Stroke Infarction Research Articles

Zoster Vaccine Lowers Stroke and Myocardial Infarction Risk in Chronic Disease

Herpes zoster increases stroke and myocardial infarction (MI) risk. The objective of this study is to evaluate the impact of live attenuated zoster vaccination on stroke and MI risk in patients at-risk for zoster including persons with hypertension, diabetes mellites, obesity, hypercholesterolemia, chronic kidney disease, chronic obstructive pulmonary disease, emphysema, asthma, and chronic liver disease. Retrospective cohort study utilizing continuous de-identified claims data from the IBM MarketScan® Commercial Claims and Encounters Database (collected from 2005-2018) containing data for 200 million commercially insured Americans. Participants included 27,093 adults vaccinated against zoster with at least 5 years continuous enrollment, age and sex-matched 1:5 with unvaccinated controls. Odds ratios, risk difference, and number needed to treat (NNT) evaluated the effect of vaccination on stroke and MI while controlling for relevant comorbidities. Over five years, proportions of MI (1.29% vs 1.82%; p<0.05) and stroke (1.61% vs. 2.20%; p<0.05) were lower in vaccinated versus unvaccinated individuals respectively, controlling for age and sex, with greatest benefit for people with diabetes (stroke OR [95% Confidence Limits] 0.64 [0.58, 0.71], MI 0.63 [0.57, 0.71]). Although hypertension and chronic obstructive pulmonary disease (COPD) had highest odds of stroke and MI, vaccination still provided significant risk-reduction (Hypertension: stroke 0.75 [0.68, 0.83], MI 0.73 [0.65, 0.81]; COPD: stroke 0.75 [0.68, 0.83], MI 0.74 [0.66, 0.83]). Live attenuated zoster vaccination is associated with lower risk stroke and MI in adults with at-risk comorbidities, controlling for age and sex. Vaccination may provide cardiovascular benefits beyond zoster prevention.

Percutaneous Coronary Intervention before or after Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis Involving 1531 Patients.

Background: The optimal timing to perform percutaneous coronary interventions (PCIs) in patients undergoing transcatheter aortic valve replacement (TAVR) is not well established. In this meta-analysis, we aimed to compare the outcomes of patients undergoing PCI before versus after TAVR. Methods: A comprehensive literature search was performed including Medline, Embase, and Cochrane electronic databases up to 5 April 2024 for studies that compared PCI before and after TAVR reporting at least one clinical outcome of interest (PROSPERO ID: CRD42023470417). The analyzed outcomes were mortality, stroke, and myocardial infarction (MI) at follow-up. Results: A total of 3 studies involving 1531 patients (pre-TAVR PCI n = 1240; post-TAVR PCI n = 291) were included in this meta-analysis following our inclusion criteria. Mortality was higher in the pre-TAVR PCI group (OR: 2.48; 95% CI: 1.19-5.20; p = 0.02). No differences were found between PCI before and after TAVR for the risk of stroke (OR: 3.58; 95% CI: 0.70-18.15; p = 0.12) and MI (OR: 0.66; 95% CI: 0.30-1.42; p = 0.29). Conclusions: This meta-analysis showed in patients with stable CAD undergoing TAVR that PCI after TAVR is associated with lower mortality compared with PCI before TAVR.

Association of Indoleamine 2,3-Dioxygenase (IDO) Activity with Outcome after Cardiac Surgery in Adult Patients.

Indoleamine 2,3-deoxygenase (IDO) plays an important role in the catabolism of the amino acid tryptophan. Tryptophan and its metabolites are key immune modulators. Increased IDO activity has been observed in various diseases and is associated with worse clinical outcomes. However, comprehensive research regarding its role in cardiac surgery remains limited. Therefore, we aimed to investigate perioperative changes in IDO activity and pathway metabolites, along with their impact on clinical outcomes in adult patients undergoing cardiac surgery. As an observational cohort study conducted at the Inselspital in Bern from January to December 2019, we retrospectively analyzed the data of prospectively collected biobank samples of patients undergoing cardiac surgery with the use of cardiopulmonary bypass. IDO pathway metabolite analysis was conducted by mass spectrometry. Perioperative dynamics were descriptively assessed and associated with pre-defined clinical outcome measures (30-day mortality, 1-year mortality, incidence of stroke and myocardial infarction, and length of hospital stay) through a multi-step exploratory regression analysis. A cohort of 192 adult patients undergoing cardiac surgery with the use of cardiopulmonary bypass were included (median age 67.0, IQR 60.0-73.0, 75.5% male). A significant perioperative decrease in the kynurenine/tryptophan (Kyn/Trp) ratio (-2.298, 95% CI -4.028 to -596, p = 0.009) and significant perioperative dynamics in the associated metabolites was observed. No association of perioperative changes in IDO activity and pathway metabolites with clinical outcomes was found. A significant decrease in the Kyn/Trp ratio among adult patients undergoing cardiac surgery indicates a perioperative downregulation of IDO, which stands in contrast to other pro-inflammatory conditions. Further studies are needed to investigate IDO in the setting of perioperative immunomodulation, which is a key driver of postoperative complications in cardiac surgery patients.

Derivation and Validation of a Scoring System for Predicting Poor Outcome After Posterior Circulation Ischemic Stroke in China.

Guidelines for posterior circulation ischemic stroke (PCIS) treatment are lacking and outcome prediction is crucial for patients and clinicians. We aimed to develop and validate a prognostic score to predict the poor outcome for patients with PCIS. The score was developed from a prospective derivation cohort named the Third China National Stroke Registry (August 2015-March 2018) and validated in a spatiotemporal independent validation cohort (December 2017-March 2023) in China. Patients with PCIS with acute infarctions defined as hyperintense lesions on diffusion-weighted imaging were included in this study. The poor outcome was measured as modified Rankin scale (mRS) score 3-6 at 3 months after PCIS. Multivariable logistic regression analysis was used to identify predictors for poor outcome. The prognostic score, namely PCIS Outcome Score (PCISOS), was developed by assigning points to variables based on their relative β-coefficients in the logistic model. The PCISOS was derived from 3,294 patients (median age 62 [interquartile range (IQR) 55-70] years; 2,250 [68.3%] men) and validated in 501 patients (median age 61 [IQR 53-68] years; 404 [80.6%] men). Among them, 384 (11.7%) and 64 (12.8%) had poor outcome 3 months after stroke in respective cohorts. Age, mRS before admission, NIH Stroke Scale on admission, ischemic stroke history, infarction distribution, basilar artery, and posterior cerebral artery stenosis or occlusion were identified as independent predictors for poor outcome and included in PCISOS. This easy-to-use integer scoring system identified a marked risk gradient between 4 risk groups. PCISOS performed better than previous scores, with an excellent discrimination (C statistic) of 0.80 (95% CI 0.77-0.83) in the derivation cohort and 0.81 (95% CI 0.77-0.84) in the validation cohort. Calibration test showed high agreement between the predicted and observed outcomes in both cohorts. PCISOS can be applied for patients with PCIS with acute infarctions to predict functional outcome at 3 months post-PCIS. This simple tool helps clinicians to identify patients with PCIS with higher risk of poor outcome and provides reliable outcome expectations for patients. This information might be used for personalized rehabilitation plan and patient selection for future clinical trials to reduce disability and mortality.

Effects of ultrashort wave on neuronal damage and heat shock protein 70 expression after cerebral ischemia-reperfusion injury in rats

BackgroundUltrashort wave (USW) therapy has been reported to alleviate cerebral ischemia/reperfusion (IR) injury, however the underlying mechanisms remain elusive. The aim of this study was to observe the effect of non-thermal USW therapy on neuronal damage and expression of heat shock protein 70 (HSP70) after cerebral IR in rats. MethodsFocal ischemia-reperfusion (IR) was induced in Sprague–Dawley rats by middle cerebral artery occlusion/reperfusion (MCAO/R). The Ninety-two rats (both male and female) were screened using the Zea-Longa 5 grade evaluation. Included rats were then randomly divided into blank, sham, model 1-day, model 3-day, model 7-day, USW 1-day, USW 3-day, or USW 7-day groups. All rats in the model groups received sham USW treatment, while rats in the USW groups received USW treatment, for 1, 3, or 7 days. We assessed the National Institutes of Health Stroke Scale, brain infarction volumes, ultrastructural damage scores using electron microscopy, and HSP70 expression by western blotting between the different groups. ResultsUSW treatment reduced the National Institutes of Health Stroke Scale, infarction volume, and ultrastructural neuronal damage, and increased expression of HSP70, in the hippocampal CA1 region. ConclusionsNon-thermal USW therapy may improve neurological function, decrease infarction volume, and reduce neuronal damage by increasing HSP70 expression following cerebral IR injury.

Time to Think About Myocardial Infarction in Acute Ischemic Stroke

Time to Think About Myocardial Infarction in Acute Ischemic Stroke

Cardiovascular mortality in bipolar disorder: Population-based cohort study.

Limited evidence base on cause-specific excess cardiovascular disease (CVD) mortality in bipolar disorder (BD) is a barrier to developing preventive interventions aimed at reducing the persistent mortality gap in BD. To investigate cause-specific CVD mortality in BD. We identified all individuals aged 15+ years during 2004-2018 with a diagnosis of BD using Finnish nationwide routine data. Standardised mortality ratios (SMR) with 95% confidence intervals (CI) were calculated using the mortality rates in the general population as weights. 53,273 individuals with BD (57% women; median age at BD diagnosis, 40 years), were followed up for 428,426 person-years (median, 8.2 years). There were 5988 deaths due to any cause, of which 26% were due to CVD. The leading cause of absolute excess CVD mortality was coronary artery disease (CAD). The leading causes of relative excess mortality were cardiomegaly (SMR, 4.51; 95% CI, 3.58-5.43), venous thromboembolism (3.03; 2.26-3.81), cardiomyopathy (2.46; 1.95-2.97), and hypertensive heart disease (2.12; 1.71-2.54). The leading causes of absolute CVD mortality showed markedly lower relative excess, including CAD (1.47; 1.34-1.61), ischaemic stroke (1.31; 1.06-1.54), and acute myocardial infarction (1.12; 0.98-1.25). Due to the higher relative excess mortality, structural and functional heart disorders contributed as much as atherosclerotic and ischaemic disorders to the absolute excess mortality. Cardiomyopathy and hypertensive heart disease as the leading causes of relative excess mortality emphasise the contribution of structural and functional heart disorders to the overall excess mortality alongside coronary artery disease. Interventions targeted at these modifiable causes of death should be priorities in the prevention of premature excess CVD mortality in BD.

National trend in the prevalence and mortality of COPD in South Korea from 2008 to 2017

BackgroundExisting studies on chronic obstructive pulmonary disease (COPD) in Korea lack full population coverage, relying on small sample sizes. Therefore, this study aims to investigate the prevalence and mortality of...

Cardiovascular risk in anti-VEGF treatment of neovascular age-related macular degeneration

ObjectiveAssess 5-year all-cause mortality (ACM), hemorrhagic stroke, ischemic stroke, and myocardial infarction (MI) risks in nAMD patients receiving anti-VEGF injections compared with controls. DesignPopulation-based retrospective cohort study using a U.S. federated health research network, containing de-identified data of 96 million patients from 1/1/2003 to 3/6/2023. ParticipantsnAMD Patients with anti-VEGF injections. Controls included nAMD patients without anti-VEGF injections, non-exudative AMD patients, and patients without AMD. MethodsPatients were identified using nAMD ICD-10 and anti-VEGF CPT codes and matched for age, sex, and comorbidities. Five-year relative risk of ACM (RR1), hemorrhagic stroke (RR2), ischemic stroke (RR3), and MI (RR4) in nAMD patients receiving anti-VEGF injections were calculated. ResultsA total of 27,609 nAMD patients (mean diagnosis age [SD], [78.2 (10.3)]) received anti-VEGF injections; 769 nAMD patients without injections (75.8 [12.2]), 27,599 non-exudative AMD patients (78.2 [10.3]), and 21,902 no-AMD patients (76.1 [10.5]) were identified. After matching, nAMD patients receiving injections did not show increased risk versus nAMD patients without injections (RR1, 0.66; 95% CI [0.53, 0.82]), (RR2, 1.00 [0.42, 2.38]), (RR3, 1.70 [0.92,3.13]), (RR4, 0.63 [0.33, 1.18]). No increased risk was found compared to non-exudative AMD patients (RR1, 0.99 [0.95, 1.03]), (RR2, 0.94 [0.83,1.07]), (RR3, 1.04 [0.96, 1.12]), (RR4, 0.99 [0.91, 1.08]). Increased risk for ACM was observed versus no-AMD patients (RR1, 1.21 [1.15, 1.27]), but no other differences were found (RR2, 0.81 [0.70, 0.93]), (RR3, 1.00 [0.92, 1.09]), (RR4, 0.986 [0.90, 1.09]). ConclusionAnti-VEGF injections were not associated with major cardiovascular events in nAMD patients over 5 years.

Circulating LIGHT/TNFSF14 levels are negatively associated with cardiovascular mortality, while intra-plaque levels are associated with symptomatic cerebrovascular disease

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Swedish Heart and Lung Foundation, Åke Wiberg's Foundation Background Plaque rupture is the underlying cause of most cardiovascular events, such as stroke and myocardial infarction. Co-stimulatory molecules, the immune checkpoints, are emerging as strong candidates to battle atherosclerosis progression. The co-stimulatory molecule LIGHT (tumour necrosis factor 14; TNFSF14) exists in foam cell-rich regions of atherosclerotic plaques, but whether it is associated with a high-risk plaque phenotype and cardiovascular events is not known. Purpose This study investigates the association between intra-plaque and circulating LIGHT levels and cardiovascular disease. Method Plaque levels of LIGHT/TNFSF14 were measured in plasma and homogenised carotid endarterectomy plaques by Proximity Extension Assay in subjects from the Carotid Plaque Imaging Cohort (CPIP; N=557 and 201, respectively). Homogenates were further examined by multi-plex cytokine analysis and ELISA, and tissue plaque sections through immunohistochemistry. Multivariate Cox proportional hazards analysis was performed on normalized (logarithmically transformed) values. Results Plaque, but not circulating, levels of LIGHT were associated with the occurrence of pre-operative cerebrovascular symptoms (p=0.00014). Furthermore, intra-plaque levels of LIGHT correlated strongly with the histological plaque vulnerability index (p=5x10-15): a ratio between the sum of destabilising versus stabilising plaque components (i.e. macrophages, intra-plaque haemorrhage and lipids versus smooth muscle cells and collagen) as well as with necrotic core size and the inflammatory cytokines interleukin(IL)-1β, IL-6, chemokine (C-C motif) ligand (CCL)-2, CCL4 and CCL5. Moreover, plaque LIGHT levels correlated with several components of the extracellular matrix turnover machinery, including cleaved collagen, fibromodulin, ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs-7) and matrix metalloproteinases 1, 2, 9 and 10. While plaque LIGHT levels were not predictive of cardiovascular death, circulating LIGHT levels were negatively associated with risk of cardiovascular death (after 6 ½ years) after correcting for the possible confounders age, sex, cerebrovascular symptoms, diabetes, high-sensitivity C-reactive protein, inflammatory disease, hypertension and smoking (hazard ratio=0.032, confidence interval=0.420-0.951, p=0.028). Conclusion Though intra-plaque LIGHT levels are associated with a rupture-prone plaque phenotype and pre-operative symptoms, circulating levels are associated with a lower risk of future cardiovascular mortality. This suggest that upregulation of LIGHT in atherosclerotic plaques may occur as part of a reparative rupture response and, systemically, reflect efficient wound-healing capacity.

Human atherosclerotic plaque macrophages associate with clinical presentation and follow diverse lineage differentiation routes

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Research Council Veni grant. Netherlands Heart Foundation Atherosclerosis is characterized by inflammation and lipid accumulation, leading to complications such as stroke and myocardial infarction. Various macrophage subsets are present in human atherosclerotic plaques. However, it is unclear how subsets are interrelated and contribute to the disease process and its clinical outcomes. Here, we employed single-cell RNA-seq (scRNA-seq) on blood and plaque material from carotid endarterectomy patients enrolled in the AtheroExpress (AE) cohort to define regulatory pathways of macrophage recruitment, differentiation, and development. Additionally, we used these scRNA-seq data to deconvolute a large AE bulk RNA-seq cohort to allow correlating cellular subsets in plaques with clinical traits. Interestingly, we found that macrophages and their subsets are the only cell population significantly associated with major adverse cardiac events (MACE) during a 3-year follow-up period. Subsequently, we could divide plaque macrophages into 3 populations: inflammatory, tissue-resident / lipid-associated (TREM2 high), and foamy macrophages (TREM1 high). While the latter two are correlated with MACE, the inflammatory macrophages are inversely correlated with statin use. Cellular fate analyses revealed two major paths of macrophage development in the plaque. First, non-classical monocytes entering the plaque, turning into inflammatory cells before becoming foamy and eventually dying. Second, resident-like macrophages that turn into either inflammatory- or lipid-associated macrophages, before meeting their foamy demise. Together, these findings provide important insights on macrophages in atherosclerosis and suggest new leads to discover therapeutic targets for this disease.

In Patients with Heart Failure Undergoing Carotid Endarterectomy, Locoregional Anesthesia is Not Associated with Decreased Mortality, Stroke, or Myocardial Infarction Compared to General Anesthesia

ObjectiveWhile existing literature reports no benefit of locoregional anesthesia (LRA) over general anesthesia (GA) in patients undergoing carotid endarterectomy (CEA), the effect of LRA on patients with congestive heart failure (CHF) has not been explored. This study aims to assess whether the choice of anesthesia plays a role in influencing outcomes within this population. MethodsUsing the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) files between 2005-2022 and the procedural targeted ACS-NSQIP database for CEA between 2011-2022, all patients receiving CEA were identified, and the subset of patients with CHF was included. Patient characteristics and 30-day outcomes were compared using χ2 or Fischer’s exact test as appropriate for categorical variables and the independent t-test or Mann-Whitney U test as appropriate for continuous variables. Mortality, stroke, myocardial infarction (MI), and major adverse cardiac events (MACE) were compared between patients receiving general anesthesia (GA) and locoregional anesthesia (LRA) using univariate analysis. ResultsA total of 3,040 patients (2,733 undergoing GA, 307 undergoing LRA) with a diagnosis of CHF undergoing CEA were identified. No difference in mortality (GA 3.1% vs LRA 4.6%, p=0.162), MI (GA 3.0% vs LRA 2.3%, p=0.478), stroke (2.4% vs 2.6%, p=0.805) or MACE (GA 7.4% vs LRA 8.1%, p=0.654) was observed. LRA patients had a significantly lower hospital stay compared to GA patients (1 day [IQR 1-3] vs 2 days [IQR 1-4], p<0.001). Shunt was more commonly used in patients receiving GA (32.9% vs 12.5%, p<0.001) compared to LRA. ConclusionWhile utilizing LRA compared to GA during carotid endarterectomy in patients with CHF is associated with a shorter hospital stay and less intraoperative shunting, the choice of anesthesia did not impact the outcomes of mortality, MI or stroke. Further research is needed to determine the effect of LRA on the outcomes of CEA among patients with different stages of heart failure.

Folic acid supplementation for stroke prevention: A systematic review and meta-analysis of 21 randomized clinical trials worldwide

Background & aimsThe AHA/ASA guidelines for primary stroke prevention are almost a decade old. The current recommendation regarding folic acid supplementation is based on only 8 clinical trials, and an additional 13 folate trials have been published since then. This meta-analysis aims to fill in critical evidence gaps by comprehensively evaluating 21 published trials with particular attention given to identifying the true influences through stratification. MethodsPubMed, the Cochrane Central Register of Controlled Trials, and Embase were searched from inception to April 4, 2023. This study included all randomized controlled trials (RCTs) of folic acid with stroke as one of the reporting endpoints. Relative risks and 95% confidence intervals were used to assess the association between folic acid supplementation and the risk of stroke in a random-effects model. ResultsResults from the 21 pooled RCTs totaling 115,559 participants showed that folic acid supplementation significantly reduced the risk of stroke by 10% (RR 0.90, 95%CI 0.83 to 0.98). Subgroup analyses showed that folic acid efficacy was greater in areas without fortified grain or with partially-fortified grain (RR=0.83, 95% CI 0.75 to 0.93; RR=1.04 in areas with grain fortification, P-interaction=0.003). In this group, folic acid supplementation was most efficacious in those without a history of stroke or myocardial infarction (RR=0.77, 95% CI 0.68 to 0.86; RR=0.94 for participants with a history of stroke or myocardial infarction, P-interaction=0.008). The efficacy of folic acid remained consistent regardless of baseline folate levels, folic acid dosage, baseline vitamin B12 levels, vitamin B12 dosage, homocysteine reduction, intervention duration, and whether folic acid was taken alone or in combination (all P-interaction>0.05). All 21 trials were free of attrition bias and reporting bias, and there was no significant publication bias. ConclusionsThis is by far the largest meta-analysis of RCTs regarding folic acid supplementation and stroke, demonstrating the overall benefit of folic acid for stroke prevention. Grain fortification and history of stroke or myocardial infarction may be the most important influences on the efficacy of folic acid for stroke prevention.

Diagnosis and Management of Pediatric Neuropsychiatric Systemic Lupus Erythematosus: An Update.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a potentially serious and life-threatening complication of SLE. The presentation and severity of neuropsychiatric involvement in SLE may show considerable variability. The disease can affect the neural tissue directly or may be associated with vascular involvement, mainly associated with anti-phospholipid (aPL) antibodies. A direct causal link with SLE may sometimes be challenging since there are many confounding factors and the symptoms may be non-specific. Despite its remarkable sensitivity in detecting hemorrhagic and ischemic stroke, transverse myelitis and ischemic infarction, magnetic resonance imaging (MRI) lacks the spatial resolution required to identify microvascular involvement. When standard MRI fails to detect a suspicious lesion, it is advisable to use advanced imaging modalities such as positron emission tomography (PET), single photon emission computed tomography (SPECT) or quantitative MRI, if available. Even with these advanced modalities, the specificity of neuroimaging in NPSLE remains inadequate (60-82% for MRI). Neuropsychiatric syndromes, such as cerebrovascular events, seizures and cognitive impairments appear to be associated with serum aPL antibodies. Some studies have shown that anti-ribosomal P antibodies have a low sensitivity for NPSLE and a limited contribution to the differentiation of different clinical entities. Treatment has two main goals: symptomatic relief and treatment of the disease itself. Commonly used immunosuppressants for NPSLE include cyclophosphamide (CYC), azathioprine (AZA), and mycophenolate mofetil (MMF). According to EULAR's current recommendation, strong immunosuppressants such as CYC and rituximab (RTX) should be preferred. Biologics have also been used in NPSLE. Fingolimod, eculizumab, and JAK inhibitors are potential drugs in the pipeline. Developing targeted therapies will be possible by a better understanding of the pathological mechanisms.

Dietary habits and compliance with dietary guidelines in patients with established cardiovascular disease.

Unhealthy dietary habits are an important risk factor for cardiovascular disease (CVD) and adopting a healthy diet is a central recommendation in CVD prevention. This study assessed the dietary habits of patients with established CVD, their compliance to dietary guidelines, and the relationship between guideline-compliance and recurrent cardiovascular event risk. 2656 patients with established CVD from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART) prospective cohort study, were included between 1996 and 2022. Data on dietary intake was retrospectively collected for all participants in December 2022 using a 160-item food frequency questionnaire. Compliance with dietary guidelines was quantified using an amended version of the Dutch Healthy Diet 2015 (DHD-15) index (range: 0-135). Cox proportional hazard models were used to quantify the relationship with cardiovascular events (stroke and myocardial infarction). Among 2656 CVD patients (77% male, mean age 59 ± 9 years), median energy intake was 1922 [IQR: 1536-2351] kcal/day. The median DHD-15 index was 81.7 [IQR 71.2-92.0], with high compliance scores for recommendations on legumes and fish, and low scores for recommendations on whole grains, red meat, processed meat, and dairy. A higher DHD-15 score was associated with lower stroke risk (HR 0.78, 95% CI 0.66-0.92 per 10-point increase) but not with myocardial infarction. Compliance with dietary guidelines was suboptimal in patients with established CVD. High compliance was associated with a clinically significant reduction in stroke risk in patients with established CVD, emphasizing the importance of dietary counseling.

Clinical significance of new-onset atrial fibrillation in patients with coronary artery or peripheral artery disease: results from the COMPASS trial

Abstract Background The COMPASS trial enrolled patients with coronary artery or peripheral artery disease, but excluded patients requiring oral anticoagulation. Compared to aspirin alone, rivaroxaban in addition to aspirin reduced a composite of cardiovascular death, stroke or myocardial infarction. Purpose This study aimed to explore the clinical significance of a new diagnosis of atrial fibrillation (AF) during follow-up. Methods New AF was identified from unplanned hospitalization, study drug discontinuation and adverse event reports. The associations between new-onset AF, clinical characteristics and outcomes in COMPASS participants were studied using time-updated regression modeling. Event rates were reported as per 100 patient-years (following a new diagnosis of AF vs. from randomization until the end-follow-up or new AF, whichever came first). Results During a mean follow-up of 23 months, 655 of 27,395 participants (2.4%) were newly diagnosed with AF. Advanced age, male sex, white race, higher body mass index, higher systolic blood pressure, heart failure and prior myocardial infarction were independently associated with new-onset AF. The rates of permanent discontinuation of study drug were 83.8% following a new diagnosis of AF, compared to 17.5% in participants without/before new AF. Compared to participants without/before a new diagnosis of AF, participants with new-onset AF were at increased risk of a composite of cardiovascular death, stroke or myocardial infarction (8.9 vs. 2.5 per 100 patient-years, hazard ratio [HR] 4.49, 95% confidence interval [CI] 3.37-6.00) (Figure 1). Risk increases with new-onset AF were also observed for hospitalization for heart failure (9.1 vs. 1.1 per 100 patient-years, HR 6.35, 95% CI 4.59-8.80) (Figure 2) and major bleeding (4.1 vs. 1.3 per 100 patient-years, HR 2.93, 95% CI 1.99-4.33). Conclusion In COMPASS, a new diagnosis of AF during trial follow-up was associated with a marked increase in risk of adverse outcomes.Composite outcome after new-onset AFHeart failure after new-onset AF

Enhanced isradipine sensitivity in vascular smooth muscle cells due to hypoxia-induced Cav1.2 splicing and RbFox1/Fox2 downregulation.

Calcium influx via the L-type voltage-gated Cav1.2 calcium channel in smooth muscle cells regulates vascular contraction. Calcium channel blockers (CCBs) are widely used to treat hypertension by inhibiting Cav1.2 channels. Using the vascular smooth muscle cell line, A7r5 and primary culture of cerebral vascular smooth muscle cells, we found that the expression and function of Cav1.2 channels are downregulated during hypoxia. Furthermore, hypoxia induces structural changes in Cav1.2 channels via alternative splicing. The expression of exon 9* is upregulated, whereas exon 33 is downregulated. Such structural alterations of Cav1.2 channels are caused by the decreased expression of RNA-binding proteins RNA-binding protein fox-1 homolog 1 and 2 (RbFox1 and RbFox2). Overexpression of RbFox1 and RbFox2 prevents hypoxia-induced exon 9* inclusion and exon 33 exclusion. Importantly, such structural alterations of the Cav1.2 channel partly contribute to the enhanced sensitivity of Cav1.2 to isradipine (a CCB) under hypoxia. Overexpression of RbFox1 and RbFox2 successfully reduces isradipine sensitivity in hypoxic smooth muscle cells. Our results suggest a new strategy to manage ischemic diseases such as stroke and myocardial infarction.

GR.4 Circadian rhythm influences ischemic core and penumbra volumes in pediatric and young adult populations

Background: Circadian rhythms are implicated in timing of stroke onset and infarct progression in adults, but this has not been studied in pediatric/young adult populations. Methods: We queried the RAPID Insights database from centers in USA for unique patients &lt;25 years with a CTP (10/05/2018-09/29/2023) and a minimum ischemic core volume (defined as relative cerebral blood flow (rCBF) reduction of &lt;30%) of &gt;0 cc and minimum mismatch of &gt;0 cc. Imaging time was subdivided into three epochs: Nigh (23:00 h-06:59 h), Day (07:00 h-14:59 h), and Evening (15:00 h-22:59 h). We analyzed age by pre-defined strata: &lt;2 years, 2-5, 6-11, 12-18 and 19-25. Perfusion parameters (core, perfusion volume, mismatch ratio) were analyzed using descriptive statistics. Results: 836 patients were included; 52.3% were in the 19-25 category. Median ischemic cores were larger during the Night (23.0cc [10.0 – 58.0]) compared to Day (19.0cc [8.0-42.0]) or Evening (15.0cc [7.0-33.0]), p=0.009. There was a trend towards larger perfusion volumes in the Night epoch. In the 19-25 group, perfusion volumes were significantly larger at Night (127.5cc [51.5 – 203.5]) compared to Day (74.0cc [33.0 – 139.0]) or Evening (76.0cc [38.0 – 157.5]), with larger mismatch volumes at Night. Conclusions: This is the first study to demonstrate diurnal fluctuations in perfusion parameters in a predominantly pediatric cohort.

The Impact of Postoperative Stroke and Myocardial Infarction on 1-Year Mortality Following Carotid Revascularization Using the VQI Database

The Impact of Postoperative Stroke and Myocardial Infarction on 1-Year Mortality Following Carotid Revascularization Using the VQI Database

Deciphering smooth muscle cell heterogeneity in atherosclerotic plaques and constructing model: a multi-omics approach with focus on KLF15/IGFBP4 axis

BackgroundRuptured atherosclerotic plaques often precipitate severe ischemic events, such as stroke and myocardial infarction. Unraveling the intricate molecular mechanisms governing vascular smooth muscle cell (VSMC) behavior in plaque stabilization remains a formidable challenge.MethodsIn this study, we leveraged single-cell and transcriptomic datasets from atherosclerotic plaques retrieved from the gene expression omnibus (GEO) database. Employing a combination of single-cell population differential analysis, weighted gene co-expression network analysis (WGCNA), and transcriptome differential analysis techniques, we identified specific genes steering the transformation of VSMCs in atherosclerotic plaques. Diagnostic models were developed and validated through gene intersection, utilizing the least absolute shrinkage and selection operator (LASSO) and random forest (RF) methods. Nomograms for plaque assessment were constructed. Tissue localization and expression validation were performed on specimens from animal models, utilizing immunofluorescence co-localization, western blot, and reverse-transcription quantitative-polymerase chain reaction (RT-qPCR). Various online databases were harnessed to predict transcription factors (TFs) and their interacting compounds, with determination of the cell-specific localization of TF expression using single-cell data.ResultsFollowing rigorous quality control procedures, we obtained a total of 40,953 cells, with 6,261 representing VSMCs. The VSMC population was subsequently clustered into 5 distinct subpopulations. Analyzing inter-subpopulation cellular communication, we focused on the SMC2 and SMC5 subpopulations. Single-cell subpopulation and WGCNA analyses revealed significant module enrichments, notably in collagen-containing extracellular matrix and cell-substrate junctions. Insulin-like growth factor binding protein 4 (IGFBP4), apolipoprotein E (APOE), and cathepsin C (CTSC) were identified as potential diagnostic markers for early and advanced plaques. Notably, gene expression pattern analysis suggested that IGFBP4 might serve as a protective gene, a hypothesis validated through tissue localization and expression analysis. Finally, we predicted TFs capable of binding to IGFBP4, with Krüppel-like family 15 (KLF15) emerging as a prominent candidate showing relative specificity within smooth muscle cells. Predictions about compounds associated with affecting KLF15 expression were also made.ConclusionOur study established a plaque diagnostic and assessment model and analyzed the molecular interaction mechanisms of smooth muscle cells within plaques. Further analysis revealed that the transcription factor KLF15 may regulate the biological behaviors of smooth muscle cells through the KLF15/IGFBP4 axis, thereby influencing the stability of advanced plaques via modulation of the PI3K-AKT signaling pathway. This could potentially serve as a target for plaque stability assessment and therapy, thus driving advancements in the management and treatment of atherosclerotic plaques.