Vascular Comorbidities Research Articles

Abstract WP132: Cerebral Amyloid Angiopathy And Risk Of Ischemic And Hemorrhagic Stroke

Introduction: Cerebral amyloid angiopathy (CAA), a condition characterized by beta amyloid deposition in the cerebral vasculature, is a common cause of intracerebral hemorrhage (ICH) in elderly patients. Radiographic features of CAA such as white matter hyperintensities and cerebral microbleeds are also associated with an increased risk of ischemic stroke. However, there are limited population-based data regarding the risk of incident ischemic and hemorrhagic stroke associated with clinically diagnosed CAA. Methods: We performed a retrospective cohort study using inpatient and outpatient claims from 2016 to 2018 from a nationally representative 5% sample of Medicare beneficiaries. The study exposure was a diagnosis of CAA identified using ICD-10-CM code I68.0. Participants with prevalent stroke were excluded. The primary outcome was any stroke (ischemic or hemorrhagic), and secondary outcomes were ICH, subarachnoid hemorrhage (SAH), and ischemic stroke, assessed separately. These outcomes were identified using validated ICD-10-CM diagnosis codes. Cox proportional hazards regression was used to determine the association between CAA and outcomes after adjustment for demographics and vascular comorbidities. Results: Of the 1.3 million Medicare beneficiaries included, 436 had clinically documented CAA without a prior or concurrent stroke. During a median follow-up of 3.0 years (IQR, 2.3-3.0), incident ischemic stroke occurred in 29,545 patients (2.28%), SAH in 3,340 (0.26%), and ICH in 4,338 (0.34%). In adjusted Cox models, CAA was significantly associated with an increased risk of any stroke (HR, 3.4; 95% CI, 2.5-4.7), ICH (HR, 17.1; 95% CI, 11.1-26.3), and SAH (HR, 6.2; 95% CI, 2.7-13.9). There was a nonsignificant association with ischemic stroke (HR, 1.4; 95% CI, 0.8-2.4). Conclusions: In a nationally representative cohort of Medicare beneficiaries, CAA was associated with a significantly increased risk of future ICH and SAH, but was not significantly associated with an increased risk of future ischemic stroke.

Abstract 30: Association Between Hospital-ascertained Atrial Fibrillation And Central Retinal Artery Occlusion: A Study Of 12 Million Patients

Introduction: Atrial fibrillation (AF) is a major risk factor for cerebral ischemic stroke. However, it is not known whether AF predicts the development of central retinal artery occlusion (CRAO), a form of ischemic stroke affecting the retina. Methods: A retrospective cohort study was undertaken using data from the California Healthcare Cost and Utilization Project (HCUP) State Inpatient and State Emergency Department Datasets (SID/SEDDs). Patients 18 years and older discharged from non-federal hospitals between 2005 and 2011 who did not have a history of CRAO were analyzed. The exposure variable was AF and the endpoint was CRAO, each identified using validated ICD-9-CM diagnosis codes. Association between AF and CRAO was modeled using a Fine-Gray method with death as a competing risk with adjustment for age, biological sex, race, and vascular co-morbidities. Results: A total of 12,181,778 patients were included, among these 806,397 with AF and 11,375,381 without AF. In total, 309 patients had CRAO. In an unadjusted analysis, there was a higher risk of CRAO in patients with versus without AF (HR 2.24 (95% CI: 1.51 to 3.32)). After adjustment for pre-specified covariates, there appeared to be a lower hazard of CRAO in patients with AF (aHR 0.61 (95% CI: 0.45 to 0.98)). Further analyses including cerebral ischemic stroke (aHR 1.16 (95% CI: 1.14 to 1.18)) and specifically embolic stroke (aHR 4.29 (95% CI 4.10-4.48)) as positive controls argued against overadjustment bias. We present sensitivity analyses including CRAO identified in any position of the discharge ICD list, using different ascertainment windows for AF and using broader categories of retinal ischemia. Conclusion: The incidence of CRAO was higher in patients with AF than those without AF, but the hazard of CRAO was not higher for patients with AF after adjustment for measured covariates. Endpoint and exposure ascertainment may have been limited by inclusion only of inpatient and emergency department encounters.

A meta-analysis of bevacizumab’s cardiovascular risks in patients treated for colorectal cancer.

113 Background: Bevacizumab (BVZ), a recombinant humanized monoclonal IgG antibody, is commonly used as first- and second-line adjuvant therapy in metastatic colorectal cancer. Recent guidelines have shown that a combination of three cytotoxic drug regimens FOLFOX (fluorouracil, leucovorin and oxaliplatin) along with BVZ is regarded as one of the first-line options. As we see an upward trend in using BVZ; it is crucial to analyze the side effects and potential toxicities. A frequent adverse effect with BVZ is hypertension. The prevailing hypothesis for the mechanism of BVZ induced hypertension is an increase in vascular tone due to the inhibition of VEGF-mediated vasodilation. A persistent elevation of arterial blood pressure is generally asymptomatic, but unmanaged hypertension can lead to cardiovascular complications, encephalopathy, and subarachnoid hemorrhage. Therefore, this meta-analysis aims to evaluate and assess the risk of BVZ induced hypertension. Methods: Our search included articles from PubMed, EMBASE, Web of Science, and Cochrane Library from 1980 to March 2022. Randomized controlled trials and clinical trials with BVZ as an add-on therapy mentioning cardiovascular side effects were included. Full analysis control group included various guideline directed chemotherapies and the subgroup analysis control group focused on FOLFOX therapy. A random-effects model was used with Review Manager, and a P value < 0.05 was considered significant. Results: We included a total of 17,807 patients in our study with an average age of 65 years. Analysis pooled from 19 RCTs showed that the odds of hypertension (Grade 3 or more) in patients treated with BVZ were about four times higher than the control group (OR 3.82, 95% CI 3.35-4.36, p-value < 0.00001, I2 = 78%). In a subgroup analysis, BVZ was compared with FOLFOX group, with odds of hypertension (Grade 3 or more) in BVZ group being about five times higher than in FOLFOX group (OR 5.24, 95% CI 4.06-6.77, p-value < 0.00001, I2 = 58%). Conclusions: Our meta-analysis demonstrates a significant cardiovascular risk of Bevacizumab when added to the standard regime for advanced colorectal cancer treatment. When BVZ was used as an add-on therapy to FOLFOX regimens for colorectal cancer, it was associated with about five times higher odds of developing hypertension (Grade 3 or more) in the treatment group with BVZ. Previous RCTs have demonstrated that BVZ add-on therapy to the standard regime is safe and without significant risk of toxicity. Our findings are important as they give vital information in assessing the risk-benefit ratio of adding BVZ, especially in a population with vascular comorbidities. Now that we have established the statistical significance of hypertensive risk with BVZ, it will be interesting to see how these events can be prevented in patients treated for metastatic colorectal cancer. Dedicated RCTs are needed to confirm these findings.

Abstract TMP50: Increased Pre-stroke Emergency Department Visits And Post-stroke Readmissions For Mexican-Americans Compared To Non-hispanic Whites In The Brain Attack Surveillance In Corpus Christi (BASIC) Study

Introduction: Mexican Americans (MAs) use less preventative healthcare than NHWs and this may result in in more emergency department (ED) visits or readmissions. We sought to explore ethnic differences in ED and hospital utilization immediately before and after stroke. Methods: BASIC is a stroke epidemiologic study in Corpus Christi TX. We performed probabilistic matching to identify hospital claims for all BASIC-identified index strokes (ischemic or ICH) from 2010-2020 continuously enrolled in Medicare fee-for-service (FFS). Matching was performed using demographics (including date of birth), stroke admission/discharge dates, vascular risk factors, comorbidities, and in-hospital procedures. All emergency department (ED) visits and hospital readmissions within 90 days before and after the index stroke were identified using Medicare claims. Logistic regression models were used to determine the association of MA ethnicity (compared to NHWs) with prior ED/inpatient visits and cox regression models were used to estimate the associations with subsequent ED visits/readmissions (censoring at death), adjusting for patient age, sex, stroke severity, and stroke type. Results: We identified 1,180 incident BASIC strokes that could be matched with Medicare FFS inpatient claims: 84% with ischemic stroke, 46.2% NHWs vs 45.7% MAs, mean age 76.4, median (IQR) NIHSS 5 (2-13). Both ED visits and hospitalizations were relatively common before and after stroke (Table). Compared to NHWs, MAs were more likely to have ED visits before stroke than NHWs (OR 1.5, 95%CI [1.1-2.1]) and hospitalizations after stroke (HR 1.3, [1.1-1.7], but no ethinc differences were observed in pre-stroke hospitalizations or post-stroke ED visits. ( Table ) Conclusion: The increased rate of pre-stroke ED visits in MAs suggests the potential for missed opportunities to prevent stroke may exist and merits further scrutiny.

Endothelial cell CD36 mediates stroke-induced brain injury via BBB dysfunction and monocyte infiltration in normal and obese conditions

CD36 expressed in multiple cell types regulates inflammation, vascular function, and innate immunity. Specifically, CD36 in microvascular endothelial cells (ECs) signals to elicit inflammation and causes EC death. This study investigated roles for EC-CD36 on acute stroke pathology in normal and obese conditions. Obesity induced by a high-fat diet (HD) selectively increased CD36 expression in ECs, not in monocytes/macrophages, in the post-ischemic brain. Mice deficient CD36 in ECs (ECCD36−/−) showed reduced injury size and vascular permeability in normal conditions. While control mice fed a HD developed obesity and aggravated stroke injury, ECCD36−/− mice were resistant to develop an obesity phenotype. Subjecting ECCD36−/− mice to stroke resulted in reduced injury size and BBB disruption. Moreover, the mice had reduced MCP-1 and CCR2 gene expression, resulting in reduced monocyte trafficking with improved survival and acute motor function. Reduced MCP-1 and CCR2 expression was still evident in ECCD36−/− mice subjected to severe stroke, suggesting that monocyte trafficking is an infarct-independent metabolic effect associated with specific EC-CD36 deletion. Our findings demonstrate the importance of EC-CD36 in developing vascular comorbidities and suggest that targeting EC-CD36 is a potential preventative strategy to normalize vascular risk factors, leading to improved acute stroke outcomes.

Exploring Reasons for Differential Vulnerability and Alzheimer's Disease Riskin Racial and Ethnic Minorities.

African American and Hispanic older adults are reported to have up to a 2-fold higher risk of Alzheimer's disease and related disorders (ADRD), but the reasons for this increased vulnerability have not been fully explored. The Vulnerability Index (VI) was designed to identify individuals who are at risk of developing cognitive impairment in the future, capturing 12 sociodemographic variables and modifiable medical comorbidities associated with higher ADRD risk. However, a prior limitation of the VI was that the original study cohort had limited diversity. We examined the association of the VI within and between non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment and different socioeconomic strata enrolled in a community-based dementia screening study. To explore reasons for reported higher ADRD vulnerability in African Americans and Hispanics. In a cross-sectional study of 300 non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment, we studied the association between cognitive status, the VI, and socioeconomic status (SES). When considering race/ethnicity, the presence of more vascular comorbidities drove greater vulnerability. When considering SES, vascular comorbidities played a less prominent role suggesting resources and access to care drives risk. The VI had differential effects on cognitive performance with the greatest effect in the earlier stages of impairment. Findings from this study provide a deeper understanding of the differential risk of ADRD in multicultural older adults captured by the VI and how barriers to healthcare access may increase vulnerability in racial/ethnic minorities.

Do Comorbidities and Triggers Expedite Chronicity in migraine?

Background and Aim: Several factors are suggested to be associated with an increased risk of transforming from episodic migraine (EM) to chronic migraine (CM). We aimed to examine whether some specific attack triggers and comorbidities were associated with CM. Methods: Patients followed up with a diagnosis of definite migraine for at least 1 year were divided into two groups, EM (<15 attacks per month) and CM (>15 attacks per month). The demographic and clinical data, attack-triggering factors, and comorbid diseases were compared between the groups. Results: A total of 403 (286 females) patients were analyzed; 227 (56.3%) of the migraineurs had EM and 176 (43.7%) had CM. The mean age was 40.9 ± 11.3 years in EM, and 42.2 ± 11.7 years in CM. Disease duration was longer in CM compared with EM (P = 0.007). Missing meals (P = 0.044), exposure to heavy scents/perfumes (P = 0.012), intense physical activity (P = 0.037), and withdrawal of caffeine (P = 0.012) were reported significantly higher in CM than in EM. Comorbid history of medication overuse (P < 0.001), hypertension (P = 0.048), hyperlipidemia (P = 0.025), depression (P = 0.021), chronic painful health problems (P = 0.003), iron deficiency anemia (P = 0.006), and history of surgery (P = 0.006) were found significantly high in CM. Conclusion: This study demonstrates that attack-triggering factors, vascular comorbidities, depression, medication overuse, and chronic painful health problems pose significant risks for CM. Vascular comorbidities are independent risk factors for chronification in migraine and might increase the patient's lifetime morbidity and mortality. Therefore, prompt diagnosis of migraine before the transformation to chronicity and effective early management have the utmost importance.

Association between vascular access type with profile hemodialysis patient in west Nusa Tenggara district hospital

Intoduction: Currently, the prevalence of chronic kidney disease (CKD) is an increasing public health problem. In Indonesia, CKD increased from 0.2% in 2013 to 0.38% in the year 2018. CKD requires very high maintenance and handling costs for hemodialysis. To be able to do hemodialysis, it is necessary to create vascular access as a pathway for blood circulation from the patient's body to the hemodialysis machine. This research is to determine the profile of vascular access and the association between vascular access with comorbid, age, and sex. Methods: This research is descriptive quantitative research, cross sectional. Data were taken from the registration data or medical record of CKD patient that undergo hemodialysis at West Nusa Tenggara Distric Hospital. Data collection was carried out from 10th January 2020 to 10th March 2020. By applying certain inclusion and exclusion criteria, there were 100 obtained data and subsequently were analyzed using SPSS software. Univariate and bivariate analysis using chi-square test were carried out to descrive the data distribution and the association between variables respectively. Result: Of the 100 respondents, it was found that most of them were female 57%. Most data were aged 48-58 years 43% people. The most comorbid is Diabetes Mellitus with 53% of people. The most used vascular access is AV Fistula Brachiocephalic 58.0%. Based on the Chi-Square statistical test, it shows that there is a significant association between vascular access with the comorbid disease (p <0.05) p = 0.003, and the present association between vascular access to sex was obtained p-value = 0.001 (p <0.05) and there is no significant association between the use of vascular access to age showed a value (p> 0.05) p = 0.08. Based on this study to determine vascular access, comorbid and sex are considered in decision making. Conclusion: The research shows that there is association between the vascular access type to comorbidities and gender.

Lichen sclerosus: A C5B-9 mediated chronic microvascular injury syndrome potentially reflective of common adult comorbidities

Lichen sclerosus (LS) is a cutaneous disease of unknown etiology that often involves the vulva or foreskin but also can affect extragenital sites. Regardless of the anatomic site, the histomorphology and presumably pathogenesis are similar. Perhaps a clue to the pathophysiology of LS lies in its frequent association with morphea, specifically, when occurring in an extragenital context. In our experience a striking feature evident in established lichen sclerosis (LS) is one of superficial vascular drop out whereby residual vessels exhibited endothelial cell necrosis and microvascular basement membrane zone thickening, the latter reflective of antecedent episodes of microvascular injury. We sought to understand the pathophysiology that underlies the distinct vascular changes and in doing so, shed light on the pathogenesis of LS. We examined 44 cases of LS over a period of 2019 to 2021. We were able to obtain past medical histories in 34 of the 44 cases. Regarding pathological assessment, the predominant focus was on microvascular changes. We assessed the role of C5b-9 mediated vascular injury in the pathogenesis of the vasculopathy and enhanced type I interferon signaling in vessels given the morphologic semblance to the select interferonopathy syndromes, namely fibrosing dermatomyositis and Kohlmeier Degos disease. We examined the expression of CMV DNA and protein based on prior observations in an earlier study that isolated early protein expression in the microvasculature in the setting of LS and scleroderma. From a clinical perspective, the most striking association was an older age at the time of diagnosis (mean age of 62 years and median age of 61.5 years) and the presence of vascular comorbidities of diabetes, hypertension, and hyperlipidemia in almost 80% of cases. All cases showed significant microvascular changes in the superficial corium with the most frequent findings being those of significant basement membrane zone reduplication and vascular drop out. A number of cases showed prominent microvascular deposits of C5b-9 in the zone of hyalinizing fibrosis or subjacent to the discernible table of fibroplasia in the absence of enhanced type I interferon signaling. In no case were there viral cytopathic changes associated with CMV affecting the endothelium. The studies that encode CMV DNA or protein did not show a significant role for CMV reactivation in endothelium in the majority of the studied cases. It is concluded that the pathophysiology of LS includes a microvascular injury syndrome within the papillary dermis. The mechanism of endothelial cell injury is complement mediated at least in part and could reflect an adaptive immune response targeting endothelium indicative of classic complement pathway activation when coexisting with morphea or occurring in younger individuals. A non-immune based endothelial dysfunction and complement mediated injury unrelated to antibody driven classic complement pathway activation are more likely pathogenetically in the setting of certain diseases like diabetes mellitus and hypertension. Vascular drop out can be explained by the diminished endothelial progenitor pool needed to repopulate the damaged microvessels in certain settings like hypertension and diabetes.

Association between periodontitis and blood-ocular barrier disruption.

Periodontitis causes low-grade systemic inflammation e.g., through circulatory periodontal endotoxins, and it has been associated with cardiovascular morbidity and wet age-related macular degeneration. To assess the association between clinical severity of periodontitis and aqueous flare levels in the eyes. Patients with periodontitis (N = 15) who underwent periodontal treatment by a specialized dentist between the years 2020 and 2021 at the Chin and Mouth Disease Unit, Kymenlaakso Central Hospital, Kotka, Finland were enrolled. Aqueous flare levels, a surrogate marker for blood-aqueous and blood-retinal-barrier disruption, were measured using Laser Flare Meter (FM-600, Kowa Company, Ltd., Nagoya, Japan) before and right after the periodontal treatment and at 3 months. The number of teeth, periodontal probing depth (PPD), periodontal pathogens and antimicrobial treatment were recorded. At baseline, aqueous flare levels correlated with the number of clinically-relevant PPD (>5 mm) pockets (R = 0.789, P < 0.001) and inversely correlated with the number of teeth (R = -0.587, P = 0.035). At baseline, aqueous flare levels were 15.39 ± 13.24 photon units (pu)/ms among patients with periodontal pathogens, compared with 3.29 ± 1.67 pu/ms among those without any peridontal pathogens in PCR (P = 0.018). At 3 months compared to baseline values, aqueous flare levels were reduced to <50% from baseline among 6 patients (40%), whereas the levels increased to >200% from baseline in 1 patient (7%) (repeated measures ANOVA, P < 0.026). Poor periodontal status was associated with blood-ocular-barrier breakdown. These findings could expand our understanding of the potential mechanisms and therapeutic targets against retinal vascular diseases and systemic comorbidities in patients with periodontitis.

Disability in multiple sclerosis is associated with vascular factors: An ultrasound study

BackgroundAlthough multiple sclerosis (MS) is an immune-related disorder, pharmaceutical interventions targeting the immune system do not stop or reverse disability progression; the major challenge for this condition. Studies show that disability progression in MS is associated with vascular comorbidity and brain volume loss, indicating that a multi-targeted approach is required to prevent debilitation. The aim of the present study was to examine the associations between vascular ultrasound, disability, biochemistry and lifestyle data in people with MS (pwMS). MethodsExtracranial vascular ultrasound was performed on 51 pwMS and 25 age-matched controls. Sonographic interrogation determined carotid intima-media thickness (cIMT) and abnormal blood flow patterns. Disability was assessed using the Expanded Disability Status Scale (EDSS). Biochemical and lifestyle data were obtained for all participants. ResultsThe EDSS had a highly significant positive association with the cIMT of the right (r = 0.63; p = 0.001) and left (r = 0.49; p = 0.001) common carotid arteries and negative associations with the peak systolic blood flow velocity of the right vertebral artery (r = -0.42; p = 0.01) as well as end-diastolic velocity of the left internal carotid artery (r = -0.47; p = 0.01). These associations were significantly influenced by biochemical and lifestyle factors. Both cIMT and age showed significant associations with the EDSS. When cIMT was adjusted for age in a regression analysis, the association between the EDSS and the cIMT remained significant (p < 0.01), while the age association was reduced to being significant only at 10% (p = 0.06). There was no association between the use of MS medication and the EDSS (p = 0.56). ConclusionPwMS who had increased cIMT, a surrogate marker for atherosclerosis, and reduced carotid artery blood flow velocities were at risk for greater disability over and above the effect of aging. These findings provide important information for disease management and disability prevention in pwMS. Modification of diet and lifestyle may promote the unhindered flow of essential nutritional factors into the brain in pwMS.

Impact of white matter hypodensities on outcome after intracerebral hemorrhage

ObjectivesWhite matter hypodensities (WMH), a surrogate of small vessel disease, associate with cognitive decline and stroke risk. The impact of WMH on functional outcome after intracerebral hemorrhage (ICH) has differed between studies. We aimed to examine factors associated with the severity of WMH in ICH, and whether there is an independent association between the extent of WMH and outcome. Materials and methodsThis was a prospective study of consented patients with non-traumatic primary ICH, admitted to the Helsinki University Hospital between May 2014 and December 2018. To evaluate the extent of the WMH, modified van Swieten score of the side contralateral to the ICH was obtained. Patients were grouped into 3 categories of the scores. We performed univariate and multivariable analyses to find out factors associated with the severity of WMH, and whether WMH associate with functional outcome and mortality up to 12 months, adjusted for the known major outcome predictors. ResultsIn our cohort of 417 ICH patients, WMH severity associated with older age, female sex, admission National Institutes of Health Stroke Scale (NIHSS) points, and signs of previous ischemic stroke on CT. We found an independent association between WMH severity and poor functional outcome at 3 months (OR 1.72, 95% CI 1.27-2.33), and 1 year (OR 2.16, 95% CI 1.57-2.95), and mortality at 1 year (OR 1.91, 95% CI 1.29-2.85). ConclusionsIn our ICH patients, vascular comorbidities and older age associated with the presence of WMH, which, in turn, strongly associated with poor functional outcome.

Peripheral blood leukotriene B4 and E4 as biomarkers in Alzheimer’s disease

AbstractBackgroundWe showed recently that use of leukotriene receptor antagonists, typically used in asthma therapy, was associated with preserved executive function among people with Alzheimer’s disease (AD) dementia. The aim of this study was to determine if leukotriene B4 (LTB4) and E4 (LTE4) would be associated with longitudinal changes in cognitive performance and cerebrovascular disease markers in people with AD.MethodParticipants with clinical AD or mild cognitive impairment were identified from the Ontario Neurodegenerative Disease Research Initiative. LTB4 and LTE4 were extracted from fasting serum and quantified using ultra‐high performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS). Concentrations below the limit of detection were imputed using quantile regression imputation of left‐censored data. Cognition was assessed using composite scores for executive function (Trails Making Test B, Symbol Digit Modalities Test, Stroop switching task, and verbal fluency) and memory (Rey Auditory Verbal Learning Test and Brief Visuospatial Memory Test). White matter hyperintensities (WMH), lacunes, and perivascular spaces (PVS) were quantified using T2‐weighted structural magnetic resonance imaging (MRI). Longitudinal associations between baseline LTB4 or LTE4 and cognition and imaging markers at baseline and 1‐year‐follow‐up were assessed using mixed‐effects linear regression models, controlling for baseline demographic factors, medication use, and vascular comorbidities. Findings were corrected for multiple comparisons using a 5% false discovery rate.ResultAmong 158 participants (mean age = 69.22 years, 51% female, mean education = 14.61 years), higher baseline concentrations of LTB4 were not associated with performance in executive function or memory over time nor with changes in WMH, lacunes, or PVS over time. Higher baseline concentrations of LTE4 were associated with better performance in memory over time (β = 0.153 [95% CI = 0.026, 0.287]; however, this finding did not survive correction for multiple comparisons (adjusted p = 0.260; Table 1).ConclusionIn a group of patients with AD, higher LTB4 and LTE4 in serum were not associated with changes in cognitive performance nor markers of cerebrovascular disease. These findings suggest very little potential for serum leukotrienes as biomarkers for cognitive decline of cerebrovascular disease progression in AD.

Lipid oxidation as a marker of apathy and executive dysfunction in patients at risk of vascular cognitive impairment

AbstractBackgroundApathy and executive function decline are hallmarks of vascular dysfunction in neurodegeneration and cognitive impairment. People with mild vascular cognitive impairment (mVCI) display a combined etiology of both cognitive impairment and vascular comorbidities; hence, patients with vascular risk factors are at risk for mVCI. The co‐occurrence of apathy and executive dysfunction is prevalent; however, the physiological pathway underlying these manifestations is yet to be investigated. Oxidative stress is often present in vascular dysfunction. This study investigated the relationship between oxidative stress, specifically markers of lipid oxidation, apathy, and executive dysfunction in patients at risk of mVCI.MethodPatients at risk of mVCI were recruited from a population of patients with coronary artery disease in a Cardiac Rehabilitation Program. Apathy was assessed using the Apathy Evaluation Scale and executive function with Trial Making Test B, phonemic fluency test and animal naming test. Fasting blood was collected and serum concentrations of early and late lipid oxidation markers, lipid hydroperoxides (LPH) and 8‐isoprostane (8‐ISO) respectively, were measured.ResultParticipants (n=206, Age= 63.0±7.5, 80% men, total years of education= 15.9±3.4, AES score= 28.3±8.8, composite z score for EF= 0±1) demonstrated significantly different ratios of late to early lipid oxidation markers (8‐ISO/LPH) between groups (F(3, 202) = 10.915, p &lt;0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction, only apathy, and both apathy and executive dysfunction. A multivariate linear regression model adjusting for demographics found that lipid oxidation was significantly associated with apathy (B= 4.63, p &lt; 0.001) and executive function (B= ‐0.19, p= 0.018); however, when controlling for both demographics and vascular risk factors, lipid oxidation was significantly associated with apathy alone (B= 3.11, p= 0.002).ConclusionThe results highlight an important involvement of lipid oxidation in the co‐occurrence of apathy and executive dysfunction in patients at risk of mVCI. Our results show that increased oxidative stress may contribute to the development of apathy, which may relate to why apathy is a strong risk factor for progression to dementia in at‐risk populations.

Female sex is associated with reintervention and mortality following elective endovascular abdominal aortic aneurysm repair.

Although sex differences in endovascular abdominal aortic aneurysm repair (EVAR) outcomes have been increasingly reported, the determination of contributing factors has not reached a consensus. We investigated the disparities in sex-specific outcomes after elective EVAR at our institution and evaluated the factors that might predispose women to increased morbidity and mortality. We performed a retrospective medical record review of all patients who had undergone elective EVAR from 2011 to 2020 at a suburban tertiary care center. The primary outcomes were 5-year survival and freedom from reintervention. The Fisher exact test, t tests, and Kaplan-Meier analysis using the rank-log test were used to investigate the associations between sex and outcomes. A multivariable Cox proportional hazard model controlling for age and common comorbidities evaluated the effect of sex on survival and freedom from reintervention. A total of 273 patients had undergone elective EVAR during the study period, including 68 women (25%) and 205 men (75%). The women were older on average than were than the men (76years vs 73years; P ≤ .01) and were more likely to have chronic obstructive pulmonary disease (38% vs 23%; P= .01), require home oxygen therapy (9% vs 2%; P=.04), or dialysis preoperatively (4% vs 0%; P= .02). The distribution of other common vascular comorbidities was similar between the sexes. The 30-day readmission rate was greater for the women than for the men (18% vs 8%; P= .02). The women had had significantly lower survival at 5years (48%± 7.9% vs 65%± 4.3%; P< .01) and significantly lower 1-year (women, 89%± 4.1%; vs men, 94%± 1.7%; P= .01) and 5-year (women, 69%± 8.9%; vs men, 84%± 3.3%; P= .02) freedom from reintervention. On multivariable analysis, female sex (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1-2.9), congestive heart failure (HR, 2.2; 95% CI, 1.2-3.9), and older age (HR, 1.1; 95% CI, 1.0-1.1) were associated with 5-year mortality. Female sex remained as the only variable with a statistically significant association with 5-year reintervention (HR, 2.4; 95% CI, 1.1-4.9). Female sex was associated with decreased 5-year survival and increased 1- and 5-year reintervention after elective EVAR. Data from our institution suggest that factors beyond patient age and baseline health risk likely contribute to greater surgical morbidity and mortality for women after elective EVAR.

Intermittent hypoxia conditioning as a potential prevention and treatment strategy for ischemic stroke: Current evidence and future directions.

Ischemic stroke (IS) is the leading cause of disability and death worldwide. Owing to the aging population and unhealthy lifestyles, the incidence of cerebrovascular disease is high. Vascular risk factors include hypertension, diabetes, dyslipidemia, and obesity. Therefore, in addition to timely and effective reperfusion therapy for IS, it is crucial to actively control these risk factors to reduce the incidence and recurrence rates of IS. Evidence from human and animal studies suggests that moderate intermittent hypoxia (IH) exposure is a promising therapeutic strategy to ameliorate common vascular risk factors and comorbidities. Given the complex pathophysiological mechanisms underlying IS, effective treatment must focus on reducing injury in the acute phase and promoting repair in the recovery phase. Therefore, this review discusses the preclinical perspectives on IH conditioning as a potential treatment for neurovascular injury and highlights IH pre and postconditioning strategies for IS. Hypoxia conditioning reduces brain injury by increasing resistance to acute ischemic and hypoxic stress, exerting neuroprotective effects, and promoting post-injury repair and regeneration. However, whether IH produces beneficial effects depends not only on the hypoxic regimen but also on inter-subject differences. Therefore, we discuss the factors that may influence the effectiveness of IH treatment, including age, sex, comorbidities, and circadian rhythm, which can be used to help identify the optimal intervention population and treatment protocols for more accurate, individualized clinical translation. In conclusion, IH conditioning as a non-invasive, non-pharmacological, systemic, and multi-targeted intervention can not only reduce brain damage after stroke but can also be applied to the prevention and functional recovery of IS, providing brain protection at different stages of the disease. It represents a promising therapeutic strategy. For patients with IS and high-risk groups, IH conditioning is expected to develop as an adjunctive clinical treatment option to reduce the incidence, recurrence, disability, and mortality of IS and to reduce disease burden.

COVID-19 independently predicts poor outcomes in Acute Ischemic Stroke- Insights from a multicenter study from Pakistan and United Arab Emirates

BackgroundIschemic stroke associated with coronavirus 2019 (COVID-19) has been well recognized by now. Few studies have compared COVID related versus unrelated strokes. We intend to report on a large group of Asian patients from two countries and compare COVID with non-COVID strokes admitted during the same time period. MethodsConsecutive cases of acute ischemic stroke either presenting or developing, between March 2020 and December 2021 in four tertiary care hospitals (1 in Dubai, UAE and 3 in Karachi, Pakistan) and testing positive for COVID-19 were included in the study. Patients admitted with ischemic stroke during the same time period and who tested negative for COVID-19 were also randomly selected from the four hospitals. All data was collected from the medical records of the patients and recorded on a standard questionnaire before it was entered in SPSS version 21 for analysis. ResultsThere were 139 COVID positive and 271 COVID negative patients with acute ischemic stroke included in the current study. There were significantly more males (80.6% vs 64.9%, p=0.001) and more large vessel strokes in the COVID positive group (41% vs 21.8%, p<0.001). Being COVID positive was an independent predictor of poor outcome at discharge, defined as a modified Rankin score of 3-6 (OR 3.87, 95% CI 2.21-6.77) after adjusting for country, age, sex, vascular comorbid conditions and stroke subtype. ConclusionsIn this largest series of patients with COVID related strokes from Asia, COVID-19 was an independent predictor of poor outcomes at discharge after adjusting for other variables.

Association of the CLL Comorbidity Index (CLL-CI) and International Prognostic Index (IPI) with Overall Survival (OS) and 1-Year Mortality in Patients (pts) with Relapsed or Refractory (r/r) Large B Cell Lymphoma (LBCL) Treated with CD19 Directed Autologous Chimeric Antigen Receptor T (CART) Cell Therapies

Introduction CART cell therapy has improved OS in r/r LBCL, but less than half of pts are long term survivors. Our goal was to evaluate the association of two previously developed prognostic scores, the CLL-CI and IPI (Gordon, 2021 and Sehn, 2007) with survival after CART. Methods Pts with r/r LBCL treated with standard of care CART cell therapy at the MD Anderson Cancer Center between 2017-2021 were retrospectively analyzed. Prognostic factors were assessed prior to apheresis. Comorbidities were assessed using the CLL-CI, a three-factor comorbidity score which consists of vascular, endocrine and upper gastrointestinal comorbidities as categories. Each category receives 1-point if any condition is present for a maximum score of 3. A score of 0 is low risk, 1 intermediate risk and 2-3 high-risk. Survival was estimated using the Kaplan Meier method and cause specific hazard functions, with difference assessed by log-rank. Multivariable Cox regression was used to model OS. Results In total, 218 pts were included. Median age was 61 years (range, 18-89). Median prior lines of therapy were 3 (range, 1-11). The majority of pts, 202 (93%) were treated with axicabtagene ciloleucel and 16 (7%) were treated with tisagenlecleucel. IPI score was 0-1 in 13%, 2 in 25%, 3 in 31% and 4-5 in 31%. Except for age >60, all components of the IPI were significantly associated with OS. Age >70 was associated with shorter OS. CLL-CI score was 0 in 44%, 1 in 36% and 2-3 in 21%. IPI score was significantly associated with OS (Fig 1A). Median OS was not reached (NR), 3.3, 1.7 and 0.9 years in IPI 0-1, 2, 3 and 4-5, respectively (p<.0001). CLL-CI score was also associated with OS, median 3.3, 1.5 and 1.3 years with a score of 0, 1 and 2-3, respectively (Fig 1B; p=.01). In multivariable models both IPI (HR 1.8, p=<.0001) and CLL-CI (HR 1.3, p=.03) were independently associated with OS. We also performed cause specific survival analyses by treating other causes of death as competing risks. The IPI score was not associated with toxic/infectious death (p=0.24) while CLL-CI score was (p=.004). Death due to toxic/infectious complications at 1 year occurred in 0%, 6% and 18% of pts with CLL-CI score of 0, 1 and 2-3, respectively. Interestingly, CLL-CI was not significantly associated with grade 3-4 cytokine release syndrome (p=.36). There was a trend towards higher rates of grade 3-4 immune effector cell associated neurotoxicity syndrome with high CLL-CI (p=.07). We also evaluated cause specific survival with death due to progressive disease as the outcome of interest. Median progressive disease specific survival was NR, NR, 2.2 and 1.1 years in IPI 0-1, 2, 3 and 4-5, respectively (p<.0001). Progressive disease specific survival was not associated with CLL-CI (p=.15). We further evaluated the association of toxic/infectious death, age and comorbidity. A total of 21 pts (9.6%) died within 1 year of CART due to toxic/infectious complications; 38% (N=8) of all toxic/infectious deaths were in pts with a CLL-CI score of 2-3 who were >70 years old. In pts >70 years, the rate of death at 1 year due to toxic/infectious complications was 0%, 7% and 39% in pts with a low, intermediate and high CLL-CI score, respectively (p=.009). In pts ≤70 years death at 1 year due to toxic/infectious complications occurred in 0%, 5% and 4% in CLL-CI low, intermediate and high, respectively (p=.031). Finally, we assessed the test characteristics of the IPI and CLL-CI to predict death at 1 year. Using receiver operator characteristics to assess death due to toxic/infectious, the AUC for the CLL-CI was .82 (95% CI, .73-.91) which is comparable to the AUC for IPI which was .75 (95% CI, .67-.82) when assessing death due to progressive disease. Discussion The IPI and CLL-CI, assessed prior to CART, are associated with survival in r/r LBCL. IPI is more strongly associated with death due to progressive disease and the CLL-CI with death due to toxic/infectious complications-particularly in older pts (age >70 years). It is interesting that a score previously validated in CLL also applies to LBCL and suggests vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity correlates with survival in pts with different malignancies. Future research could further elucidate the pathophysiology driving the increased risk in pts with these particular comorbidities. And mitigating toxicity and infection in high CLL-CI pts treated with CART should also be a focus of future research Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Hypothyroidism and the Risk of Cognitive Dysfunction: A Meta-Analysis.

The purpose of this meta-analysis was to assess whether there is an association between hypothyroidism and the risk of cognitive dysfunction. PubMed, Cochrane Library, and Embase were searched for relevant studies published from database inception to 4 May 2022, using medical subject headings (MeSHs) and keywords. Eight studies involving 1,092,025 individuals were included, published between 2010 and 2021. The pooled analysis showed that there was no association between hypothyroidism and cognitive dysfunction (OR = 1.13, 95% CI = 0.84-1.51, p = 0.426), including both all-cause dementia (OR = 1.04, 95% CI = 0.76-1.43, p = 0.809) and cognitive impairment (OR = 1.50, 95% CI = 0.68-3.35, p = 0.318). Neither overt hypothyroidism (OR = 1.19, 95% CI = 0.70-2.02, p = 0.525) nor subclinical hypothyroidism (OR = 1.04, 95% CI = 0.73-1.48, p = 0.833) was associated with cognitive dysfunction. Neither prospective cohort (OR = 1.08, 95% CI = 0.77-1.51, p = 0.673) nor cross-sectional studies (OR = 1.23, 95% CI = 0.63-2.42, p = 0.545) had any effect on the association. Interestingly, the risk of cognitive dysfunction was significantly increased in the group not adjusted for vascular comorbidity (OR = 1.47, 95% CI = 1.07-2.01, p = 0.017), while it was reduced in the adjusted group (OR =0.82, 95% CI = 0.79-0.85, p &lt; 0.001). This meta-analysis shows that hypothyroidism was associated with a reduced risk of cognitive dysfunction after adjustment for vascular-disease comorbidities. More prospective observational studies are needed in the future to investigate the relationship between hypothyroidism and cognitive dysfunction.

Reintervention does not affect long-term survival after fenestrated endovascular aneurysm repair.

Fenestrated endovascular aneurysm repair (FEVAR) is increasingly used in the treatment of juxtarenal aortic aneurysms and short-neck infrarenal aneurysms. Reinterventions (REIs) occur frequently, contributing to patient morbidity and resource utilization. We sought to determine whether REI affects long-term survival after FEVAR. A single-institution retrospective review of all Cook Zenith fenestrated (ZFEN; Cook Medical, Inc, Bloomington, IN) repairs was performed. Patients with ≥6months of follow-up and without adjunctive branch modifications were included. REI was defined as any aneurysm, device, target branch, or access-related intervention after the index procedure. REIs were categorized as early (<30days) or late (≥30days), by indication (ie, branch, endoleak, limb related, access related, other), and by target branch or device components. Patients were stratified into REI vs no REI groups and branch REI vs non-branch REI groups. Of 219 consecutive ZFEN repairs from 2012 to 2021, 158 patients met the inclusion criteria. Of these 158 patients, 41 (26%) required a total of 51 REIs (10 early and 41 late) during a mean follow-up of 33.9months. The most common indication for REI was branch-related (31 of 51; 61%), with the renal arteries the most frequently affected (26 of 51; 51%). The only differences found in baseline, aneurysm, and device characteristics were a higher mean Society for Vascular Surgery comorbidity score (9.6 vs 7.9; P= .04) and larger suprarenal neck angle (23.3° vs 17.1°; P= .04) in the no REI group. In contrast, the REI group had a larger mean proximal seal zone diameter (26.3mm vs 25.1mm; P= .03) and device diameter (31.9mm vs 30.0mm; P= .002) compared with the no REI group. Technical success and operative characteristics were similar between the groups, except for a longer mean fluoroscopy time (74.9minutes vs 60.8minutes; P= .01) and longer median length of stay (2 vs 2days; P= .006) for the REI group. Although the rate of early (<30days) major adverse events was greater for the REI group (24.4% vs 6.0%; P= .001), the difference in 30-day mortality was not statistically significant (4.9% vs 0.9%; P= .10). On Kaplan-Meier analysis, freedom from REI at 1 and 5years was 85.7% and 62.6%, respectively, for the overall cohort. No difference was found in the estimated 5-year survival between the REI and no REI groups (62.8% vs 63.5%; log-rank, P= .87) and branch REI and non-branch REI groups (71.8% vs 49.9%; log-rank, P= .16). On multivariate analysis, REI was not an independent predictor for mortality. However, age, Society for Vascular Surgery comorbidity score, and preoperative maximum aneurysm diameter each increased the hazard of death (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.12 [P= .007]; HR, 1.10; 95% CI, 1.01-1.18 [P= .02]; HR, 1.05; 95% CI, 1.02-1.08 [P= .003], respectively). After ZFEN, 41 patients (26%) had required a total of 51 REIs, with most occurring ≥30days after the index procedure, and 61% were branch related, with no influence on 5-year survival. Age, comorbidity, and baseline aneurysm diameter independently predicted mortality. The use of FEVAR mandates lifelong surveillance and protocols to maintain branch patency. Despite their relative frequency, REIs did not influence 5-year postprocedural survival.