Medial Arterial Calcification: A Significant and Independent Contributor of Peripheral Artery Disease

Abstract

Over 200 million individuals worldwide are estimated to have peripheral artery disease (PAD). Although the term peripheral can refer to any outer branch of the vasculature, the focus of this review is on lower-extremity arteries. The initial sequelae of PAD often include movement-induced cramping pain in the hips and legs or loss of hair and thinning of the skin on the lower limbs. PAD progresses, sometimes rapidly, to cause nonhealing ulcers and critical limb ischemia which adversely affects mobility and muscle tone; acute limb ischemia is a medical emergency. PAD causes great pain and a high risk of amputation and ultimately puts patients at significant risk for major adverse cardiovascular events. The negative impact on patients' quality of life, as well as the medical costs incurred, are huge. Atherosclerotic plaques are one cause of PAD; however, emerging clinical data now shows that nonatherosclerotic medial arterial calcification (MAC) is an equal and distinct contributor. This ATVB In Focus article will present the recent clinical findings on the prevalence and impact of MAC in PAD, discuss the known pathways that contribute specifically to MAC in the lower extremity, and highlight gaps in knowledge and tools that limit our understanding of MAC pathogenesis.

Keywords: atherosclerosis; extremities; ischemia; medial sclerosis; peripheral artery disease; vascular calcification.

Figure 1:

Peripheral artery disease (PAD) stems from reduced blood flow to the lower extremities and historically has been attributed to atherosclerotic plaques. Now, emerging clinical and genetic data show that medial arterial calcification (MAC) alone can lead to vaso-occlusion. The molecular mechanisms driving MAC pathogenesis are distinct from the pathways driving atherosclerotic plaque calcification. While both atherosclerotic plaque and MAC cause PAD, the vasculature above the knee is more prone to the former, and vessels below the knee the latter. Future studies must focus on developing non-invasive tools for physicians to determine whether PAD in a particular patient stems from atherosclerosis, MAC, or both, such that therapies (i.e. statins) are targeted properly to maximize patient outcomes. Further, defining the distinct molecular mechanisms driving MAC may uncover novel therapeutic targets.