962-1.513). On the other hand, we found a reduced risk of composite arterial thromboembolism outcome in patients with MGUS (adjusted OR 0.617, 95% CI 0.555-0.685). Individual components analysis showed a reduction in the risk of acute thromboembolic cardiac events (adjusted OR 0.636, 95% CI 0.546-741) and acute ischemic cerebrovascular events (adjusted OR 0.595, 95% CI 0.514-689), but no significant difference was noted in the third group which included other arterial thromboembolic events (adjusted OR 1.343, 95% CI 0.779-2.317). Conclusion: Patients with MGUS had increased odds of developing acute venous thromboembolism, especially deep vein thrombosis, when compared to patients who had no history of MGUS. Interestingly, MGUS patients had reduced odds of developing acute cardiac and cerebrovascular arterial thromboembolic events. More research is required to assess the optimal approach for venous thromboembolism prophylaxis in MGUS patients.