MAC and IAC represent distinct pathophysiologies that correlate with traditional cardiovascular risk factors in different ways (1, 33). As both forms of calcification in the majority of PAD patients, it is hard to assess the proportional impact of specific risk factors to their development.

MAC is most commonly associated with age, diabetes and chronic kidney disease (CKD) (34–39). It is recognized as an age-associated pathology (39). The aged VSMCs have been correlated with the upregulation of molecules that drive osteogenic differentiation (40, 41). It was suggested that aged VSMCs might play a key role in driving osteo/chondrogenic change and calcification in PAD (40, 41). Diabetes and CKD are considered inflammatory conditions. The TNF-α, inflammatory cytokine, and inflammation-induced oxidative stress have been shown to contribute to arterial calcification linked with diabetes by promoting pro-calcific Msx2-Wnt signaling cascades (42, 43). Additionally, metabolic disorders in diabetes and CKD lead to vascular mineralization. High serum phosphate levels not only facilitate the precipitation of hydroxyapatite crystals but also modulate critical signaling pathways central to MAC pathophysiology: the phenotypic shift of VSMCs to osteoblast-like cells, VSMCs apoptosis, extracellular matrix remodeling, and the suppression of monocyte/macrophage differentiation into osteoclast-like cells (44, 45). Multiple overlapping mechanisms by which diabetes could result in arterial calcification were proposed: inflammation, hyperglycemia, advanced glycation end products, circulation of osteoprogenitor cells, and reduced levels of matrix gamma carboxy glutamic acid protein (46–49).

Studies on IAC, report positive associations with smoking and dyslipidemia (35, 50). Nicotine found in tobacco promotes vascular calcification, and its mechanisms involve the hyperactivation of inflammatory responses, oxidative stress, autophagy, increased cell apoptosis, extracellular matrix degradation, and disruption of endothelial function (51–53). LDL causes the formation of atherosclerosis through various mechanisms, including the upregulation of inflammatory cytokines and adhesion molecules on vascular endothelial cells, increased transport of oxPLs, inhibition of nitric oxide synthesis, resulting in vascular remodeling, and promotion of smooth muscle cell proliferation and foam cell formation (54).

These studies highlight the various risk factors that contribute to the complex pathophysiology of LLAC and offer valuable practical guidelines for the therapeutic and preventive management of LLAC.

Intimal calcification is associated with atherosclerotic luminal stenosis, a critical factor in the genesis of territorial hypoperfusion. In the intracranial arteries and coronary arteries, the clinical and pathologic studies demonstrated a significant correlation between calcium burden and occlusive disease (55–57). In the lower extremities, two studies used CTA to investigate the relationship between calcium burden and the severity of lumen stenosis. Zettervall et al. found that LLAC was related to the severity of ischemia in patients with PAD and had shown a moderate correlation with the severity of occlusive disease. However, there was a weak correlation when included only those patients with critical limb-threatening ischemia (CLTI) (58). This phenomenon could be caused by vascular calcification of PAD is mostly located in the media and might even be more obvious in CLTI (7). Yan et al. further found that the LLAC of the aortoiliac artery was relatively weak (36). One possible mechanism the iliac artery had a relatively large diameter, making it less affected by the calcium volume of the vessel wall. Nevertheless, the retrospective design of these studies and their quantitative measurements of LLAC negatively impact the reliability of identifying a connection between LLAC and vascular stenosis. Large prospective studies using more precise measurement tools are still needed to confirm the correlation between LLAC and vascular stenosis.

Historically, MAC is thought to be limited to the media and not associated with luminal stenosis (28). However, the accumulation of calcification within the media layer can lead to vascular deformation and the extension of calcified plaques into the lumen. Additionally, medial calcification can also lead to subendothelial hyperplasia, causing nonatheromatous intimal thickening and resulting in luminal stenosis (30, 59). A study in patients with CKD showed that there was a connection between the severity of MAC in abdominal arteries and carotid intima–media thickness (60). Although it happens in different vascular beds, this may indicate that MAC loading of the vascular wall can result in adverse remodeling. In both diabetic and nondiabetic limbs, Ferrier observed a strong correlation between advanced MAC and significant obstruction of the metatarsal artery (61). In small vessels, which are disproportionately influenced by MAC, this can lead to catastrophic consequences on the lumen cross-section area, including the potential pruning of pedal end arteries with far-reaching adverse effects on tissue perfusion (62).

MAC caused a significant change in the vessel wall structure and function. The accumulation of calcium deposits in the media between the elastic fiber induces arterial stiffening, resulting in degradation of compliance and vasodilation restriction (63, 64). Nonetheless, while the adverse impact of MAC in the aorta on stiffening, systolic blood pressure, and coronary perfusion has been extensively researched, the pathological effect of MAC in other vascular beds is poorly understood (65, 66). The peripheral arterial system stiffens in PAD with MAC. 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.

As mentioned before, IAC and MAC coexist in patients with PAD (69). By restricting positive vascular remodeling and promoting negative one, MAC can have an impact on atherosclerosis (70). Additionally, it can cause subendothelial hyperplasia, which can aid in the development of atherosclerotic plaque (30). Consequently, when MAC and atherosclerosis coexist in the same artery segment, the signs of PAD are more severe and develop more quickly.

The relationship between calcification and acute coronary artery embolism has been confirmed (71, 72). In patients with CLTI, the histopathology in the lower limb arterial is characterized by luminal occlusion of the lower leg vascular and is accompanied by inconspicuous atherosclerosis (73). One study indicates that the presence of calcium deposit is independently and inversely associated with acute thrombosis in patients with PAD (74). Due to the most widely used imaging technologies (CT and DSA) cannot differentiate between medial and intimal calcium deposits, making it challenging to assess their specific contribution to arterial thrombosis development.

A histopathological investigation of 60 patients with CLTI who had amputation reported a 5.6% prevalence of arterial thrombotic occlusion. Interestingly, 70% of the specimens were predominantly MAC without significant atherosclerotic plaque (7). Another study examining arterial specimens from 95 patients who had amputation reported that 67.5% of the samples had occlusive thrombosis without significant atherosclerotic plaque (73). 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).

LLAC is commonly observed in patients with PAD, and it has been linked to the severity of PAD symptoms (58). A growing interest among researchers in the clinical significance of LLAC is due to findings indicating that severe calcification independently correlates with major amputation and mortality. Methods for evaluating LLAC are not yet unified, and different studies use different measurement methods. Guzman et al. first used agaston score to assess calcification in the tibial artery (4). In patients with PAD, they found that the highest tibial arterial calcification scores were linked to worsening levels of limb ischemia and it identifies high-risk populations for amputation. Building on this scoring method, Chowdhury et al. evaluated LLAC and found that higher scores were an independent predictor for cardiovascular events and all-cause mortality (3).

Treatment PAD includes endovascular revascularization and open surgical operations. The available data show that LLAC limits the success of peripheral arterial revascularization. In patients with femoropopliteal artery occlusions, Itoga et al. demonstrated that 100% calcification on preoperative CT was a predictor of technical failure of endovascular revascularization (75). Due to the small vessel caliber, tibial artery occlusion is difficult to analyze. Kang et al. used the semiquantitative analysis of CTA to categorize calcification severity in tibial arteries and found that extensive calcification is also a predictor of technical failure in the tibial artery region (5). Consequently, the success rate of revascularization is lower in patients with severe calcification and improvement is often short-term, leading to a late lumen loss. In 2014, a study showed that the presence of annular calcium distribution seems to be the strongest predictor of optimal drug absorption when drug-eluting balloons are used (76). Tepe et al. retrospective study used PACSS scoring to show grade 4 was significantly correlated with 6-month primary patency after drug-coated balloons angioplasty for femoropopliteal lesion (77). Additionally, circumferential calcification was strongly correlated with a less favorable late lumen loss. The reasons for increased late lumen loss in severely calcified lesions are as follows. Firstly, the biological efficacy of drug-eluting balloon treatment relies on adequate drug transfer and accumulation in the target artery. However, the presence of annular calcification in the arterial wall may be an impermeable barrier for the drug, thus diminishing efficacy of the therapy and bare metal stent use was associated with better patency outcomes (78, 79). Second, annular calcification reduces vascular compliance and may lead to subacute vascular recoil, triggering increased late lumen loss. Moreover, above studies received different treatment methods, including stents, atherectomy, or drug-eluting balloons, the observations would not be applied to all types. Future studies need to compare the outcomes of calcification between common treatment modalities in larger samples to draw firmer conclusions.

LLAC can not only serve as a predictor of success rate of revascularization procedures and greater restenosis but also impact the prognosis after revascularization therapies, including function outcome and postintervention mortality. Megale et al. showed that the LLAC scores are linked to an increased risk of mortality, regardless of the revascularization method used (80). To better assess and predict limb-related outcomes, various clinical scoring systems have been developed. LLAC evaluation can further stratify the existing clinical scores. Huynh et al. established a scoring system focusing on calcification morphology, circumference, and length in the common iliac artery, found that incorporation of this score into the Vascular Quality Initiative mortality prediction model improved risk stratification for patients who were initially classified as lower-risk group risk for mortality (81). The Society for Vascular Surgery WIfI (wound, ischemia, foot infection) system stratifies the risk of amputation, independent of the vascular anatomy. The global limb anatomic staging system (GLASS) enables assessment of the anatomic complexity and target artery pathway for surgical intervention (82, 83). Nevertheless, the relative contribution of arterial occlusive disease below the ankle is not known. The MAC has been most frequently described in the foot artery plaque lesions (84). Recently, a study by Liu et al. used foot x-rays to develop a simple scoring system to assess pedal artery calcification in patients with CLTI undergoing infrainguinal revascularization (85). Higher pedal calcification scores were correlated with a high risk of major amputation. These studies not only establish a clear relationship between MAC and adverse limb outcomes, but also demonstrate the potential of the MAC score to complement the current standard of noninvasive tests, WIfI staging, and GLASS in constructing a more comprehensive view of each patient's disease process, anatomy, and evolving limb threat in addition to better direct the therapy of patients with CLTI. Further large-scale studies are needed to verify and compare these results.