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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.

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.

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

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.

There is a lack of consistency among the ACC/AHA and ESC Guidelines on the treatment of patients with lower extremity PAD to a targeted LDL-c level. A review of the current guidelines, as well as the evidence that exists for use of various lipid-lower therapies in patients with PAD, is needed to guide clinical practice and to examine the current gaps in evidence that exist. There is evidence that statins and PCSK9 inhibitors reduce the risks of major adverse cardiovascular and limb events in patients with PAD. Most statin and non-statin trials have examined the association of LLT use with clinical outcomes, and not the association between the degree of LDL-c lowering and the reduction in risk of clinical outcomes. As such, there is a lack of agreement between the American and European PAD Guidelines over whether to treat patients with PAD to a targeted LDL-c goal. Both statins and PCSK9 inhibitors have been shown to reduce the risk of major cardiovascular and limb events in patients with PAD. Further research is needed to determine if target driven LDL-c lowering is associated with improved outcomes in patients with PAD.

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.

More than 200,000 individuals are hospitalized with an acute pulmonary embolism in the United States annually. Despite advances in diagnosis and treatment, pulmonary embolism accounts for nearly 1% of all cardiovascular-related deaths each year in the United States alone. Those who survive an acute episode remain at a risk of recurrent events as well as ongoing dyspnea, reduced quality of life, and chronic thromboembolic pulmonary hypertension. Recognized risk factors for pulmonary embolism include advanced age, obesity, smoking, malignancy, immobilization from any cause, pregnancy and the postpartum period, oral contraceptives, and hormone replacement therapy. Numerous heritable and acquired thrombophilias increase the risk of pulmonary embolism. Additionally, inflammation and autoimmune disorders are increasingly recognized as potent risk factors for pulmonary embolism. This review contains 3 figures, 6 tables, 54 references. Key Words: anticoagulation, deep vein thrombosis, epidemiology, genetics, inflammation, malignancy, pulmonary embolism, thrombosis, venous thromboembolism

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.

Carotid artery atherosclerosis is a major risk factor for both stroke and cardiovascular disease. Appropriate management of asymptomatic patients with carotid artery stenosis (CAS) remains unclear. Although several randomized clinical trials support revascularization in asymptomatic patients with severe CAS to reduce stroke risk, the participants in these trials did not receive optimal medical therapy (OMT) by today's standards. For many individuals, medical therapy may provide excellent risk reduction without the periprocedural risk of endarterectomy or stenting. In this review, we discuss the risk factors for CAS and stroke and examine the data for each component of OMT in these patients.

Vascular compression can occur when local anatomy facilitates positional compression of a vessel. Symptoms are determined by the vascular bed supplied by the compressed vessel. These vascular compression syndromes arise in the thorax (thoracic outlet syndrome), abdomen (median arcuate ligament syndrome and nutcracker syndrome) and in the limbs (May-Thurner syndrome and adventitial cyst). While vascular compression is very common, clinical syndromes developing as a result of compression are rare.

Limb swelling can develop suddenly or over the course of years. A correct diagnosis requires consideration of whether the swelling is acute or chronic, symmetric or asymmetric, localized or generalized, and congenital or acquired. Edema develops when the rate of capillary filtration exceeds venous and lymphatic drainage, either because of inadequate lymphatic flow or increased capillary filtration. A careful approach to diagnosis in this setting can allow recognition of diseases requiring urgent treatment as well as allowing appropriate treatment.

There are a number of conditions can impair the blood supply to the kidneys and mesentery, although atherosclerosis is the most common etiology. Additional possibilities include emboli, in situ thrombosis, extrinsic compression, dissection and fibromuscular dysplasia. The first step to diagnosing mesenteric vascular disease is to recognize that there is altered flow to the kidney or mesentery.

The goal of vascular testing is to characterize vessel structure and function. In many cases, a comprehensive history and physical examination are sufficient to make a dignosis (McDermott, Circ Res 116(9):1540–1550, 2015). However, in instances when more information is necessary, the history and physical will direct appropriate diagnostic testing. The modality is chosen according to the needs of a particular patient as well as availability and local expertise. Modalities include physiologic testing, ultrasound (US), computed tomography (CT) and magnetic resonance (MR) imaging (Table 1.1). Specific uses of these methods are discussed further in the disease specific sections of this text. These noninvasive methods are distinct from invasive angiography, where intervention can be performed at the time of diagnosis.

Leg pain is common and there are many etiologies for non-joint leg pain. Vascular, neurologic and musculoskeletal conditions are all important causes of leg pain. It is essential to understand pain character, location, timing and triggers to identify the cause of leg pain. Examination includes an assessment of leg temperature, color, pulses, reflexes, sensation and dynamic maneuvers. Vascular causes such as peripheral artery disease and venous claudication must be considered among these causes of leg pain.

Peripheral artery disease (PAD) is a term referring to obstruction of arterial flow to an end organ, the leg most often being the organ when this term is used. PAD most commonly refers to atherosclerotic disease, and atherosclerotic PAD is most common in those over 65 years of age as well as those with a history of diabetes or cigarette smoking. However, other diseases can obstruct lower extremity arterial flow including arteritis, embolism, fibromuscular dysplasia, and dissection and should be considered especially when the individual with PAD has no atherosclerotic risk factors.

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.

Two days after undergoing uncomplicated bilateral total knee arthroplasties, a 72-year-old man had a temperature of 101°F and a pruritic, erythematous rash that originated on his trunk and spread peripherally to his arms and upper thighs over the course of 24 hours.

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.

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 …

As genomic testing becomes more accessible for both clinical indications and patients’ personal curiosity, cardiologists are increasingly asked to interpret the results in terms of future risk of disease. In many cases, patients hope that such testing will yield detailed, personalized recommendations regarding their own medical care as well as their family’s. However, given the lack of formal instruction in genomic analysis during cardiovascular training, a gap exists between some patients’ desires and our own abilities to incorporate genomic information into practice. Patient care and biomedical research will undoubtedly be increasingly influenced by genomic medicine efforts in the coming years. In his 2016 budget proposal, President Obama allocated $215 million to fund the Precision Medicine Initiative.1 The goal of this program is to develop data lakes compiling vast arrays of patient data, including genomic information and detailed phenotypic, epigenomic, proteomic, transcriptomic, and metabolomic data. By using the computational power of such an effort, clinicians will hopefully be able to better predict disease and tailor therapies at the population and individual levels. Given the enormous resource investment and global burden of cardiovascular disease, the cardiovascular community will likely play a key role in this movement. Therefore, it is critical that we begin to incorporate training modules on genomic …

Numerous cross-sectional studies of venous thromboembolism (VTE) have identified plasma homocysteine as a potential risk factor for VTE. In contrast, prospective data are sparse with limited studies conducted among women. Given current interest in expanded indications for anticoagulation therapy, we

Background: Although the resting ankle-brachial index (ABI) is commonly used to diagnose peripheral artery disease (PAD), limited data suggest several indices measured after exercise may have increased sensitivity for identifying PAD. The aim of this study was to determine the utility of resting ABI

Intravenous sedation and analgesia are important therapies during mechanical ventilation (MV). However, daily interruption of these medications is associated with improved outcomes in mechanically ventilated patients. We tested a clinical pathway for the use of sedation and analgesia during MV in a cardiac intensive care unit (CICU).We evaluated all mechanically ventilated patients in a CICU during two phases: phase 1 prior to pathway implementation (PRE) and phase 2 post-pathway implementation (POST). A total of 198 patients (98 PRE and 100 POST) and 1012 days of intubation (574 PRE and 434 POST) were included in this analysis. We found an increase in the frequency of daily interruptions of sedation post-implementation (49.3% PRE and 58.4% POST, p=0.0041). There was a significant decrease in the mean duration of MV in the POST vs PRE periods (5.0±2.3 vs 6.1±2.8 days, p=0.015). There was also a significant decrease in total neuroimaging studies (9 vs 49, p=0.001) and a trend toward a decrease in tracheostomies (3.0% vs 6.1%, p=0.33). Mean CICU length of stay (LOS) and hospital LOS respectively were 10.4 days and 16.8 days PRE and 10.4 days and 17.9 days POST (p=0.99 and p=0.55). Mortality did not differ (PRE 36.7% vs POST 32.0% p=0.55).Implementation of a pragmatic pathway for sedation and analgesia in a CICU was associated with an increase in the daily interruption of sedation and a corresponding decrease in the duration of MV days and the need for neuroimaging.