Antioxidant treatment in peripheral artery disease: the rationale is there, but what about clinical results?

https://doi.org/10.1016/j.coph.2018.01.008Get rights and content

Peripheral arterial disease is a major cause of morbidity and disability and has been consistently associated with an adverse overall prognosis. Oxidative stress has been linked to vascular disease, with several suggested pathogenetic mechanisms, leading to various insults of the arterial wall and, ultimately, to atherothrombotic disease. Considering that the pathophysiological background is quite compelling, attenuation of oxidative processes by means of various substances with antioxidant properties has been conceived as a promising therapeutic target. However, clinical results have been mostly disappointing and ‘antioxidant’ therapies are still far from being integrated into treatment algorithms for vascular disease.

Introduction

Peripheral artery disease (PAD) is a term primarily used for describing obstructive atherosclerotic lesions affecting the arterial vasculature of the lower extremities [1••]. During the last decade alone, global ageing, increased incidence of diabetes and smoking resulted in a 23% increase in the number of PAD patients [2]. Contemporary data show that worldwide more than 200 million people are affected with over 40 million of them living in Europe. Past the age of 65, its prevalence is exponentially increasing and by the age of 80 one fifth of the general population is suffering from PAD. In Western Europe, mortality directly related to PAD was estimated to 3.5 per 100 000 individuals while cardiovascular mortality within 5 years after diagnosis of stable PAD is 11–23% [3] (these patients mostly die from complications related to coronary artery disease and stroke). Risk factors are similar to those for other atherosclerotic diseases (carotid artery disease, coronary artery disease, and so on). Smoking exhibits strong association with PAD and heavy smokers have a four-fold higher risk of developing IC compared to non-smokers [4]. Diabetes is another well-described risk factor with reports showing that for every 1% increase in glycosylated hemoglobin there is a corresponding 26% increase in PAD risk [5]. Important associations with hypertension and hypercholesterolemia have also been described [2].

Central to the pathogenesis of atherosclerosis are pathways that result in oxidative stress (Figure 1). Oxidative stress is commonly defined as the redox status present when an imbalance exists between antioxidant mechanisms and oxidative activity species, including reactive oxygen (ROS), nitrogen (RNS), non-radical and free radical species [6]. Its contribution to the atherogenic process has been well described in other papers [7, 8•]. In this short review we will focus on the main clinical studies connecting oxidative stress with PAD and discuss the pharmacologic interventions tested so far in an effort to mitigate oxidative damage.

Section snippets

Effects on vessels

In the majority of clinical trials, investigators measured the level of oxidative stress specific biomarkers [9] in the serum of PAD patients and compared it with controls. Loffredo et al. [10] examined whether an imbalance between oxidative stress and nitric oxide (NO) exists in these patients. Nitrite and nitrate (NOx) were selected as markers of NO generation and 8-hydroxy-2-deoxyguanosine (8-OHdG) as a marker of oxidative stress. Samples were collected from 40 PAD patients and 40 controls.

Conclusion

The oxidative stress ‘hypothesis’, as a contributor to atherosclerotic disease, is an attractive premise, supported by a large number of bench studies. However, the translation of this basic evidence to meaningful beneficial effects at bedside has been fraught with frustration and disappointment. Evidence specifically regarding peripheral arterial disease is sparse and at this time there is no basis to support recommendations for interventions aimed at the redox milieu.

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (44)

  • S.K. Myung et al.

    Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials

    BMJ

    (2013)
  • V. Aboyans et al.

    2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries

    Eur Heart J

    (2017)
  • F.G. Fowkes 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)
  • L. Norgren et al.

    Inter-society consensus for the management of peripheral arterial disease

    Int Angiol

    (2007)
  • E. Selvin et al.

    Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus

    Ann Intern Med

    (2004)
  • J.A. Leopold et al.

    Oxidative risk for atherothrombotic cardiovascular disease

    Free Radic Biol Med

    (2009)
  • A.J. Kattoor et al.

    Oxidative stress in atherosclerosis

    Curr Atheroscler Rep

    (2017)
  • S.M. Krishna et al.

    A review of the pathophysiology and potential biomarkers for peripheral artery disease

    Int J Mol Sci

    (2015)
  • L. Loffredo et al.

    Imbalance between nitric oxide generation and oxidative stress in patients with peripheral arterial disease: effect of an antioxidant treatment

    J Vasc Surg

    (2006)
  • L. Loffredo et al.

    Oxidative-stress-mediated arterial dysfunction in patients with peripheral arterial disease

    Eur Heart J

    (2007)
  • G. Brevetti et al.

    Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle–brachial pressure index

    Circulation

    (2003)
  • L. Loffredo et al.

    NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease

    Int J Cardiol

    (2013)
  • Cited by (0)

    View full text