Publications by authors named "Joshua A Beckman"

202 Publications

Using genetics to detangle the relationships between red cell distribution width and cardiovascular diseases: a unique role for body mass index.

Open Heart 2021 Sep;8(2)

Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Objective: Red cell distribution width (RDW) is an enigmatic biomarker associated with the presence and severity of multiple cardiovascular diseases (CVDs). It is unclear whether elevated RDW contributes to, results from, or is pleiotropically related to CVDs. We used contemporary genetic techniques to probe for evidence of aetiological associations between RDW, CVDs, and CVD risk factors.

Methods: Using an electronic health record (EHR)-based cohort, we built and deployed a genetic risk score (GRS) for RDW to test for shared genetic architecture between RDW and the cardiovascular phenome. We also created GRSs for common CVDs (coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, venous thromboembolism) and CVD risk factors (body mass index (BMI), low-density lipoprotein, high-density lipoprotein, systolic blood pressure, diastolic blood pressure, serum triglycerides, estimated glomerular filtration rate, diabetes mellitus) to test each for association with RDW. Significant GRS associations were further interrogated by two-sample Mendelian randomisation (MR). In a separate EHR-based cohort, RDW values from 1-year pre-gastric bypass surgery and 1-2 years post-gastric bypass surgery were compared.

Results: In a cohort of 17 937 subjects, there were no significant associations between the RDW GRS and CVDs. Of the CVDs and CVD risk factors, only genetically predicted BMI was associated with RDW. In subsequent analyses, BMI was associated with RDW by multiple MR methods. In subjects undergoing bariatric surgery, RDW decreased postsurgery and followed a linear relationship with BMI change.

Conclusions: RDW is unlikely to be aetiologically upstream or downstream of CVDs or CVD risk factors except for BMI. Genetic and clinical association analyses support an aetiological relationship between BMI and RDW.
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http://dx.doi.org/10.1136/openhrt-2021-001713DOI Listing
September 2021

An estimate of the economic burden of venous leg ulcers associated with deep venous disease.

Vasc Med 2021 Aug 16:1358863X211028298. Epub 2021 Aug 16.

Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Introduction: Venous leg ulcers (VLU) embody the most severe stage of the broad spectrum of chronic venous disease. Approximately 40% of patients with VLU present with the underlying deep venous disease (DVD). Although the data are scarce, these deep venous disease-related VLU (DRV) are thought to have higher recurrence rates and a substantial economic burden. The objective of this study was to assess the economic burden of DRV across Australia, France, Germany, Italy, Spain, the UK, and the USA.

Methods: A comprehensive literature review was undertaken to identify publications documenting the incidence and prevalence of VLU and DRV, medical resource utilization, and associated costs of DRV. Findings from this literature review were used to estimate the economic burden of illness, including direct medical costs over a 12-month interval following initial presentation of a newly formed DRV.

Results: Total annual incidence of new or recurrent DRV in Australia, France, Germany, Italy, Spain, UK, and the US are estimated at 122,000, 263,000, 345,000, 253,000, 85,000, 230,000, and 643,000 events, respectively, in 2019. Incidence ranges from 0.73 to 3.12 per 1000 persons per year. The estimated annual direct medical costs for patients managed conservatively in these geographies total ~ $10.73 billion (USD) or $5527 per person per year.

Conclusion: The availability of published data on the costs of VLU care varies widely across countries considered in this analysis. Although country-specific VLU practice patterns vary, there is a uniform pattern of high-cost care.
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http://dx.doi.org/10.1177/1358863X211028298DOI Listing
August 2021

Summoning STRENGTH to Question the Placebo in REDUCE-IT.

Circulation 2021 Aug 9;144(6):407-409. Epub 2021 Aug 9.

Leon H. Charney Division of Cardiology, Department of Medicine, Grossman School of Medicine, Langone Center for Prevention of Cardiovascular Disease, New York University (J.A. Bostrom, J.S.B.), New York, NY.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054539DOI Listing
August 2021

Making Lemonade Out of the Lemons of Lesion Preparation.

JACC Cardiovasc Interv 2021 Jun;14(12):1362-1363

Vanderbilt University Medical Center, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1016/j.jcin.2021.04.025DOI Listing
June 2021

Effectiveness of Blood Lipid Management in Patients With Peripheral Artery Disease.

J Am Coll Cardiol 2021 Jun;77(24):3016-3027

Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA; CPC Clinical Research, Aurora, Colorado, USA.

Background: Low-density lipoprotein cholesterol (LDL-C) is associated with heightened risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in peripheral artery disease (PAD). Lipid-lowering therapies (LLT) that reduce LDL-C decrease this risk.

Objectives: The authors examined LLT use and actual achieved LDL-C in PAD.

Methods: PAD patients in MarketScan from 2014 to 2018 were identified. Outcomes included LLT use, defined as high-intensity (HI) (high-intensity statin, statin plus ezetimibe, or PCSK9 inhibitor), low-intensity (any other lipid regimen), or no therapy, and follow-up LDL-C. Factors associated with LDL-C <70 mg/dl were identified with multivariable logistic regression.

Results: Among 250,103 PAD patients, 20.5% and 39.5% were treated at baseline with HI and low-intensity LLT, respectively; 40.0% were on no LLT. Over a 15-month median follow-up period, HI LLT use increased by 1.5%. Among 18,747 patients with LDL-C data, at baseline, 25.1% were on HI LLT, median LDL-C was 91 mg/dl, and 24.5% had LDL-C <70 mg/dl. Within the HI LLT subgroup, median LDL-C was 81 mg/dl, and 64% had LDL-C ≥70 mg/dl. At follow-up, HI LLT use increased by 3.7%, median LDL-C decreased by 4.0 mg/dl, and an additional 4.1% of patients had LDL-C <70 mg/dl. HI LLT use was greater after follow-up MACE (55.0%) or MALE (41.0%) versus no ischemic event (26.1%). After MACE or MALE, LDL-C was <70 mg/dl in 41.5% and 36.1% of patients, respectively, versus 27.1% in those without an event. Factors associated with follow-up LDL-C <70 mg/dl included smoking, hypertension, diabetes, prior lower extremity revascularization, and prior myocardial infarction but not prior acute or critical limb ischemia.

Conclusions: In PAD, LLT use is suboptimal, LDL-C remains elevated, and LLT intensity is a poor surrogate for achieved LDL-C. Less aggressive lipid management was observed in PAD versus cardiovascular disease, highlighting missed opportunities for implementation of proven therapies in PAD.
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http://dx.doi.org/10.1016/j.jacc.2021.04.060DOI Listing
June 2021

Vascular Impact of Cancer Therapies: The Case of BTK (Bruton Tyrosine Kinase) Inhibitors.

Circ Res 2021 Jun 10;128(12):1973-1987. Epub 2021 Jun 10.

Division of Cardiovascular Medicine (M.R.F., J.A.B., J.J.M.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Novel targeted cancer therapies have revolutionized oncology therapies, but these treatments can have cardiovascular complications, which include heterogeneous cardiac, metabolic, and vascular sequelae. Vascular side effects have emerged as important considerations in both cancer patients undergoing active treatment and cancer survivors. Here, we provide an overview of vascular effects of cancer therapies, focusing on small-molecule kinase inhibitors and specifically inhibitors of BTK (Bruton tyrosine kinase), which have revolutionized treatment and prognosis for B-cell malignancies. Cardiovascular side effects of BTK inhibitors include atrial fibrillation, increased risk of bleeding, and hypertension, with the former 2 especially providing a treatment challenge for the clinician. Cardiovascular complications of small-molecule kinase inhibitors can occur through either on-target (targeting intended target kinase) or off-target kinase inhibition. We will review these concepts and focus on the case of BTK inhibitors, highlight the emerging data suggesting an off-target effect that may provide insights into development of arrhythmias, specifically atrial fibrillation. We believe that cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into human cardiovascular biology.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.318259DOI Listing
June 2021

Advances in Revascularization for Peripheral Artery Disease: Revascularization in PAD.

Circ Res 2021 Jun 10;128(12):1885-1912. Epub 2021 Jun 10.

Division of Vascular and Endovascular Surgery, University of California, San Francisco (P.A.S., M.S.C.).

Effective revascularization of the patient with peripheral artery disease is about more than the procedure. The approach to the patient with symptom-limiting intermittent claudication or limb-threatening ischemia begins with understanding the population at risk and variation in clinical presentation. The urgency of revascularization varies significantly by presentation; from patients with intermittent claudication who should undergo structured exercise rehabilitation before revascularization (if needed) to those with acute limb ischemia, a medical emergency, who require revascularization within hours. Recent years have seen the rapid development of new tools including wires, catheters, drug-eluting technology, specialized balloons, and biomimetic stents. Open surgical bypass remains an important option for those with advanced disease. The strategy and techniques employed vary by clinical presentation, lesion location, and lesion severity. There is limited level 1 evidence to guide practice, but factors that determine technical success and anatomic durability are largely understood and incorporated into decision-making. Following revascularization, medical therapy to reduce adverse limb outcomes and a surveillance plan should be put in place. There are many hurdles to overcome to improve the efficacy of lower extremity revascularization, such as restenosis, calcification, microvascular disease, silent embolization, and tools for perfusion assessment. This review highlights the current state of revascularization in peripheral artery disease with an eye toward technologies at the cusp, which may significantly impact current practice.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.318261DOI Listing
June 2021

Association of Aortic Stiffness With Biomarkers of Neuroinflammation, Synaptic Dysfunction, and Neurodegeneration.

Neurology 2021 07 24;97(4):e329-e340. Epub 2021 May 24.

From the Vanderbilt Memory & Alzheimer's Center (E.E.M., D.L., J.L., S.J.S., F.E.C., K.R.P., M.E.M., K.A.G., T.J.H., A.L.J.), Department of Biostatistics (D.L.), Radiology & Radiological Sciences (J.G.T., S.N., J.J.C.), Department of Neurology (K.R.P., M.E.M., K.A.G., T.J.H., A.L.J.), Division of Cardiovascular Medicine (S.P.B., J.A.B., A.L.J.), Department of Medicine, and Vanderbilt Genetics Institute (T.J.H.), Vanderbilt University Medical Center, Nashville, TN; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Molndal, Sweden; Department of Neurodegenerative Disease (H.Z.), University College London Institute of Neurology, Queen Square; and United Kingdom Dementia Research Institute at University College London (H.Z.), UK.

Objectives: To test the hypothesis that increased aortic stiffening is associated with greater CSF evidence of core Alzheimer disease pathology (β-amyloid [Aβ], phosphorylated tau [p-tau]), neurodegeneration (total tau [t-tau]), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light [NFL]), and neuroinflammation (YKL-40, soluble triggering receptor expressed on myeloid cells 2 [sTREM2]), we analyzed pulse wave velocity (PWV) data and CSF data among older adults.

Methods: Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic PWV (meters per second) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations after adjustment for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis, ε4, and hypertension on each biomarker.

Results: One hundred forty-six participants were examined (age 72 ± 6 years). Aortic PWV interacted with age on p-tau (β = 0.31, = 0.04), t-tau, (β = 2.67, = 0.05), neurogranin (β = 0.94, = 0.04), and sTREM2 (β = 20.4, = 0.05). Among participants >73 years of age, higher aortic PWV related to higher p-tau (β = 2.4, = 0.03), t-tau (β = 19.3, = 0.05), neurogranin (β = 8.4, = 0.01), and YKL-40 concentrations (β = 7,880, = 0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β = -10.76, = 0.03) and hypertension status on YKL-40 (β = 18,020, < 0.001).

Conclusions: Among our oldest participants, ≥74 years of age, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and reduced blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.
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http://dx.doi.org/10.1212/WNL.0000000000012257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362359PMC
July 2021

Reducing Nontraumatic Lower-Extremity Amputations by 20% by 2030: Time to Get to Our Feet: A Policy Statement From the American Heart Association.

Circulation 2021 Apr 25;143(17):e875-e891. Epub 2021 Mar 25.

Nontraumatic lower-extremity amputation is a devastating complication of peripheral artery disease (PAD) with a high mortality and medical expenditure. There are ≈150 000 nontraumatic leg amputations every year in the United States, and most cases occur in patients with diabetes. Among patients with diabetes, after an ≈40% decline between 2000 and 2009, the amputation rate increased by 50% from 2009 to 2015. A number of evidence-based diagnostic and therapeutic approaches for PAD can reduce amputation risk. However, their implementation and adherence are suboptimal. Some racial/ethnic groups have an elevated risk of PAD but less access to high-quality vascular care, leading to increased rates of amputation. To stop, and indeed reverse, the increasing trends of amputation, actionable policies that will reduce the incidence of critical limb ischemia and enhance delivery of optimal care are needed. This statement describes the impact of amputation on patients and society, summarizes medical approaches to identify PAD and prevent its progression, and proposes policy solutions to prevent limb amputation. Among the actions recommended are improving public awareness of PAD and greater use of effective PAD management strategies (eg, smoking cessation, use of statins, and foot monitoring/care in patients with diabetes). To facilitate the implementation of these recommendations, we propose several regulatory/legislative and organizational/institutional policies such as adoption of quality measures for PAD care; affordable prevention, diagnosis, and management; regulation of tobacco products; clinical decision support for PAD care; professional education; and dedicated funding opportunities to support PAD research. If these recommendations and proposed policies are implemented, we should be able to achieve the goal of reducing the rate of nontraumatic lower-extremity amputations by 20% by 2030.
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http://dx.doi.org/10.1161/CIR.0000000000000967DOI Listing
April 2021

The Open Vein Hypothesis and Postthrombotic Syndrome: Not Dead Yet.

Circulation 2021 Mar 22;143(12):1239-1241. Epub 2021 Mar 22.

Vanderbilt Translational and Clinical Cardiovascular Research Center, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989011PMC
March 2021

Exercise Training and Revascularization in the Management of Symptomatic Peripheral Artery Disease.

JACC Basic Transl Sci 2021 Feb 22;6(2):174-188. Epub 2021 Feb 22.

Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Exercise therapy and lower extremity revascularization both improve walking performance in symptomatic patients with peripheral artery disease. The combination of therapies provides greater benefit than either alone and may reduce the need for subsequent revascularization procedures, but further trials with longer follow-up are needed for the outcome of subsequent revascularization.
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http://dx.doi.org/10.1016/j.jacbts.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907537PMC
February 2021

Asymptomatic peripheral artery disease: Silent but deadly.

Prog Cardiovasc Dis 2021 Mar-Apr;65:2-8. Epub 2021 Feb 20.

Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Peripheral Artery Disease (PAD) is a manifestation of atherosclerosis characterized by diminished perfusion of the limb and a state of dysmetabolism. The asymptomatic PAD phenotype is a relatively recent classification. It is unknown how many people currently live with asymptomatic PAD because there are no universal screening recommendations for patients at risk for PAD. Patients with asymptomatic PAD suffer from a similar risk profile of morbidity and mortality as their counterparts with claudication. Despite this increased risk, there is a dearth of clinical investigations into therapies that specifically benefit the asymptomatic PAD population. At present, current pharmacotherapies that have been studied in PAD patient populations do not stratify by symptom status. We believe that further investigation of the impact of existing therapies in this unique population presents an opportunity to reduce morbidity and mortality due to PAD. This can only be achieved in combination with wide-spread adoption of screening for asymptomatic PAD.
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http://dx.doi.org/10.1016/j.pcad.2021.02.009DOI Listing
July 2021

High Output Heart Failure Associated With Arteriovenous Fistula in the Setting of Kidney Transplantation.

Kidney Int Rep 2021 Feb 10;6(2):544-551. Epub 2020 Nov 10.

Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879118PMC
February 2021

Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study.

BMJ 2021 02 11;372:n311. Epub 2021 Feb 11.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Objective: To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States.

Design: Observational cohort study.

Setting: Nationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system.

Participants: All 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation.

Main Outcome Measures: The main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion.

Results: Of 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses.

Conclusions: Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.
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http://dx.doi.org/10.1136/bmj.n311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876672PMC
February 2021

Early initiation of prophylactic anticoagulation for prevention of COVID-19 mortality: a nationwide cohort study of hospitalized patients in the United States.

medRxiv 2020 Dec 11. Epub 2020 Dec 11.

Importance: Deaths among patients with coronavirus disease 2019 (COVID-19) are partially attributed to venous thromboembolism and arterial thromboses. Anticoagulants prevent thrombosis formation, possess anti-inflammatory and anti-viral properties, and may be particularly effective for treating patients with COVID-19.

Objective: To evaluate whether initiation of prophylactic anticoagulation within 24 hours of admission is associated with decreased risk of death among patients hospitalized with COVID-19.

Design: Observational cohort study.

Setting: Nationwide cohort of patients receiving care in the Department of Veterans Affairs, the largest integrated healthcare system in the United States.

Participants: All patients hospitalized with laboratory-confirmed SARS-CoV-2 infection March 1 to July 31, 2020, without a history of therapeutic anticoagulation.

Exposures: Prophylactic doses of subcutaneous heparin, low-molecular-weight heparin, or direct oral anticoagulants.

Main Outcomes And Measures: 30-day mortality. Secondary outcomes: inpatient mortality and initiating therapeutic anticoagulation.

Results: Of 4,297 patients hospitalized with COVID-19, 3,627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3,600) received subcutaneous heparin or enoxaparin. We observed 622 deaths within 30 days of admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospitalization. In inverse probability of treatment weighted analyses, cumulative adjusted incidence of mortality at 30 days was 14.3% (95% CI 13.1-15.5) among those receiving prophylactic anticoagulation and 18.7% (95% CI 15.1-22.9) among those who did not. Compared to patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30-day mortality (HR 0.73, 95% CI 0.66-0.81). Similar associations were found for inpatient mortality and initiating therapeutic anticoagulation. Quantitative bias analysis demonstrated that results were robust to unmeasured confounding (e-value lower 95% CI 1.77). Results persisted in a number of sensitivity analyses.

Conclusions And Relevance: Early initiation of prophylactic anticoagulation among patients hospitalized with COVID-19 was associated with a decreased risk of mortality. These findings provide strong real-world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial therapy for COVID-19 patients upon hospital admission.
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http://dx.doi.org/10.1101/2020.12.09.20246579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743107PMC
December 2020

Vascular medicine in the COVID-19 era: The Vanderbilt experience.

J Vasc Nurs 2020 Dec 30;38(4):176-179. Epub 2020 Jul 30.

Vascular Medicine Section, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Translational and Clinical Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jvn.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392174PMC
December 2020

Metabolomics reveals the impact of Type 2 diabetes on local muscle and vascular responses to ischemic stress.

Clin Sci (Lond) 2020 09;134(17):2369-2379

Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A.

Objective: Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction.

Methods: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release.

Results: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and β-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, β-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05).

Conclusions: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function.
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http://dx.doi.org/10.1042/CS20191227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176641PMC
September 2020

Screening Asymptomatic Kidney Transplant Candidates-Primum Non Nocere.

JAMA Intern Med 2020 10;180(10):1366-1367

Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.

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http://dx.doi.org/10.1001/jamainternmed.2020.2674DOI Listing
October 2020

Trimethylamine-N-Oxide, More Red Meat for the Vascular Scientists.

Hypertension 2020 07 10;76(1):40-41. Epub 2020 Jun 10.

Division of Clinical Pharmacology (C.A.S.), Vanderbilt University Medical Center, Nashville, TN.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310574PMC
July 2020

Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research.

Thromb Haemost 2020 Jul 30;120(7):1004-1024. Epub 2020 May 30.

New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, United States.

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.
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http://dx.doi.org/10.1055/s-0040-1713152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516364PMC
July 2020

Active smoking is associated with higher rates of incomplete wound healing after endovascular treatment of critical limb ischemia.

Vasc Med 2020 10 27;25(5):427-435. Epub 2020 May 27.

Division of Cardiology, Rocky Mountain Regional VA Medical Center, University of Colorado, Denver, CO, USA.

The association between active smoking and wound healing in critical limb ischemia (CLI) is unknown. Our objective was to examine in a retrospective cohort study whether active smoking is associated with higher incomplete wound healing rates in patients with CLI undergoing endovascular interventions. Smoking status was assessed at the time of the intervention, comparing active to no active smoking, and also during follow-up visits at 6 and 9 months. Cox regression analysis was conducted to compare the incomplete wound healing rates of the two groups during follow-up. A total of 264 patients (active smokers: = 41) were included. Active smoking was associated with higher rates of incomplete wound healing in the 6-month univariate Cox regression analysis (hazard ratio (HR) for incomplete wound healing: 4.54; 95% CI: 1.41-14.28; = 0.012). The 6-month Kaplan-Meier (KM) estimates for incomplete wound healing were 91.1% for the active smoking group versus 66% for the non-current smoking group. Active smoking was also associated with higher rates of incomplete wound healing in the 9-month univariable (HR for incomplete wound healing: 2.32; 95% CI: 1.11-4.76; = 0.026) and multivariable analysis (HR for incomplete wound healing: 9.09; 95% CI: 1.06-100.0; = 0.044). The 9-month KM estimates for incomplete wound healing were 75% in the active smoking group versus 54% in the non-active smoking group. In conclusion, active smoking status at the time of intervention in patients with CLI is associated with higher rates of incomplete wound healing during both 6- and 9-month follow-up.
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http://dx.doi.org/10.1177/1358863X20916526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076886PMC
October 2020

Cardiovascular Risk Factors and Perioperative Myocardial Infarction After Noncardiac Surgery.

Can J Cardiol 2021 02 5;37(2):224-231. Epub 2020 May 5.

The Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA; Department of Surgery, New York University School of Medicine, New York, New York, USA. Electronic address:

Background: Perioperative cardiovascular events are a leading cause of morbidity and mortality after noncardiac surgery. We propose a simplified method for perioperative risk stratification.

Methods: In a retrospective cohort study we identified patients who underwent noncardiac surgery between 2009 and 2015 in the US National Surgical Quality Improvement Program. Multivariable logistic regression models adjusted for age, sex, race, and surgery type were generated to estimate the effect of traditional cardiovascular risk factors (hypertension, diabetes mellitus, current smoking) on odds of perioperative myocardial infarction (MI). Time to event analysis was conducted using competing risk analysis, with MI as the outcome event and death as the competing risk.

Results: A total of 3,848,501 noncardiac surgeries were identified. Postoperative MI occurred in 0.37% of patients and 1.04% of patients died. The 30-day event rate of perioperative MI increased in a stepwise fashion with additional risk factors (0.42% for 1, 0.82% for 2, and 1.08% for 3; P for trend < 0.001) after accounting for the competing risk of death. Compared with those with no risk factors, patients with 1, 2, and 3 risk factors had increased odds of MI (adjusted odds ratio [aOR], 2.07 [95% confidence interval (CI), 1.96-2.19]; aOR, 3.63 [95% CI, 3.43-3.85]; and aOR, 5.54 [95% CI, 5.09-6.04], respectively). Perioperative MI was rare (0.10%) in patients without risk factors.

Conclusions: Patients with cardiovascular risk factors are at increased risk of perioperative MI, those without risk factors are at low risk. Further evaluation is needed to determine the effect of a simplified risk score in the perioperative setting.
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http://dx.doi.org/10.1016/j.cjca.2020.04.034DOI Listing
February 2021

Mortality and Paclitaxel-Coated Devices: An Individual Patient Data Meta-Analysis.

Circulation 2020 06 6;141(23):1859-1869. Epub 2020 May 6.

Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN (J.A.B.).

Background: Paclitaxel-containing devices (PTXDs) significantly reduce reintervention in patients with symptomatic femoropopliteal peripheral artery disease. A recent aggregate-data meta-analysis reported increased late mortality in patients with peripheral artery disease treated with PTXDs. We performed an individual patient data meta-analysis to evaluate mortality.

Methods: Manufacturers of US Food and Drug Administration-approved and commercially available devices in the United States provided deidentified individual patient data for independent analysis. Cox proportional hazards 1-stage meta-analysis models using intention-to-treat methods were used for the primary analysis. A secondary analysis of recovered missing vital status data was performed. The impact of control crossover to PTXDs, cause-specific mortality, and drug dose mortality were assessed.

Results: A total of 2185 subjects and 386 deaths from 8 PTXD trials with 4-year median follow-up were identified. The primary analysis indicated a 38% (95% CI, 6% to 80%) increased relative mortality risk, corresponding to 4.6% absolute increase, at 5 years associated with PTXD use. Control and treatment arm loss to follow-up and withdrawal were 24% and 23%, respectively. With inclusion of recovered vital status data, the excess relative mortality risk was 27% (95% CI, 3%-58%). This observation was consistent across various scenarios, including as-treated analyses, with no evidence of increased risk over time with PTXDs. Mortality risk tended to be increased for all major causes of death. There were no subgroup differences. No drug dose-mortality association was identified.

Conclusions: This individual patient data meta-analysis, based on the most complete available data set of mortality events from PTXD randomized controlled trials, identified an absolute 4.6% increased mortality risk associated with PTXD use.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029645PMC
June 2020

Sex as a Biological Variable in Atherosclerosis.

Circ Res 2020 04 23;126(9):1297-1319. Epub 2020 Apr 23.

From the Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (J.J.M., I.Z.J.).

Atherosclerosis is a chronic inflammatory vascular disease and the predominant cause of heart attack and ischemic stroke. Despite the well-known sexual dimorphism in the incidence and complications of atherosclerosis, there are relatively limited data in the clinical and preclinical literature to rigorously address mechanisms underlying sex as a biological variable in atherosclerosis. In multiple histological and imaging studies, overall plaque burden and markers of inflammation appear to be greater in men than women and are predictive of cardiovascular events. However, while younger women are relatively protected from cardiovascular disease, by the seventh decade, the incidence of myocardial infarction in women ultimately surpasses that of men, suggesting an interaction between sex and age. Most preclinical studies in animal atherosclerosis models do not examine both sexes, and even in those that do, well-powered direct statistical comparisons for sex as an independent variable remain rare. This article reviews the available data. Overall, male animals appear to have more inflamed yet smaller plaques compared to female animals. Plaque inflammation is often used as a surrogate end point for plaque vulnerability in animals. The available data support the notion that rather than plaque size, plaque inflammation may be more relevant in assessing sex-specific mechanisms since the findings correlate with the sex difference in ischemic events and mortality and thus may be more reflective of the human condition. Overall, the number of preclinical studies directly comparing plaque inflammation between the sexes is extremely limited relative to the vast literature exploring atherosclerosis mechanisms. Failure to include both sexes and to address age in mechanistic atherosclerosis studies are missed opportunities to uncover underlying sex-specific mechanisms. Understanding the mechanisms driving sex as a biological variable in atherosclerotic disease is critical to future precision medicine strategies to mitigate what is still the leading cause of death of men and women worldwide.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185045PMC
April 2020

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review.

J Am Coll Cardiol 2020 06 17;75(23):2950-2973. Epub 2020 Apr 17.

Center for Bioethics and Social Science in Medicine, University of Michigan, Ann Arbor, Michigan; Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan.

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.jacc.2020.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164881PMC
June 2020

The Big MAC Attack on Peripheral Artery Disease.

Circulation 2020 04 13;141(15):1211-1213. Epub 2020 Apr 13.

Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN (A.W.A., J.A.B.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656982PMC
April 2020
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