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.

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.

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.

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.

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.

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.

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.