The Role of Genetics in Managing Peripheral Arterial Disease.

BACKGROUND: Genome wide association studies (GWAS) have allowed for a rapid increase in our understanding of the underlying genetics and biology of many diseases. By capitalizing on common genetic variation between individuals, GWAS can identify DNA variants associated with diseases of interest. A variety of statistical methods can be applied to GWAS results which allows for risk factor identification, stratification, and to identify potential treatments. Peripheral artery disease (PAD) is a common vascular disease that has been shown to have a strong genetic component. This article provides a review of the modern literature and our current understanding of the role of genetics in PAD. METHODS: All available GWAS studies on PAD were reviewed. A literature search involving these studies was conducted and relevant articles applying the available GWAS data were summarized to provide a comprehensive review of our current understanding of the genetic component in PAD. RESULTS: The largest available GWAS on PAD has identified 19 genome wide significant loci, with factor V Leiden and genes responsible for circulating lipoproteins being implicated in the development of PAD. Mendelian randomization (MR) studies have identified risk factors and causal associations with smoking, diabetes, and obesity and many other traits; protein-based MR has also identified circulating lipid and clotting factor levels associated with the incidence of PAD. Polygenic risk scores may allow for improved prediction of disease incidence and allow for early identification of at-risk patients but more work needs to be done to validate this approach. CONCLUSIONS: Genetic epidemiology has allowed for an increased understanding of PAD in the past decade. Genome-wide association studies have led to improved detection of genetic contributions to PAD, and further genetic analyses have validated risk factors and may provide options for improved screening in at-risk populations. Ongoing biobank studies of chronic limb threatening ischemia patients and the increasing ancestral diversity in biobank enrollment will allow for even further exploration into the pathogenesis and progression of PAD.

Using a polygenic score to account for genomic risk factors in a model to detect individuals with dilated ascending thoracic aortas.

Background: Ascending thoracic aortic dilation is a complex trait that involves modifiable and non-modifiable risk factors and can lead to thoracic aortic aneurysm and dissection. Clinical risk factors have been shown to predict ascending thoracic aortic diameter. Polygenic scores (PGS) are increasingly used to assess clinical risk for multifactorial diseases. The degree to which a PGS can improve aortic diameter prediction is not known. In this study we tested the extent to which the addition of a PGS to clinical prediction algorithms improves the prediction of aortic diameter. Methods: The patient cohort comprised 6,790 Penn Medicine Biobank (PMBB) participants with available echocardiography and clinical data linked to genome-wide genotype data. Linear regression models were used to integrate PGS weights derived from a large genome wide association study of thoracic aortic diameter in the UK biobank and were compared to the performance of the standard and a reweighted variation of the recently published AORTA Score. Results: Cohort participants were 56% male, had a median age of 61 years (IQR 52-70) with a mean ascending aortic diameter of 3.4 cm (SD 0.5). Compared to the AORTA Score which explained 28.4% (95% CI 28.1% to 29.2%) of the variance in aortic diameter, AORTA Score + PGS explained 28.8%, (95% CI 28.1% to 29.6%), the reweighted AORTA score explained 30.4% (95% CI 29.6% to 31.2%), and the reweighted AORTA Score + PGS explained 31.0% (95% CI 30.2% to 31.8%). The addition of a PGS to either the AORTA Score or the reweighted AORTA Score improved model sensitivity for the identifying individuals with a thoracic aortic diameter ≥ 4 cm. The respective areas under the receiver operator characteristic curve for the AORTA Score + PGS (0.771, 95% CI 0.756 to 0.787) and reweighted AORTA Score + PGS (0.785, 95% CI 0.770 to 0.800) were greater than the standard AORTA Score (0.767, 95% CI 0.751 to 0.783) and reweighted AORTA Score (0.780 95% CI 0.765 to 0.795). Conclusions: We demonstrated that inclusion of a PGS to the AORTA Score results in a small but clinically meaningful performance enhancement. Further investigation is necessary to determine if combining genetic and clinical risk prediction improves outcomes for thoracic aortic disease.

Delayed referral of venous ulcers increases resource usage.

OBJECTIVE: Venous insufficiency is often not readily recognized as a contributing etiology to nonhealing wounds by nonvascular surgery specialists, potentially delaying appropriate treatment to achieve wound healing and increasing healthcare costs. The objective of the present study was to understand the time and resources used before the definitive treatment of venous ulcers. METHODS: A single-institution retrospective medical record review of C6 patients undergoing radiofrequency saphenous and perforator vein ablation from May 2016 to January 2018 identified 56 patients with 67 diseased limbs. The numbers of inpatient, emergency department, and wound care visits and the intervals to vein ablation from the initial evaluation of the ulceration by a healthcare provider were collected. The demographics, comorbidities, previous venous interventions, wound characteristics, duplex ultrasound imaging, and available wound healing follow-up through July 2018 were assessed for all patients. RESULTS: For the 67 limbs examined, 588 total healthcare visits were performed for wound assessment before a referral to a vascular surgeon, with 413 visits at a wound care center (70% of all visits). Other specialty visits included emergency medicine (17.9% of limbs) and rheumatology (22.4% of limbs). Six patients (nine limbs) were admitted to inpatient services for treatment of their ulceration. Overall, the patients were seen an average of 8.6 ± 9.7 times for their ulcer with the wound center before determination of a contributing venous etiology and subsequent treatment. These visits translated to a median of 230 days (interquartile range, 86.5-1088 days) between the first identification of the ulcer by healthcare providers and subsequent accurate diagnosis and definitive treatment of their venous disease with radiofrequency saphenous and perforator vein ablation. After intervention, 18.64% of the limbs had healed at 1 month, 33.92% had healed at 3 months, 50% had healed at 6 months, and 82.92% had healed by 12 months. CONCLUSIONS: An earlier and accurate diagnosis of the venous contribution to ulcers and subsequent appropriate treatment of venous etiologies in wound formation by a vascular venous specialist could significantly improve healing and minimize resource usage.