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BACKGROUND: People with HIV (PWH) have an increased risk of cardiovascular disease. Previous cross-sectional data suggest there is a higher prevalence of abdominal aortic aneurysm (AAA) in PWH than in those without HIV. Whether PWH have an increased risk of incident AAA compared with those without HIV is unknown. METHODS: We analyzed data among participants without prevalent AAA from the Veterans Aging Cohort Study, a prospective, observational, longitudinal cohort of veterans with HIV matched 1:2 with veterans without HIV infection. We calculated AAA rates by HIV status and assessed the association between HIV infection and incident AAA using Cox proportional hazards models. We defined AAA using the International Classification of Diseases, 9th or 10th revision, or Current Procedural Terminology codes and adjusted all models for demographic characteristics, cardiovascular disease risk factors, and substance use. Secondary analyses examined the association between time-varying CD4+ T-cell count or HIV viral load and incident AAA. RESULTS: Among 143 001 participants (43 766 with HIV), over a median follow-up of 8.7 years, there were 2431 incident AAA events (26.4% among PWH). Rates of incident AAA per 1000 person-years were similar among PWH (2.0 [95% CI, 1.9–2.2]) and people without HIV (2.2 [95% CI, 2.1–2.3]). There was no evidence that HIV infection increased the risk of incident AAA compared with no HIV infection (adjusted hazard ratio, 1.02 [95% CI, 0.92–1.13]). In adjusted analyses with time-varying CD4+ T-cell counts or HIV viral load, PWH with CD4+ T-cell counts 3 (adjusted hazard ratio, 1.29 [95% CI, 1.02–1.65]) or HIV viral load ≥500 copies/mL (adjusted hazard ratio, 1.29 [95% CI, 1.09–1.52]) had an increased risk of AAA compared with those without HIV. CONCLUSIONS: HIV infection is associated with an increased risk of AAA among those with low CD4+ T-cell counts or elevated HIV viral load over time.

Importance The benefit of an electronic support system for the prescription and adherence to oral anticoagulation therapy among patients with atrial fibrillation (AF) and atrial flutter at heightened risk for of stroke and systemic thromboembolism is unclear. Objective To evaluate the effect of a combined alert intervention and shared decision-making tool to improve prescription rates of oral anticoagulation therapy and adherence. Design, Setting, and Participants A prospective single arm study of 939 consecutive patients treated at a large tertiary healthcare system. Exposures An electronic support system comprising 1) an electronic alert to identify patients with AF or atrial flutter, a CHA2DS2-VASc score ≥ 2, and not on oral anticoagulation and 2) electronic shared decision-making tool to promote discussions between providers and patients regarding therapy. Main Outcomes and Measures The primary endpoint was prescription rate of anticoagulation therapy. The secondary endpoint was adherence to anticoagulation therapy defined as medication possession ratio ≥ 80% during the 12 months of follow-up. Results Between June 13, 2018 and August 31, 2018, the automated intervention identified and triggered a unique alert for 939 consecutive patients with AF or atrial flutter, a CHA2DS2-VASc score ≥2 who were not on oral anticoagulation. The median CHA2DS2-VASc score among all patients identified by the alert was 2 and the median untreated duration prior to the alert was 495 days (interquartile range 123-1,831 days). Of the patients identified by the alert, 345 (36.7%) initiated anticoagulation therapy and 594 (63.3%) did not: 68.7% were treated with a non-Vitamin K antagonist oral anticoagulant (NOAC), 22.0% with warfarin, and 9.3 % combination of NOAC and warfarin. Compared with historical anticoagulation rates, the electronic alert was associated with a 23.6% increase in anticoagulation prescriptions. The overall 1-year rate of adherence to anticoagulant therapy was 75.4% (260/345). Conclusion and Relevance An electronic automated alert can successfully identify patients with AF and atrial flutter at high risk for stroke, increase oral anticoagulation prescription, and support high rates of adherence.

BACKGROUND AND AIMS: Polyvascular disease is an independent predictor of major adverse cardiovascular events (MACE). The relationship between the number of diseased arterial beds and MACE is unknown. How MACE risk changes in individuals with type 2 diabetes (T2D) is also understudied. Furthermore, it is unknown whether heart failure (HF) status and hemoglobin A1c (HbA1c) levels influence outcomes in polyvascular disease. This analysis from the Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL) aimed to examine the risk associated with increasing number of diseased arterial beds on MACE and all-cause mortality (ACM). METHODS: Cox models were used to test associations between the number of diseased arterial beds and MACE and ACM. Prespecified interaction testing between number of diseased arterial beds with baseline HF, HbA1c (≤8% vs. >8%), and treatment assignment was performed. RESULTS: Overall, 14,751 participants were included; 26.5% were without atherosclerosis, 58.9% had 1-bed, 12.3% had 2-bed, and 2.3% had 3-bed disease. An increasing burden of atherosclerotic disease was associated with increasing risk of MACE (adjusted HR [aHR] 1.71 [95% CI 1.46–2.02]; 2.61 [2.17–3.15]; 3.46 [2.69–4.45] for 1, 2, and 3 beds, respectively, p < 0.001 for all) and ACM (1.94 [1.56–2.42]; 3.03 [2.33–3.95]; 3.66 [2.59–5.18] for 1, 2, and 3 beds, respectively, p < 0.001 for all). Prespecified interaction testing did not reveal any significant associations. CONCLUSIONS: In patients with T2D, compared to those without atherosclerotic vascular disease, risk of MACE and ACM increases incrementally with each additional diseased arterial bed.

Peripheral artery disease is a highly morbid yet undertreated atherosclerotic disease. The cornerstones of peripheral artery disease therapy consist of smoking cessation, lipid-lowering therapy, and hypertension treatment. More recently, clinical trials have demonstrated that novel antiplatelet and antithrombotic therapies reduce the risk of both cardiovascular and limb events in this patient population. In this review, we highlight the components of optimal medical therapy of peripheral artery disease and the evidence base for these therapies.

ImportanceReported risk of incident peripheral artery disease (PAD) by sex and race varies significantly and has not been reported in national cohorts among individuals free of baseline PAD.ObjectiveTo evaluate the association of sex and race, as well as prevalent cardiovascular risk factors, with limb outcomes in a national cohort of people with normal baseline ankle-brachial indices (ABIs).Design, setting, and participantsThis cohort study was conducted using data from participants in the Veterans Affairs Birth Cohort Study (born 1945-1965), with follow-up data between January 1, 2000, and December 31, 2016. Baseline demographics were collected from 77 041 participants receiving care from the Veterans Health Administration with baseline ABIs of 0.90 to 1.40 and no history of PAD. Data were analyzed from October 2019 through September 2022.ExposuresSex, race, diabetes, and smoking status.Main Outcomes and MeasuresIncident PAD, defined as subsequent ABI less than 0.90, surgical or percutaneous revascularization, or nontraumatic amputation.ResultsOf 77 041 participants with normal ABIs (73 822 [95.8%] men; mean [SD] age, 60.2 [5.9] years; 13 080 Black [18.2%] and 54 377 White [75.6%] among 71 911 participants with race and ethnicity data), there were 6692 incident PAD events over a median [IQR] of 3.9 [1.7-6.9] years. Incidence rates were lower for women than men (incidence rates [IRs] per 1000 person-years, 7.4 incidents [95% CI, 6.2-8.8 incidents] vs 19.2 incidents [95% CI, 18.7-19.6 incidents]), with a lower risk of incident PAD (adjusted hazard ratio [aHR], 0.49 [95% CI, 0.41-0.59]). IRs per 1000 person-years of incident PAD were similar for Black and White participants (18.9 incidents [95% CI, 17.9-20.1 incidents] vs 18.8 incidents [95% CI, 18.3-19.4]). Compared with White participants, Black participants had increased risk of total PAD (aHR, 1.09 [95% CI, 1.02-1.16]) and nontraumatic amputation (aHR, 1.20 [95% CI, 1.06-1.36]) but not surgical or percutaneous revascularization (aHR, 1.10 [95% CI, 0.98-1.23]) or subsequent ABI less than 0.90 (aHR, 1.04 [95% CI, 0.95-1.13]). Diabetes (aHR, 1.62 [95% CI, 1.53-1.72]) and smoking (eg, current vs never: aHR, 1.76 [95% CI, 1.64-1.89]) were associated with incident PAD. Incident PAD was rare among individuals without a history of smoking or diabetes (eg, among 632 women: IR per 1000 people-years, 2.1 incidents [95% CI, 1.0-4.5 incidents]) despite an otherwise–high-risk cardiovascular profile (eg, 527 women [83.4%] with hypertension).Conclusions and RelevanceThis study found that the risk of PAD was approximately 50% lower in women than men and less than 10% higher for Black vs White participants, while the risk of nontraumatic amputation was 20% higher among Black compared with White participants.

Atherosclerotic lower extremity peripheral artery disease (PAD) is increasingly recognized as an important cause of cardiovascular morbidity and mortality that affects >230 million people worldwide. Traditional cardiovascular risk factors, including advanced age, smoking, and diabetes, are strongly linked to an increase risk of PAD. Although PAD has been historically underappreciated compared with coronary artery disease and stroke, greater attention on PAD in recent years has led to important new epidemiological insights in the areas of thrombosis, inflammation, dyslipidemia, and microvascular disease. In addition, the concept of polyvascular disease, or clinically evident atherosclerosis in multiple arterial beds, is increasingly identified as a particularly malignant cardiovascular disease worthy of special clinical attention and further study. It is noteworthy that PAD may increase the risk of adverse outcomes in similar or even greater magnitude than coronary disease or stroke. In this review, we highlight important new advances in the epidemiology of PAD with a particular focus on polyvascular disease, emerging biomarkers, and differential risk pathways for PAD compared with other atherosclerotic diseases.

Introduction: Inflammation is causally related to atherothrombosis. Interleukin-1β (IL-1β) and interleukin-18 (IL-18) require NLRP3 inflammasome for activation and have downstream effects on interleukin-6 (IL-6), a marker previously associated with high risk of coronary artery and cerebrovascular disease (CCVD). However, data pertaining to peripheral artery disease (PAD) are sparse and could offer druggable targets in this disease. Methods: We conducted a prospective cohort study of 4248 patients with type 2 diabetes or metabolic syndrome and prior coronary artery disease who participated in the NIH-funded Cardiovascular Inflammation Reduction Trial (CIRT). Participants were followed for up to 5 years for incident CCVD and symptomatic PAD events. Randomized treatment with low-dose methotrexate (vs. placebo) had no effect on event rates or plasma levels of inflammatory biomarkers. Baseline levels of IL-1β, IL-18, and IL-6 were tested for association with incident vascular events. Kaplan-Meier curves and Cox proportional hazards models (adjusted for traditional risk factors) were estimated. Results: In multivariable adjusted analyses, hazard ratios for the lowest (referent) to highest baseline quartiles of IL-6 were 1.0, 1.5, 1.8, and 2.0 (p-trend Conclusion: In this contemporary cohort of secondary prevention patients, elevated IL-6 was associated with both incident CCVD and PAD. These data support exploration of direct IL-6 inhibition for PAD prevention, a strategy currently being pursued to reduce risk of coronary artery and cerebrovascular disease.

BACKGROUND: Elevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease. OBJECTIVES: The purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD). METHODS: In a prospective case-cohort study within the Women’s Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. RESULTS: The risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR](Q4): 3.05 [95% confidence interval (CI): 1.46 to 6.39]; ptrend = 0.002; PAD HR(Q4): 2.58 [95% CI: 1.18 to 5.63]; p(trend) = 0.019), whereas sdLDL-C was significantly associated with MI alone (HR(Q4): 3.71 [95% CI: 1.59 to 8.63]; p(trend) < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B

Atherosclerotic peripheral artery disease (PAD) is associated with functional limitations and an increased risk of poor cardiovascular outcomes. Although men are traditionally viewed at higher risk of PAD than women, the true prevalence and incidence is inconsistent among available reports. Some of this variability is due to differences in PAD-related symptoms among women as well as sex-based differences in diagnostic tests, such as the ankle-brachial index, and it is critical for future epidemiologic studies to account for these differences. Generally, women with PAD experience greater functional impairment and decline then men and are less likely to receive guideline-directed medical therapy. In some settings, women are also more likely to present at later stages of disease and more often undergo lower limb amputation than men. Animal data exploring the biological underpinnings of these sex differences are limited, but several mechanisms have been postulated, including differential plaque morphology, alterations in the immune response, and hormonal variation and protection. Epidemiologic data suggest a link between inflammation and PAD and also reveal sex differences in lipid profiles associated with PAD risk. In this review, we discuss available data on sex differences in PAD with additional focus on potential biological explanations for these differences. We also emphasize important knowledge gaps in this area, including underrepresentation of women in PAD clinical trials, in order to help guide future investigations and eliminate sex disparities in PAD.

Background:The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).Methods:The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2022 Statistical Update is the product of a full year’s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year’s edition includes data on the monitoring and benefits of cardiovascular health in the population and an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, and the global burden of cardiovascular disease and healthy life expectancy.Results:Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.Conclusions:The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

BACKGROUND: Up to 50% of patients with proximal deep venous thrombosis (DVT) will develop the post-thrombotic syndrome (PTS) characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality-of-life. While catheter-based interventions enabling restoration of blood flow (RBF) have demonstrated little benefit on PTS, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. Here in experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution. METHODS: First, experimental stasis DVT was generated in C57/BL6 mice (N=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical de-ligation with or without intravenous recombinant tissue plasminogen activator (rtPA), administered two days after de-ligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed IVC specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post-hoc analysis of the ATTRACT pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on VEINES quality-of-life (VEINES-QoL) and Villalta scores for specific symptom-onset-to-randomization (SOR) timeframes. RESULTS: Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared to controls. In mice without RBF, rtPA administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. Notably, in mice already exhibiting RBF by day 4, rtPA administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate SOR timeframe of 4-8 days demonstrated maximal benefits in VEINES-QoL and Villalta scores (between group difference=8.41 and 1.68 respectively, p8 days. CONCLUSIONS: Taken together, these data illustrate that within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce PTS in DVT patients.

Background: Polygenic risk scores (PRS) may enhance risk stratification for coronary heart disease among young adults. Whether a coronary heart disease PRS improves prediction beyond modifiable risk factors in this population is not known. Methods: Genotyped adults aged 18 to 35 years were selected from the CARDIA study (Coronary Artery Risk Development in Young Adults; n=1132) and FOS (Framingham Offspring Study; n=663). Systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, triglycerides, smoking, and waist circumference or body mass index were measured at the visit 1 exam of each study, and coronary artery calcium, a measure of coronary atherosclerosis, was assessed at year 15 (CARDIA) or year 30 (FOS). A previously validated PRS for coronary heart disease was computed for each subject. The C statistic and integrated discrimination improvement were used to compare improvements in prediction of elevated coronary artery calcium between models containing the PRS, risk factors, or both. Results: There were 62 (5%) and 93 (14%) participants with a coronary artery calcium score >20 (CARDIA) and >300 (FOS), respectively. At these thresholds, the C statistic changes of adding the PRS to a risk factor–based model were 0.015 (0.004–0.028) and 0.020 (0.001–0.039) in CARDIA and FOS, respectively. When adding risk factors to a PRS-based model, the respective changes were 0.070 (0.033–0.109) and 0.051 (0.017–0.079). The integrated discrimination improvement, when adding the PRS to a risk factor model, was 0.027 (−0.006 to 0.054) in CARDIA and 0.039 (0.0005–0.072) in FOS. Conclusions: Among young adults, a PRS improved model discrimination for coronary atherosclerosis, but improvements were smaller than those associated with modifiable risk factors.

Background: The mechanism of adverse limb events associated with peripheral artery disease remains incompletely understood. We investigated whether microvascular disease is associated with amputation in a large cohort of veterans to determine whether microvascular disease diagnosed in any location increases the risk of amputation alone and in concert with peripheral artery disease. Methods: Participants in the Veterans Aging Cohort Study were recruited from April 1, 2003 through December 31, 2014. We excluded participants with known prior lower limb amputation. Using time-updated Cox proportional hazards regression, we analyzed the effect of prevalent microvascular disease (retinopathy, neuropathy, and nephropathy) and peripheral artery disease status on the risk of incident amputation events after adjusting for demographics and cardiovascular risk factors. Results: Among 125 674 veterans without evidence of prior amputation at baseline, the rate of incident amputation over a median of 9.3 years of follow-up was 1.16 per 1000 person-years, yielding a total of 1185 amputations. In time-updated multivariable-adjusted analyses, compared with those without peripheral artery disease or microvascular disease, microvascular disease alone was associated with a 3.7-fold (95% CI, 3.0–4.6) increased risk of amputation; peripheral artery disease alone conferred a 13.9-fold (95% CI, 11.3–17.1) elevated risk of amputation; and the combination of peripheral artery disease and microvascular disease was associated with a 22.7-fold (95% CI, 18.3–28.1) increased risk of amputation. Conclusions: Independent of traditional risk factors, the presence of microvascular disease increases the risk of amputation alone and synergistically increases risk in patients with peripheral artery disease. Further research is needed to understand the mechanisms by which this occurs.

Supplemental Digital Content is available in the text., Background: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk. Methods: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies. Results: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; P=0.003) and CAD (marginal inclusion probability, 0.92; P=0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84–0.91]; P=9×10−10) and CAD (odds ratio,0.66 [95% CI, 0.63–0.69]; P=4×10−73), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29–4.60]; P

Objective: Case-control studies have identified plasma homocysteine as a risk marker for venous thromboembolism (VTE). Prospective data, particularly among women, are sparse. We examined whether plasma homocysteine associates with incident VTE in 2 large prospective cohorts of women. Approach and Results: In the WHS (Women’s Health Study), a prospective cohort study of 27 555 women ≥45 years old and free of cardiovascular disease and VTE, we assessed baseline homocysteine concentration along with other thrombotic biomarkers for association with future VTE (n=743), pulmonary embolism (n=363), and deep vein thrombosis (n=545). We used a second cohort of 2672 women (n=102 VTE events) in the WAFACS (Women’s Antioxidant and Folic Acid Cardiovascular Study) to corroborate our findings. In age-adjusted analyses, elevated homocysteine, hsCRP (high-sensitivity C-reactive protein), fibrinogen, and sICAM-1 (soluble intercellular adhesion molecule-1) were associated with incident VTE ( P for extreme quartile comparisons and P -trend Q4 , 1.31 [95% CI, 1.06–1.63]). Elevated homocysteine levels were associated with unprovoked pulmonary embolism (HR Q4 , 2.13 [95% CI, 1.30–3.51]) and deep vein thrombosis (HR Q4 , 1.59 [95% CI, 1.05–2.40]) but not provoked events. In WAFACS, elevated homocysteine levels were also associated with VTE events ( P -trend 0.023). Conclusions: Higher plasma homocysteine levels associate with VTE events in 2 cohorts of middle-aged and older women. Among VTE subtypes, homocysteine was associated with unprovoked, but not provoked, events. These data suggest a plausible biological role for homocysteine in the development of VTE. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00000479, NCT00000541.

Patients with coronavirus disease 2019 (COVID-19) are at heightened risk of venous thromboembolic events (VTE), though there is no data examining when these events occur following a COVID-19 diagnosis. We therefore sought to characterize the incidence, timecourse of events, and outcomes of VTE during the COVID-19 pandemic in a national healthcare system using data from Veterans Affairs Administration.

BackgroundCirculating lipid and lipoprotein levels have consistently been identified as risk factors for atherosclerotic cardiovascular disease (ASCVD), largely on the basis of studies focused on coronary artery disease (CAD). The relative contributions of specific lipoproteins to risk of peripheral artery disease (PAD) have not been well-defined. Here, we leveraged large scale genetic association data to identify genetic proxies for circulating lipoprotein-related traits, and employed Mendelian randomization analyses to investigate their effects on PAD risk.MethodsGenome-wide association study summary statistics for PAD (Veterans Affairs Million Veteran Program, 31,307 cases) and CAD (CARDIoGRAMplusC4D, 60,801 cases) were used in the Mendelian Randomization Bayesian model averaging (MR-BMA) framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B lowering on PAD risk using gene regions that proxy potential lipid-lowering drug targets. Transcriptome-wide association studies were performed to identify genes relevant to circulating levels of prioritized lipoprotein subfractions.ResultsApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability 0.86, p = 0.003) and CAD (marginal inclusion probability 0.92, p = 0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (OR 0.87 per 1 standard deviation decrease in ApoB, 95% CI 0.84 to 0.91, p = 9 × 10−10) and CAD (OR 0.66, 95% CI 0.63 to 0.69, p = 4 × 10−73), with a stronger predicted effect of ApoB-lowering on CAD (ratio of ORs 1.33, 95% CI 1.25 to 1.42, p = 9 × 10−19). Among ApoB-containing subfractions, extra-small VLDL particle concentration (XS.VLDL.P) was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability 0.91, p = 2.3 × 10−4), while large LDL particle concentration (L.LDL.P) was the most likely subfraction associated with CAD risk (marginal inclusion probability 0.95, p = 0.011). Genes associated with XS.VLDL.P and L.LDL.P included canonical ApoB-pathway components, although gene-specific effects varied across the lipoprotein subfractions.ConclusionApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, diverse effects of ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions on ASCVD, and distinct subfraction-associated genes suggest possible biologic differences in the role of lipoproteins in the pathogenesis of PAD and CAD.

Coronavirus disease of 2019 poses significant risks for patients with vascular disease. Telemedicine can help clinicians provide care for patients with vascular disease while adhering to social-distancing guidelines. In this article, we review the components of telemedicine used in the vascular medicine practice at the Vanderbilt University Medical Center. In addition, we describe inpatient and outpatient diagnosis-based algorithms to help select patients for telemedicine versus in-person evaluation.

Introduction: Peripheral arterial disease (PAD) is a common and underdiagnosed disease associated with significant morbidity and increased risk of major adverse cardiovascular events. Targeted screening of individuals at high risk for PAD could facilitate early diagnosis and allow for prompt initiation of interventions aimed at reducing cardiovascular and limb events. However, no widely accepted PAD risk stratification tools exist. Hypothesis: We hypothesized that machine learning algorithms can identify patients at high risk for PAD, defined by ankle-brachial index (ABI) Methods: Using data from the Vanderbilt University Medical Center EHR, ABIs were extracted for 8,093 patients not previously diagnosed with PAD at the time of initial testing. A total of 76 patient characteristics, including demographics, vital signs, lab values, diagnoses, and medications were analyzed using both a random forest and least absolute shrinkage and selection operator (LASSO) regression to identify features most predictive of ABI Results: The machine learning models identified several features independently correlated with PAD (age, BMI, SBP, DBP, pulse pressure, anti-hypertensive medication, diabetes medication, smoking, and statin use). The test statistic produced by the logistic regression model was correlated with PAD status in our validation set. At a chosen threshold, the specificity was 0.92 and the positive predictive value was 0.73 in this high-risk population. Conclusions: Machine learning can be applied to build unbiased models that identify individuals at risk for PAD using easily accessible information from the EHR. This model can be implemented either through a high-risk flag within the medical record or an online calculator available to clinicians.

BACKGROUND: Despite current guidelines suggesting a benefit for dual anti-platelet therapy (DAPT) following peripheral vascular intervention (PVI), there is limited data on anti-platelet prescribing patterns post-procedure. We attempted to determine variables associated with DAPT prescription following lower extremity (LE) PVI. METHODS: Retrospective analysis of patients undergoing LE PVI in the Vascular Quality Initiative (2017–2018) was performed. Participants not on anticoagulation or DAPT prior to the procedure were considered for final analysis. Post-discharge anti-platelet therapy (APT) regimen rates were determined (none, aspirin only, P2Y12 inhibitor only, and DAPT). Multivariate logistic regression was performed to determine variables associated with DAPT initiation compared to those discharged on single agent or no anti-platelet therapy. RESULTS: A total of 16,597 procedures were included for analysis, with 49% initiated on DAPT post-PVI. Male gender (odds ratio (OR) 1.12, 95% confidence interval (CI) 1.05, 1.20), smoking (OR 1.20, 95% CI 1.09, 1.32), and coronary artery disease (OR 1.19, 95% CI 1.11, 1.27) were associated with an increased likelihood of post-PVI DAPT prescription. Procedures requiring multiple types of interventions (OR 1.28, 95% CI 1.15, 1.42), stent placement (OR 1.16, 95% CI 1.06, 1.27), and with complications (OR 1.31, 95% CI 1.14, 1.52) were also positively associated with DAPT prescription. CONCLUSIONS: In patients not already receiving anti-coagulation or on DAPT at the time of LE PVI, prescription of DAPT following intervention is approximately 50%. Multiple factors were associated with the decision for DAPT versus single APT, and further study is required to understand how this affects post-intervention adverse limb and cardiovascular events.

Background: Despite strong and consistent prospective associations of elevated low-density lipoprotein (LDL) cholesterol concentration with incident coronary and cerebrovascular disease, data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle (LDL-P) concentration, rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein (HDL) cholesterol (HDL-C), may be the primary lipid driver of PAD risk. Methods: The study population was a prospective cohort study of 27 888 women ≥45 years old free of cardiovascular disease at baseline and followed for a median of 15.1 years. We tested whether standard lipid concentrations, as well as nuclear magnetic resonance spectroscopy–derived lipoprotein measures, were associated with incident symptomatic PAD (n=110) defined as claudication and/or revascularization. Results: In age-adjusted analyses, while LDL cholesterol was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very LDL (VLDL) particle (VLDL-P) subclasses, increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle (HDL-P) concentration (all P for extreme tertile comparisons adj ] 2.03; 95% CI, 1.14–3.59), small LDL-P (HR adj 2.17; 95% CI, 1.10–4.27), very large VLDL-P (HR adj 1.68; 95% CI, 1.06–2.66), medium VLDL-P (HR adj 1.98; 95% CI, 1.15–3.41), and TC:HDL-C (HR adj , 3.11; 95% CI, 1.67–5.81). HDL was inversely associated with risk; HR adj for extreme tertiles of HDL-C and HDL-P concentration were 0.30 ( P trend < 0.0001) and 0.29 ( P trend < 0.0001), respectively. These components of atherogenic dyslipidemia, including small LDL-P, medium and very large VLDL-P, TC:HDL-C, HDL-C, and HDL-P, were more strongly associated with incident PAD than incident coronary and cerebrovascular disease. Finally, the addition of LDL-P and HDL-P concentration to TC:HDL-C measures identified women at heightened PAD risk. Conclusions: In this prospective study, nuclear magnetic resonance–derived measures of LDL-P, but not LDL cholesterol, were associated with incident PAD. Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and nuclear magnetic resonance–derived measures of HDL, were significant risk determinants. These data help clarify prior inconsistencies and may elucidate a unique lipoprotein signature for PAD compared to coronary and cerebrovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov/ . Unique Identifier: NCT00000479.

Although the resting ankle–brachial index (ABI) is commonly used as a httptool to diagnose peripheral artery disease (PAD), several additional indices measured after exercise may have increased sensitivity for identifying PAD. The aim of this study was to determine the utility of resting ABI and three post-exercise physiological parameters for diagnosing PAD confirmed by arterial imaging studies. For each qualifying study, we assessed the performance measures for identifying PAD for resting ABI < 0.90, exercise ABI < 0.90, a decrease in ABI > 20% with exercise, and a decrease in ankle pressure > 30 mmHg with exercise. Of the 199 exams that met our inclusion criteria, imaging showed a > 75% stenotic lesion in at least one limb in 138 (69%) of patients. For stenoses > 75%, resting ABI < 0.90 had a sensitivity of 64% (95% CI: 56–72%) and exercise ABI < 0.90 had a sensitivity of 88% (95% CI: 82–93%). The sensitivity for a post-exercise ABI decrease > 20% was 67% (95% CI: 59–75%) and the sensitivity for a decrease in ankle pressure > 30 mmHg was 4% (95% CI: 2–9%). For individuals with a normal resting ABI but stenotic lesions > 75% confirmed by imaging (n=49), the addition of exercise ABI testing correctly identified an additional 25% of this population. Overall, exercise ABI < 0.90 exhibits a greater sensitivity for detecting PAD compared to resting ABI. Furthermore, exercise ABI < 0.90 had added clinical utility in patients with normal resting ABIs and was superior to other commonly used exercise indices.

Background: The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain. Methods: We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRP OT ) and LDL-C OT measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. Results: At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was −60.5% (95% confidence interval [CI], −61.2 to −59.8; P P =0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRP OT 3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81–1.66), and 1.62 (95% CI, 1.14–2.30) ( P -trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-C OT . Comparable adjusted hazard ratios for LDL-C OT (50 mg/dL) were 1.0, 0.87, and 1.21, respectively ( P -trend=0.16). Relative risk reductions with bococizumab were similar across hsCRP OT groups ( P -interaction=0.87). Conclusions: In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01975376, NCT01975389.

Article, see p 1435 Atherosclerotic peripheral artery disease (PAD) is a growing, yet underappreciated global health issue.1 PAD affects >200 million individuals worldwide,2 and atherosclerotic disease of the lower extremities confers a high risk of cardiovascular events and death.3 Patients with PAD have a 2.5-fold increased risk of myocardial infarction and a 3.1-fold increased risk of stroke in comparison with healthy individuals.3 In addition, individuals with PAD are at heightened risk for lower extremity ulceration, acute limb ischemia, surgical and percutaneous revascularization, and amputation. Given the prevalence and morbidity of PAD, there is a clear need for therapies that improve PAD-specific outcomes, such as amputation, and reduce the risk of other major cardiovascular events that are common among patients with atherosclerosis, as well. Current professional society guidelines recommend statin therapy for all individuals with PAD.4,5 Unfortunately, much of the data regarding lipid-lowering therapy for PAD have been extrapolated from studies of coronary artery disease, and few studies have specifically examined limb outcomes. The Heart Protection Study randomly assigned 20 536 subjects, 6748 of whom carried a diagnosis of PAD, to either simvastatin 40 mg daily or placebo with a mean follow-up of 5 years.6 In the overall study population, simvastatin was associated with a 16% relative risk reduction in peripheral vascular events, which was driven primarily by a 20% reduction in noncoronary revascularization. It is noteworthy that this end point included not only lower extremity arterial procedures, but …

Targeted oncology therapies have revolutionized cancer treatment over the last decade and have resulted in improved prognosis for many patients. This advance has emanated from elucidation of pathways responsible for tumorigenesis followed by targeting of these pathways by specific molecules. Cardiovascular care has become an increasingly critical aspect of patient care in part because patients live longer, but also due to potential associated toxicities from these therapies. Because of the targeted nature of cancer therapies, cardiac and vascular side effects may additionally provide insights into the basic biology of vascular disease. We herein provide the example of tyrosine kinase inhibitors utilized in chronic myelogenous leukemia to illustrate this medical transformation. We describe the vascular considerations for the clinical care of chronic myelogenous leukemia patients as well as the emerging literature on mechanisms of toxicities of the individual tyrosine kinase inhibitors. We additionally postulate that basic insights into toxicities of novel cancer therapies may serve as a new platform for investigation in vascular biology and a new translational research opportunity in vascular medicine.

Atherosclerosis within 2 or more arterial beds has been termed polyvascular disease. Although polyvascular disease has long been associated with heightened cardiovascular risk, much is still unknown regarding its pathophysiology and management. In this past decade, the field of cardiovascular disease has experienced exponential growth in terms of antithrombotic and lipid-lowering therapies aimed at mitigating ischemic events. This review describes the inherent risk associated with polyvascular disease in contemporary observational and clinical trial populations and summarizes novel therapies in this high-risk population.

OBJECTIVE: Insulin resistance is associated with increased lipolysis and elevated concentrations of free fatty acids, which in turn contribute to impaired vascular function. We hypothesized that lowering free fatty acids with acipimox, a nicotinic acid derivative that impairs free fatty acid efflux, would improve endothelial function, measured by flow-mediated dilation, in individuals with metabolic syndrome. METHODS: Eighteen subjects with metabolic syndrome and 17 healthy controls were enrolled and treated with acipimox 250 mg orally every 6 hours, or placebo, for 7 days in a randomized, double-blind, crossover trial. RESULTS: Acipimox reduced free fatty acid concentrations among individuals with metabolic syndrome to near normal levels (P=0.01), but there was no change among healthy controls (P=0.17). Acipimox did not improve endothelial-dependent flow-mediated dilation in either group (metabolic syndrome: P=0.42, and healthy controls: P=0.16), although endothelial-independent nitroglycerin-mediated dilation among those with metabolic syndrome tended to increase (20.3%, P=0.06). There were no changes in blood lipids or markers of inflammation following therapy. There was minimal correlation between change in flow-mediated dilation and baseline measures of body-mass index (ρ=−.09) or waist circumference (ρ=−0.15). CONCLUSIONS: In groups with normal or elevated baseline free fatty acids, short-term reductions do not improve endothelial function assessed by flow-mediated dilation.

PURPOSE OF REVIEW: This review of the literature aims to discuss the evidence linking different lipid and apolipoprotein measures to peripheral artery disease. RECENT FINDINGS: Measures of atherogenic dyslipidemia, including elevations in total cholesterol and total cholesterol:high-density lipoprotein cholesterol as well as low levels of high-density lipoprotein cholesterol, are strongly associated with future risk of peripheral artery disease. Compared to coronary artery disease, there are fewer data showing an association between low-density lipoprotein cholesterol and future risk of peripheral artery disease. Novel lipid measures, including nuclear magnetic resonance-derived lipoproteins and oxidized lipids, may lead to better assessments of future peripheral artery disease risk. SUMMARY: These data highlight the important differences between lipid risk factors for peripheral and coronary artery disease. Improved understanding of these distinctions may lead to new therapeutic options for patients with peripheral artery disease.

Background: Elevated triglyceride rich lipoproteins (TRLs) and small dense LDL (sdLDL) levels are hallmarks of atherogenic dyslipidemia and the cholesterol content of these particles is hypothesized to drive atherosclerotic risk. However, laboratory quantitation has thus far been impractical with limited prospective clinical data utilizing directly measured levels of this cholesterol burden. Methods: We conducted a prospective case-cohort study within the Women’s Health Study. Randomly selected CVD case subjects (n=500) were compared to a reference subcohort (n=496). TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens. Cox proportional hazards models were used to compute quartile-specific multivariable-adjusted HRs for total CVD and individual outcomes of coronary and cerebrovascular disease (CCVD) and peripheral artery disease (PAD). Clinical models also adjusted for LDL-C and hsCRP. Results: TRL-C and sdLDL-C were strongly correlated ( ρ =0.716, padj Q4 vs Q1: total events 1.87, 95% CI 1.14 - 3.06, p=0.012; CCVD 1.81, 95% CI 1.05 - 3.09, p = 0.030; PAD 2.43, 95% CI 1.11 - 5.31, p=0.039). In contrast, elevated sdLDL-C associated with incident CCVD but not PAD (HR adj Q4 vs Q1: total events 1.85, 95% CI 1.04 - 3.31, p=0.014; CCVD 2.17, 95% CI 1.14 - 4.13, p = 0.006; PAD 1.34, 95% CI 0.54 - 3.33, p=0.389). Conclusion: Directly measured TRL-C and sdLDL-C concentrations are strongly linked to incident CVD with potentially differential effects for PAD. These findings may indicate a greater potential benefit of therapeutics targeting TRL-C rather than LDL in the prevention of PAD.

There are no large national cohorts examining the incidence of peripheral artery disease (PAD) among participants previously tested for PAD by ankle-brachial index (ABI) at baseline. Such data are critical as prevalent PAD often goes unrecognized. We analyzed 164,441 participants in the Veterans

Plasma biomarkers of cardiometabolic health are invaluable tools for cardiovascular disease (CVD) and type 2 diabetes (T2D) risk stratification. Data driven patient classification may offer unbiased insights into dominant biologic risk factors that determine avenues for risk reduction. We conducted

As biologic, epidemiologic, and clinical trial data have demonstrated, inflammation is a key driver of atherosclerosis. Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors. Randomized trials have shown that statins reduce hsCRP, and the magnitude of hsCRP reduction is proportional to the reduction in cardiovascular risk. Additionally, these trials have demonstrated that many individuals remain at increased risk due to persistent elevations in hsCRP despite significant reductions in low-density lipoprotein cholesterol (LDL-C) levels. This “residual inflammatory risk” has increasingly become a viable pharmacologic target. In this review, we summarize the data linking inflammation to atherosclerosis with a particular focus on residual inflammatory risk. Additionally, we detail the results of Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), which showed that directly reducing inflammation with an IL-1β antagonist reduces cardiovascular event rates independent of LDL-C. These positive data are contrasted with neutral evidence from CIRT in which low-dose methotrexate neither reduced the critical IL-1β to IL-6 to CRP pathway of innate immunity, nor reduced cardiovascular event rates.

PURPOSE OF REVIEW: Numerous studies have begun to unravel the genetic basis of not only aortic disease but also other forms of commonly encountered vascular diseases. The goal of this review is to provide clinicians a reference to help identify and diagnose different types of vascular disease with a genetic underpinning. RECENT FINDINGS: Ongoing studies have identified numerous genes involved in the TGF-β signaling pathway that are also associated with thoracic aortic aneurysm and dissection, and it is possible to test for pathogenic variants in these genes in the clinical setting using commercially available genetic testing panels. Additional studies have begun to identify genetic variants associated with an increased risk of bicuspid aortic valve, abdominal aortic aneurysm, and fibromuscular dysplasia. SUMMARY: With increased availability of low-cost genetic testing, clinicians are now able to not only definitively diagnose some vascular syndromes but also provide information on the risk of disease in other family members, as well as provide guidance in terms of family planning. As the cost of genetic testing continues to drop with the benefit of increasing insurance coverage, genetic data will increasingly become part of clinical care for many patients with vascular disease.

Despite strong and consistent prospective associations of elevated low-density lipoprotein (LDL) cholesterol concentration with incident coronary and cerebrovascular disease, data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle (LDL-P) concentration, rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein (HDL) cholesterol (HDL-C), may be the primary lipid driver of PAD risk.The study population was a prospective cohort study of 27 888 women ≥45 years old free of cardiovascular disease at baseline and followed for a median of 15.1 years. We tested whether standard lipid concentrations, as well as nuclear magnetic resonance spectroscopy-derived lipoprotein measures, were associated with incident symptomatic PAD (n=110) defined as claudication and/or revascularization.In age-adjusted analyses, while LDL cholesterol was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very LDL (VLDL) particle (VLDL-P) subclasses, increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle (HDL-P) concentration (all P for extreme tertile comparisons0.05). Findings persisted in multivariable-adjusted models comparing extreme tertiles for elevated total LDL-P (adjusted hazard ratio [HRIn this prospective study, nuclear magnetic resonance-derived measures of LDL-P, but not LDL cholesterol, were associated with incident PAD. Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and nuclear magnetic resonance-derived measures of HDL, were significant risk determinants. These data help clarify prior inconsistencies and may elucidate a unique lipoprotein signature for PAD compared to coronary and cerebrovascular disease.URL: https://www.clinicaltrials.gov/ . Unique Identifier: NCT00000479.

Inflammation is a critical pathway in the pathogenesis of atherosclerosis. Previous studies have shown that plasma levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, are associated with cardiovascular disease independent of traditional risk factors. Randomized trial data have also shown that statins reduce not only hsCRP but also cardiovascular event rates independent of their effect on low-density lipoprotein cholesterol (LDL-C) level. More recently, the CANTOS trial showed that directly reducing inflammation with canakinumab, an interleukin (IL)-1β neutralizing monoclonal antibody, could also reduce cardiovascular event rates. These mark the first phase 3 trial results validating inflammation as a viable target for preventing cardiovascular disease. In this review, we recap the role of inflammation in cardiovascular disease and highlight previous trial data showing its modulation with statins and other agents. We also detail the CANTOS trial results and discuss its implications for clinicians as well as future directions for anti-inflammatory therapy in the prevention of cardiovascular disease.

Information about a real patient is presented in stages (boldface type) to expert clinicians (Drs Beckman and Sobieszczyk), who respond to the information and share their reasoning with the reader (regular type). A discussion by the authors follows. Patient presentation: An otherwise healthy 29-year-old white woman presented to our emergency department with leg pain and edema. She was well until 2 weeks before, when she developed lower back pain following a 3-hour flight. Her pain progressed despite treatment with ice packs, nonsteroidal anti-inflammatory drugs, and stretching, and it became so severe that she was unable to sit comfortably at work. Five days before presentation, she began noticing tightness in both thighs and subtle swelling of both legs, as well. Over the subsequent 48 hours, she experienced rapidly worsening bilateral lower extremity swelling, primarily in her thighs, accompanied by pain in her legs. She denied dyspnea, palpitations, chest pain, abdominal distension, or lightheadedness. Her symptoms worsened to the point where ambulation was difficult, thus prompting her visit to the emergency department. Additional medical history was notable for no previous illnesses or surgeries. Medications included ethinyl estradiol and levonorgestrel (a combination oral contraceptive). She had no known drug allergies. She denied tobacco or illicit drug use and consumed alcohol in moderation. There was no family history of venous thromboembolism (VTE), stroke, or sudden death. Dr Beckman: Lower extremity edema is commonly seen in both right- and left-sided heart failure, and in individuals with advanced liver and kidney disease, as well. However, this case is notable for the rapid progression of her symptoms, and the lack of dyspnea or other symptoms suggestive of cardiopulmonary disease. Her description of severe pain, tension, and swelling in her extremities indicates significant impairment to venous drainage, which is most likely caused by deep vein thrombosis (DVT). Although …