Hey MAC, you are not an innocent bystander


Atherosclerotic disease, intimal calcification, is one cause of peripheral arterial disease (PAD) and is the most referenced. Vascular calcification is a pathology in the vascular system with various forms. The first description of medial sclerosis in blood vessels of the extremities, now known as Monckeberg's sclerosis, appeared in the medical journal Virchows Archiv in Berlin (1903).1 Silbert et al. (1953) described this form of medial artery calcification (MAC) as having no symptoms or signs of impaired circulation.2 However, new research is bringing forth clinical data that shows MAC, in the absence of atherosclerosis, is an equal contributor to PAD.

Medial artery calcification (MAC) 

Both intimal calcification and MAC contribute to non-healing wounds in critical limb ischemia (CLI) and PAD patients; but they are independent disease states and driven by different and distinct processes. Patients can experience PAD symptoms without intimal calcification or luminal stenosis. MAC patients can have classical intermittent claudication pain up to 30% of the time, yet most individuals do not experience or identify any leg pain. Severe MAC is associated with diabetic nephropathy, retinopathy, and macrovascular complications. A diagnosis can be made via radiographic findings or from the use of ultrasound (US). One recent study found that ultrasound (US), an affordable, simple, and reliable test, is a more sensitive imaging technique than conventional radiography to detect lower limb MAC, potentially making it an excellent tool to identify high-risk wound care patients, especially those with DM and CKD.5, 7

It is widely recognized that DM patients demonstrate calcification of the arteries below the knee. Vessel occlusion due to thrombus is common, yet, 67% of occlusive thrombi occur without a significant atherosclerotic plaque or intimal stenosis.4 Most atherosclerotic sclerotic blockages occur in the arteries above the knee, while MAC-related thrombus was found in arteries below the knee. Patients with intimal and MAC peripheral arterial disease are at a higher risk of developing peripheral wounds, digit/foot tissue loss, and higher amputation rates for the lower extremity. Due to arteriole stiffness, decreased arterial compensation reduces tissue perfusion, leading to microcirculatory distortion. A pilot study found that a contrast-free MRI showed impaired calf muscle perfusion in people with diabetes and MAC.5 One of the possible explanations is that patients with tibial artery calcification have microvascular disease that leads to altered skeletal muscle perfusion, and exercise vasodilation is compromised in the medial and small arterioles with reduced capacitance due to the rigid microvascular structures. Ultimately, increased arterial stiffness reduces the downstream blood flow and skeletal muscle microcirculation, even without intimal calcification or stenosis. MAC is a poly-vascular disease with genetic, epigenetic, age, and disease-related mechanisms of action.

Vitamin K2

Vitamin K2 may be a significant player in the cardiovascular health of patients. Arterial stiffness is a surrogate marker for cardiovascular morbidity and mortality. Recent evidence shows that vitamin K-dependent proteins play a vital role in cardiovascular disease. One such protein that has a pivotal role is the Matrix Gala protein (MGP). It is commonly considered the most potent inhibitor of vascular calcification, along with Bone Gala protein/osteocalcin. Some exciting research is on the horizon regarding wound care patients and the correlations between arterial stiffness, endothelial dysfunction, and wound healing. There may be a relationship between vitamin K2-MK7-dependent regulation of endothelial function via the MGP to inhibit osteogenic properties in vascular endothelial cells. Long-term depletion of vitamin K in patients on anticoagulation therapy have noted significant vascular calcifications. Nevertheless, despite a significant reduction in the biomarker, MGP, two large studies failed to demonstrate any improvement in vascular calcification with supplemental vitamin K2-MK7.6


Vascular calcification was initially considered a byproduct of aging. However, we are now learning it is a highly regulated cell-mediated pathway. In 2015, O'Neil et al. published the first histopathological study on MAC and amputated limbs from patients with critical limb ischemia.3,5,7 Their findings noted that nearly all the vessels in the lower extremity arteries showed intimal thickening and luminal narrowing. Yet, there were low or no lipids present in the narrow areas. Around 72% of the arteries had MAC, and only 43% had intimal calcification.3,4,6,7,8 In the areas with intimal calcification, it was contiguous with MAC and precipitated along the elastic lamina within the vessels. Perhaps, vessel wall stiffening alone can trigger a sudden lack of blood flow. With a new understanding of MAC, we might be able to assist our patients with PAD via an affordable and safe option, like Vitamin K2-MK7; providing us with a viable and promising pathway to improve the vascular health of our wound care patients.


  1.  Mönckeberg JG. Uber die reine Mediaverkalkung der Extremitätenarterien und ihr verhalten zur Arteriosklerose. Virchows Arch Pathol Anat. 1903;171:141–67. doi: 10.1007/BF01926946.
  2. Silbert, S., Lippmann, H.I. and Gordon, E., 1953. Monckeberg's arteriosclerosis. Journal of the American Medical Association, 151(14), pp.1176-1179.
  3. O’Neill, W.C., Han, K.H., Schneider, T.M. and Hennigar, R.A., 2015. Prevalence of nonatheromatous lesions in peripheral arterial disease. Arteriosclerosis, thrombosis, and vascular biology, 35(2), pp.439-447.
  4. St Hilaire C. Medial Arterial Calcification: A Significant and Independent Contributor of Peripheral Artery Disease. Arterioscler Thromb Vasc Biol. 2022 Mar;42(3):253-260. doi: 10.1161/ATVBAHA.121.316252. Epub 2022 Jan 27. PMID: 35081727; PMCID: PMC8866228.
  5. Zheng J, Li R, Zayed MA, Yan Y, An H, Hastings MK. Pilot study of contrast-free MRI reveals significantly impaired calf skeletal muscle perfusion in diabetes with incompressible peripheral arteries. Vasc Med. 2021 Aug;26(4):367-373. doi: 10.1177/1358863X21996465. Epub 2021 Mar 22. PMID: 33749394; PMCID: PMC8822493.
  6. Hariri E, Kassis N, Iskandar JP, Schurgers LJ, Saad A, Abdelfattah O, Bansal A, Isogai T, Harb SC, Kapadia S. Vitamin K2-a neglected player in cardiovascular health: a narrative review. Open Heart. 2021 Nov;8(2):e001715. doi: 10.1136/openhrt-2021-001715. PMID: 34785587; PMCID: PMC8596038.
  7. Baubeta Fridh E, Andersson M, Thuresson M, Sigvant B, Kragsterman B, Johansson S, Hasvold P, Falkenberg M, Nordanstig J. Amputation Rates, Mortality, and Pre-operative Comorbidities in Patients Revascularised for Intermittent Claudication or Critical Limb Ischaemia: A Population Based Study. Eur J Vasc Endovasc Surg. 2017 Oct;54(4):480-486. doi: 10.1016/j.ejvs.2017.07.005. Epub 2017 Aug 7. PMID: 28797662.
  8. Suzuki E, Kashiwagi A, Nishio Y, Egawa K, Shimizu S, Maegawa H, Haneda M, Yasuda H, Morikawa S, Inubushi T, Kikkawa R. Increased arterial wall stiffness limits flow volume in the lower extremities in type 2 diabetic patients. Diabetes Care. 2001 Dec;24(12):2107-14. doi: 10.2337/diacare.24.12.2107. PMID: 11723092. 
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