Inflammatory, Metabolic, and Coagulation Effects on Medial Arterial Calcification in Patients with Peripheral Arterial Disease

Abstract

Calcium deposits in the vessel wall in the form of hydroxyapatite can accumulate in the intimal layer, as in atherosclerotic plaque, but also in the medial layer, as in medial arterial calcification (MAC) or medial Möenckeberg sclerosis. Once considered a passive, degenerative process, MAC has recently been shown to be an active process with a complex but tightly regulated pathophysiology. Atherosclerosis and MAC represent distinct clinical entities that correlate in different ways with conventional cardiovascular risk factors. As both entities coexist in the vast majority of patients, it is difficult to estimate the relative contribution of specific risk factors to their development. MAC is strongly associated with age, diabetes mellitus, and chronic kidney disease. Given the complexity of MAC pathophysiology, it is expected that a variety of different factors and signaling pathways may be involved in the development and progression of the disease. In this article, we focus on metabolic factors, primarily hyperphosphatemia and hyperglycemia, and a wide range of possible mechanisms by which they might contribute to the development and progression of MAC. In addition, we provide insight into possible mechanisms by which inflammatory and coagulation factors are involved in vascular calcification processes. A better understanding of the complexity of MAC and the mechanisms involved in its development is essential for the development of potential preventive and therapeutic strategies.

Aging of the Arterial System

“…A clear factor of reduced wall distensibility of the arterial wall during aging is the calcium deposition within the arterial wall [ 16 ]. Although it is not clear why aging is characterized by an increased calcification of the vessel wall, it has been postulated that inflammation and oxidative stress may play a role, as both occur during aging.…”

Lower limb arterial calcification and its clinical relevance with peripheral arterial disease

“…Inflammation and specific genotypes also present a critical regulatory in the development of medial calcification. Inflammation indirectly influences the pathogenesis of medial calcification by impacting the signaling pathways involved in its pathogenesis ( 15 , 21 ). Tumor necrosis factor-α (TNF-α) is the most important cytokine, involved in both bone and vascular physiology.…”

“…This will probably influence localized blood flow, and it has also been suggested that it may exacerbate the consequences of aortic stiffness and affect brain and heart health ( 67 ). Pulse wave velocity is a diagnostic tool for peripheral arterial disease and a measurement of arterial stiffness, but it does not offer direct insights into the anatomical characteristics or biological processes of atherosclerotic plaques ( 21 , 68 ). Further research is needed to define these mechanisms.…”

“…The same study revealed that MAC-related thrombosis was more prevalent in the inferior knee arteries, whereas atherosclerotic plaque rupture-related thrombosis was more common above the knee. The possible mechanism is that medial calcification leads to blood stasis due to loss of pulsatile blood flow, which increases the risk of arterial thrombosis ( 21 ). This suggests that the mechanism of arterial occlusion in PAD may be more related to thromboembolism than thrombosis at the site of plaque rupture as commonly reported in coronary artery disease ( 73 ).…”

“…In patients with aging, diabetes, and CKD, in whom media calcification is significantly more prevalent ( 37 ). Although the pathogenesis is better understood, there is still no effective treatment and preventive strategy for MAC ( 21 ). The current way relies on the existing risk factors, which means that there is no specific treatment.…”