Hypertension: Causes and Consequences of Circadian Rhythms in Blood Pressure.

Hypertension is extremely common, affecting approximately 1 in every 2 adults globally. Chronic hypertension is the leading modifiable risk factor for cardiovascular disease and premature mortality worldwide. Despite considerable efforts to define mechanisms that underlie hypertension, a potentially major component of the disease, the role of circadian biology has been relatively overlooked in both preclinical models and humans. Although the presence of daily and circadian patterns has been observed from the level of the genome to the whole organism, the functional and structural impact of biological rhythms, including mechanisms such as circadian misalignment, remains relatively poorly defined. Here, we review the impact of daily rhythms and circadian systems in regulating blood pressure and the onset, progression, and consequences of hypertension. There is an emphasis on the impact of circadian biology in relation to vascular disease and end-organ effects that, individually or in combination, contribute to complex phenotypes such as cognitive decline and the loss of cardiac and brain health. Despite effective treatment options for some individuals, control of blood pressure remains inadequate in a substantial portion of the hypertensive population. Greater insight into circadian biology may form a foundation for novel and more widely effective molecular therapies or interventions to help in the prevention, treatment, and management of hypertension and its related pathophysiology.

Circadian Biology and the Neurovascular Unit.

Mammalian physiology and cellular function are subject to significant oscillations over the course of every 24-hour day. It is likely that these daily rhythms will affect function as well as mechanisms of disease in the central nervous system. In this review, we attempt to survey and synthesize emerging studies that investigate how circadian biology may influence the neurovascular unit. We examine how circadian clocks may operate in neural, glial, and vascular compartments, review how circadian mechanisms regulate cell-cell signaling, assess interactions with aging and vascular comorbidities, and finally ask whether and how circadian effects and disruptions in rhythms may influence the risk and progression of pathophysiology in cerebrovascular disease. Overcoming identified challenges and leveraging opportunities for future research might support the development of novel circadian-based treatments for stroke.

Circadian and Diurnal Regulation of Cerebral Blood Flow.

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.

Molecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates.

Stroke-induced cerebral microvascular dysfunction contributes to aggravation of neuronal injury and compromises the efficacy of current reperfusion therapies. Understanding the molecular alterations in cerebral microvessels in stroke will provide original opportunities for scientific investigation of novel therapeutic strategies. Toward this goal, using a recently optimized method which minimizes cell activation and preserves endothelial cell interactions and RNA integrity, we conducted a genome-wide transcriptomic analysis of cerebral microvessels in a mouse model of stroke and compared these transcriptomic alterations with the ones observed in human, nonfatal, brain stroke lesions. Results from these unbiased comparative analyses have revealed the common alterations in mouse stroke microvessels and human stroke lesions and identified shared molecular features associated with vascular disease (e.g., Serpine1/Plasminogen Activator Inhibitor-1, Hemoxygenase-1), endothelial activation (e.g., Angiopoietin-2), and alterations in sphingolipid metabolism and signaling (e.g., Sphigosine-1-Phosphate Receptor 2). Sphingolipid profiling of mouse cerebral microvessels validated the transcript data and revealed the enrichment of sphingomyelin and sphingoid species in the cerebral microvasculature compared to brain and the stroke-induced increase in ceramide species. In summary, our study has identified novel molecular alterations in several microvessel-enriched, translationally relevant, and druggable targets, which are potent modulators of endothelial function. Our comparative analyses have revealed the presence of molecular features associated with cerebral microvascular dysfunction in human chronic stroke lesions. The results shared here provide a detailed resource for therapeutic discovery of candidates for neurovascular protection in stroke and potentially, other pathologies exhibiting cerebral microvascular dysfunction.

Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies.

Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. These dysfunctions reflect defects that appear to be inherited and secondary to environmental exposures, including vascular risk factors. Interrogation in preclinical models shows consistent and converging molecular and cellular interactions across the endothelial-glial-neural unit that increasingly explain the human macroscopic observations and identify common patterns of pathology despite different triggers. Importantly, these insights may offer new targets for therapeutic intervention focused on restoring endothelial-glial physiology.

Brain vascular damage-induced lymphatic ingrowth is directed by Cxcl12b/Cxcr4a.

After ischemic stroke, promotion of vascular regeneration without causing uncontrolled vessel growth appears to be the major challenge for pro-angiogenic therapies. The molecular mechanisms underlying how nascent blood vessels (BVs) are correctly guided into the post-ischemic infarction area remain unknown. Here, using a zebrafish cerebrovascular injury model, we show that chemokine signaling provides crucial guidance cues to determine the growing direction of ingrown lymphatic vessels (iLVs) and, in turn, that of nascent BVs. The chemokine receptor Cxcr4a is transcriptionally activated in the iLVs after injury, whereas its ligand Cxcl12b is expressed in the residual central BVs, the destinations of iLV ingrowth. Mutant and mosaic studies indicate that Cxcl12b/Cxcr4a-mediated chemotaxis is necessary and sufficient to determine the growing direction of iLVs and nascent BVs. This study provides a molecular basis for how the vessel directionality of cerebrovascular regeneration is properly determined, suggesting potential application of Cxcl12b/Cxcr4a in the development of post-ischemic pro-angiogenic therapies.

Lipoprotein Particles in Cerebrospinal Fluid.

The brain is the most lipid-rich organ in the body, and the intricate interplay between lipid metabolism and pathologies associated with neurodegenerative disorders is being increasingly recognized. The brain is bathed in cerebrospinal fluid (CSF), which, like plasma, contains lipid-protein complexes called lipoproteins that are responsible for extracellular lipid transport. Multiple CSF lipoprotein populations exist, some of which are produced de novo in the central nervous system and others that appear to be generated from protein constituents that are produced in the periphery. These CSF lipoproteins are thought to play key roles in maintaining lipid homeostasis in the central nervous system, while little else is known due to their limited accessibility and their low abundance in CSF. Recent work has provided new insights into the compositional complexity of CSF lipoprotein families and their metabolism in cerebral circulation. The purpose of this review is to summarize our current state of knowledge on the composition, origin, and metabolism of CSF lipoproteins.

The vascular contribution of apolipoprotein E to Alzheimer's disease.

Alzheimer's disease, the most prevalent form of dementia, imposes a substantial societal burden. The persistent inadequacy of disease-modifying drugs targeting amyloid plaques and neurofibrillary tangles suggests the contribution of alternative pathogenic mechanisms. A frequently overlooked aspect is cerebrovascular dysfunction, which may manifest early in the progression of Alzheimer's disease pathology. Mounting evidence underscores the pivotal role of the apolipoprotein E gene, particularly the apolipoprotein ε4 allele as the strongest genetic risk factor for late-onset AD, in the cerebrovascular pathology associated with Alzheimer's disease. In this review, we examine the evidence elucidating the cerebrovascular impact of both central and peripheral apolipoprotein E on the pathogenesis of Alzheimer's disease. We present a novel three-hit hypothesis, outlining potential mechanisms that shed light on the intricate relationship among different pathogenic events. Finally, we discuss prospective therapeutics targeting the cerebrovascular pathology associated with apolipoprotein E and explore their implications for future research endeavors.

Gastrodin alleviates premature senescence of vascular endothelial cells by enhancing the Nrf2/HO-1 signalling pathway.

Endothelial dysfunction is an independent risk factor for stroke. The dysfunction of endothelial cells (EC) is closely concerned with EC senescence. Gastrodin (GAS) is an organic compound extracted from the dried root mass of the Orchidaceae plant Gastrodiae gastrodiae. It is used clinically to treat diseases such as vertebrobasilar insufficiency, vestibular neuronitis and vertigo. In the present study, we used hydrogen peroxide (H2 O2 )-induced human umbilical vein endothelial cells (HUVECs) to establish an in vitro EC senescence model and to investigate the role and mechanism of GAS in EC senescence. It's found that H2 O2 -treated HUVECs increased the proportion of senescence-associated ß-galactosidase (SA ß-gal) positive cells and the relative protein expression levels of senescence-associated cyclin p16 and p21. In addition, GAS reduced the proportion of SA ß-gal positive cells and the relative protein expression levels of p16 and p21, and increased the proliferation and migration ability of HUVECs. Meanwhile, GAS increased the expression of the anti-oxidative stress protein HO-1 and its nuclear expression level of Nrf2. The anti-senescence effect of GAS was blocked when HO-1 expression was inhibited by SnPPIX. Furthermore, absence of HO-1 abolished the effect of GAS on HUVEC proliferation and migration. In conclusion, GAS ameliorated H2 O2 -induced cellular senescence and enhanced cell proliferation and migration by enhancing Nrf2/HO-1 signalling in HUVECs. These findings of our study expanded the understanding of GAS pharmacology and suggested that GAS may offer a potential therapeutic agent for stroke.

Adaptation in the spinal cord after stroke: Implications for restoring cortical control over the final common pathway.

Control of voluntary movement is predicated on integration between circuits in the brain and spinal cord. Although damage is often restricted to supraspinal or spinal circuits in cases of neurological injury, both spinal motor neurons and axons linking these cells to the cortical origins of descending motor commands begin showing changes soon after the brain is injured by stroke. The concept of 'transneuronal degeneration' is not new and has been documented in histological, imaging and electrophysiological studies dating back over a century. Taken together, evidence from these studies agrees more with a system attempting to survive rather than one passively surrendering to degeneration. There tends to be at least some preservation of fibres at the brainstem origin and along the spinal course of the descending white matter tracts, even in severe cases. Myelin-associated proteins are observed in the spinal cord years after stroke onset. Spinal motor neurons remain morphometrically unaltered. Skeletal muscle fibres once innervated by neurons that lose their source of trophic input receive collaterals from adjacent neurons, causing spinal motor units to consolidate and increase in size. Although some level of excitability within the distributed brain network mediating voluntary movement is needed to facilitate recovery, minimal structural connectivity between cortical and spinal motor neurons can support meaningful distal limb function. Restoring access to the final common pathway via the descending input that remains in the spinal cord therefore represents a viable target for directed plasticity, particularly in light of recent advances in rehabilitation medicine.

Proteomic mapping reveals dysregulated angiogenesis in the cerebral arteries of rats with early-onset hypertension.

Hypertension is associated with the presence of vascular abnormalities, including remodeling and rarefaction. These processes play an important role in cerebrovascular disease development; however, the mechanistic changes leading to these diseases are not well characterized. Using data-independent acquisition-based mass spectrometry analysis, here we determined the protein changes in cerebral arteries in pre- and early-onset hypertension from the spontaneously hypertensive rat (SHR), a model that resembles essential hypertension in humans. Our analysis identified 125 proteins with expression levels that were significantly upregulated or downregulated in 12-week-old spontaneously hypertensive rats compared to normotensive Wistar Kyoto rats. Using an angiogenesis enrichment analysis, we further identified a critical imbalance in angiogenic proteins that promoted an anti-angiogenic profile in cerebral arteries at early onset of hypertension. In a comparison to previously published data, we demonstrate that this angiogenic imbalance is not present in mesenteric and renal arteries from age-matched SHRs. Finally, we identified two proteins (Fbln5 and Cdh13), whose expression levels were critically altered in cerebral arteries compared to the other arterial beds. The observation of an angiogenic imbalance in cerebral arteries from the SHR reveals critical protein changes in the cerebrovasculature at the early onset of hypertension and provides novel insights into the early pathology of cerebrovascular disease.

Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study.

BACKGROUND: The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects. METHODS: This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model. RESULTS: Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF. CONCLUSIONS: Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.

Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

Mechanical Thrombectomy Workshops Improve Procedural Knowledge and Skills Among Neurointerventional Teams in Low- to Middle-Income Countries.

BACKGROUND: While mechanical thrombectomy (MT) is proven to be lifesaving and disability sparing, there remains a disparity in its access in low- to middle-income countries. We hypothesized that team-based MT workshops would improve MT knowledge and skills. METHODS: We designed a 22-hour MT workshop, conducted as 2 identical events: in English (Jamaica, January 2022) and in Spanish (Dominican Republic, May 2022). The workshops included participating neurointerventional teams (practicing neurointerventionalists, neurointerventional nurses, and technicians) focused on acute stroke due to large vessel occlusion. The course faculty led didactic and hands-on components, covering topics from case selection and postoperative management to device technology and MT surgical techniques. Attendees were evaluated on stroke knowledge and MT skills before and after the course using a multiple choice exam and simulated procedures utilizing flow models under fluoroscopy, respectively. Press conferences for public education with invited government officials were included to raise stroke awareness. RESULTS: Twenty-two physicians and their teams from 8 countries across the Caribbean completed the didactic and hands-on training. Overall test scores (n=18) improved from 67% to 85% (P<0.002). Precourse and postcourse hands-on assessments demonstrated reduced time to completion from 36.5 to 21.1 minutes (P<0.001). All teams showed an improvement in measures of good MT techniques, with 39% improvement in complete reperfusion. Eight teams achieved a Thrombolysis in Cerebral Infarction score of 3 on pre-course versus 15 of 18 teams on post-course. There was a significant reduction in total potentially dangerous maneuvers (70% pre versus 20% post; P<0.002). Universally, the workshop was rated as satisfactory and likely to change practice in 93% Dominican Republic and 75% Jamaica. CONCLUSIONS: A team-based hands-on simulation approach to MT training is novel, feasible, and effective in improving procedural skills. Participants viewed these workshops as practice-changing and instrumental in creating a pathway for increasing access to MT in low- to middle-income countries.

Comparing Outcomes of Thrombectomy Versus Intravenous Thrombolysis Based on Middle Cerebral Artery M2 Occlusion Features.

BACKGROUND: Current evidence provides limited support for the superiority of endovascular thrombectomy (EVT) in patients with M2 segment middle cerebral artery occlusion. We aim to investigate whether imaging features of M2 segment occlusion impact the effectiveness of EVT. METHODS: We conducted a retrospective cohort study from January 2017 to January 2022, drawing data from the CASE II registry (Computer-Based Online Database of Acute Stroke Patients for Stroke Management Quality Evaluation), which specifically documented patients with acute ischemic stroke presenting with M2 segment occlusion undergoing reperfusion therapy. Patients were stratified into the intravenous thrombolysis (IVT) group (IVT alone) and EVT group (IVT plus EVT or EVT alone). The primary outcome was a modified Rankin Scale score 0 to 2 at 90 days. Secondary outcomes included additional thresholds and distribution of modified Rankin Scale scores, 24-hour recanalization, early neurological deterioration, and relevant complications during hospitalization. Safety outcomes encompassed intracranial hemorrhagic events at 24 hours and mortality at 90 days. Binary logistic regression analyses with propensity score matching were used. Subgroup analyses were performed based on the anatomic site of occlusion, including right versus left, proximal versus distal, dominant/co-dominant versus nondominant, single versus double/triple branch(es), and anterior versus central/posterior branch. RESULTS: Among 734 patients (43.3% were females; median age, 73 years) with M2 segment occlusion, 342 (46.6%) were in the EVT group. Propensity score matching analysis revealed no statistical difference in the primary outcome (odds ratio, 0.860 [95% CI, 0.611-1.209]; P=0.385) between the EVT group and IVT group. However, EVT was associated with a higher incidence of subarachnoid hemorrhage (odds ratio, 6.655 [95% CI, 1.487-29.788]; P=0.004) and pneumonia (odds ratio, 2.015 [95% CI, 1.364-2.977]; P<0.001). Subgroup analyses indicated that patients in the IVT group achieved better outcomes when presenting with right, distal, or nondominant branch occlusion (Pall interaction<0.05). CONCLUSIONS: Our study showed similar efficiency of EVT versus IVT alone in acute M2 segment middle cerebral artery occlusion. This suggested that only specific patient subpopulations might have a potentially higher benefit of EVT over IVT alone. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04487340.

Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Outdoor Light at Night, Air Pollution, and Risk of Cerebrovascular Disease: A Cohort Study in China.

BACKGROUND: We sought to explore the associations of outdoor light at night (LAN) and air pollution with the risk of cerebrovascular disease (CeVD). METHODS: We included a total of 28 302 participants enrolled in Ningbo, China from 2015 to 2018. Outdoor LAN and air pollution were assessed by Satellite-derived images and land-use regression models. CeVD cases were confirmed by medical records and death certificates and further subdivided into ischemic and hemorrhagic stroke. Cox proportional hazard models were used to estimate hazard ratios and 95% CIs. RESULTS: A total of 1278 CeVD cases (including 777 ischemic and 133 hemorrhagic stroke cases) were identified during 127 877 person-years of follow-up. In the single-exposure models, the hazard ratios for CeVD were 1.17 (95% CI, 1.06-1.29) for outdoor LAN, 1.25 (1.12-1.39) for particulate matter with an aerodynamic diameter ≤2.5 µm, 1.14 (1.06-1.22) for particulate matter with aerodynamic diameter ≤10 µm, and 1.21 (1.06-1.38) for NO2 in every interquartile range increase. The results were similar for ischemic stroke, whereas no association was observed for hemorrhagic stroke. In the multiple-exposure models, the associations of outdoor LAN and PM with CeVD persisted but not for ischemic stroke. Furthermore, no interaction was observed between outdoor LAN and air pollution. CONCLUSIONS: Levels of exposure to outdoor LAN and air pollution were positively associated with the risk of CeVD. Furthermore, the detrimental effects of outdoor LAN and air pollution might be mutually independent.

Long-term Cardiovascular, Cerebrovascular, and Other Thrombotic Complications in COVID-19 Survivors: A Retrospective Cohort Study.

BACKGROUND: Growing evidence suggests that some coronavirus disease 2019 (COVID-19) survivors experience a wide range of long-term postacute sequelae. We examined the postacute risk and burden of new-incident cardiovascular, cerebrovascular, and other thrombotic complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a highly vaccinated multiethnic Southeast Asian population, during Delta predominance. METHODS: This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals who had a positive SARS-CoV-2 test between 1 September and 30 November 2021 when Delta predominated community transmission. Concurrently, we constructed a test-negative control group by enrolling individuals between 13 April 2020 and 31 December 2022 with no evidence of SARS-CoV-2 infection. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular, cerebrovascular, and other thrombotic complications using doubly robust competing-risks survival analysis. Risks were reported using 2 measures: hazard ratio (HR) and excess burden (EB) with 95% confidence intervals. RESULTS: We included 106 012 infected cases and 1 684 085 test-negative controls. Compared with the control group, individuals with COVID-19 exhibited increased risk (HR, 1.157 [1.069-1.252]) and excess burden (EB, 0.70 [.53-.88]) of new-incident cardiovascular and cerebrovascular complications. Risks decreased in a graded fashion for fully vaccinated (HR, 1.11 [1.02-1.22]) and boosted (HR, 1.10 [.92-1.32]) individuals. Conversely, risks and burdens of subsequent cardiovascular/cerebrovascular complications increased for hospitalized and severe COVID-19 cases (compared to nonhospitalized cases). CONCLUSIONS: Increased risks and excess burdens of new-incident cardiovascular/cerebrovascular complications were reported among infected individuals; risks can be attenuated with vaccination and boosting.

Impact of Sleep Disorders and Disturbed Sleep on Brain Health: A Scientific Statement From the American Heart Association.

Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

Overweight in Adolescence and Young Adulthood in Association With Adult Cerebrovascular Disease: The NFBC1966 Study.

BACKGROUND: Risk factors for cerebrovascular disease in adulthood are well known. However, research on individuals' risk factors throughout their life span has been limited. This prospective cohort study aims to determine the effect of body mass index (BMI) and its changes in adolescence and young adulthood on early onset cerebrovascular disease. METHODS: This study includes 10 491 people (5185 women) from the Northern Finland Birth Cohort 1966. Height, weight, and BMI were measured at ages 14 and 31 years. Sex- and age-specific BMI ranges were used to define overweight and obesity. Data on ischemic and hemorrhagic cerebrovascular diseases between ages 14 and 54 years were extracted from national hospital and death registers. Cox proportion hazard models (95% CI) were used to estimate associations between BMI or its changes and cerebrovascular disease, while adjusting for sex, smoking, educational level, BMI at the other time point, and age at menarche for women. Additionally, sex-BMI interactions were calculated. RESULTS: A total of 452 individuals (4.7%) experienced cerebrovascular disease during the follow-up. The risk of ischemic cerebrovascular disease was increased for overweight women at ages 14 years (hazard ratio [HR], 2.49 [95% CI, 1.44-4.31]) and 31 years (HR, 2.13 [95% CI, 1.14-3.97]), as well as for obese women at ages 14 years (HR, 1.87 [95% CI, 0.76-4.58) and 31 years (HR, 2.67 [95% CI, 1.26-5.65]), with normal weight as the reference. These results were independent of earlier or later BMI. Similar associations were not found among men. The risk of hemorrhagic cerebrovascular disease was increased at age 31 years both among obese women (HR, 3.49 [95% CI, 1.13-10.7) and obese men (HR, 5.75 [95% CI, 1.43-23.1). The risk of any cerebrovascular disease related to overweight at age 14 years was 2.09× higher among girls than boys (95% CI, 1.06-4.15). The risk of ischemic cerebrovascular disease related to obesity at age 31 years was 6.96× higher among women than men (95% CI, 1.36-35.7). CONCLUSIONS: Among women, being overweight in adolescence or young adulthood increases the risk of cerebrovascular disease, especially ischemic, independent of their earlier or later BMI.