peripheral vascular disease research paper

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• Review Article
• Published: 07 January 2022

Update on the pathophysiology and medical treatment of peripheral artery disease

• Jonathan Golledge   ORCID: orcid.org/0000-0002-5779-8848 1 , 2 , 3  

Nature Reviews Cardiology volume  19 ,  pages 456–474 ( 2022 ) Cite this article

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• Pathogenesis
• Peripheral vascular disease
• Therapeutics

Approximately 6% of adults worldwide have atherosclerosis and thrombosis of the lower limb arteries (peripheral artery disease (PAD)) and the prevalence is rising. PAD causes leg pain, impaired health-related quality of life, immobility, tissue loss and a high risk of major adverse events, including myocardial infarction, stroke, revascularization, amputation and death. In this Review, I describe the pathophysiology, presentation, outcome, preclinical research and medical management of PAD. Established treatments for PAD include antithrombotic drugs, such as aspirin and clopidogrel, and medications to treat dyslipidaemia, hypertension and diabetes mellitus. Randomized controlled trials have demonstrated that these treatments reduce the risk of major adverse events. The drug cilostazol, exercise therapy and revascularization are the current treatment options for the limb symptoms of PAD, but each has limitations. Novel therapies to promote collateral and new capillary growth and treat PAD-related myopathy are under investigation. Methods to improve the implementation of evidence-based medical management, novel drug therapies and rehabilitation programmes for PAD-related pain, functional impairment and ischaemic foot disease are important areas for future research.

Peripheral artery disease (PAD) is present in 6% of adults and is associated with leg pain, walking impairment and high risk of major adverse cardiovascular events, including amputation and death.

PAD usually presents with leg pain, ischaemic ulceration or gangrene and is usually caused by atherosclerosis and thrombosis, although all current animal models use surgically created hindlimb ischaemia.

Treatment options for the leg symptoms of PAD include cilostazol, exercise therapy and revascularization, with novel therapies under investigation including autologous cell therapy, organic nitrates and antioxidants.

Antithrombotic and LDL-cholesterol-lowering medications, smoking cessation and treatment of hypertension and diabetes mellitus reduce the risk of major adverse events, but programmes to improve uptake of these measures are needed.

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Acknowledgements

J.G. received grants from the National Health and Medical Research Council (1180736), Heart Foundation, Tropical Australian Academic Health Centre, Townsville Hospital and Health Service Study, Education and Research Trust Fund and Queensland Government. J.G. holds a Practitioner Fellowship from the National Health and Medical Research Council (1117601) and a Senior Clinical Research Fellowship from the Queensland Government. The author thanks S. Thangaimani, J. Phie and C. Burrows (James Cook University, Australia) for help with production of the figures for initial submission and A. Golledge for help with proof reading. He thanks all the past and current researchers from the Queensland Research Centre for Peripheral Vascular Disease and collaborators for their ongoing research on peripheral artery disease, which has contributed towards the insights included in this Review. Finally, the author apologizes to scientists whose research could not be included in this Review owing to space limitations.

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The author has received honoraria from Amgen and Bayer for giving lectures on PAD.

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Minimally invasive interventional (such as stenting) or open surgical (such as endarterectomy) procedures to improve distal blood supply.

Muscle damage with various causes, including impaired muscle blood supply owing to peripheral artery disease.

The expansion of existing collateral arteries to improve distal blood supply.

The sprouting of new capillaries and formation of new networks of small vessels to improve distal blood supply.

Administering stem or progenitor cells to encourage angiogenesis.

Administering harmless viruses that have been modified to carry a gene of interest into the local tissue.

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Golledge, J. Update on the pathophysiology and medical treatment of peripheral artery disease. Nat Rev Cardiol 19 , 456–474 (2022). https://doi.org/10.1038/s41569-021-00663-9

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Pathophysiology of peripheral arterial disease (pad): a review on oxidative disorders.

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Share and Cite

Signorelli, S.S.; Marino, E.; Scuto, S.; Di Raimondo, D. Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders. Int. J. Mol. Sci. 2020 , 21 , 4393. https://doi.org/10.3390/ijms21124393

Signorelli SS, Marino E, Scuto S, Di Raimondo D. Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders. International Journal of Molecular Sciences . 2020; 21(12):4393. https://doi.org/10.3390/ijms21124393

Signorelli, Salvatore Santo, Elisa Marino, Salvatore Scuto, and Domenico Di Raimondo. 2020. "Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders" International Journal of Molecular Sciences 21, no. 12: 4393. https://doi.org/10.3390/ijms21124393

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Peripheral Artery Disease (PAD) Research

Language switcher.

Research that improves the health of people with peripheral artery disease (PAD) is part of NHLBI’s larger commitment to understanding and treating cardiovascular disease. PAD is caused by atherosclerosis that restricts blood flow through the arteries supplying the legs. PAD may be silent (without symptoms) or cause muscle pain with exertion such as walking or climbing stairs. Severe disease, termed critical limb ischemia (CLI) and present in only a small percentage of those with PAD, is associated with risk of amputation. Awareness that people with PAD often also have atherosclerosis of arteries supplying other organs such as the heart, and brain, is important because the risk of heart attack and stroke is elevated. Appropriate medical therapy to reduce risk should be an integral part of addressing PAD.

Studies funded and led by the NHLBI focus on ways to treat and prevent both atherosclerosis in general and PAD in particular. NHLBI’s research has revealed specific risk factors for developing PAD, including smoking and having diabetes, which can be treated with lifestyle interventions and medications. Researchers have also been working to improve existing treatments and develop new ones, some of which are described below.

NHLBI research that really made a difference

• NHLBI’s Claudication: Exercise Versus Endoluminal Revascularization ( CLEVER ) study showed that a supervised exercise program was more effective at improving treadmill walking capacity than angioplasty with or without stenting of an occluded blood vessel, or using or medicines alone. The results of CLEVER and other research studies including the Improving Functioning in Peripheral Arterial Disease trial, led the Centers for Medicare & Medicaid Services to reimburse supervised exercise training (SET) programs for symptomatic PAD.
• The Low InTensity Exercise Intervention in PAD ( LITE ) trial demonstrated that a home-based coaching program incorporating high-intensity but not low-intensity walking exercise improved walking performance in people with symptomatic PAD. This type of intervention does not require travel to a training center and is likely to be more accessible than traditional in-center SET programs.
• Researchers found that African Americans taking part in the Jackson Heart Study and the Atherosclerosis Risk in Communities Study had an increased risk of PAD if they smoked. Smoking was associated with PAD in a dose-dependent manner: People who smoked twice as much or for twice as long as others were twice as likely to develop PAD.

Current research funded by the NHLBI

Our Division of Cardiovascular Sciences , which includes the Vascular Biology and Hypertension Branch, oversees much of the research on PAD we fund.

Find related funding opportunities and program contacts in Atherothrombosis and Coronary Artery Disease and Vascular Biology and Hypertension research.

Current research on PAD treatments

PAD is  a challenging condition to treat because the recommended treatment — regular walking — can be painful, difficult to undertake due to other co-existing health conditions such as arthritis, and/or not practicable in the home or community environment. NIH-funded research is working on ways to increase walking endurance and circulation in the legs by using mechanical devices.

• Conventional ultrasound therapy for PAD involves using sound waves to increase blood flow in the legs. Until now, this therapy has been available only in clinical settings. NHLBI-funded researchers have developed an ultrasound device for people with PAD to wear when resting or sleeping. The device is like a sleeve worn over the legs and has its own portable power generator. Researchers hope to find out if this therapy improves blood flow in the legs.
• Participants in the INTERCEDE (INTERmittent pneumatic ComprEssion for Disability rEversal in PAD) trial wear inflatable cuffs wrapped around their feet, ankles, and calves for 2 hours every day. Every 20 seconds, the cuffs rapidly inflate and then rapidly deflate. This increases blood flow through the legs. Researchers will look at whether the device improves walking performance, how it changes leg muscles and blood flow, and whether those changes last.
• Small implantable sensors are being developed to monitor tissue oxygen levels in limbs of PAD patients during and after procedures done to restore blood flow.

Find more NHLBI-funded studies on PAD treatments  at the NIH RePORTER.

Eliminating health disparities in PAD

Health disparities exist whenever a person’s membership in a racial, ethnic, age, or other type of group makes them more likely to get or develop a disease or less likely to be diagnosed or treated for a disease. Researchers have found, for example, that African American smokers are three times more likely to develop PAD than white smokers. NHLBI-funded research is working to determine what health disparities exist, what causes them, and how to address them. One fundamental way NHLBI will achieve these goals is to ensure diversity in enrollment in all PAD research studies that involve people.

• The NHLBI is funding PASOS (Peripheral Artery Disease Study of SOL, an ancillary study of the Hispanic Community Health Study/Study of Latinos ). As part of the study, researchers screen more than 6,000 participants age 45 and older for early signs of PAD, including reduced blood flow in the legs. They also use fitness trackers to measure activity levels. Participants with borderline poor circulation will be followed more closely to see what factors predict who will develop PAD.
• The Variant Determinants of African American Limb Pathology in Peripheral Arterial Disease study hopes to learn more about how variants of a gene, BAG3, known to exist in both African Americans with critical limb ischemia (CLI) and with cardiomyopathy, may disrupt normal reparative links between muscle damaged by lack of oxygen and new blood vessel growth. If the hypothesis is correct, this gene may become a therapeutic target. Findings may help explain why African Americans with PAD disproportionately suffer from CLI.

Find more NHLBI-funded studies on health disparities and PAD at the NIH RePORTER.

Current research to better understand PAD

NHLBI-funded research has contributed to the understanding of the basic biology behind PAD. But there is still more to learn. This basic knowledge is what often help scientists develop future treatments.

• A large NHLBI-funded multisite clinical trial, BEST-CLI , will compare effectiveness of two standard treatment strategies for CLI treatment: Endovascular and open surgical bypass revascularization. Extensive data on clinical course, adverse events, and clinical outcomes including amputation, major reintervention, and death will be collected over a period of 2 years.
• Hematopoietic stem cells and progenitor cells are found in bone marrow and circulating blood and develop into other cells including blood cells. Researchers want to know whether giving people with PAD a protein that stimulates the release of stem cells from the bone marrow will promote the growth of blood vessels in the legs, improve circulation, and increase walking endurance.
• Sometimes, to better understand a disease, researchers build computer models based on real-life experiments they have run. These models allow them to change variables and see what the outcomes of those changes might be. NHLBI-funded researchers are doing just that to study PAD. Their state-of-the-art computer model will represent the way new blood vessels form, grow, and provide oxygen-carrying blood to the legs and feet. Researchers hope that this work will provide a better understanding of PAD and help suggest new treatments.
• Researchers believe they have worked out the details of a cellular pathway that explain the lack of circulation and oxygen in the lower extremities of patients with PAD. They now want to test their hypothesis by giving people with PAD a protein that promotes the growth of blood vessels by blocking another protein that inhibits vessel growth. The researchers hope this will improve circulation in people with PAD.

Find more NHLBI-funded studies on understanding PAD at the NIH RePORTER. 

Learn about research that confirms the safety of drug-coated stents and other devices used to open up blocked arteries in the legs of patients with PAD.

PAD research labs at the NHLBI

Our Division of Intramural Research , which includes investigators from the Translational Vascular Medicine Branch and its Experimental Atherosclerosis Laboratory , performs research on PAD.

Related PAD programs

• Researchers in the NHLBI-funded  Multi-Ethnic Study of Atherosclerosis (MESA) followed a group of study participants for 10 years and found that nearly 5% of them developed PAD. However, participants who scored higher on the American Heart Association’s Life’s Simple 7 checklist for maximizing heart health were less likely to have PAD; their risk decreased about 17% for each of the Life’s Simple 7 criteria they met. Learn more about this study:  Life’s Simple 7 and Peripheral Artery Disease: The Multi-Ethnic Study of Atherosclerosis .
• NHLBI’s Vascular Interventions/Innovations and Therapeutic Advances (VITA) Program studies and develops promising tests and treatments for blood vessel diseases, including PAD, and vascular access for hemodialysis. VITA has developed a new approach for treating people who have serious complications from PAD. One problem with angioplasty (a common treatment for PAD to open narrowed or blocked arteries) is the risk that the blood vessels will scar and re-narrow. A VITA project developed bioengineered tubes that one day could be used instead of a person’s own blood vessels or donor vessels for bypass revascularization . They are unique because the body’s immune system will not reject them as foreign. Learn more about the VITA program:  Next-generation replacement blood vessels target kidney and heart disease .

Explore more NHLBI research on PAD

The sections above provide you with the highlights of NHLBI-supported research on PAD. You can explore the full list of NHLBI-funded studies on the NIH RePORTER .

To find more studies:

• Type your search words into the  Quick Search  box and press enter. 
• Check  Active Projects  if you want current research.
• Select the  Agencies  arrow, then the  NIH  arrow, then check  NHLBI .

If you want to sort the projects by budget size — from the biggest to the smallest — click on the  FY Total Cost by IC  column heading.

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An usually early presentation of peripheral arterial disease in a 30-year-old woman

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Herbert Oye, Arham Aslam, An usually early presentation of peripheral arterial disease in a 30-year-old woman, Journal of Surgical Case Reports , Volume 2021, Issue 10, October 2021, rjab457, https://doi.org/10.1093/jscr/rjab457

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Peripheral vascular disease is commonly thought to be a disease of elderly patients. However, with certain environmental factors and predetermined genetics, it can present much earlier in life. This case report demonstrates a case of severe peripheral vascular disease in a 30-year-old woman with an 11-year history of smoking. We report the case of a 30-year-old woman who presented to our clinic with a 9-year history of peripheral vascular disease. She complained of worsening claudication in both lower extremities and intermittent pain at rest. A CT arteriogram was conducted and showed significant stenosis of both left and right iliac arteries, as well as stenosis of the distal aorta. In the setting of certain genetic and environmental factors, the presentation of peripheral vascular disease can occur significantly earlier in life.

With roughly 6.5 million Americans over the age of 40 affected by peripheral vascular disease [ 1 ], it is commonly thought to be a disease of the aged. In the setting of certain risk factors, such as diabetes, hypercholesterolemia, hypertension and smoking, atherosclerotic plaques take years to build-up enough to cause significant stenosis. Although all vessels may be affected, the lower extremities are more commonly involved in the symptoms of peripheral vascular disease. We report the case of a 30-year-old woman who presented to our clinic with worsening symptoms of peripheral vascular disease.

The patient was a 30-year-old woman who was diagnosed with peripheral vascular disease 9 years prior to this encounter. She presented to our clinic with complaints of worsening pain in the lower extremities with activity and sometimes pain at rest. The patient had a medical history of hypertension and admitted to non-compliance with medication. She has been smoking cigarettes for 11 years and usually consumes 1 pack per day. In addition, she reported a strong family history of coronary artery disease. The patient was taken to the office-based lab located within the clinic and was prepared sterilely for a catheter arteriogram.

Catheter arteriogram results showed significant occlusion of the left iliac artery ( Figs 3 and 4 ), the right iliac artery ( Fig. 1 ), as well as the distal abdominal aorta ( Fig. 2 ). There were numerous collateral vessels noted, indicating the presence of long-standing proximal stenosis ( Fig. 1 ). The decision was made to use angioplasty to help widen the areas of stenosis. An 8 mm × 40 mm Passeo balloon was advanced from the right femoral artery into the left iliac artery ( Fig. 7 ) and insufflated to 6 mmHg ( Fig. 6 ). The balloon was allowed to remain expanded for 1 min and then was deflated. Next, the distal aorta was repaired in a similar fashion. The balloon was advanced into the distal aorta from the right femoral access and insufflated to 12 mmHg ( Fig. 8 ). The balloon was allowed to remain expanded for 90 s.

Fluoroscopy of right iliac artery showing vast collateral vascular formation, indicating long-standing proximal obstruction.

Fluoroscopy of distal aorta showing narrowing.

Fluoroscopy of bilateral iliac arteries showing significant arterial disease.

Angioplasty of right iliac artery being performed.

Angioplasty of left iliac artery being performed.

Fluoroscopy of guidewire being passed into left iliac artery.

Angioplasty of distal aorta being performed.

Fluoroscopy showing dilation of the distal aorta post-angioplasty.

Fluoroscopy showing dilation of the right iliac vessel post-angioplasty.

Fluoroscopy of right iliac artery showing improved perfusion.

Fluoroscopy of left iliac artery showing improved perfusion.

Fluoroscopy of left popliteal artery showing good perfusion.

Fluoroscopy of right popliteal artery showing good perfusion.

Lastly, the right iliac artery ( Fig. 5 ) was treated using the same method ( Fig. 10 ). After completion of the angioplasty procedure, catheter arteriogram was repeated to visualize the effectiveness of the procedure in relieving the extensive stenosis. The imaging revealed almost complete restoration of the diameter of both left and right iliac arteries ( Figs 11 and 12 ). The distal aorta also showed improved diameter after the procedure ( Fig. 9 ). Angiogram of both lower extremities was also performed. The catheter was passed distal to the stenosis that was previously present in the left iliac artery, to help visualize perfusion of its distal branches ( Figs 13 and 14 ). The catheter was removed from the right femoral artery and reinserted in a distal fashion, to help visualize downstream perfusion. The right popliteal artery was well visualized on angiogram ( Fig. 15 ), signifying strong perfusion. The patient was strongly advised to discontinue smoking cigarettes. In addition, the patient was advised to maintain regular physical exercise as tolerated and take baby aspirin daily to prevent thrombotic events.

The patient in this case developed peripheral vascular disease at an unusually early age than is expected. This may be a result of modifiable risk factors, such as hypertension, obesity and smoking. While pain in the lower extremities in young adults is commonly caused by trauma or muscular pathologies, the differential of peripheral arterial disease should also be considered. This is especially true in the setting of comorbid conditions and risk factors. The treatment of peripheral arterial disease focuses on reducing exposure to the risk factors, such as quitting smoking and regular exercise. Pharmacological options include antiplatelet agents, such as aspirin, to prevent thrombotic events. Cilostazol, a phosphodiesterase-3 inhibitor, has been shown to reduce the symptoms of claudication in patients with peripheral arterial disease.

The unique nature of significant peripheral arterial disease in a relatively young patient with a strong family history of coronary artery disease and smoking, carries significant comorbidity concerns for the future. We elected not to stent the vessels at this time, due to the small caliber of the vessels. With continued smoking, the placement of stents in this patient’s vessels may induce thrombosis.

Endovascular intervention in this young patient in the form of angioplasty alone, showed good promise and avoided the need for stenting. Endovascular intervention can delay the need for a major aortobifemoral bypass in this young patient, as well as thrombotic complications associated with stenting.

Virani   SS , Alonso   A , Benjamin   EJ , Bittencourt   MS , Callaway   CW , Carson   AP , et al.    Heart disease and stroke statistics—2020 update: a report from the American Heart Associationexternal icon . Circulation.   2020 ; 141 : e139 – 596 .

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• arteriography
• peripheral vascular diseases
• environmental factors
• constriction, pathologic
• iliac artery
• older adult
• distal zone of aorta

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Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis

Affiliations.

• 1 Centre for Bioscience, Faculty of Science & Engineering, Manchester Metropolitan University, Manchester, UK.
• 2 Institute of Clinical Chemistry, University and University Hospital Zurich, University Heart Center, Zurich, Switzerland.
• 3 Laboratory of Translational Nutrition Biology, Swiss Federal Institute of Technology, Zurich, Switzerland.
• 4 Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, Medical Faculty, University of Basel, Basel, Switzerland.
• 5 Leviev Heart Center, Chaim Sheba Medical Center, Tel Hashomer, Israel.
• 6 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
• 7 Cardiology Department, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
• 8 Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
• 9 Department of Cardiology, Dupuytren University Hospital, Inserm U-1094, Limoges University, Limoges, France.
• 10 Department of Cardiology, Center for Molecular Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden.
• 11 INSERM U1116, Université de Lorraine, Centre Hospitalier Régional Universitaire de Nancy, Vandoeuvre les Nancy, France.
• 12 Cardiovascular Program-ICCC, IR-Hospital de la Santa Creu i Sant Pau, CiberCV, Autonomous University of Barcelona, Barcelona, Spain.
• 13 Unit of Cardiology, Karolinska Institute and Karolinska University Hospital, Solna, Stockholm, Sweden.
• 14 Catheterization Laboratory, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
• 15 'CarolDavila' University of Medicine and Pharmacy, Bucharest, Romania.
• 16 Vanderbilt University School of Medicine, Nashville, TN, USA.
• 17 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
• 18 Department of Medicine, Jagiellonian University Collegium Medicum, Cracow, Poland.
• 19 Laboratory of Clinical Chemistry and Hematology, University Medical Centre Utrecht, The Netherlands.
• 20 Department of Infection, Immunity and Cardiovascular Disease, Bateson Centre & INSIGNEO Institute, University of Sheffield, Sheffield S10 2RX, UK.
• 21 Insigneo Institute for In Silico Medicine, Sheffield, UK.
• 22 Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
• 23 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
• 24 Department of Cardiovascular Medicine, Medical Faculty, University of Münster, Münster, Germany.
• 25 SRH Central Hospital Suhl, Suhl, Germany.
• 26 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillian-Universität (LMU) München, Munich, Germany.
• 27 German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
• 28 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
• 29 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
• 30 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
• PMID: 32282914
• PMCID: PMC7797212
• DOI: 10.1093/cvr/cvaa085

Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.

Keywords: Cardiovascular; Endothelial function.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected].

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Endothelial dysfunction describes multiple phenotypic…

Endothelial dysfunction describes multiple phenotypic states. Left panel: In homeostatic conditions, the healthy…

Schematic representation of the endothelial…

Schematic representation of the endothelial factors underlying cardiovascular risk. ECFCs, endothelial colony-forming cells;…

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Characteristics of motor evoked potentials in patients with peripheral vascular disease

• Sarai, Pawandeep
• Luff, Charlotte
• Rohani-Shukla, Cyrus
• Strutton, Paul H.

With an aging population, it is common to encounter people diagnosed with peripheral vascular disease (PVD). Some will undergo surgeries during which the spinal cord may be compromised and intraoperative neuromonitoring with motor evoked potentials (MEPs) is employed to help mitigate paralysis. No data exist on characteristics of MEPs in older, PVD patients, which would be valuable for patients undergoing spinal cord at-risk surgery or participating in neurophysiological research. Transcranial magnetic stimulation, which can be delivered to the awake patient, was used to stimulate the motor cortex of 20 patients (mean (±SD)) age 63.2yrs (±11.5) with confirmed PVD, every 10 minutes for one hour with MEPs recorded from selected upper and lower limb muscles. Data were compared to that from 20 healthy volunteers recruited for a protocol development study (28yrs (±7.6)). MEPs did not differ between patient's symptomatic and asymptomatic legs. MEP amplitudes were not different for a given muscle between patients and healthy participants. Except for vastus lateralis, disease severity did not correlate with MEP amplitude. There were no differences over time in the coefficient of variation of MEP amplitude at each time point for any muscle in patients or in healthy participants. Although latencies of MEPs were not different between patients and healthy participants for a given muscle, they were longer in older participants. The results obtained suggest PVD alone does not impact MEPs; there were no differences between more symptomatic and less symptomatic legs. Further, in general, disease severity did not corelate with MEP characteristics. With an aging population, more patients with PVD and cardiovascular risk factors will be participating in neurophysiological studies or undergoing surgery where spinal cord integrity is monitored. Our data show that MEPs from these patients can be easily evoked and interpreted.

heart health center / heart a-z list / peripheral vascular disease article

Peripheral Vascular Disease (PVD)

• Medical Author: Melissa Conrad Stöppler, MD
• Medical Editor: Daniel Lee Kulick, MD, FACC, FSCAI

What is peripheral vascular disease (PVD)?

Are atherosclerosis and peripheral vascular disease related, what are the symptoms of peripheral vascular disease, who is at risk for peripheral vascular disease, how does atherosclerosis cause disease, is there a test to diagnose peripheral vascular disease, what is the treatment for peripheral vascular disease, medications for peripheral vascular disease, angioplasty to treat peripheral vascular disease, surgery to treat peripheral vascular disease, what are the complications of peripheral vascular disease, preventing peripheral vascular disease.

Peripheral vascular disease (PVD) refers to diseases of the blood vessels (arteries and veins) located outside the heart and brain. While there are many causes of peripheral vascular disease, doctors commonly use the term peripheral vascular disease to refer to peripheral artery disease (peripheral arterial disease, PAD), a condition that develops when the arteries that supply oxygen-rich blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis .

Atherosclerosis is a gradual process whereby hard cholesterol substances (plaques) are deposited in the walls of the arteries. This buildup of cholesterol plaques causes hardening of the artery walls and narrowing of the inner channel (lumen) of the artery. When this happens in the peripheral circulation, peripheral vascular disease is the result. The atherosclerosis process begins early in life (as early as teens in some people). When atherosclerosis is mild and the arteries are not substantially narrowed, atherosclerosis causes no symptoms. Therefore, many adults typically are unaware that their arteries are gradually accumulating cholesterol plaques. However, when atherosclerosis becomes advanced with aging , it can cause critical occlusive disease of the arteries resulting in tissue ischemia (lack of blood and oxygen).

Arteries that are narrowed by advanced atherosclerosis can cause diseases in different organs. For example, advanced atherosclerosis of the coronary arteries (arteries that supply heart muscles) can lead to angina , coronary heart disease , and heart attacks . Advanced atherosclerosis of the carotid and cerebral arteries (arteries that supply blood to the brain) can lead to strokes and transient ischemic attacks ( TIA ). Advanced atherosclerosis in the lower extremities can lead to pain while walking or exercising ( claudication ), deficient wound healing, and/or leg ulcers.

Atherosclerosis is often generalized, meaning it affects arteries throughout the body. Therefore, patients with heart attacks are also more likely to develop strokes and peripheral vascular disease, and vice versa.

Approximately half of the people with peripheral artery disease do not experience any symptoms. For patients with symptoms, the most common symptoms are intermittent claudication and rest pain .

• Intermittent claudication refers to arm or leg pain or cramping in the arms or legs that occurs with exercise and goes away with rest. The severity and location of the pain of intermittent claudication vary depending upon the location and extent of blockage of the involved artery. The most common location of intermittent claudication is the calf muscle of the leg, leading to calf or leg pain while walking. The pain in the calf muscle occurs only during exercise such as walking, and the pain steadily increases with continued walking until the patient has to stop due to intolerable pain. Then the pain quickly subsides during rest. Intermittent claudication can affect one or both legs.
• Rest pain in the legs occurs when the artery occlusion is so critical that there is not enough blood and oxygen supply to the legs even at rest which represents a more serious form of the condition. The pain typically affects the feet , is usually severe, and occurs at night when the patient is lying down, face up.

Other symptoms and signs of peripheral artery disease include:

• Numbness of the legs or feet
• Weakness and atrophy (diminished size and strength) of the calf muscle
• A feeling of coldness in the legs or feet
• Changes in the color of the feet; feet turn pale when they are elevated, and turn dusky red during independent position
• Hair loss over the top of the feet and thickening of the toenails
• Poor wound healing in the legs or feet
• Painful ulcers and/or gangrene in areas of the feet where blood supply is lost; typically in the toes

Peripheral artery disease (or peripheral arterial disease) affects approximately 10 million adults in the U.S. About 5% of people over the age of 50 are believed to suffer from peripheral artery disease. Peripheral artery disease is slightly more common in men than in women and most often occurs in older persons (over the age of 50). The known risk factors for peripheral artery disease are those that predispose to the development of atherosclerosis.

Risk factors for peripheral artery disease include:

• High blood cholesterol (elevated levels of the "bad" LDL cholesterol and triglycerides
• Low blood levels of the "good" HDL cholesterol
• Cigarette smoking
• Diabetes mellitus (both type 1 and type 2 diabetes )
• High blood pressure ( hypertension ) or a family history of hypertension
• A family history of atherosclerotic disease
• Chronic renal failure
• Overweight or obesity
• Physical inactivity

In peripheral artery disease, the risk factors are additive, so a person with a combination of two risk factors -- diabetes and smoking , for example -- has an increased likelihood of developing more severe peripheral artery disease than a person with only one risk factor.

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Atherosclerosis causes disease in two ways. 1) Atherosclerosis can limit the ability of the narrowed arteries to increase delivery of blood and oxygen to the tissues of the body during times when oxygen demand needs to be increased, for example, during exertion; or 2) complete obstruction of an artery by a thrombus or embolus (thrombus and embolus are forms of blood clots ), which results in tissue death (necrosis). Exertional angina and intermittent claudication are two examples of insufficient delivery of blood and oxygen to meet tissue demand; whereas strokes and heart attacks are examples of death of tissue caused by complete artery obstruction by blood clots.

There are many similarities between coronary heart disease (or coronary artery disease , which is atherosclerosis involving the arteries of the heart) and peripheral artery disease, and the two conditions may coexist in the same individual. For example, patients with exertional angina typically have no symptoms at rest. However, during exertion, the critically narrowed coronary arteries are incapable of increasing blood and oxygen delivery to meet the increased oxygen needs of the heart muscles. Lack of blood and oxygen causes chest pain (exertional angina). Exertional angina typically subsides when the patient rests. In patients with intermittent claudication, the narrowed arteries in the lower extremities (for example, a narrowed artery at the groin) cannot increase blood and oxygen delivery to the calf muscles during walking. These patients experience pain in the calf muscles that will only subside after resting.

Patients with unstable angina have critically narrowed coronary arteries that cannot deliver enough blood and oxygen to the heart muscle even at rest. These patients have chest pain at rest and are at imminent risk of developing heart attacks. Patients with severe artery occlusion in the legs can develop rest pain (usually in the feet). Rest pain represents such severe occlusion that there is the insufficient blood supply to the feet even at rest. They are at risk of developing foot ulcers and gangrene.

When atherosclerosis narrows the arteries, blood tends to clot in the narrowed areas, forming a thrombus, a type of blood clot (plural thrombi). Sometimes pieces of the blood clot break off and travel in the bloodstream until they are trapped in a narrower point in the artery beyond which they cannot pass. A thrombus or piece of thrombus that travels to another point is called an embolus. Thrombi and emboli can cause sudden and complete artery blockage, leading to tissue necrosis (death of tissue due to lack of oxygen).

For example, complete blockage of a coronary artery by a thrombus causes heart attack , while complete blockage of the carotid or cerebral artery causes ischemic stroke . Emboli originating from atherosclerosis in the aorta (the main artery delivering blood to the body) can obstruct small arteries in the feet, resulting in painful and blue (cyanotic) toes, foot ulcers, and even gangrene.

What are collateral vessels or collateral circulation?

Sometimes, despite the presence of a severe blockage in an artery, the involved area does not become painful or lose its blood supply due to the presence of collateral vessels. Collateral circulation means that the particular area is supplied by more than one artery so that the blockage of a single vessel does not result in a severe degree of blood loss. Collateral circulation can develop over time to help provide oxygenated blood to an area where an artery is narrowed. Doctors believe that regular supervised exercise can stimulate the growth and development of collateral circulation and relieve symptoms of intermittent claudication.

What are the other causes of peripheral vascular diseases?

Several conditions such as vasculitis may cause damage to blood vessels throughout the body. Injuries to blood vessels (from accidents such as auto accidents or sports injuries), blood-clotting disorders, and damage to blood vessels during surgery can also lead to the inadequate blood supply to body tissues (ischemia).

Tissue ischemia can also occur in the absence of atherosclerosis or other abnormalities of arteries. One example of a condition in which the blood vessels themselves are not damaged is Raynaud's disease , which is believed to occur due to spasms in blood vessels brought on by stress or a cold environment.

Since atherosclerosis of the peripheral arteries (PAD) is by far the most common cause of peripheral vascular disease, the rest of this article focuses on peripheral artery disease.

The doctor will perform a physical exam and look for signs and symptoms of peripheral artery disease, for example, weak or absent artery pulses in the extremities, bruits (sounds that can be heard through a stethoscope), blood pressure changes, and skin color and nail changes

In addition to the history of symptoms and the physical signs of peripheral artery disease imaging tests can be used in the diagnosis of the condition. Imaging tests include:

• Doppler ultrasound - This form of ultrasound (measurement of high-frequency sound waves that are reflected off of tissues) can detect and measure blood flow. Doppler ultrasound is used to measure blood pressures behind the knees and at the ankles. In patients with significant peripheral artery disease in the legs, the blood pressure in the ankles will be lower than the blood pressure in the arms (brachial blood pressure). The ankle-brachial index (ABI) is a number derived from dividing the ankle blood pressure by the brachial blood pressure. An ankle-brachial index of 0.9 to 1.3 is normal, an ABI less than 0.9 indicate the presence of peripheral artery disease in the arteries in the legs, and an ABI below 0.5 usually indicates severe arterial occlusion in the legs.
• Duplex ultrasound - This is a color-assisted non-invasive technique to study the arteries. Ultrasound probes can be placed on the skin overlying the arteries and can accurately detect the site of artery stenosis as well as to measure the degree of obstruction.
• Angiography - An angiography is an imaging procedure to study the blood vessels of the extremities, similar to the way a coronary angiogram provides an image of the blood vessels supplying the heart. It is the most accurate test to detect the location(s) and severity of artery occlusion, as well as collateral circulations. Small hollow plastic tubes (catheters) are advanced from a small skin puncture at the groin (or the arm), under X-ray guidance, to the aorta and the arteries. Iodine contrast "dye," is then injected into the arteries while an X-ray video is recorded. Angiogram gives the doctor a picture of the location and severity of narrowed artery segments. This information is important in helping the doctor select patients for angioplasty or surgical bypass (see below).
• Because X-ray angiography is invasive with potential side effects (such as injury to blood vessels and contrast dye reactions), it is not used for the initial diagnosis of peripheral artery disease. It is only used when a patient with severe peripheral artery disease symptoms is considered for angioplasty or surgery. Several different imaging methods have been used in angiography examinations, including X-rays , magnetic resonance imaging ( MRI ), and computed tomography (CT) scans.
• Magnetic resonance imaging (MRI) angiography uses magnetism, radio waves, and a computer to produce images of body structures and has the advantage of avoiding X-ray radiation exposure.

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Treatment goals for peripheral artery disease include:

• Relieve the pain of intermittent claudication.
• Improve exercise tolerance by increasing the walking distance before the onset of claudication.
• Prevent critical artery occlusion that can lead to foot ulcers, gangrene, and amputation.
• Prevent heart attacks and strokes.

Treatment of peripheral artery disease includes lifestyle measures, supervised exercises, medications, angioplasty, and surgery.

Lifestyle changes

• Smoking cessation eliminates a major risk factor for disease progression, and it lowers the incidences of pain at rest and amputations. Smoking cessation also is important to prevent heart attacks and strokes.
• A healthy diet can help lower blood cholesterol and other lipid levels and may help control blood pressure.
• Keep other risk fa ctors, such as diabetes, lipid levels, and blood pressure under control by following medical advice regarding medications and lifestyle changes.

Supervised exercise

Proper exercise can condition the muscles to use oxygen effectively and can speed the development of collateral circulation. Clinical trials have shown that regular supervised exercise can reduce symptoms of intermittent claudication and allow individuals to walk longer before the onset of claudication. Ideally, your health care provider should prescribe an exercise program tailored to your specific needs.

Rehabilitation programs supervised by healthcare professionals such as nurses or physical therapists may help. Exercise at least three times a week, each session lasting longer than 30 to 45 minutes for the best results. Exercise usually involves walking on a monitored treadmill until claudication develops; walking time is then gradually increased with each session. Patients are also monitored for the development of chest pain or heart rhythm irregularities during exercise.

While lifestyle changes may be enough treatment for some people with peripheral artery disease, others may require medication. Examples of medications used to treat peripheral artery disease include antiplatelet or anti-clotting agents, cholesterol-lowering drugs such as statins , and medications that increase blood supply to the extremities such as cilostazol ( Pletal ) and pentoxifylline ( Trental ), and medications that control high blood pressure .

• Antiplatelet medications (such as aspirin and clopidogrel [ Plavix ]) make the blood platelets less likely to stick to one another to form blood clots. Low-dose aspirin (81 to 325 mg/day) is usually prescribed indefinitely because it is also helpful in preventing strokes and heart attacks in patients with peripheral artery disease. Clopidogrel (Plavix) is an alternative to aspirin for those who are allergic or cannot tolerate aspirin. Antiplatelet medications also help prevent the occlusion of blood vessels after angioplasty or bypass surgery.
• Anticoagulant medications act to prevent blood clotting. Both heparin and warfarin ( Coumadin , Jantoven ) are anticoagulant medications. Anticoagulants are sometimes prescribed for people with peripheral artery disease if they are at increased risk for the formation of blood clots; these agents are used much less frequently than antiplatelet agents in patients with peripheral artery disease.
• Cholesterol-lowering drugs of the statin class have been shown in numerous large clinical trials to help prevent heart attacks and strokes and prolong survival among patients with atherosclerosis. Statins have also been shown to slow the progression of peripheral artery disease, decrease atherosclerosis in the arteries, and improve claudication symptoms.
• Cilostazol (Pletal) is a medication that can help increase physical activity (enabling one to walk a greater distance without the pain of claudication). Cilostazol works by causing dilation of the arteries and an increased supply of oxygenated blood to be delivered to the arms and legs. Cilostazol is recommended for some patients with claudication when lifestyle modifications and exercise are ineffective. Side effects are generally mild and include headache , diarrhea , and dizziness . Cilostazol should not be used in patients with heart failure because of concern over increased mortality in heart failure patients using medications similar to cilostazol.
• Pentoxifylline (Pentoxyl, Trental) improves blood flow to the extremities by decreasing the viscosity ("stickiness") of blood, enabling more efficient blood flow. Side effects are fewer than with cilostazol, but its benefits are weaker and have not been conclusively proven by all studies.
• Dru gs to control hypertension may also be prescribed. Current recommendations are to treat hypertension in patients with peripheral artery disease to prevent strokes and heart attacks.

Angioplasty, also known as percutaneous transluminal angioplasty, or PTA, is a non-surgical procedure that can widen a narrowed or blocked artery. A thin tube (catheter) is inserted into an artery in the groin or arm and advanced to the area of narrowing. A tiny balloon on the tip of the catheter is then inflated to enlarge the narrowing in the artery. This procedure is also commonly performed to dilate narrowed areas in the coronary arteries that supply blood to the heart muscle.

Sometimes the catheter technique is used to insert a stent (a cylindrical wire mesh tube) into the affected area of the artery to keep the artery open. In other cases, thrombolytic medications (medications that dissolve blood clots) may be delivered to the blocked area via a catheter.

Angioplasty does not require general anesthesia. Usually, a local anesthetic at the area of catheter insertion and a mild sedative is given. Major complications of angioplasty are rare but can occur. These include damage to the artery or blood clot formation, excessive bleeding from the catheter insertion site, and abrupt vessel closure (blockage of the treated area occurring within 24 hours of the procedure).

Despite these risks, the overall incidence of complications is low and the benefits of angioplasty (no general anesthesia, no surgical incision, and the ability to return to normal activities within a couple of days) outweigh its risks. Usually, a one-night hospital stay is required when angioplasty is performed.

Angioplasty is used when a patient has claudication that limits his or her activities and does not respond to exercise medications, and lifestyle measures. Most doctors also recommend angioplasty when the disease is very severe, and there is a focal, localized narrowing that is accessible via a catheter. If a patient is too ill to have surgery and has severe ischemia (decreased oxygen in the tissues) that threatens the loss of a limb, angioplasty may also be attempted.

Some cases of peripheral artery disease may be more difficult to treat by angioplasty. For example, blockages in multiple small arteries of the legs or blockages in extremely small vessels may not be treatable by this method.

Surgical treatment for peripheral artery disease involves either bypass vascular surgery performed by a vascular surgeon or an endarterectomy. Indications for surgical treatment of peripheral artery disease include lesions that, for anatomical reasons, may be difficult to treat by angioplasty. Examples include lesions covering long segments of a vessel, vessels with multiple narrowed areas, or long areas of narrowing. Bypass surgery involves using a vein from your body or a portion of a synthetic vessel (known as grafts) to create a detour around the blockage. One end of the graft is sewn to the damaged artery above the blockage and the other end is sewn below the blocked area. Blood flow is then able to bypass the area of narrowing or blockage Bypass surgery is a major surgical procedure requiring general anesthesia and a hospital stay.

Endarterectomy is a procedure in which the surgeon cleans out plaque buildup inside the artery of the affected leg or arm.

In rare cases, the decreased circulation to the extremities characteristic of peripheral artery disease can lead to open, non-healing sores, ulcers, gangrene, or other limb-threatening injuries to the extremities. The areas that do not receive adequate blood flow are also more prone to develop infections and, in extreme cases, amputation may be necessary.

Peripheral vascular disease related to atherosclerosis can be prevented by minimizing the risk factors that are controllable, such as eating a heart-healthy diet , maintaining a h ealthy weight, not smoking, getting regular exercise, and maintaining good control of blood sugar levels if you have diabetes.

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Progress in aorta and peripheral cardiovascular disease research

Lucia mazzolai.

1 Division of Angiology, Heart and Vessel Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland

Adriano Alatri

Alessandra bura rivière.

2 Division of Vascular Medicine, Heart, Vessels and Metabolisms Department, Toulouse University Hospital, Toulouse, France

Marco De Carlo

3 Cardiothoracic and Vascular Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

Christian Heiss

4 Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK

Christine Espinola-Klein

5 Section Angiology, Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany

Oliver Schlager

6 Division of Angiology, Department of Medicine II, Medical University of Vienna, Waehringer Gürtel 18-20, 1090 Vienna, Austria

Henrik Sillesen

7 Department of Vascular Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Daniel Staub

8 Division of Angiology, University Hospital Basel, University of Basel, Basel, Switzerland

José F Rodriguez-Palomares

9 Cardiology Department, Hospital General Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR), CIBER-CV, Barcelona, Spain

Aline Verstraeten

10 Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium

Victor Aboyans

11 Department of Cardiology, Dupuytren-2 University Hospital, and Inserm 1094 & IRD, Limoges University, Limoges, France

Although coronavirus disease 2019 seems to be the leading topic in research number of outstanding studies have been published in the field of aorta and peripheral vascular diseases likely affecting our clinical practice in the near future. This review article highlights key research on vascular diseases published in 2020. Some studies have shed light in the pathophysiology of aortic aneurysm and dissection suggesting a potential role for kinase inhibitors as new therapeutic options. A first proteogenomic study on fibromuscular dysplasia (FMD) revealed a promising novel disease gene and provided proof-of-concept for a protein/lipid-based FMD blood test. The role of NADPH oxidases in vascular physiology, and particularly endothelial cell differentiation, is highlighted with potential for cell therapy development. Imaging of vulnerable plaque has been an intense field of research. Features of plaque vulnerability on magnetic resonance imaging as an under-recognized cause of stroke are discussed. Major clinical trials on lower extremity peripheral artery disease have shown added benefit of dual antithrombotic (aspirin plus rivaroxaban) treatment.

1. Introduction

The year 2020 was overshadowed by the spread of the novel coronavirus disease 2019 (COVID-19). Four months after the first cases in China, Varga et al. 1 described the involvement of the vascular endothelium in patients with COVID-19.

Nevertheless, the year 2020 was also characterized by outstanding publications in the field of aortic and peripheral vascular diseases, potentially improving the clinical management in the future.

This article summarizes the main findings from key studies published in 2020 on the basic science, epidemiology, imaging, and clinical trials addressing aortic and peripheral arterial and venous diseases. A specific chapter on vascular complications secondary to COVID-19 infection is also addressed. For this review, the authors performed a systematic review of published research papers in major vascular areas (arterial, venous, aorta, basic science, clinical trials, and COVID). The final selection was discussed within the group through a consensus.

2. Basic science

2.1 aortic aneurysm and dissection.

In 2020, multiple putative aortic aneurysm and dissection (AoAD) therapeutical targets were identified, two of which are detailed here.

In two small-scale case–control cohorts, a common missense variant in the alcohol-metabolizing aldehyde dehydrogenase 2 protein (ALDH2 p.Glu504Lys; gnomAD v2.1.1 MAF total : 1.8% vs. MAF Asians : 10.1%) previously linked to increased coronary artery disease risk, was suggested to be associated with protection from AoAD. 2 Further proof of a direct relationship between ALDH2 activity and AoAD risk was next pursued in two different AoAD mouse models. In angiotensin II- or 3-aminopropionitrile fumarate-infused mice, ALDH2 inhibition by the isoflavone daidzin was shown to partially rescue the aortopathy phenotype as demonstrated by mitigation of elastic fibre fragmentation, near-normalization of aortic wall thickness, and a concomitant reduction in the incidence of AoAD. 2 Further disentanglement of molecular mechanisms underlying this protective effect exposed a critical role for miR-31-5p-dependent inhibition of the pathological contractile-to-synthetic vascular smooth muscle cell (VSMC) phenotype switch. Specifically, ALDH2 loss-of-function represses the expression of miR-31-5p, which results in elevated myocardin levels and, consequently, increased expression of the VSMCs’ contractile apparatus genes (i.e. α-SMA, SM22-α, and calponin). 2

AoAD is also an important complication of the vascular Ehlers–Danlos syndrome (vEDS), caused by heterozygous mutations in the collagen Type III alpha 1 chain ( COL3A1 ) gene. Contrary to some other heritable aortopathies (e.g. Marfan syndrome), vEDS-related dissections or ruptures can occur without prior aneurysm formation, and involve also muscular arteries. Bowen et al. 3 created two vEDS mouse models ( Col3a1 G209S/+ and Col3a1 G938D/+ ) corresponding to known human vEDS-causing mutations and presenting with sudden death due to aortic dissection or rupture in the absence of prior dilatation and major architectural wall deterioration. Comparative aortic transcriptome analysis of mutant mice and their wild-type (WT) littermates suggested excessive signalling through the PLC/IP3/PKC/ERK axis as a key disease culprit. Whereas administration of blood pressure-lowering agents such as beta-blockers did not improve survival rates, pharmacological treatment with ERK1/2 or PKCβ inhibitors (i.e. riboxistaurin, cobimetinib, and hydralazine) improved survival from 52% to 90–97%, conferring considerable translational weight to the transcriptome findings. Similar to humans, pregnancy/lactation- and male puberty-associated exacerbation of aortic dissection/rupture risk were observed in the vEDS mice, all of which could be rescued by oxytocin and androgen signalling attenuation, respectively. Altogether, these studies put forward ALDH2, miR-31-5p, and the PLC/IP3/PKC/ERK axis as novel targets for AoAD prevention and, in the latter case, emphasized the role of androgen signalling and breastfeeding (oxytocin) in vEDS-related aortic dissection/rupture risk.

Niacin is known to prevent atherosclerosis via anti-inflammatory effects by activating the G protein-coupled receptor GPR109A on immune cells. An experimental study in mice indicates now that niacin could prevent abdominal aortic aneurysm (AAA) development independent of GPR109A. 4 The authors show that niacin markedly blunted AAA formation in two mouse models (angiotensin II and CaCl 2 ) with lowered inflammatory responses and matrix degradation. Importantly, deletion of GPR109A gene did not prevent the protective effects. Nicotinamide led to very similar results with increases in NAD+ concentrations and Sirt1 activity suggesting that both niacin and nicotinamide could become novel therapeutic agents to prevent AAA. Nicotinamide or related molecules may have the advantage of not causing flushing, a side effect of niacin linked to GPR109A.

2.2 Fibromuscular dysplasia

Fibromuscular dysplasia (FMD) affects predominantly middle-aged women and causes stenosis, tortuosity, aneurysm, and/or dissection of medium-sized arteries. It is often asymptomatic, and its aetiology poorly understood. A first FMD plasma proteomics and lipidomics study in 90 multifocal FMD patients and 100 age/sex-matched control individuals revealed differential abundance of 105 proteins and 16 lipid sub-classes (particularly triglycerides and fatty acids). 5 Of these, 37 proteins and 10 lipid sub-classes were confirmed as being up- or downregulated in an independent validation cohort of 23 FMD patients and 28 controls. Using machine learning approaches, a combined protein and lipid signature reaching, respectively, a sensitivity and specificity of 78.3% and 64.3% was developed. Additionally, protein quantitative trait locus mapping and subsequent Bayesian network classification suggested CD2AP, PODXL2, and TACC3 to be upstream of FMD development and, therefore, to be candidate disease drivers. Moreover, an independent genetic association study in 506 FMD patients and 876 healthy individuals revealed a significant relationship between single-nucleotide polymorphisms in the upstream region of CD2AP expressed by endothelial cells of medium-sized arteries. 5 Like PODXL2, CD2AP has been suggested to play a role in vascular leucocyte adhesion and rolling, and increased FMD risk [top-hit: rs9296551; ∼odds ratio (OR) 1.36]. This first proteogenomic FMD study revealed a promising novel disease gene and provided proof-of-concept for a protein/lipid-based FMD blood test.

2.3 Atherosclerosis

Chronic inflammation and autoimmunity play important roles in the atherosclerosis development and stability of atherosclerotic plaques. Recently, relevance of co-stimulatory immune checkpoint protein glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) in atherogenesis has been shown. 6 GITR is known for activating and regulating effects on T cells. A novel role of GITR is proposed, in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. GITR expression was elevated in carotid endarterectomy specimens from 100 patients with symptomatic carotid disease vs. those extracted from asymptomatic patients ( n  = 93). GITR was essentially found in macrophages, endothelial cells, and T cells, and similar patterns were also observed in femoral endarterectomy samples. 6 GITR expression correlated with signs of plaque vulnerability. Furthermore, patients with cardiovascular (CV) disease showed elevated soluble plasma GITR levels compared to healthy controls. In 28-week-old Gitr −/− Apoe −/− mice extension of aortic atherosclerosis was reduced, and plaques showed a more stable phenotype with fewer macrophages, smaller necrotic core, and a thicker fibrous cap. Lymphocytes were not affected by GITR deficiency. Monocyte and macrophage cell migration, activation, and mitochondrial function were differently modulated in Apoe −/− and Gitr −/− Apoe −/− mice. In Gitr −/− Apoe −/− mice, monocytes showed decreased integrins and reactive oxygen species (ROS) levels as well as reduced endothelium recruitment. Along the same line, macrophages showed reduced migratory capacity and lower cytokines production. Altogether ( Figure  1 ), these data indicate that GITR plays a pivotal role and is a potential therapeutic target in atherosclerosis.

GITR-mediated atherogenesis (reproduced with permission from Shami et al. 6 ). GITR, glucocorticoid-induced tumour necrosis factor receptor family-related protein.

Cell membrane exteriorization of phosphatidylserine and phosphatidylethanolamine (PE) occurring during apoptosis within plaques contributes to several high-risk features of vulnerable plaque. Recently, molecular imaging with PE-avid radiolabeled oxytetracycline in experimental atherosclerotic lesions was investigated in rabbits. 7 The 99m Tc-oxytetracycline uptake was >two-fold higher in the test group of 21 rabbits on high-fat diet for 16 weeks vs. 6 rabbits on normal chow (controls) and 6 negative radiotracer control animals ( 99m Tc-linear oxytetracycline without PE-binding capability). On histology, oxytetracycline uptake correlated to lesion severity and macrophage burden. This study represents a notable step towards atherosclerosis molecular imaging using radiolabeled oxytetracycline to localize lipid-rich areas with high levels of apoptotic macrophages in an experimental model. Further clinical studies in humans are awaited to detect vulnerable high-risk plaques.

A few interesting papers highlighted the important and complex role of NADPH oxidases in vascular physiology beyond their role as ROS producers and atherosclerosis mediators. A review of a large body of literature shows that endothelial cell differentiation requires ROS and NADPH oxidases (Nox1, 2, 4, and 5) and these are important local modulators of the signalling networks regulating differentiation of stem cells to endothelial cells. 8

Understanding the specific roles of NADPH oxidases may also help to further develop cell-based therapies. For instance, in cord blood-derived endothelial colony-forming cells, Nox4 could be a future therapeutic target as it enhances the reparative functions of these cells supporting the creation of a pro-reparative microenvironment and effective post-ischaemic revascularization. 9 The requirement for Nox4-derived ROS in vivo was highlighted by a mouse study demonstrating that Nox4-derived H 2 O 2 plays a key role in exercise-induced vascular adaptations. 10 Exercise led to an increased H 2 O 2 release in the aorta of WT mice with adaptations of the eNOS and Ppargc1a pathway, and intracellular calcium release. In Nox4 −/− mice, the physical activity performance and vascular protective effects of exercise were inhibited.

3. Epidemiology and prevention

A recent analysis from the Framingham Heart Study and the Danish nationwide administrative registries showed strong familial association of aortic aneurysm. 11 Children of parents with aorta sized in the upper quartile (adjusted for age, sex, and body surface area) had a three-fold increased risk of being themselves in that aortic diameter upper quartile. Additionally, first-degree relatives of patients with ascending aortic aneurysm had a 6.7-fold increased risk in developing an ascending aortic aneurysm, and a 9.2-fold risk for aortic dissection. These observations support the use of systematic screening for aortic diseases in affected families. 12

Patients with lower extremity artery disease (LEAD) have a high risk for major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Recent analysis of UK electronic health reports showed a 15% decrease in LEAD incidence between 2006 and 2015 [from 236 to 202 per 100 000 person-years; adjusted incidence rate ratio (IRR) 0.85, 95% confidence interval (CI) 0.82–0.88]. However, CV mortality for incident LEAD did not decline significantly (adjusted IRR 0.84, 95% CI 0.70–1.00), at variance with the significant 43% fall in mortality for incident coronary artery disease. 13

New insights on the pathophysiological mechanisms underlying the dismal prognosis of patients with chronic limb-threatening ischaemia come from a study demonstrating the association between CD34+ cell migration and long-term CV mortality. In coculture, CD34+ cells imprinted naive endothelial cells, increasing apoptosis and reducing network formation. 14 An altered paracrine signalling from CD34+ cells to the endothelium may contribute to the increased CV risk in these patients.

The lack of improvement in CV prognosis of LEAD patients extends also to limb prognosis, as demonstrated by a new analysis from the 2017 Global Burden of Disease study. 15 Data from 16 European countries, Canada, Australia, and the USA between 1990 and 2017 showed wide time trend variability among countries and between sexes regarding amputation proximal to toes, in the absence of uniform improvements. New data on the impact of revascularization on limb prognosis in claudicants were reported in a retrospective analysis of 11 887 elective endovascular procedures. 16 One-year amputation rate was 1.1%; independent predictors of major amputation were congestive heart failure (OR 6.5, 95% CI 2.4–17.2), American Society of Anesthesiologists Class IV (OR 9.3, 95% CI 1.9–44.9), non-white race (OR 3.3, 95% CI 1.5–7.4), and tibial-level intervention (OR 6.3, 95% CI 1.5–26.1).

Women were previously considered to have poorer prognosis when affected by LEAD, but this has been contradicted by two recent post hoc analyses of large randomized-controlled studies (RCTs). In the EUCLID (Examining Use of Ticagrelor in PAD) trial, women with LEAD were at lower risk for MACE compared with men [9.5% vs. 11.2%; adjusted hazard ratio (HR) 0.77; P  < 0.001], but had similar rates of MALE (2.6% vs. 3.0%; adjusted HR 0.90; P  = 0.37). 17 Similarly, in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) trial, women had similar rates for MACE and major bleeding. There were no sex-related interaction regarding the benefits in reducing MACE under low-dose rivaroxaban plus aspirin vs. aspirin alone (women: HR 0.72; men: HR 0.76; P interaction = 0.75) or major bleeding (women: HR 2.22; men: HR 1.60; P interaction = 0.19). 18

Benefits of a more potent antithrombotic therapy in LEAD patients were recently confirmed in a meta-analysis encompassing seven RCTs comparing various antithrombotic regimens. 19 More vs. less intense antithrombotic therapy reduced significantly the risk of limb revascularization, limb amputation, and stroke ( Figure  2 ), without significant effects on myocardial infarction and CV death, but at cost of increased risk of (major) bleeding, highlighting the importance of individualized risk/benefit assessment.

Forest plot of risk of adverse events with more intense vs. less intense antithrombotic therapy in patients with lower extremity artery disease. The 95% CIs are denoted by lines (modified from Savarese et al. 19 ). CI, confidence interval; CV, cardiovascular.

The largest diameter of the aorta is considered as the main risk factor for aortic rupture and dissection and, therefore, this criterion is recommended to guide interventions. However, the measurement of aortic diameter (especially at the aortic root) has multiple limitations. Several imaging techniques and measurement protocols exist suggesting that established thresholds of aortic diameters might not be fully adequate. Therefore, it is highly recommended to be very exhaustive when performing aortic measurements, indicating in detail the methodology used. 20

To overcome these limitations, new parameters have been recently introduced. Ascending aortic length (length > 13 cm) has been associated with a five-fold increase in aortic events (rupture, dissection, or death). 21 Furthermore, increased aortic stiffness (aortic strain reduction) correlated with higher incidence of dissection or surgery in Marfan patients. 22 A recent study showed that both ascending aortic length and volume improve prediction of aortic dissection in case of ascending aortic aneurysms. 23 Patients ( n  = 25) with type A acute aortic dissection who had a computed tomography (CT) within the prior 2 years were compared to those with thoracic aortic aneurysm and no-acute aortic dissection ( n  = 75), and healthy controls ( n  = 258). Aortic diameter was similar between patients with and without acute aortic dissection (45 vs. 46 mm, respectively, P  = 0.075), as well as aortic volume (126 vs. 124 cm 3 , respectively, P  = 0.909) with differences in aortic length (90 vs. 84 mm, respectively, P  = 0.031). Aortic volume and length showed, respectively, a five-fold and a seven-fold sensitivity in predicting acute aortic dissection while the aortic length presented 70% positive predictive value.

Not only the carotid artery stenosis severity, but also the atherosclerotic plaque composition and morphology are increasingly recognized as important features determining stroke risk. High-resolution, contrast-enhanced carotid magnetic resonance imaging (MRI) enables non-invasive characterization of carotid artery plaques (CAP), including features of plaque vulnerability as intraplaque haemorrhage, thin and/or ruptured fibrous cap, large lipid-rich and/or necrotic core, and mural thrombus. The CAPIS study investigated a causal role between complicated CAP and specific MRI plaque features with cryptogenic stroke. 24 Using a subtle prospective study, 234 patients with acute ischaemic stroke restricted to single carotid artery territory on brain MRI, and unilateral or bilateral CAP were recruited. Among patients with cryptogenic stroke ( n  = 104), prevalence of ipsilateral complicated CAP on MRI was significantly higher ipsilateral (31%) vs. contralateral to the infarct (12%; P  = 0.0005). The prevalence of ipsilateral complicated CAP in cryptogenic stroke was also significantly higher than in patients with cardioembolic or small vessel stroke (15%; P  = 0.02), but significantly lower than in those with large artery stroke and ipsilateral 50–69% carotid stenosis (68%; P  = 0.003). These finding substantiate the role of complicated non-stenotic CAP with imaging features of plaque vulnerability on MRI as an under-recognized cause of stroke. Further studies are needed to determine a possible interventional approach in patients with such lesions.

Non-invasive assessment of limb perfusion and its impact in predicting wound healing and amputation outcome could be of particular importance in patients with critical limb ischaemia (CLI). Different methods for skin or muscle perfusion imaging have been developed, using hyperspectral, laser Doppler, MR-based methods, and contrast-enhanced ultrasound techniques, with poor clinical application. In a prospective study of 25 patients with diabetes and CLI, pedal perfusion was assessed before and after revascularization, using 99m Tc-tetrofosimin single-photon-emission computed tomography (SPECT)/CT perfusion imaging of segmented angiosomes of the foot. 25 SPECT/CT detected a significantly lower regional microvascular perfusion response in patients undergoing amputation compared to those with saved limbs at 3 and 12 months after revascularization. The amputation-free survival rate was significantly higher at 3 and 12 months for high-perfusion than low-perfusion responders to revascularization. Therefore, SPECT/CT imaging could provide new prognostic information on regional perfusion response to lower extremity revascularization.

5. Clinical trials

Several clinical trials have been published in 2020 ( Table  1 ). The TEDY study investigated whether telmisartan 40 mg daily could slow small AAAs growth, as measured by ultrasound and CT scanning. 26 Among the 207 patients included in the intention-to-treat analysis, no significant difference in ultrasound-assessed AAA growth rates was found among those under telmisartan (1.68 mm/year) vs. placebo (1.78 mm/year, P  = 0.66). Similarly, telmisartan did not significantly affect AAA growth assessed by CT-measured AAA diameter or volume.

Summary of major clinical trials in the field of aorta and peripheral vascular diseases in 2020

AAA, abdominal aortic aneurysm; ACS, acute coronary syndrome; ALI, acute limb ischaemia; DVT, deep vein thrombosis; HR, hazard ratio; LEAD, lower extremity artery disease; MI, myocardial infarction; MRI, magnetic resonance imaging; PAD, peripheral arterial disease; PE, pulmonary embolism; RCT, randomized-controlled study; VTE, venous thromboembolism.

The presence of mural thrombosis is considered as contributive to the AAA growth. The TicAAA study, randomized 144 patients with AAA to receive either ticagrelor 90 mg twice daily or placebo. 27 After 12 months, the AAA volume growth rate assessed by MRI did not differ between the ticagrelor and the placebo groups (9.1% vs. 7.5% , P  =   0.205). Neither the AAA diameter nor the intraluminal thrombus volume change differed between treatment groups.

Both TEDY and TicAAA trials were of short duration (1 year) and potential benefits with longer treatment durations need further investigations. In addition, the percentage proportion of female patients was low (TEDY 12%, TicAAA 4.2%), which does not allow any conclusion with respect to sex differences in treatment effects.

The VOYAGER trial tested whether rivaroxaban 2.5 mg b.i.d. + aspirin 100 mg (dual pathway inhibition, DPI) was superior to aspirin 100 mg alone (control) in preventing thrombotic events after lower limbs revascularization. This multicentre, prospective RCT included 6564 patients (26% females) undergoing infra-iliac arterial revascularization. 28 Primary efficacy outcome was a composite of acute limb ischaemia, major amputation for vascular causes, myocardial infarction, ischaemic stroke, or death from CV causes. It occurred in 17.3% patients in the DPI vs. 19.9% in the control group (HR 0.85, 95% CI 0.76–0.96; P  = 0.009). The most frequent component of the primary endpoint, acute limb ischaemia, occurred in 5.2% in the DPI and 7.8% in the control group (HR 0.67, 95% CI 0.55–0.82). No heterogeneity with respect to patients' sex was reported. TIMI major bleeding occurred in 2.65% patients in the DPI and in 1.87% in the control group (HR 1.43, 95% CI 0.97–2.10; P  = 0.07). Overall, for every 10 000 patients treated for 1 year DPI would prevent 181 primary efficacy outcome events at the cost of 29 principal safety outcome events. The number needed to treat at 3 years was 39.

These results challenge the concept of single or dual antiplatelet therapy (DAPT) after peripheral revascularization. DPI was superior to aspirin monotherapy but was not tested against DAPT, although clopidogrel was allowed in the trial for up to 6 months in both arms. However, the use of DAPT after peripheral endovascular therapy is empirical and has never been validated in a specific RCT. In addition, an economic evaluation showed that combination of rivaroxaban 2.5 mg b.i.d. with aspirin 100 mg is a cost-effective treatment option for patients with chronic CAD or LEAD compared to aspirin alone. 33

Regarding endovascular treatment of LEAD, the use of paclitaxel-coated balloons and stents has been challenged following a systematic review and meta-analysis in 2018 suggesting mortality excess. 34 These safety concerns initiated an unplanned interim analysis of the randomized, open-label, registry-based SWEDEPAD trial, aiming to assess potential effects of drug-eluting technology on the incidence of amputation among patients with chronic limb-threatening ischaemia and health-related quality of life among 2289 patients (45% females) with intermittent claudication. 29 Over a mean follow-up of 2.5 years, the mortality did not differ between the drug-coated device group and the uncoated device group (HR 1.06, 95% CI 0.92–1.22). 29 Furthermore, the mortality did not differ between patients with chronic limb-threatening ischaemia (HR 1.04, 95% CI 0.90–1.21) and those with intermittent claudication (HR 1.18, 95% CI 0.72–1.93). While these findings relieve concerns on a suggested mortality risk after paclitaxel use in LEAD interventions, SWEDEPAD still has to be interpreted with caution as an unintended interim analysis.

5.3 Venous thromboembolism

The Caravaggio study was a prospective open-label non-inferiority RCT comparing apixaban to dalteparin in 1155 cancer patients (51% females) with a venous thromboembolism (VTE) episode. 32 Recurrent VTE occurred in 5.6% in the apixaban group and 7.9% in the dalteparin group (HR 0.63, P  < 0.001 for non-inferiority, P  = 0.09 for superiority). In patients <65 years apixaban was more effective than dalteparin in the prevention of recurrent VTE. No difference in major bleeding was observed between both arms. The rate of the combined cumulative incidence of recurrent VTE or major bleeding did not differ between groups.

Together with previous trials, 35–37 the Caravaggio trial further promotes the use of direct oral anticoagulants in patients with cancer. Clinicians should take into consideration individual bleeding risks, concomitant medication, and cancer types (e.g. patients with brain tumours, known intracerebral metastases, or acute leukaemia were excluded from Caravaggio) in cancer patients with VTE.

5.4 Proprotein convertase subtilisin/kexin type 9 inhibition in VTE and LEAD

Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein cholesterol (LDL-C) receptors and subsequently raises LDL-C. 38 Modulation of VTE (deep vein thrombosis or pulmonary embolism) and LEAD (CLI, limb revascularization, or amputation for ischaemia) by PCSK9 inhibitors was assessed through prespecified analysis of two large clinical trials. The ODYSSEY-OUTCOMES trial compared alirocumab to placebo in 18 924 patients with recent acute coronary syndrome and uncontrolled dyslipidaemia with maximum-tolerated statin treatment. 30 After a median follow-up of 2.8 years, LEAD-related events occurred in 246 patients and VTE events in 92 patients. Alirocumab significantly reduced the risk of LEAD events (HR 0.69; P  = 0.004). The reduction was proportional with baseline lipoprotein(a) ( P trend  = 0.03), but not with LDL-C levels ( P trend  = 0.50). Fewer, although non-significant, VTE events were recorded in the alirocumab group (HR 0.67; P  = 0.06). VTE risk was numerically higher in the highest baseline quartile of lipoprotein(a) without significant trend across quartiles ( P trend  = 0.22) and without association with baseline quartile of LDL-C corrected ( P trend  = 0.85).

A post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) also assessed the VTE risk in 27 564 patients with stable atherosclerosis and hyperlipidaemia on statin therapy, randomized to evolocumab or placebo. 31 After a median follow-up of 2.2 years, the risk of VTE was reduced under evolocumab (HR 0.71; P  = 0.05). There was no relation between baseline LDL-C levels and magnitude of VTE risk reduction. In patients with higher baseline lipoprotein(a) levels, evolocumab reduced VTE risk by 48% (HR 0.52; P  = 0.017), whereas, in those with lower baseline lipoprotein(a) levels, evolocumab had no effect on VTE risk ( P interaction  = 0.087 for HR; P heterogeneity  = 0.037 for absolute risk reduction). There was a significant interaction between baseline lipoprotein(a) concentrations and magnitude of VTE risk reduction ( P interaction  = 0.04).

In both trials, female patients as well as non-white patients were underrepresented. Nevertheless, when combining data from both trials in a meta-analysis, a 31% relative risk reduction in VTE was observed with PCSK9 inhibition vs. placebo (HR 0.69; P  = 0.007). 31

In conclusion, PCSK9 inhibition reduce the risk of LEAD events and could reduce VTE risk. However, further specific studies are required to confirm this class effect.

Although COVID-19 is primary known as a respiratory disease caused by the SARS-CoV-2 virus, vascular complications including coagulopathy, arterial ischaemic events, and VTE are also common. 39 Indeed, hyperinflammatory and prothrombotic states characterize COVID-19 disease. Vascular endothelial cells play a pivotal role in the COVID-19 disease pathophysiology, both as target organ and as contributing contributor to inflammation and thrombosis. 39 SARS-CoV-2 infects directly the endothelium via the angiotensin-converting enzyme 2 receptor inducing endotheliitis. The systemic cytokine storm induced by SARS-CoV-2 virus affects also the endothelium. These changes result in endothelium dysfunction, likely contributing to poor patient outcome ( Figure  3 ). 39

Potential endothelial dysregulation by SARS-CoV-2 (reproduced with permission from Evans et al. 39 ). ACE2, angiotensin-converting enzyme 2 receptor; ROS, reactive oxygen species.

COVID-19 is associated with high VTE prevalence. In a recent meta-analysis, including 48 observational studies (18 093 patients) reporting VTE incidence in hospitalized patients with COVID-19, 40 overall VTE incidence was 17.0%, with 7.1% in patients admitted to the ward and 27.9% in those admitted to the intensive care unit. Most of these patients were receiving pharmacological prophylaxis, suggesting the need for intensive anticoagulation. A number of studies, evaluating optimal dose and course of thromboprophylaxis in hospitalized COVID-19 patients, are ongoing.

Several autopsy studies contributed to clarify the pathophysiology of COVID-19 disease. Ackermann et al . 41 evaluated features of seven lungs from COVID-19 infected patients, to those of patients died from acute respiratory distress syndrome secondary to influenza A (H1N1), and control lungs of age-matched uninfected patients. Both COVID-19 and H1N1 influenza patients shared some histologic pattern such as diffuse alveolar damage with perivascular T-cell infiltration. However, COVID-19 patients presented a typical pattern including severe endothelial injury associated with intracellular SARS-CoV-2 virus, and disrupted endothelial cell membranes. In addition, COVID-19 lungs showed widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries. Finally, significant angiogenesis was shown in the lungs of affected patients. 41 In light of these findings, many of the pulmonary embolisms described in the literature in COVID-19 patients may actually be episodes of in situ thrombosis.

Finally, concomitant CV disease or risk factors may aggravate the clinical course of COVID-19 disease as shown in a number of meta-analyses. Evaluating 25 studies and 65 484 patients, Ssentongo et al. 42 showed the association of CV disease and 10 pre-existing comorbidities with COVID-19 mortality. Compared to those without comorbidities, risk of death was significantly higher in patients with CV disease (RR 2.25), hypertension (RR 1.82), diabetes (RR 1.48), congestive heart failure (RR 2.03), chronic kidney disease (RR 3.25), and cancer (RR 1.47). 42

7. Conclusions

During this very special past year, a number of studies paved the way towards a better understanding of several vascular diseases, including atherosclerosis, FMD, aneurysms, and elastopathies, identifying new targets for diagnosis or therapy. In the clinical field, several seminal trials filled the big gap of knowledge on the use of antithrombotic therapies in vascular diseases. COVID-19, the unpredicted ‘guest-star’ of research in 2020 showed major repercussions in the CV system, and here again, the better understanding of its pathophysiology and extensive use of antithrombotic therapies improved the outcome of millions of patients within <10 months although optimal antithrombotic dosage in these patients remains to be determined.

Authors’ contributions

L.M. and V.A. conceived and designed the manuscript, drafted the manuscript, and revised it for important intellectual content. A.A., A.B.R., M.D.C., C.H., C.E.-K., O.S., H.S., D.S., J.R.P., and A.V. made substantial contributions to the conception and design of the manuscript, and drafted the manuscript or revised it for important intellectual content. All authors approved the final version of the manuscript and agreed to be accountable for the work.

Conflict of interest: none declared.