R3i Editorials

August 2021
Understanding vein graft failure: a role for PPARalpha in pathobiology
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Peripheral artery disease (PAD) is a common but often underdiagnosed and undertreated condition. Recent estimates indicate that PAD affects more than 230 million people globally 1, and prevalence is increasing as populations age and cardiovascular risk factors, including diabetes and dyslipidaemia, become more common 1,2. Indeed, between 2000 and 2015, the prevalence of PAD increased by about 45%, disproportionately higher in middle- and lower-income countries than in high-income countries 1. The burden of disease is substantial; PAD is a major contributor to years lived with disability, particularly among those patients with severe PAD requiring amputation 3,4.

While there has been some improvement in pharmacotherapeutic approaches 5,6, for patients with severe occlusive disease surgical treatment using autologous vein grafts or prosthetic graft bypass is needed. Both approaches are limited by short‐term failure and low long‐term patency which impact survival and event‐free survival 7. Clearly, there is an unmet need to better understand the mechanisms that contribute to vein graft failure.

Relevant to this question is new evidence demonstrating a role for peroxisome proliferator-activated receptor alpha (PPARα) pathway in vein graft failure. Decano and co-workers 8 applied a systems approach to investigate potential pathogenic mechanisms, using an experimental vein graft mouse model. PPARα agonism was shown to exert anti-atherogenic and anti-inflammatory effects during vein graft lesion development. In vitro studies showed that PPARα modulated macrophage metabolism, resulting in a lessening of inflammatory properties. The enrichment of metabolic and inflammatory pathways in the experimental mouse model suggests that macrophages are key players in vein graft failure, and that their effects may be modulated by PPARα.

To further establish the suppressive role of PPARα in vein graft lesion development, researchers tested the effects of treatment with low dose pemafibrate, a novel selective PPARα modulator (SPPARMα) in the experimental mouse model. Pemafibrate treatment suppressed vein-graft lesion development; the neointima of pemafibrate-treated mice contained fewer macrophages than that of control grafts, whereas there was no difference in smooth muscle content. This effect appeared to be independent of triglyceride-lowering 8. In another experimental model of arteriovenous fistula (AVF) construction, pemafibrate treatment improved AVF patency and suppressed lesion progression 8.
Not only are these findings novel, but the use of a systems approach aids understanding of the underlying mechanisms involved in the development of vein graft failure. Findings from this study are pivotal to identify new targets, such as PPARα, with a view to developing and testing new pharmacotherapeutic approaches, such as SPPARMα. Such insights will be critical to prevent vein graft failure, and ultimately reduce the burden of PAD.

References

  1. Song P Rudan D Zhu Y, et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis.
    Lancet Glob Health 2019;7:e1020-e1030.
    2. 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;382:1329–40.
    3. Kohn CG, Alberts MJ, Peacock WF, et al. Cost and inpatient burden of peripheral artery disease: Findings from the National Inpatient Sample. Atherosclerosis 2019;286:142-6.
    4. GBD 2017. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1789-858.
    5. Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: Insights from the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018;137:338-50.
    6. Anand SS, Caron F, Eikelboom JW, et al. Major adverse limb events and mortality in patients with peripheral artery disease: The COMPASS Trial. J Am Coll Cardiol 2018;71:2306-15.
    7. Owens CD, Gasper WJ, Rahman AS, Conte MS. Vein graft failure. J Vasc Surg 2015;61:203–16.
    8. Decano JL, Singh SA, Gasparotto Bueno C, et al. Systems approach to discovery of therapeutic targets for vein graft disease PPARα pivotally regulates metabolism, activation, and heterogeneity of macrophages and lesion development. Circ Res 2021;DOI:10.1161/CIRCULATIONAHA.119.043724