Changes in the Proteome of the Circle of Willis during Aging Reveal Signatures of Vascular Disease.

Approximately 70% of all strokes occur in patients over 65 years old, and stroke increases the risk of developing dementia. The circle of Willis (CoW), the ring of arteries at the base of the brain, links the intracerebral arteries to one another to maintain adequate cerebral perfusion. The CoW proteome is affected in cerebrovascular and neurodegenerative diseases, but changes related to aging have not been described. Here, we report on a quantitative proteomics analysis comparing the CoW from five young (2-3-month-old) and five aged male (18-20-month-old) mice using gene ontology (GO) enrichment, ingenuity pathway analysis (IPA), and iPathwayGuide tools. This revealed 242 proteins that were significantly dysregulated with aging, among which 189 were upregulated and 53 downregulated. GO enrichment-based analysis identified blood coagulation as the top biological function that changed with age and integrin binding and extracellular matrix constituents as the top molecular functions. Consistent with these findings, iPathwayGuide-based impact analysis revealed associations between aging and the complement and coagulation, platelet activation, ECM-receptor interaction, and metabolic process pathways. Furthermore, IPA analysis revealed the enrichment of 97 canonical pathways that contribute to inflammatory responses, as well as 59 inflammation-associated upstream regulators including 39 transcription factors and 20 cytokines. Thus, aging-associated changes in the CoW proteome in male mice demonstrate increases in metabolic, thrombotic, and inflammatory processes.

A novel STING variant triggers endothelial toxicity and SAVI disease.

Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease, and contribute to a better understanding of how aberrant STING activation can cause pathology.

Sodium Intake and Incident Atrial Fibrillation in Individuals With Vascular Disease.

Importance: Numerous prospective cohort studies have reported a J-shaped association of urinary sodium excretion with cardiovascular events and mortality. Objective: To study the association between sodium intake and incident atrial fibrillation (AF). Design, Setting, and Participants: This cohort study included participants in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) multicenter, randomized clinical trials comparing the effect of ramipril 10 mg daily with telmisartan 80 mg daily, or their combination (ONTARGET) or 80 mg telmisartan daily with placebo (TRANSCEND) for the outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. ONTARGET and TRANSCEND included 31 546 participants with vascular disease or high-risk diabetes, and this study excluded participants without a urine sample for sodium measurement, missing data for key covariates, a history of AF, or AF detected in the first year after enrollment. Analyses were performed in July 2023 to May 2024. Exposure: Estimated sodium intake from a morning fasting urine sample (Kawasaki formula). Main Outcomes and Measures: The main outcome was incident AF. The association between estimated sodium intake and incident AF was modeled using multivariable adjusted Cox regression and cubic splines. Results: A total of 27 391 participants (mean [SD] age, 66.3 [7.2] years; 19 310 [70.5%] male) were included. Mean (SD) estimated sodium intake was 4.8 (1.6) g/d. During a mean (SD) follow-up of 4.6 (1.0) years, 1562 participants (5.7%) had incident AF. After multivariable adjustment, a J-shaped association between sodium intake and AF risk was observed (P for nonlinearity = .03). Sodium intake of 8 g/d or greater (3% of participants) was associated with incident AF (hazard ratio, 1.32; 95% CI, 1.01-1.74) compared with sodium intake of 4 to 5.99 g/d. Cubic splines showed that sodium intake greater than 6 g/d (19% of participants) was associated with a 10% increased AF risk per additional 1-g/d sodium intake (hazard ratio, 1.10; 95% CI, 1.03-1.18), but with no further lowering of AF risk at lower levels of sodium intake. Conclusions and Relevance: In this cohort study of sodium intake and AF risk, there was a J-shaped association between sodium intakes and AF risk in patients with cardiovascular disease or diabetes. Lowering sodium intake for AF prevention is best targeted at individuals who consume high sodium diets.

Spontaneous coronary artery dissection (SCAD) with cardiac arrest at presentation: A subanalysis from the DISCO registry.

INTRODUCTION: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute myocardial infarction (AMI), which primarily affects young women without traditional cardiovascular risk factors, often presenting as sudden cardiac death. This study aims to investigate the prevalence, characteristics, predictors, and outcomes of cardiac arrest in SCAD patients. METHODS: The DISCO IT/SPA registry, an international retrospective multicenter study, enrolled 375 SCAD patients from 26 centers in Italy and Spain. Patients were categorized based on the presence or absence of cardiac arrest at admission. Data on demographics, clinical presentation, treatment, angiographic findings, and outcomes were collected. Angiograms were independently reviewed, and outcomes included major adverse cardiovascular events (MACE) and in-hospital bleeding. RESULTS: Among 375 SCAD patients, 20 (5.3%) presented with cardiac arrest. Both groups were similar in age, gender distribution, and conventional risk factors, except for a lower prevalence of dyslipidemia in the cardiac arrest group. ST-segment elevation myocardial infarction (STEMI) presentation and angiographic type 2b were independent predictors of cardiac arrest. Revascularization was more frequent in the cardiac arrest group. In-hospital outcomes, except for longer hospitalization, did not differ. On follow-up (average 21 months), MACE rates were similar between groups. CONCLUSIONS: Cardiac arrest is a notable complication in SCAD, mostly presenting with ventricular fibrillation. The prognosis of SCAD patients presenting with cardiac arrest did not differ from those without, reporting a similar rate of events both in-hospital and during long-term follow-up. STEMI presentation and angiographic type 2b were identified as independent predictors of cardiac arrest in SCAD.

Overcoming big bottlenecks in vascular regeneration.

Bioengineering and regenerative medicine strategies are promising for the treatment of vascular diseases. However, current limitations inhibit the ability of these approaches to be translated to clinical practice. Here we summarize some of the big bottlenecks that inhibit vascular regeneration in the disease applications of aortic aneurysms, stroke, and peripheral artery disease. We also describe the bottlenecks preventing three-dimensional bioprinting of vascular networks for tissue engineering applications. Finally, we describe emerging technologies and opportunities to overcome these challenges to advance vascular regeneration.

Implantable Cardioverter-Defibrillator Placement in Spontaneous Coronary Artery Dissection: A Case Report.

BACKGROUND Spontaneous coronary artery dissection can present with acute coronary syndrome, ventricular arrhythmias, or sudden cardiac death. Implantable cardioverter-defibrillator placement in patients with spontaneous coronary artery dissection is controversial. The purpose of publishing this case is to inform physicians of potential benefits of implantable cardioverter-defibrillator implantation in patients with spontaneous coronary artery dissection. CASE REPORT A 55-year-old woman presented with chest pain, with an electrocardiogram revealing anterior ST-elevation myocardial infarction and troponin peak of 53.8 ng/mL. Coronary angiography revealed mid-left anterior descending artery occlusion, with appearance of spontaneous coronary artery dissection that was not amenable to revascularization. The decision was made to treat medically. In recovery, the patient experienced ventricular fibrillation arrest. The patient was defibrillated once with achievement of return of spontaneous circulation. An Impella CP was placed to stabilize the patient. After the patient was stabilized, an implantable cardioverter-defibrillator was placed. CONCLUSIONS Data on potential benefits of implantable cardioverter-defibrillator placement in patients with spontaneous coronary artery dissection are limited. Most patients with spontaneous coronary artery dissection recover normal coronary architecture; however, there are no guidelines for implantable cardioverter-defibrillator placement in patients with spontaneous coronary artery dissection. Patients with spontaneous coronary artery dissection with high-risk features may benefit from implantable cardioverter-defibrillator for secondary prevention of ventricular arrhythmia and sudden cardiac death, as shown with this case.

Economic evaluation of the effect of needle and syringe programs on skin, soft tissue, and vascular infections in people who inject drugs: a microsimulation modelling approach.

BACKGROUND: Needle and syringe programs (NSP) are effective harm-reduction strategies against HIV and hepatitis C. Although skin, soft tissue, and vascular infections (SSTVI) are the most common morbidities in people who inject drugs (PWID), the extent to which NSP are clinically and cost-effective in relation to SSTVI in PWID remains unclear. The objective of this study was to model the clinical- and cost-effectiveness of NSP with respect to treatment of SSTVI in PWID. METHODS: We performed a model-based, economic evaluation comparing a scenario with NSP to a scenario without NSP. We developed a microsimulation model to generate two cohorts of 100,000 individuals corresponding to each NSP scenario and estimated quality-adjusted life-years (QALY) and cost (in 2022 Canadian dollars) over a 5-year time horizon (1.5% per annum for costs and outcomes). To assess the clinical effectiveness of NSP, we conducted survival analysis that accounted for the recurrent use of health care services for treating SSTVI and SSTVI mortality in the presence of competing risks. RESULTS: The incremental cost-effectiveness ratio associated with NSP was $70,278 per QALY, with incremental cost and QALY gains corresponding to $1207 and 0.017 QALY, respectively. Under the scenario with NSP, there were 788 fewer SSTVI deaths per 100,000 PWID, corresponding to 24% lower relative hazard of mortality from SSTVI (hazard ratio [HR] = 0.76; 95% confidence interval [CI] = 0.72-0.80). Health service utilization over the 5-year period remained lower under the scenario with NSP (outpatient: 66,511 vs. 86,879; emergency department: 9920 vs. 12,922; inpatient: 4282 vs. 5596). Relatedly, having NSP was associated with a modest reduction in the relative hazard of recurrent outpatient visits (HR = 0.96; 95% CI = 0.95-0.97) for purulent SSTVI as well as outpatient (HR = 0.88; 95% CI = 0.87-0.88) and emergency department visits (HR = 0.98; 95% CI = 0.97-0.99) for non-purulent SSTVI. CONCLUSIONS: Both the individuals and the healthcare system benefit from NSP through lower risk of SSTVI mortality and prevention of recurrent outpatient and emergency department visits to treat SSTVI. The microsimulation framework provides insights into clinical and economic implications of NSP, which can serve as valuable evidence that can aid decision-making in expansion of NSP services.

Migraine headache in patients with spontaneous coronary artery dissection: A report of the iSCAD Registry.

INTRODUCTION: Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of myocardial infarction. Migraine headache has been reported to be common among patients with SCAD, but the degree of migraine-related disability has not been quantified. METHODS: Clinical data and headache variables were obtained from the baseline assessment of the prospective, multicenter iSCAD Registry. Migraine-related disability was quantified using the self-reported Migraine Disability Assessment (MIDAS). Demographic, clinical, psychosocial, and medical characteristics from data entry forms were compared between patients with and without migraine. RESULTS: Of the 773 patients with available data, 46% reported previous or current migraines. Those with migraines were more likely to be women (96.9% vs 90.3%, p = 0.0003). The presence of underlying carotid fibromuscular dysplasia was associated with migraine (35% vs 27%, p = 0.0175). There was not a significant association with carotid artery dissection and migraine. Current migraine frequency was less than monthly (58%), monthly (24%), weekly (16%), and daily (3%). Triptan use was reported in 32.5% of patients, and 17.5% used daily migraine prophylactic medications. Using the MIDAS to quantify disability related to migraine, 60.2% reported little or no disability, 14.4% mild, 12.7% moderate, and 12.7% severe. The mean MIDAS score was 9.9 (mild to moderate disability). Patients with SCAD had higher rates of depression and anxiety (28.2% vs 17.7% [p = 0.0004] and 35.3% vs 26.7% [p = 0.0099], respectively). CONCLUSIONS: Migraines are common, frequent, and a source of disability in patients with SCAD. The association between female sex, anxiety, and depression may provide some insight for potential treatment modalities.

Spontaneous coronary artery dissection (SCAD): A contemporary review.

Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of myocardial infarction that most frequently affects younger women, making it an important cause of morbidity and mortality within these demographics. The evolution of intracoronary imaging, improved diagnosis with coronary angiography, and ongoing research efforts and attention via social media, has led to increasing recognition of this previously underdiagnosed condition. In this review, we provide a summary of the current body of knowledge, as well as focused updates on the pathogenesis of SCAD, insights on genetic susceptibility, contemporary diagnostic tools, and immediate, short- and long-term management.

Progress in ultrasmall ferrite nanoparticles enhanced T1 magnetic resonance angiography.

Contrast-enhanced magnetic resonance angiography (CE-MRA) plays a critical role in diagnosing and monitoring various vascular diseases. Achieving high-sensitivity detection of vascular abnormalities in CE-MRA depends on the properties of contrast agents. In contrast to clinically used gadolinium-based contrast agents (GBCAs), the new generation of ultrasmall ferrite nanoparticles-based contrast agents have high relaxivity, long blood circulation time, easy surface functionalization, and high biocompatibility, hence showing promising prospects in CE-MRA. This review aims to comprehensively summarize the advancements in ultrasmall ferrite nanoparticles-enhanced MRA for detecting vascular diseases. Additionally, this review also discusses the future clinical translational potential of ultrasmall ferrite nanoparticles-based contrast agents for vascular imaging. By investigating the current status of research and clinical applications, this review attempts to outline the progress, challenges, and future directions of using ultrasmall ferrite nanoparticles to drive the field of CE-MRA into a new frontier of accuracy and diagnostic efficacy.

The genetics of spontaneous coronary artery dissection: a scoping review.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a multifactorial process that involves predisposing factors and precipitating stressors. Genetic abnormality has been implicated to play a mechanistic role in the development of SCAD. This systematic review aims to summarize the current evidence concerning the link between SCAD and genetic abnormalities. METHODS: We reviewed original studies published until May 2023 that reported SCAD patients with a genetic mutation by searching PubMed, Embase Ovid, and Google Scholar. Registries, cohort studies, and case reports were included if a definitive SCAD diagnosis was reported, and the genetic analysis was performed. Exclusion criteria included editorials, reviews, letters or commentaries, animal studies, meeting papers, and studies from which we were unable to extract data. Data were extracted from published reports. RESULTS: A total of 595 studies were screened and 55 studies were identified. Among 116 SCAD patients with genetic abnormalities, 20% had mutations in the COL gene, 13.70% TLN1 gene, and 8.42% TSR1 gene. Mutations affecting the genes encoding COL and TLN1 were most frequently reported (20 and 13.7%, respectively). Interestingly, 15 genes of this collection were also reported in patients with thoracic aortic diseases as well. The genetic commonality between fibromuscular dysplasia (FMD) and SCAD was also included. CONCLUSION: In this review, the inherited conditions and reported genes of undetermined significance from case reports associated with SCAD are collected. A brief description of the encoded protein and the clinical features associated with pathologic genes is provided. Current data suggested that the diagnostic yield of genetic studies for patients with SCAD would be low and routine genetic screening of such patients with no clinical features indicative of associated disorders remains debatable. This review can be used as a guide for clinicians to recognize inherited syndromic and nonsyndromic disorders associated with SCAD.

Applications, challenges, and prospects of induced pluripotent stem cells for vascular disease.

Vascular disease, including heart disease, stroke, and peripheral arterial disease, is one of the leading causes of death and disability and represents a significant global health issue. Since the development of human induced pluripotent stem cells (hiPSCs) in 2007, hiPSCs have provided unique and tremendous opportunities for studying human pathophysiology, disease modeling, and drug discovery in the field of regenerative medicine. In this review, we discuss vascular physiology and related diseases, the current methods for generating vascular cells (eg, endothelial cells, smooth muscle cells, and pericytes) from hiPSCs, and describe the opportunities and challenges to the clinical applications of vascular organoids, tissue-engineered blood vessels, and vessels-on-a-chip. We then explore how hiPSCs can be used to study and treat inherited vascular diseases and discuss the current challenges and future prospects. In the future, it will be essential to develop vascularized organoids or tissues that can simultaneously undergo shear stress and cyclic stretching. This development will not only increase their maturity and function but also enable effective and innovative disease modeling and drug discovery.

Prevalence, treatment efficacy, and risk factors of vascular complications in acute pancreatitis: A case-control study.

OBJECTIVE: We aimed to investigate the prevalence of vascular complications in acute pancreatitis (AP), to compare patient outcomes using various treatments, and to explore the related risk factors. METHODS: Consecutive AP patients admitted from January 2010 to July 2017 were retrospectively included. Demographics, vascular complications, laboratory indices, and imaging findings were collected. Univariate and multivariate analyses were used to explore potential risk factors of vascular complications. RESULTS: Of 3048 AP patients, 808 (26.5%) had vascular complications, including visceral vein thrombosis, sinistral portal hypertension, and arterial complications. And 38 (4.7%) patients received anticoagulant therapy and had a higher rate of recanalization (P < 0.001). Bleeding occurred in 95 (11.8%) patients, who received further treatment. Multivariate analysis identified male gender (odds ratio [OR] 1.650, 95% confidence interval [CI] 1.101-2.472), hyperlipidemia (OR 1.714, 95% CI 1.356-2.165), disease recurrence (OR 3.727, 95% CI 2.713-5.118), smoking (OR 1.519, 95% CI 1.011-2.283), hemoglobin level (OR 0.987, 95% CI 0.981-0.993), white blood cell (WBC) count (OR 1.094, 95% CI 1.068-1.122), non-vascular local complications (OR 3.018, 95% CI 1.992-4.573), computed tomography severity index (CTSI) (OR 1.425, 95% CI 1.273-1.596), and acute physiology and chronic health evaluation (APACHE) II score (OR 1.057, 95% CI 1.025-1.090) were related to vascular complications. CONCLUSIONS: Vascular complications in AP is prevalent and their treatment is challenging. Further investigations are warranted to determine the optimal treatment strategy. Independent risk factors included male gender, hyperlipidemia, disease recurrence, smoking, WBC count, non-vascular local complications, CTSI, and APACHE II score.

Myocardial Infarction in Young Adults: Diagnosis Begins Through Inspection.

Spontaneous coronary artery dissection (SCAD) is an atypical cause of myocardial infarction, predominantly seen in women. Among various predisposing factors, genetic vasculopathies such as connective tissue diseases significantly contribute to SCAD. This report discusses a 36-year-old male diagnosed with vascular type Ehlers-Danlos syndrome following an anterior myocardial infarction and explores relevant literature.

Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans.

Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3'-5' DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

Tortuosity in non-atherosclerotic vascular diseases is associated with age, arterial aneurysms, and hypertension.

BACKGROUND: Increased arterial tortuosity has been associated with various cardiovascular complications. However, the extent and role of arterial tortuosity in non-atherosclerotic vascular diseases remain to be fully elucidated. This study aimed to assess arterial tortuosity index (ATI) in patients with non-atherosclerotic vascular diseases and the associated factors. METHODS: This is a retrospective analysis of patients with non-atherosclerotic vascular diseases referred to the Malformation and Rare Vascular Disease Center at the University Hospital in Lausanne (Switzerland). Computed tomography angiography (CTA) images performed between October 2010 and April 2022 were retrieved and the aortic tortuosity index (ATI) was calculated. Patients were classified based on diagnosis into the following groups: arterial dissection & aneurysm, arteritis & autoimmune disease, hereditary connective tissue diseases, and fibromuscular dysplasia (FMD). Univariate and multivariate logistic regression analysis was used to determine potentially relevant predictors of aortic tortuosity. RESULTS: The mean age upon computed tomography angiography (CTA) was 46.8 (standard deviation [SD] 14.6) years and 59.1% of the patients were female. Mean ATI was higher in patients over 60 years old (1.27), in those with arterial aneurysms (mean: 1.11), and in those diagnosed with hypertension (mean: 1.13). When only patients over 60 years old were considered, those diagnosed with connective tissue diseases had the highest ATI. At multivariate regression analysis, increasing age (p < 0.05), presence of arterial aneurysms (p < 0.05), and hypertension (p < 0.05) were independently associated with ATI. CONCLUSIONS: The ATI may be a promising tool in diagnostic evaluation, cardiovascular risk stratification, medical or surgical management, and prognostic assessment in several non-atherosclerotic vascular conditions. Further studies with longitudinal design and larger cohorts are needed to validate the role of ATI in the full spectrum of vascular diseases.

Financial Well-Being Among US Adults with Vascular Conditions: Differential Impacts Among Blacks and Hispanics.

Background: The ability to meet current and ongoing financial obligations, known as financial well-being (FWB), is not only associated with the likelihood of adverse health events but is also affected by unexpected health care expenditures. However, the relationship between FWB and common health outcomes is not well understood. Using data available in the Financial Well-Being Scale from the Consumer Financial Protection Bureau, we evaluated the impact of four vascular conditions-cardiovascular disease (CVD), stroke, high blood pressure (BP), and high cholesterol-on FWB and how these impacts varied between racial and ethnic groups. Methods: Using the Understanding America Survey-a nationally representative, longitudinal panel-we identified adults with self-reported diagnoses between 2014 and 2020 of high cholesterol, high BP, stroke, and CVD. We used stratified, longitudinal mixed regression models to assess the association between these diagnoses and FWB. Each condition was modeled separately and included sex, age, marital status, household size, income, education, race/ethnicity, insurance, body mass index, and an indicator of the condition. Racial and ethnic differentials were captured using group-condition interactions. Results: On average, Whites had the highest FWB Scale score (69.0, SD=21.8), followed by other races (66.7, SD=21.0), Hispanics (59.3, SD=21.6), and Blacks (56.2, SD=21.4). In general, FWB of individuals with vascular conditions was lower than that of those without, but the impact varied between racial and ethnic groups. Compared with Whites (the reference group), Blacks with CVD (-7.4, SD=1.0), stroke (-8.1, SD=1.5), high cholesterol (-5.7, SD=0.7), and high BP (6.1, SD=0.7) had lower FWB. Similarly, Hispanics with high BP (-3.0, SD=0.6) and CVD (-6.3, SD=1.3) had lower FWB. Income, education, insurance, and marital status were also correlated with FWB. Conclusions: These results indicated differences in the financial ramifications of vascular conditions among racial and ethnic groups. Findings suggest the need for interventions targeting FWB of individuals with vascular conditions, particularly those from minority groups.