International Union of Angiology consensus document on vascular compression syndromes.

Vascular compression syndromes (VCS) are rare diseases, but they may cause significant symptoms interfering with the quality of life (QoL) of patients who are often in their younger age. Given their infrequent occurrence, multiform clinical and anatomical presentation, and absence of dedicated guidelines from scientific societies, further knowledge of these conditions is required to investigate and treat them using modern imaging and surgical (open or endovascular) techniques. This consensus document will focus on known VCS, affecting the arterial and venous system. The position paper, written by members of International Union of Angiology (IUA) Youth Committee and senior experts, will show an overview of pathophysiology, diagnostic, and therapeutical approaches for patients with VCS. Furthermore, this document will provide also unresolved issues that require more research that need to be addressed in the future.

Using the Evaluating Devices Using Claims and RegisTry Data (EDUCATe) Plan within the Vascular Implant Surveillance and Interventional Outcomes Network (VISION) to Analyze the Long-Term Outcomes following Endovascular Aortic Aneurysm Repair.

BACKGROUND: Implanted devices undergo clinical trials to assess their safety and effectiveness. However, pivotal device trials are limited in their follow-up while postmarket surveillance may incompletely capture late failure. Linking clinical trials to Medicare claims can address these limitations. This study matched patients from investigational device exemption (IDE) clinical trials for endovascular aortic aneurysm repair (EVAR) to Medicare claims-based registry data to compare long-term device outcomes between the 2 sources. METHODS: Patient-level data from 2 industry-sponsored IDE trials of EVAR devices was provided by a single industry partner. Trial data were matched at the patient level to data from the Vascular Implant Surveillance and Interventional Outcomes Network (VISION), a registry that is a part of the Society for Vascular Surgery Patient Safety Organization. The primary outcomes analyzed were survival and freedom from aneurysm-related reintervention. RESULTS: Of 159 clinical trial patients, 134 were eligible for claims-based matching and 115 (85.5%) were successfully matched to VISION registry data. For the matched cohort, the Kaplan-Meier estimated survival was 94.8% at 1 year, 82.6% at 3 years, and 68.1% at 5 years. Estimates for freedom from reintervention were 90% at 1 year, 82.4% at 3 years, and 78.1% at 5 years. The estimates for survival were nearly identical between the clinical trial data and that found in the VISION data (log-rank P = 0.89). Freedom from reintervention was similar between the groups, with IDE trial reported freedom from reintervention of 87.3% and 73.3%, compared to VISION of 92.6% and 83% at 1 and 5 years, respectively (log-rank P = 0.13). CONCLUSIONS: Clinical trial patients who undergo EVAR can be successfully matched to claims-based registry data to improve long-term device surveillance and outcomes reporting. Claims-based results agreed well with IDE trial results for patients through 5 years, supporting the accuracy of claims-based data for longer-term surveillance. Linking clinical trial and claims-based registry data can lead to robust device monitoring.

Disparities in peripheral artery disease care: A review and call for action.

Peripheral artery disease (PAD), the pathophysiologic narrowing of arterial blood vessels of the lower leg due to atherosclerosis, is a highly prevalent disease that affects more than 6 million individuals 40 years and older in the United States, with sharp increases in prevalence with age. Morbidity and mortality rates in patients with PAD range from 30% to 70% during the 5- to 15-year period after diagnosis and PAD is associated with poor health outcomes and reduced functionality and quality of life. Despite advances in medical, endovascular, and open surgical techniques, there is striking variation in care among population subgroups defined by sex, race and ethnicity, and socioeconomic status, with concomitant differences in preoperative medication optimization, amputation risk, and overall health outcomes. We reviewed studies from 1995 to 2021 to provide a comprehensive analysis of the current impact of disparities on the treatment and management of PAD and offer action items that require strategic partnership with primary care providers, researchers, patients, and their communities. With new technologies and collaborative approaches, optimal management across all population subgroups is possible.

Racial Equity in Cannabis Policy: Diversity in the Massachusetts Adult-Use Industry at 18-months.

Background: Cannabis criminalization disproportionately harms communities of color in the United States. In Massachusetts' legal recreational ("adult-use") cannabis industry, state regulations intend to promote diverse participation. We assessed short-term racial/ethnic and gender diversity across the industry and in senior-level positions with greater opportunities to build wealth (i.e., board members, executives, directors). Methods: We extracted race/ethnicity and gender from required registration forms submitted to state regulators for each person working in a licensed adult-use cannabis business from October 2018 to April 2020 (n=4,883). We conducted descriptive analysis and negative binomial regression to assess characteristics associated with senior positions. Results: As of April 2020, racial/ethnic and gender diversity in the Massachusetts adult-use cannabis market (n=4,883) was 75% white, 7% Latino, 6% Black/African American, similar to the state labor market, and 65% male. Diversity was more limited in senior positions. Agents in senior positions (n=403) were 84% white, 2% Latino, 5% Black/African American, and 82% male. Senior-level participation was markedly low for women of color. Conclusion: Despite legislative and regulatory commitment, diversity lacks in senior positions in this emerging cannabis market. States considering adult-use cannabis markets, and those that have already done so, should monitor participation to identify inequities and adapt initiatives to ensure Black/African American and Latino communities socially and economically benefit from state legalization.

Unsupervised Learning for Automated Detection of Coronary Artery Disease Subgroups.

Background The promise of precision population health includes the ability to use robust patient data to tailor prevention and care to specific groups. Advanced analytics may allow for automated detection of clinically informative subgroups that account for clinical, genetic, and environmental variability. This study sought to evaluate whether unsupervised machine learning approaches could interpret heterogeneous and missing clinical data to discover clinically important coronary artery disease subgroups. Methods and Results The Genetic Determinants of Peripheral Arterial Disease study is a prospective cohort that includes individuals with newly diagnosed and/or symptomatic coronary artery disease. We applied generalized low rank modeling and K-means cluster analysis using 155 phenotypic and genetic variables from 1329 participants. Cox proportional hazard models were used to examine associations between clusters and major adverse cardiovascular and cerebrovascular events and all-cause mortality. We then compared performance of risk stratification based on clusters and the American College of Cardiology/American Heart Association pooled cohort equations. Unsupervised analysis identified 4 phenotypically and prognostically distinct clusters. All-cause mortality was highest in cluster 1 (oldest/most comorbid; 26%), whereas major adverse cardiovascular and cerebrovascular event rates were highest in cluster 2 (youngest/multiethnic; 41%). Cluster 4 (middle-aged/healthiest behaviors) experienced more incident major adverse cardiovascular and cerebrovascular events (30%) than cluster 3 (middle-aged/lowest medication adherence; 23%), despite apparently similar risk factor and lifestyle profiles. In comparison with the pooled cohort equations, cluster membership was more informative for risk assessment of myocardial infarction, stroke, and mortality. Conclusions Unsupervised clustering identified 4 unique coronary artery disease subgroups with distinct clinical trajectories. Flexible unsupervised machine learning algorithms offer the ability to meaningfully process heterogeneous patient data and provide sharper insights into disease characterization and risk assessment. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00380185.

Leveraging Machine Learning and Artificial Intelligence to Improve Peripheral Artery Disease Detection, Treatment, and Outcomes.

Peripheral artery disease is an atherosclerotic disorder which, when present, portends poor patient outcomes. Low diagnosis rates perpetuate poor management, leading to limb loss and excess rates of cardiovascular morbidity and death. Machine learning algorithms and artificially intelligent systems have shown great promise in application to many areas in health care, such as accurately detecting disease, predicting patient outcomes, and automating image interpretation. Although the application of these technologies to peripheral artery disease are in their infancy, their promises are tremendous. In this review, we provide an introduction to important concepts in the fields of machine learning and artificial intelligence, detail the current state of how these technologies have been applied to peripheral artery disease, and discuss potential areas for future care enhancement with advanced analytics.

Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability.

AIMS: Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. METHODS AND RESULTS: Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. CONCLUSION: CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.

18F-Fluorodeoxyglucose-Positron Emission Tomography Imaging Detects Response to Therapeutic Intervention and Plaque Vulnerability in a Murine Model of Advanced Atherosclerotic Disease-Brief Report.

OBJECTIVE: This study sought to determine whether 18F-fluorodeoxyglucose-positron emission tomography/computed tomography could be applied to a murine model of advanced atherosclerotic plaque vulnerability to detect response to therapeutic intervention and changes in lesion stability. Approach and Results: To analyze plaques susceptible to rupture, we fed ApoE-/- mice a high-fat diet and induced vulnerable lesions by cast placement over the carotid artery. After 9 weeks of treatment with orthogonal therapeutic agents (including lipid-lowering and proefferocytic therapies), we assessed vascular inflammation and several features of plaque vulnerability by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography and histopathology, respectively. We observed that 18F-fluorodeoxyglucose-positron emission tomography/computed tomography had the capacity to resolve histopathologically proven changes in plaque stability after treatment. Moreover, mean target-to-background ratios correlated with multiple characteristics of lesion instability, including the corrected vulnerability index. CONCLUSIONS: These results suggest that the application of noninvasive 18F-fluorodeoxyglucose-positron emission tomography/computed tomography to a murine model can allow for the identification of vulnerable atherosclerotic plaques and their response to therapeutic intervention. This approach may prove useful as a drug discovery and prioritization method.

Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade.

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.

Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis.

Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of 'Trojan horse' nanoparticles to prevent atherosclerotic cardiovascular disease.

Benefit of multidisciplinary wound care center on the volume and outcomes of a vascular surgery practice.

OBJECTIVE: Multidisciplinary care is recommended for the treatment of patients with ischemic and diabetic wounds. In addition to integrating care from multiple specialties, outpatient wound care centers provide an opportunity for continuity and organization of care after revascularization or hospitalization. The purpose of this study was to assess changes in the practice patterns and outcomes of patients treated by a tertiary care vascular surgery practice after the introduction of an affiliated outpatient wound care center. METHODS: A prospective institutional database was used to identify patients who underwent lower-extremity revascularization, amputation, or surgical debridement during consecutive 3-year periods before (BWC; n = 735) and after (AWC; n = 1503) the opening of an affiliated wound care center. Patients were included if they underwent intervention for atherosclerotic peripheral arterial disease or diabetic foot ulcers (DFUs). Changes in case volume, surgical indication, and procedural characteristics were assessed. Clinical outcomes included freedom from lower-extremity amputations and mortality. RESULTS: We identified a total of 1751 procedures performed in 1249 limbs that met inclusion criteria. After the opening of the wound clinic, procedures related to limb salvage represented a greater proportion of overall cases performed by the vascular service (19% vs 26%; P < .0001). The volume of lower-extremity interventions increased by 64%, from 662 procedures in the BWC period to 1085 procedures in the AWC period. There was no difference in type of revascularization performed between the two study periods, although surgical debridements (from 8.9% to 13%; P = .01) and infrapopliteal endovascular interventions (from 21% to 28%; P = .04) significantly increased. Compared with BWC patients, AWC patients more frequently presented with DFUs (7.3% vs 13%; P = .002) and chronic wounds (39% vs 45%; P = .05). At 1 year of follow-up, major amputation rates were significantly lower in the AWC group than in the BWC cohort (5.5% vs 8.8%; P = .04). Treatment during the AWC period was associated with a reduced risk of major amputation (adjusted hazard ratio, 0.41; 95% confidence interval, 0.27-0.62; P < .001), but no difference in all-cause mortality. CONCLUSIONS: The opening of an outpatient wound center affiliated with a tertiary vascular surgical practice was associated with a higher volume of limb salvage patients and procedures. The risk of major amputation decreased following the opening of the wound care center. Integrating vascular surgeons into wound centers may result in a synergistic system that promotes more aggressive and effective limb salvage.

Nanoparticle Therapy for Vascular Diseases.

Nanoparticles promise to advance strategies to treat vascular disease. Since being harnessed by the cancer field to deliver safer and more effective chemotherapeutics, nanoparticles have been translated into applications for cardiovascular disease. Systemic exposure and drug-drug interactions remain a concern for nearly all cardiovascular therapies, including statins, antithrombotic, and thrombolytic agents. Moreover, off-target effects and poor bioavailability have limited the development of completely new approaches to treat vascular disease. Through the rational design of nanoparticles, nano-based delivery systems enable more efficient delivery of a drug to its therapeutic target or even directly to the diseased site, overcoming biological barriers and enhancing a drug's therapeutic index. In addition, advances in molecular imaging have led to the development of theranostic nanoparticles that may simultaneously act as carriers of both therapeutic and imaging payloads. The following is a summary of nanoparticle therapy for atherosclerosis, thrombosis, and restenosis and an overview of recent major advances in the targeted treatment of vascular disease.

Clinical and Genetic Determinants of Varicose Veins.

BACKGROUND: Varicose veins are a common problem with no approved medical therapies. Although it is believed that varicose vein pathogenesis is multifactorial, there is limited understanding of the genetic and environmental factors that contribute to their formation. Large-scale studies of risk factors for varicose veins may highlight important aspects of pathophysiology and identify groups at increased risk for disease. METHODS: We applied machine learning to agnostically search for risk factors of varicose veins in 493 519 individuals in the UK Biobank. Predictors were further studied with univariable and multivariable Cox regression analyses (2441 incident events). A genome-wide association study of varicose veins was also performed among 337 536 unrelated individuals (9577 cases) of white British descent, followed by expression quantitative loci and pathway analyses. Because height emerged as a new candidate risk factor, we performed mendelian randomization analyses to assess a potential causal role for height in varicose vein development. RESULTS: Machine learning confirmed several known (age, sex, obesity, pregnancy, history of deep vein thrombosis) and identified several new risk factors for varicose vein disease, including height. After adjustment for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (hazard ratio for upper versus lower quartile, 1.74; 95% CI, 1.51-2.01; P<0.0001). A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development and skeletal/limb biology. Mendelian randomization analysis provided evidence that increased height is causally related to varicose veins (inverse-variance weighted: odds ratio, 1.26; P=2.07×10-16). CONCLUSIONS: Using data from nearly a half-million individuals, we present a comprehensive genetic and epidemiological study of varicose veins. We identified novel clinical and genetic risk factors that provide pathophysiological insights and could help future improvements of treatment of varicose vein disease.

Inhibition of endo-lysosomal function exacerbates vascular calcification.

Vascular calcification is a pathologic response to mineral imbalances and is prevalent in atherosclerosis, diabetes mellitus, and chronic kidney disease. When located in the media, it is highly associated with increased cardiovascular morbidity and mortality, particularly in patients on dialysis. Vascular calcification is tightly regulated and controlled by a series of endogenous factors. In the present study, we assess the effects of lysosomal and endosomal inhibition on calcification in vascular smooth muscle cells (VSMCs) and aortic rings. We observed that lysosomal function was increased in VSMCs cultured in calcification medium containing 3.5 mM inorganic phosphate (Pi) and 3 mM calcium (Ca2+) for 7 days. We also found that the lysosomal marker lysosome-associated membrane protein 2 was markedly increased and colocalized with osteogenic markers in calcified aortas from vitamin D3-treated rats. Interestingly, both the lysosomal inhibitor chloroquine and the endosomal inhibitor dynasore dose-dependently enhanced Pi + Ca2+-mediated VSMC calcification. Inhibition of lysosomal and endosomal function also promoted osteogenic transformation of VSMCs. Additionally, lysosome inhibition increased Pi-induced medial calcification of aortic rings ex vivo. These data suggest that the endosome-lysosome system may play a protective role in VSMC and medial artery calcification.

National Trends and Geographic Variation in Bilateral Internal Mammary Artery Use in the United States.

BACKGROUND: The goal of this study was to characterize the adoption rate and regional variation in bilateral internal mammary artery (BIMA) use during coronary artery bypass grafting (CABG) in the United States. METHODS: Observational study of 100% sample of fee-for-service Medicare beneficiaries aged 65 years or older, continuously enrolled in Parts A and B from 2009 to 2014 (n = 162,860,439). Rates of beneficiaries receiving a BIMA versus single internal mammary artery (SIMA) during CABG are expressed per 1,000 beneficiaries and aggregated by Hospital Referral Region (HRR). An HRR is a validated unit for quantifying regional variation in health care. RESULTS: The absolute national rate of BIMA use declined during the study period from 0.21 claims per 1,000 beneficiaries in 2009 to 0.13 in 2014 (p < 0.001). When indexed to overall CABG volume, no change was seen in the frequency of BIMA use over time (p = 0.883). SIMA use ranged from 1.3 to 8.5 claims per 1,000 Medicare beneficiaries, whereas BIMA use ranged from 0 to 1.5 (p < 0.001). A significant correlation was found between regional volume of SIMA use and likelihood of BIMA use (correlation coefficient 0.673, p < 0.001). Although both SIMA and BIMA use correlated with regional volume of diagnostic cardiac catheterization, the correlation was stronger for SIMA use (correlation coefficient 0.962 versus 0.682, p < 0.001). CONCLUSIONS: Over the past 5 years, no growth was seen in BIMA use among Medicare beneficiaries, and the frequency of BIMA use during CABG remained low. There was significant regional variation in BIMA use, however, which demonstrates opportunity for continued growth of BIMA grafting.

Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.

Dry eye disorders, including Sjögren's syndrome, constitute a common problem in the aging population, with limited effective therapeutic options available. The cAMP-activated Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR) is a major prosecretory channel at the ocular surface. We investigated whether compounds that target CFTR can correct the abnormal tear film in dry eye. Small-molecule activators of human wild-type CFTR identified by high-throughput screening were evaluated in cell culture and in vivo assays, to select compounds that stimulate Cl(-)-driven fluid secretion across the ocular surface in mice. An aminophenyl-1,3,5-triazine, CFTRact-K089, fully activated CFTR in cell cultures with EC50 ∼250 nM and produced an ∼8.5 mV hyperpolarization in ocular surface potential difference. When delivered topically, CFTRact-K089 doubled basal tear volume for 4 h and had no effect in CF mice. CFTRact-K089 showed sustained tear film bioavailability without detectable systemic absorption. In a mouse model of aqueous-deficient dry eye produced by lacrimal ablation, topical administration of 0.1 nmol CFTRact-K089 3 times daily restored tear volume to basal levels, preventing corneal epithelial disruption when initiated at the time of surgery and reversing it when started after development of dry eye. Our results support the potential utility of CFTR-targeted activators as a novel prosecretory treatment for dry eye.-Flores, A. M., Casey, S. D., Felix, C. M., Phuan, P. W., Verkman, A. S., Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.