Depression and peripheral arterial disease: A call to action

Joel Ramirez and Marlene Grenon

With “an indisputable association between depression and peripheral arterial disease (PAD)”—nearly a third of PAD patients experience comorbid depression or depressive symptoms—Joel Ramirez and Marlene Grenon here call for vascular interventionalists to take a more active role in their patient’s mental health: increasing the awareness of the links between these two conditions, recognising the symptoms of depression, and referring patients to a mental health specialist where appropriate.

Peripheral arterial disease (PAD) is a major global health problem that has been estimated to affect more than 200 million people worldwide with an increasing incidence.1 PAD has been associated with an increased risk of limb amputation, adverse cardiovascular events, and mortality, as well as impaired quality of life, which have collectively resulted in a high economic burden on society.2 Despite widespread campaigns to improve cardiovascular health, the prevalence of PAD is expected to increase with the ageing world population. Given the large impact that PAD has, it is important that as interventionalists we are able to adequately identify, prevent, and treat modifiable risk factors for PAD.

Although not commonly recognised by interventionalists, the incidence of depression has been rising, particularly in young adults. Depression is a leading cause of disability worldwide,3 and has become a well-recognised risk factor for the development and progression of coronary artery disease (CAD). In fact, depression has been formally recognised by the American Heart Association (AHA) as a risk factor for CAD incidence and adverse outcomes, which has resulted in the creation of guidelines for depression screening in this patient population.4 Given the overlap between risk factors for CAD and PAD, investigators have recently begun to examine the association between depression and PAD.

My colleagues and I have dedicated our recent research efforts to the problem of depression and PAD. Our understanding of the risk factors for the development and progression of PAD used to be narrower, as we primarily only considered traditional risk factors such as smoking, hypertension, hyperlipidaemia, and diabetes, among others. We now have a more comprehensive understanding of this disease and have recognised that mental illness, specifically depression, may play a role in the development of PAD and adverse outcomes among patients with PAD.

It has been reported that nearly a third of patients with PAD have comorbid depression or have experienced depressive symptoms.5 Among patients with PAD, depressive symptoms have been associated with worse claudication, decreased patency after peripheral revascularisation, and increased incidence of major amputation, adverse cardiac events, and mortality.6 From a pathophysiological perspective, our findings support mechanistic pathways linking depression to PAD. We have shown that worse depressive symptoms are correlated with higher levels of inflammation,7 which may mediate the development of PAD and adverse outcomes. Aside from its pro-inflammatory properties, we recently reviewed6 a tremendous body of evidence that suggests that depression can dysregulate the metabolic system, the hypothalamic-pituitary-axis, and the coagulation pathway, all of which are crucial to the proper functioning of the cardiovascular system. Although the relationship between depression and PAD is convincing, there are currently a paucity of reports examining how antidepressants or behavioral therapy alters the risk of PAD incidence or outcomes in this patient population. However, a recent study by Arya et al has observed that among patients with PAD and depression, the absence of antidepressant use was associated with an increased risk of limb loss.8

The scientific evidence supporting a relationship between depression and PAD is growing. To address this new burden of disease, we need to generate innovative solutions and engage leaders in vascular medicine and surgery. The first step in addressing the role of depression in PAD is increasing awareness of the relationships that have been reported.6 While outside the comfort zone of most interventionalists, understanding the role that depression plays in PAD could provide additional insight into opportunities to improve outcomes in this patient population. We have a responsibility to address the well-being of our patients, by enabling open dialogue about mental health and by ensuring that our patients are receiving proper screening and treatment for mental illness. Although most interventionalists are uncomfortable treating or managing mental illness, as the impact of depression on PAD becomes more clear, it is essential that we recognise the signs and symptoms of depression, and refer patients to mental health specialists or primary care physicians for appropriate diagnosis and treatment.

Our understanding of the pathophysiology that implicates depression with the development of atherosclerosis is largely based upon CAD animal models and patients with CAD. Although CAD has a similar pathophysiology to PAD, there are some differences, and research specific to PAD will be necessary to better understand the relationship between depression and PAD. Furthmore, our understanding of the clinical impact that depression has on PAD is currently limited to a few studies.6 We strongly encourage that investigators conduct basic science, translational, and clinical research examining the association between depression and PAD. For clinical and translational research studies, we recommend collecting data related to depression and/or eliciting a brief psychiatric history, documenting antidepressant medications or utilisation of behavioral therapy, and screening for depression using validated questionnaires, such as the Patient Health Questionnaire-9 or Geriatric Depression Scale Short Form. These variables can also be easily collected for secondary aims in other studies of patients with PAD. Additional research investigating the impact of depression on incidence, progression, and outcomes of PAD is necessary, in order to clarify the mechanisms linking these diseases. As research examining the relationship between depression and PAD becomes more robust, we hope that screening and treatment guidelines will be created in order to influence everyday clinical practice. Given that there are similar guidelines from the AHA that exist for depression and CAD, this seems reasonable.4

Furthermore, innovative digital health solutions that aim to approach the treatment of depression in ways that are more adapted to the needs of our population (such as telehealth and on-the-go apps) are becoming more available. Utilising these technologies may allow for improved identification and management of depression in patients with PAD. We encourage vascular clinicians and investigators to engage with this rapidly evolving landscape of innovation and digital health, where disruption may help improve the care that patients with PAD receive.

There exists an indisputable association between depression and PAD. Although our understanding of this relationship is currently limited by existing research, we should increase the awareness of the importance of depression among patients with PAD and those at high risk for PAD, as well as refer patients to mental health specialists or primary care physicians for screening, diagnosis, or treatment when appropriate. Additionally, when designing studies of PAD, we strongly recommend collecting information on mental health and specifically depression. Lastly, we call for vascular interventionalists to become more engaged in innovative digital health solutions that are becoming increasingly available for the treatment of chronic diseases and mental health.

Joel Ramirez is a vascular surgeon in the Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, USA.

Marlene Grenon is a vascular surgeon in the Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, USA, and at Evry Health, Dallas, USA.

1. Fowkes FG, Rudan D, Rudan I, et al Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013; 382: 1329-1340. 2013/08/07. DOI: 10.1016/S0140-6736(13)61249-0.
2. Morley RL, Sharma A, Horsch AD, et al Peripheral artery disease. BMJ 2018; 360: j5842. 2018/02/09. DOI: 10.1136/bmj.j5842.
3. Ferrari AJ, Charlson FJ, Norman RE, et al Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med 2013; 10: e1001547. 2013/11/14. DOI: 10.1371/journal.pmed.1001547.
4. Lichtman JH, Bigger JT, Jr., Blumenthal JA, et al Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Psychiatric Association. Circulation 2008; 118: 1768-1775. 2008/10/01. DOI: 10.1161/CIRCULATIONAHA.108.190769.
5. McDermott MM, Greenland P, Guralnik JM, et al Depressive symptoms and lower extremity functioning in men and women with peripheral arterial disease. J Gen Intern Med 2003; 18: 461-467. 2003/06/26.
6. Ramirez JL, Drudi LM and Grenon SM. Review of Biologic and Behavioral Risk Factors Linking Depression and Peripheral Artery Disease. Vasc Med 2018; In Press.
7. Hernandez NV, Ramirez JL, Khetani SA, et al Depression severity is associated with increased inflammation in veterans with peripheral artery disease. Vasc Med 2018; 23: 445-453. 2018/07/24. DOI: 10.1177/1358863X18787640.
8. Arya S, Lee S, Zahner GJ, et al The association of comorbid depression with mortality and amputation in veterans with peripheral artery disease. J Vasc Surg 2018 2018/03/29. DOI: 10.1016/j.jvs.2017.10.092.


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