Ischemic Myocardial Infarction Research Articles

The molecular interaction of six single-stranded DNA aptamers to cardiac troponin I revealed by docking and molecular dynamics simulation.

Cardiac troponin I (cTnI) is a cardiac biomarker for diagnosing ischemic heart disease and acute myocardial infarction. Current biochemical assays use antibodies (Abs) due to their high specificity and sensitivity. However, there are some limitations, such as the high-cost production of Abs due to complex instruments, reagents, and steps; the variability of Abs quality from batch to batch; the low stability at high temperatures; and the difficulty of chemical modification. Aptamer overcomes the limitations of antibodies, such as relatively lower cost, high reproducibility, high stability, and ease of being chemically modified. Aptamers are three-dimensional architectures of single-stranded RNA or DNA that bind to targets such as proteins. Six aptamers (Tro1-Tro6) with higher binding affinity than an antibody have been identified, but the molecular interaction has not been studied. In this study, six DNA aptamers were modeled and docked to cTnI protein. Molecular docking revealed that the interaction between all aptamer and cTnI happened in the similar cTnI region. The interaction between aptamer and cTnI involved hydrophobic interaction, hydrogen bonds, π-cation interactions, π-stack interactions, and salt-bridge formation. The calculated binding energy of all complexes was negative, which means that the complex formation was thermodynamically favorable. The electrostatic energy term was the main driving force of the interaction between all aptamer and cTnI. This study could be used to predict the behavior of further modified aptamer to improve aptamer performance.

Long-Term Clinical Implications of High-Risk Cardiac Computed Tomography Findings in Patients With Acute Ischemic Stroke.

Cardiac computed tomography (CT) acquired during the initial acute stroke imaging protocol (acute cardiac CT) is increasingly used to screen for cardioembolism, but information on the long-term clinical implications of its findings is lacking. We performed a prospective, single-center cohort study in which consecutive patients with ischemic stroke underwent ECG-gated acute cardiac CT and were followed up for 2 years. The primary outcome was functional outcome assessed using the modified Rankin Scale. Secondary outcomes were death and occurrence of major adverse cardiovascular events (composite of recurrent ischemic stroke, myocardial infarction, and cardiovascular death). We compared patients with and without a high-risk structural source of embolism on acute cardiac CT. Of 452 included patients, 55 (12.2%) had a high-risk source of embolism, predominantly cardiac thrombi (38 patients) and signs of endocarditis (8 patients). Follow-up at 2 years was complete for 430 (95.1%) patients. Patients with a high-risk source of embolism had a worse functional outcome (median modified Rankin Scale, 6 [IQR, 2-6] versus 2 [IQR, 1-5]; adjusted common odds ratio, 2.92 [95% CI, 1.62-5.25]), increased mortality rate (52.7% versus 23.7%; adjusted hazard ratio [HR], 3.28 [95% CI, 1.94-5.52]), and major adverse cardiovascular events (38.9% versus 17.5%; adjusted HR, 3.20 [95% CI, 1.80-5.69]). A high-risk source of embolism was not associated with recurrent ischemic stroke (11.1% versus 9.6%; adjusted HR, 1.30 [95% CI, 0.49-3.44]). Structural high-risk sources of embolism on acute cardiac CT in patients with ischemic stroke were associated with poor long-term functional outcome and occurrence of major adverse cardiovascular events but not with recurrent stroke.

Modulation in serum and hematological parameters as a prognostic indicator of COVID-19 infection in hypertension, diabetes mellitus, and different cardiovascular diseases.

SARS-CoV-2 infection affects and modulates serum as well as hematological parameters. However, whether it modifies these parameters in the existing disease conditions, which help in the erection of specific treatments for the disease, is under investigation. Here, we aimed to determine whether serum and hematological parameters alteration in various diseases, diabetes mellitus (DM), hypertension (HTN), ischemic heart disease (IHD) and myocardial infarction (MI) conditions correlate and signal SARS-CoV-2 infection, which could be used as a rapid diagnosis tool for SARS-CoV-2 infection in disease conditions. To assess the projected goals, we collected blood samples of 1,113 male and female patients with solo and multiple disease conditions of DM/HTN/IHD/MI with severe COVID-19, followed by biochemical analysis, including COVID-19 virus detection by RT-qPCR. Furthermore, blood was collected from age-matched disease and healthy individuals 502 and 660 and considered as negative control. In our results, we examined higher levels of serum parameters, including D-dimer, ferritin, hs-CRP, and LDH, as well as hematological parameters, including TLC in sole and multiple diseases (DM/HTN/IHD/MI) conditions compared to the control subjects. Besides, the hematological parameters, including Hb, RBC, and platelet levels, decreased in the patients. In addition, we found declined levels of leukocyte count (%), lymphocyte (%), monocyte (%), and eosinophil (%), and elevated level of neutrophil levels (%) in all the disease patients infected with SARS-CoV-2. Besides, NLR and NMR ratios were also statistically significantly (p < 0.05) high in the patients with solo and multiple disease conditions of DM/HTN/IHD/MI infected with the SARS-CoV-2 virus. In conclusion, rapid alteration of sera and hematological parameters are associated with SARS-CoV-2 infections, which could help signal COVID-19 in respective disease patients. Moreover, our results may help to improve the clinical management for the rapid diagnosis of COVID-19 concurrent with respective diseases.

Platelet Biorheology and Mechanobiology in Thrombosis and Hemostasis: Perspectives from Multiscale Computation.

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s-1) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s-1) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.

Selective binding of cationic fibrinogen-mimicking chitosan nanoparticles to activated platelets and efficient drug release for antithrombotic therapy

Thrombosis is the main cause of catastrophic events including ischemic stroke, myocardial infarction and pulmonary embolism. Acetylsalicylic acid (ASA) therapy offers a desirable approach to antithrombosis through a reduction of platelet reactivity. However, major bleeding complications, severe off-target side effects, and resistance or nonresponse to ASA greatly attenuate its clinical outcomes. Herein, we report a cationic fibrinogen-mimicking nanoparticle, denoted as ASA-RGD-CS@TPP, to achieve activated-platelet-targeted delivery and efficient release of ASA for safer and more effective antithrombotic therapy. This biomimetic antithrombotic system was prepared by one-pot ionic gelation between cationic arginine-glycine-aspartic acid (RGD)-grafted chitosan (RGD-CS) and anionic tripolyphosphate (TPP). The platform exhibited selective binding to activated platelets, leading to efficient release of ASA and subsequent attenuation of platelet functions, including the remarkable inhibition of platelet aggregation through a potent blockage of cyclooxygenase-1 (COX-1). After intravenous administration, ASA-RGD-CS@TPP displayed significantly prolonged circulation time and successful prevention of thrombosis in a mouse model. ASA-RGD-CS@TPP was demonstrated to significantly enhance antithrombotic therapy while showing minimal coagulation and hemorrhagic risks and excellent biocompatibility in vivo as compared to free ASA. This platform provides a simple, safe, effective and targeted strategy for the development of antithrombotic nanomedicines.

SALVIANOLIC ACID A ATTENUATES ANGIOTENSIN II-INDUCED CARDIAC FIBROSIS THROUGH REGULATING THE TXNIP SIGNALING PATHWAY.

Cardiac fibrosis, characterized by excessive collagen accumulation in heart tissues, poses a significant clinical challenge in various heart diseases and complications. Although salvianolic acid A (Sal A) from Danshen ( Salvia miltiorrhiza ) has shown promise in the treatment of ischemic heart disease, myocardial infarction, and atherosclerosis, its effects on cardiac fibrosis remain unexplored. Our study investigated the efficacy of Sal A in reducing cardiac fibrosis and elucidated its underlying molecular mechanisms. We observed that Sal A demonstrated significant cardioprotective effects against Angiotensin II (Ang II)-induced cardiac remodeling and fibrosis, showing a dose-dependent reduction in fibrosis in mice and suppression of cardiac fibroblast proliferation and fibrotic protein expression in vitro . RNA sequencing revealed that Sal A counteracted Ang II-induced upregulation of Txnip, and subsequent experiments indicated that it acts through the inflammasome and ROS pathways. These findings establish the antifibrotic effects of Sal A, notably attenuated by Txnip overexpression, and highlight its significant role in modulating inflammation and oxidative stress pathways. This underscores the importance of further research on Sal A and similar compounds, especially regarding their effects on inflammation and oxidative stress, which are key factors in various cardiovascular diseases.

Multimodal detection and analysis of microplastics in human thrombi from multiple anatomically distinct sites

Microplastic (MP) pollution has emerged as a significant environmental concern worldwide. While extensive research has focused on their presence in marine organisms and ecosystems, their potential impact on human health, particularly on the circulatory system, remains understudied. This project aimed to identify and quantify the mass concentrations, polymer types, and physical properties of MPs in human thrombi surgically retrieved from both arterial and venous systems at three anatomically distinct sites, namely, cerebral arteries in the brain, coronary arteries in the heart, and deep veins in the lower extremities. Furthermore, this study aimed to investigate the potential association between the levels of MPs and disease severity. Thrombus samples were collected from 30 patients who underwent thrombectomy procedures due to ischaemic stroke (IS), myocardial infarction (MI), or deep vein thrombosis (DVT). Pyrolysis-gas chromatography mass spectrometry (Py-GC/MS) was employed to identify and quantify the mass concentrations of the MPs. Laser direct infrared (LDIR) spectroscopy and scanning electron microscopy (SEM) were used to analyse the physical properties of the MPs. Demographic and clinical information were also examined. A rigorous quality control system was used to eliminate potential environmental contamination. MPs were detected by Py-GC/MS in 80% (24/30) of the thrombi obtained from patients with IS, MI, or DVT, with median concentrations of 61.75μg/g, 141.80μg/g, and 69.62μg/g, respectively. Among the 10 target types of MP polymers, polyamide 66 (PA66), polyvinyl chloride (PVC), and polyethylene (PE) were identified. Further analyses suggested that higher concentrations of MPs may be associated with greater disease severity (adjusted β=7.72, 95% CI: 2.01-13.43, p<0.05). The level of D-dimer in the MP-detected group was significantly higher than that in the MP-undetected group (8.3±1.5μg/L vs 6.6±0.5μg/L, p<0.001). Additionally, LDIR analysis showed that PE was dominant among the 15 types of identified MPs, accounting for 53.6% of all MPs, with a mean diameter of 35.6μm. The shapes of the polymers detected using LDIR and SEM were found to be heterogeneous. This study presents both qualitative and quantitative evidence of the presence of MPs, and their mass concentrations, polymer types, and physical properties in thrombotic diseases through the use of multimodal detection methods. Higher concentrations of MPs may be associated with increased disease severity. Future research with a larger sample size is urgently needed to identify the sources of exposure and validate the observed trends in the study. This study was funded by the SUMC Scientific Research Initiation Grant (SRIG, No. 009-510858038), Postdoctoral Research Initiation Grant (No. 202205230031-3), and the 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant (No. 2020LKSFG02C).

Clopidogrel induced reduction in neutrophil count: An overlooked beneficial effect?

Complement-stimulated neutrophils are able to adhere to the endothelium and damage endothelial cells both in vitro and in vivo. These blood cells participate in the early stages, growth and complications of atherosclerotic plaques. Recent findings, based on mendelian randomization analysis, support the concept that high neutrophil counts are a causal risk factor for ischemic heart disease and myocardial infarction . Clopidogrel decreases leukocyte count and inflammatory markers in patients with acute coronary syndromes; this off-target effect, which is independent of the antiplatelet action, may help explaining secondary prevention data showing a superiority of clopidogrel over aspirin in reducing new cardiovascular events.

The Impact of Statin Treatment Duration on the Risk of New-Onset Diabetes Mellitus and Recurrent Vascular Events in Ischemic Stroke Patients: A Linked Data Analysis

Introduction: Although statin therapy reduces cardiovascular events, statin use is associated with the risk of new-onset diabetes mellitus (NODM). Using a linked dataset, we evaluated the effect of statin treatment on vascular outcomes and NODM development in patients with ischemic stroke. Methods: From the dataset, we identified 20,250 patients with acute ischemic stroke who had neither a prior history of DM nor a previous history of statin use before the index stroke. Patients were divided into statin users and non-users. The outcomes were NODM and vascular outcomes, including recurrent ischemic stroke and acute myocardial infarction (AMI). Results: Of the 20,250 patients, 13,706 (67.7%) received statin treatment after the index stroke. For the risk of NODM, a time-response relationship was observed between the use of statins and NODM; a longer post-stroke follow-up duration substantially increased the risk of NODM. Among those with ischemic strokes exceeding 3 years, statin users had an approximately 1.7-fold greater risk of NODM than statin non-users. Statin therapy significantly reduced the risk of recurrent ischemic stroke by 54% (HR 0.46, 95% CI, 0.43–0.50, p Conclusion: Statin therapy following ischemic stroke increased the occurrence of NODM in patients over a period of 3 years. Despite the increased risk of NODM, statin therapy shows a beneficial effect in reducing major cardiovascular events such as recurrent ischemic stroke and AMI in patients with ischemic stroke.

Abstract P431: Heparin-Warfarin Administered for Pulmonary Vein Thrombi Partially Dissolves Thrombi and Ameliorates Mild to Moderate Type 2 Diabetes Mellitus

Background: Pulmonary infection generates arterial thrombi, an important component of which are neutrophil extracellular traps, to defend the host. Pulmonary vein thrombi (PVTs) are underrated compared to arterial thrombi. In 2014, we reported that at least 61% (35 of 57) of elderly patients with chest pain had PVTs, as estimated using cardiac computed tomography (CT), and in 2022, we reported that 98.6% (215 of 218) of senior patients with age-related diseases such as hypertension, dyslipidemia, and type 2 diabetes mellitus (T2DM) had PVTs, as evaluated using cardiac CT and transesophageal echocardiography. T2DM is a common disease that can cause atherosclerosis, leading to ischemic stroke and acute myocardial infarction. It is important to better understand the mechanisms of T2DM and how to treat T2DM patients. The relationships between PVTs and T2DM are still unclear. Additionally, the relationships between heparin-warfarin therapy and T2DM are unknown. Methods: We identified PVTs in 15 T2DM patients (73.5 ± 9.9 y.o., range 50 y.o. to 88 y.o.; 10 males and 5 females) using both cardiac CT and transesophageal echocardiography. Among the 15 patients, two did not take DM medications; one took one DM medication; one took two DM medications; five took three DM medications; four took 4 DM medications; one took 5 DM medications; and one was treated with insulin. Results: The PVTs were partially dissolved by standard doses of heparin and warfarin given at the same time for one month. During the treatment, blood glucose levels were examined 30 minutes before breakfast, lunch, dinner and sleep. Between one and two weeks, the blood glucose levels of 10 patients decreased, especially before lunch, and some patients showed symptoms of hypoglycemia; therefore, the number of administered DM medications was decreased to zero for 6 patients and to one for 4 patients. After one month, the patients’ HbA1c levels had decreased slightly. We treated 10 patients with warfarin for the next several months, none of whom needed to resume DM medications, although their blood glucose tended to increase slightly. Three patients with comparatively severe T2DM showed no change in blood glucose following therapy. Conclusions: Heparin-warfarin therapy partially dissolved PVTs and decreased DM medications in patients with mild to moderate T2DM.

Abstract P305: Room for Improved Secondary Prevention of Major Cardiovascular Events Among the Population With New Onset Diabetes: A Longitudinal Latent Class Trajectory Analysis

Background: After a diagnosis of diabetes, specialist physicians may play a key role in the secondary prevention of major cardiovascular events (MACE). Yet, trajectories of visits to specialists are heterogenous and their efficacy in the prevention of MACE remains unexplored. Goal: To assess whether trajectories of visits to specialists are associated with MACE among new cases of diabetes. Methods: Using the Quebec Integrated Chronic Disease Surveillance System, we identified new cases of diabetes ≥20 years old during fiscal year 2013, who had no prior history of MACE (ischemic cardiopathy, stroke, myocardial infarction or cardiovascular death). Firstly, individual trajectories according to the presence/absence of ≥1 ambulatory visit to a specialist (cardiologist, internist, endocrinologist) were compiled over consecutive 3-month periods up to 2 years following diagnosis. Patients with no visit were compiled in a “primary care only” group, while others were classified in groups using latent class growth analysis. Patients who had a MACE during this period were excluded. Secondly, the risk of MACE occuring after the 2 years following diagnosis up to December 31 st 2019 was compared between groups using a marginal Cox proportional hazards regression model, adjusted with inverse probability weighting and providing adjusted hazard ratio (aHR) with 95% confidence intervals (CI). Results: Among the 24,782 patients included, 5 groups were identified ( Figure 1 ). A total of 2,837 MACE occurred. Compared with the “primary care only group”, those who consulted a specialist were at higher risk of MACE (Regular/frequent visits: aHR: 1.50 [95% CI: 1.26 to 1.66]; Late visits: aHR: 1.41 [1.13 to 1.73]; Regular/sparce visits: 1.38 [1.27 to 1.51]; Early visits: 1.36 [1.19 to 1.54]), while no difference was observed between these groups. Conclusions: Although confounding by indication cannot be totally ruled out, these results may suggest room for improvement in the secondary prevention of MACE after a diabetes diagnosis.

Abstract 40: Causal Aspects of Preeclampsia and Gestational Hypertension for Risk of Future Cardiovascular Diseases

Introduction: Preeclampsia is a multifactorial disease and a cause of maternal and neonatal morbidity and mortality. Observational studies show that women with preeclampsia have increased risk of cardiovascular diseases later in life. Whether this association is causal is however uncertain. Hypothesis: We assessed the hypothesis that preeclampsia and gestational hypertension are causal risk factors for future cardiovascular diseases, including ischemic heart disease, myocardial infarction, stroke, ischemic stroke, atrial fibrillation, and heart failure. Methods: For this purpose, we performed one-sample Mendelian randomization (MR) analyses using individual level data from 202,876 white British women from the UK Biobank. Subsequently, two-sample MR analyses were performed using summary level data from FinnGen and from the to date largest consortia for each endpoint individually and then pooled in fixed-effects meta-analyses. Genetic instruments for preeclampsia and gestational hypertension were from the most updated genome-wide association study (n=20,064 preeclampsia cases; n=703,117 controls; n=11,027 gestational hypertension cases; n=412,788 controls). Results: In one-sample MR analyses, the odds ratios (95% CI) for preeclampsia were 1.26 (1.11-1.43) for ischemic heart disease, 1.26 (0.99-1.60) for myocardial infarction, 1.28 (1.04-1.57) for stroke, and 1.37 (1.08-1.74) for ischemic stroke; for gestational hypertension the odds ratios (95% CI) were 1.17 (1.07-1.28) for ischemic heart disease, 1.16 (0.98-1.36) for myocardial infarction, 1.35 (1.17-1.56) for stroke, 1.36 (1.15-1.60) for ischemic stroke, 1.16 (1.04-1.29) for atrial fibrillation, and 1.22 (1.04-1.43) for heart failure. The two-sample MR analyses confirmed all associations from one-sample MR analyses with similar results from multiple sensitivity analyses. The MR-Egger results did not suggest pleiotropy. Conclusion: Genetic predisposition to preeclampsia or gestational hypertension was associated with increased risk of cardiovascular diseases later in life, suggesting preeclampsia as a likely causal factor.

Andexanet alfa versus non-specific treatments for intracerebral hemorrhage in patients taking factor Xa inhibitors - Individual patient data analysis of ANNEXA-4 and TICH-NOAC.

Data comparing the specific reversal agent andexanet alfa with non-specific treatments in patients with non-traumatic intracerebral hemorrhage (ICH) associated with factor-Xa inhibitor (FXaI) use are scarce. The study aimed to determine the association between the use of andexanet alfa compared with non-specific treatments with the rate of hematoma expansion and thromboembolic complications in patients with FXaI-associated ICH. We performed an individual patient data analysis combining two independent, prospective studies: ANNEXA-4 (180 patients receiving andexanet alfa, NCT02329327) and TICH-NOAC (63 patients receiving tranexamic acid or placebo ± prothrombin complex concentrate, NCT02866838). The primary efficacy outcome was hematoma expansion on follow-up imaging. The primary safety outcome was any thromboembolic complication (ischemic stroke, myocardial infarction, pulmonary embolism, or deep vein thrombosis) at 30 days. We used binary logistic regression models adjusted for baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively. Among 243 participants included, the median age was 80 (IQR 75-84) years, baseline hematoma volume was 9.1 (IQR 3.4-21) mL and anti-Xa activity 118 (IQR 78-222) ng/mL. Times from last FXaI intake and symptom onset to treatment were 11 (IQR 7-16) and 4.7 (IQR 3.0-7.6) h, respectively. Overall, 50 patients (22%) experienced hematoma expansion (ANNEXA-4: n=24 (14%); TICH-NOAC: n=26 (41%)). After adjusting for pre-specified confounders (baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively), treatment with andexanet alfa was independently associated with decreased odds for hematoma expansion (aOR 0.33, 95% CI 0.13-0.80, p = 0.015). Overall, 26 patients (11%) had any thromboembolic complication within 30 days (ANNEXA-4: n=20 (11%); TICH-NOAC: n=6 (10%)). There was no association between any thromboembolic complication and treatment with andexanet alfa (aOR 0.70, 95% CI 0.16-3.12, p = 0.641). The use of andexanet alfa compared to any other non-specific treatment strategy was associated with decreased odds for hematoma expansion, without increased odds for thromboembolic complications.

Nicotinamide ribose ameliorates myocardial ischemia/reperfusion injury by regulating autophagy and regulating oxidative stress.

Nicotinamide riboside (NR) has been reported to play a protective role in myocardial ischemia-reperfusion (I/R) injury when used in association with other drugs; however, the individual effect of NR is unknown. In the present study Evan's blue/triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, echocardiography, western blotting, reverse transcription-quantitative PCR, and the detection of myocardial injury-associated markers and oxidative stress metabolites were used to explore the ability of NR to alleviate cardiac I/R injury and the relevant mechanisms of action. In a mouse model of I/R injury, dietary supplementation with NR reduced the area of myocardial ischemic infarction, alleviated pathological myocardial changes, decreased inflammatory cell infiltration and attenuated the levels of mitochondrial reactive oxygen species (ROS) and creatine kinase myocardial band (CK-MB). In addition, echocardiography suggested that NR alleviated the functional damage of the myocardium caused by I/R injury. In H9c2 cells, NR pretreatment reduced the levels of lactate dehydrogenase, CK-MB, malondialdehyde, superoxide dismutase and ROS, and reduced cell mortality after the induction of hypoxia/reoxygenation (H/R) injury. In addition, the results indicated NR activated sirt 1 via the upregulation of nicotinamide adenine dinucleotide (NAD+) and protected the cells against autophagy. The sirt 1 inhibitor EX527 significantly attenuated the ability of NR to inhibit autophagy, but had no significant effect on the ROS content of the H9c2 cells. In summary, the present study suggests that NR protects against autophagy by increasing the NAD+ content in the body via the sirt 1 pathway, although the sirt 1 pathway does not affect oxidative stress.

Association Between Atrial Fibrillation Symptoms and Clinical Outcomes: A Prospective Multicenter Registry Study

The presence of symptoms plays an important role in determining whether to focus on rhythm control or rate control when treating atrial fibrillation (AF). Previous comparative studies on the clinical outcomes of symptomatic and asymptomatic AF have yielded inconsistent results, and a link between AF symptoms and left atrial (LA) remodeling is not established. Patients selected from the COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, which is a prospective, multicenter study consisting of patients with non-valvular AF, were grouped into 2 groups: symptomatic and asymptomatic. The primary outcome was a composite of the following cardiovascular outcomes: all-cause death, ischemic stroke, transient ischemic attack, systemic embolism, myocardial infarction, and heart failure hospitalization. Of 10,210 patients with AF, 4,327 (42%) had symptomatic AF. The asymptomatic group had an older mean age, more men, and more patients with hypertension and diabetes mellitus than the symptomatic group. The asymptomatic group had a larger left atrium (LA) diameter (43.6 vs 42.2 mm, p <0.001) than the symptomatic group. During a median follow-up of 32.9 (29.5 to 36.4) months, the asymptomatic and symptomatic groups showed similar incidences of the primary outcome (1.44 vs 1.45 per 100 person-years; log-rank, p = 0.8). In conclusion, the absence of AF symptoms is associated with increased LA. However, symptomatic and asymptomatic patients with AF have a similar risk of cardiovascular outcomes. This suggests that beneficial treatment for AF may be considered regardless of whether patients have symptomatic or asymptomatic AF.

Short-Term and Long-Term Risk of Recurrent Vascular Event by Cause After Ischemic Stroke in Young Adults

Cause of ischemic stroke in young people is highly variable; however, the risk of recurrence is often presented with all subtypes of stroke grouped together in classification systems such as the Trial of ORG (danaparoid sodium [Orgaran]) 10172 in Acute Stroke Treatment (TOAST) criteria, which limits the ability to individually inform young patients with stroke about their risk of recurrence. To determine the short-term and long-term risk of recurrent vascular events after ischemic stroke at a young age by stroke cause and to identify factors associated with recurrence. This cohort study used data from the Observational Dutch Young Symptomatic Stroke Study, a prospective, multicenter, hospital-based cohort study, conducted at 17 hospitals in the Netherlands between 2013 and 2021. Eligible participants included 30-day survivors of an initial, neuroimaging-proven ischemic stroke (aged 18-49 years). Data analysis was conducted from June to July 2023. Diagnosis of a first-ever, ischemic stroke via neuroimaging. The primary outcome was short-term (within 6 months) and long-term (within 5 years) recurrence risk of any vascular event, defined as fatal or nonfatal recurrent ischemic stroke, transient ischemic attack, myocardial infarction, and revascularization procedure. Predefined characteristics were chosen to identify factors associated with risk of recurrence (cause of stroke, age, sex, stroke severity, and cardiovascular health factors). A total of 1216 patients (median [IQR] age, 44.2 [38.4-47.7] years; 632 male [52.0%]; 584 female [48.0%]) were included, with a median (IQR) follow-up of 4.3 (2.6-6.0) years. The 6-month risk of any recurrent ischemic event was 6.7% (95% CI, 5.3%-8.1%), and the 5-year risk was 12.2% (95% CI, 10.2%-14.2%)The short-term risk was highest for patients with cervical artery dissections (13.2%; 95% CI, 7.6%-18.7%). Other factors associated with a recurrent short-term event were atherothrombotic stroke, rare causes of stroke, and hypertension. The long-term cumulative risk was highest for patients with atherothrombotic stroke (22.7%; 95% CI, 10.6%-34.7%) and lowest for patients with cryptogenic stroke (5.8%; 95% CI, 3.0%-8.5%). Cardioembolic stroke was associated with a recurrent long-term event, as were diabetes and alcohol abuse. The findings of this cohort study of 1216 patients with an ischemic stroke at a young age suggest that the risk of recurrent vascular events was high and varied by cause of stroke both for short-term and long-term follow-up, including causes that remained concealed when combined into 1 category in the routinely used TOAST criteria. This knowledge will allow for more personalized counseling of young patients with stroke.

Rising Cardiac Troponin: A Prognostic Biomarker for Mortality After Acute Ischemic Stroke.

Elevated cardiac troponin (cTn) is detected in 10% to 30% of patients with acute ischemic stroke (AIS) and correlates with poor functional outcomes. Serial cTn measurements differentiate a dynamic cTn pattern (rise/fall >20%), specific for acute myocardial injury, from elevated but stable cTn levels (nondynamic), typically attributed to chronic cardiac/noncardiac conditions. We investigated if the direction of the cTn change (rising versus falling) affects mortality and outcome. We retrospectively screened consecutive patients with AIS admitted to 5 stroke centers for elevated cTn at admission and at least 1 additional cTn measurement within 48 hours. The pattern of cTn was defined as rising if >20% increase from baseline, falling if >20% decrease, or nondynamic if ≤20% change in either direction. Logistic regression analyses were performed to assess the association of cTn patterns and 7-day mortality and unfavorable discharge disposition. Of 3789 patients with AIS screened, 300 were included. Seventy-two had a rising pattern, 66 falling, and 162 nondynamic. In patients with AIS with rising cTn, acute ischemic myocardial infarction was present in 54%, compared with 33% in those with falling cTn (P<0.01). Twenty-two percent of patients with a rising pattern had an isolated dynamic cTn in the absence of any ECG or echocardiogram changes, compared with 53% with falling cTn. A rising pattern was associated with higher risk of 7-day mortality (adjusted odds ratio [OR]=32 [95% CI, 2.5-415.0] rising versus aOR=1.3 [95% CI, 0.1-38.0] falling versus nondynamic as reference) and unfavorable discharge disposition (aOR=2.5 [95% CI, 1.2-5.2] rising versus aOR=0.6 [95% CI, 0.2-1.5] versus falling). Rising cTn is independently associated with increased mortality and unfavorable discharge disposition in patients with AIS.

Risk of Stroke and Myocardial Infarction Among Initiators of Triptans

Triptans are contraindicated in patients with ischemic heart disease or previous myocardial infarction, and caution is advised when prescribing these drugs to patients with vascular risk factors. However, controlled observational studies have either shown no association or an apparent lower risk, possibly owing to a channeling of triptans to individuals at low risk of cardiovascular outcomes, and it remains unclear whether avoiding triptan treatment for these patients is meaningful. To establish whether an association between triptans and ischemic events could be demonstrated using a self-controlled design because this type of design is robust to the previously mentioned type of confounding. All people in nationwide Danish registries who were initiating triptans and all the ischemic events that they experienced were identified. A case-crossover design was used to estimate odds ratios (OR) for associations between first-ever triptan use and ischemic outcomes, comparing triptan exposure in the 2-week period up to the event with four 2-week reference periods. Data were obtained for the period January 1995 to August 2022. Included from the population of Denmark were individuals redeeming a prescription for any triptan and experiencing at least 1 of 3 predefined ischemic outcomes. No one was excluded. Initiation of any triptan. Acute myocardial infarction, ischemic stroke, or nonspecified stroke. Identified were a total of 429 612 individuals (median [IQR] age, 38 [28-48] years; 325 687 female [75.8%]) who redeemed a first prescription for a triptan in the study period. Of these patients, 11 (0.003%) had a myocardial infarction with the first triptan prescription in either a focal or referent window (odds ratio [OR], 3.3; 95% CI, 1.0-10.9), 18 (0.004%) had ischemic stroke (OR, 3.2; 95% CI, 1.3-8.1), and 35 (0.008%) had ischemic/nonspecified stroke (OR, 3.0; 95% CI, 1.5-5.9). Case patients had a median age of approximately 60 years and had a high-risk cardiovascular profile. Results of this case-crossover study suggest that triptan initiation was associated with higher risk of ischemic stroke and myocardial infarction. For the individual patient with low background cardiovascular risk, the risk of an ischemic event after triptan initiation was very low.

Abstract WP229: Comparing the Real-World Effects of Once-Weekly Semaglutide and Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Outcomes, Health Care Resource Utilization, and Medical Costs in Individuals With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease

When compared with placebo, glucagon-like peptide-1 receptor agonists such as once-weekly semaglutide (semaglutide OW T2D) improve cardiovascular outcomes in people with type 2 diabetes (T2D), whereas dipeptidyl peptidase-4 inhibitors (DPP-4is) do not. However, no head-to-head trials of these 2 incretin-based drug classes have been conducted. This retrospective cohort study used 2018-2022 data from the Optum ® Clinformatics ® Data Mart to compare on-treatment time with incidence of ischemic stroke, myocardial infarction (MI), and 2-point major adverse cardiovascular events (MACE; composite of ischemic stroke and MI); health care resource utilization; and medical costs in new adult users of semaglutide OW T2D and DPP-4is with T2D and atherosclerotic cardiovascular disease (ASCVD). Patients were followed until drug discontinuation, enrollment end, or an event. Baseline characteristics ( Table ) were balanced using inverse probability of treatment weighting. On average, patients were aged 70 years, with 5.6- and 4.3-year history of T2D and ASCVD, respectively. Survival analyses were conducted to compare risks during exposure. Users of semaglutide OW T2D (weighted n=14,461) had 46%, 36%, and 40% lower relative risk of ischemic stroke, MI, and 2-point MACE, respectively, compared with users of DPP-4is (weighted n=38,630; all P ≤0.001; Figure ). Users of semaglutide OW T2D also had decreased ASCVD-related and all-cause hospitalizations, outpatient visits, hospitalization costs, and total medical costs (all P &lt;0.05). This study suggests that semaglutide OW T2D reduces the risk of stroke and MI while reducing medical costs relative to DPP-4is in adults with T2D and ASCVD.

Abstract WMP27: Strategies to Mitigate Tenecteplase (TNK) Dosing Errors in Acute Ischemic Stroke

Tenecteplase (TNK) is currently being used for IV thrombolysis in acute ischemic stroke. “Tenecteplase is the first thrombolytic that can be administered over five seconds in a single dose.” (Genetech, 2023). While this is a great advance for thromboembolic pathology, dosing errors can cause devastating patient harm including death. This off-label use can lead to dosing errors related to the TNK packaging, which only states dosing for myocardial infarction. The dosing for myocardial infarction is 0.5 mg/kg while the dosing for stroke is 0.25 mg/kg. (Bach, 2023; Campbell et al., 2018; Wang et al., 2023). While implementing TNK for acute ischemic stroke, discrepancies were also noted in the rounding of the TNK dose. Dosages were rounded to the onehundredth decimal point, and clear labeling on the package was not evident. The significance of underdosing or overdosing of TNK may not achieve the desired patient outcome and may increase the risk of complications such as hemorrhage, anaphylaxis, thromboembolism, arrhythmia, intracranial hemorrhage, extended hospitalizations, and death. (Bach, 2023) Education was created and disseminated to inform physicians and nursing of the appropriate dosing of TNK for acute ischemic stroke. A TNK dosing chart was included with the pre-existing stroke packets to reinforce learning. The TNK dosing chart was updated to round the TNK dose to the nearest tenth of a decimal, then one step further with the chart showing the dosage to weight ranges. Interdisciplinary collaboration occurred with informatics, physicians, pharmacy, and nursing to get order sets to match the rounding rules. Lastly, special labeling was created for the packaging of Tenecteplase TNK to include dosing for acute ischemic stroke. Since the implementation of this quality improvement project, both nursing and physicians are more aware of the correct dosing of TNK for acute ischemic stroke and myocardial infarction. Mitigating the problem of unclear TNK dosing has prevented dosing errors for acute ischemic stroke and myocardial infarction as well as the negative outcomes associated with a medication error involving a high-alert medication.