Carotid Artery Calcification: What We Know So Far

Carotid artery calcification (CAC) is a well-known marker of atherosclerosis and is linked to a high rate of morbidity and mortality. CAC is divided into two types: intimal and medial calcifications, each with its own set of risk factors. Vascular calcification is now understood to be an active, enzymatically regulated process involving dystrophic calcification and endothelial dysfunction at an early stage. This causes a pathogenic inflammatory response, resulting in calcium phosphate deposition in the form of microcalcifications, which causes plaque formation, ultimately becoming unstable with sequelae of complications. If the inflammation goes away, hydroxyapatite crystal formation takes over, resulting in macro-calcifications that help to keep the plaque stable. As CAC can be asymptomatic, it is critical to identify it early using diagnostic imaging. The carotid artery calcification score is calculated using computed tomography angiography (CTA), which is a confirmatory test that enables the examination of plaque composition and computation of the carotid artery calcification score. Magnetic resonance angiography (MRA), which is sensitive as CTA, duplex ultrasound (DUS), positron emission tomography, and computed tomography (PET-CT) imaging with (18) F-Sodium Fluoride, and Optical Coherence Tomography (OCT) are some of the other diagnostic imaging modalities used. The current therapeutic method starts with the best medical care and is advised for all CAC patients. Carotid endarterectomy and carotid stenting are two treatment options that have mixed results in terms of effectiveness and safety. When patient age and anatomy, operator expertise, and surgical risk are all considered, the agreement is that both techniques are equally beneficial.


Introduction And Background
Carotid Artery Calcification (CAC) has been recognized as a symptom of aging for decades. Vascular calcification, once thought to be a passive and degenerative process, is now widely recognized as an active and self-regulating process involving complex cellular and enzymatic components. Vascular calcification is well documented to play a role in the progression of atherosclerosis, and it can be found in 80-90% of atheromas [1]. Calcification can develop in the medial and intimal layers of smaller elastic vessels, such as the intracranial and cervical carotid arteries [2]. Atheromatous plaques arise because of intimal calcification, which can lead to vascular stenosis, occlusion, or other secondary degenerative alterations [2]. Symptomatic carotid artery stenosis, ischemic stroke, blindness, cognitive impairment, and severe morbidity and mortality are all possible outcomes of such changes. Current research on CAC epidemiology and risk factors, pathogenesis, and the best clinical diagnostic and management approaches are reviewed in this article.

Review
In a cohort analysis of 1132 patients, predominant intimal calcification was found in 30.9% and medial calcification in 46.9%, with few isolated risk factors in the middle [3]. Overweight and obesity are major determinants of metabolic syndrome, an all-too-common and all-too-serious clinical and public health challenge. Clinicians have traditionally evaluated each of the major risk factors contributing to metabolic syndrome on an individual basis. There is evidence, however, that the risk factors are more than additive. Age, male gender, positive family history, and higher pulse pressures all contribute to the occurrence of CAC linked with both types of calcifications [1]. Carotid artery calcification was found in 75% of males over 75years-old and 62% of females over 75-years-old in a comprehensive review [4]. Clinical research in recent years has found that people of Asian and Caucasian descent had a higher prevalence of cerebral arterial calcification [5][6][7]. As Wu et al. point out, the Rotterdam research, the biggest population-based cohort study in a general community with 2,495 participants, backs this up [5,8]. The Rotterdam study established carotid artery calcification as a substantial risk factor for stroke in the White population after assessing cerebral carotid artery calcification volume on CT scans in 2,323 stroke-free older Caucasian patients. The findings also revealed that cerebral carotid artery calcification contributes more to all-cause strokes than large-artery atherosclerosis, contrary to popular belief [5,9].
Diabetes, hypercholesterolemia, smoking, and hypertension are all known risk factors for the development of cardiovascular and systemic atherosclerotic disease in CAC [5]. Smoking and high blood pressure are two risk factors for dominant intimal calcification. Hypertension damages endothelial cells, resulting in proinflammatory activity and decreased vascular contractility, which leads to atherosclerosis. Type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), end-stage renal disease (ESRD), and osteoporosis, all of which have an inherent calcium-phosphate imbalance, are major risk factors for Monckeberg medial calcification. Men and T2DM patients are more likely to develop this form of vascular calcification. Patients with ESRD who showed medial calcification were younger, had a higher prevalence of the calcium-phosphate problem and were hemodialysis dependent [10]. Calciphylaxis is a specific manifestation of medial calcification reported in hemodialysis patients [5,[10][11][12][13][14][15].

Pathogenesis and pathophysiology
Some similarities and variations exist between the mechanisms underlying intimal and medial calcification. Microcalcifications, also known as spotty calcifications, occur during the first stage of intimal calcification, which is characterized by an acute inflammatory response. Several investigations have established that these little calcium deposits (0.5 to 15 m) are an insidious source of plaque instability, since they have been found in high-risk, unstable, and ruptured plaques in abundance [2,[16][17][18].
Endothelial dysfunction of the vascular intima results in the deposition of low-density lipoprotein particles (LDLs) within the intimal layer of the artery, which starts the pathological process of microcalcification development. The presence of low-density lipoprotein cholesterol (LDLC), oxidative stress, and other harmful elements cause an inflammatory reaction within the artery wall, resulting in the release of cytokines including tumor necrosis factor (TNF) and Interleukin-1ß (IL-1ß) [2,19]. Monocytes, vascular smooth muscle cells (VSMCs), and other inflammatory cells in the intima migrate and proliferate in response to these cytokines [2,19]. When monocytes attempt to phagocytize deposited LDLs, they form lipidladen macrophages, also known as foam cells. The oxidation of lipoproteins is an unpleasant and unanticipated side effect of this. These oxidized lipids are particularly hazardous to macrophages, causing apoptosis or necrosis [16]. When macrophages die, phagocytized material is released from the cells in vesicles, which act as a nidus for calcium phosphate deposition. Macrophages and VSMCs release vesicles during intimal calcification, while VSMCs release them during medial calcification [10]. A plaque forms when inflammatory material microcalcifies and develops a necrotic core beneath it.
The process of artery damage, necrosis, and surface microcalcification continue indefinitely if acute inflammation persists, and the vascular layer never entirely recovers. This creates an intrinsically unstable plaque that is prone to rupture and thrombus development [16][17][18].
If the inflammation eventually subsides, plaque reformation and stability can take place. Chondrocyte-like VSMCs direct a regulated mineralization process and the production of stabilizing macrocalcification, which drives plaque remodeling [16].
BMP2 and BMP4 cause medial VSMCs and macrophages to develop into osteoblast-like phenotypes during medial calcification. The vascular extracellular matrix is then transformed into a cartilaginous matrix by these cells. The matrix of the cartilage is calcified, and hydroxyapatite crystals develop. Endochondral ossification of bone is the same process [2,5,12]. These crystal aggregates eventually merge to generate macro-calcification calcified sheets or plaques.
Because BMPs are tightly regulated and can be suppressed by a variety of modulator proteins, including Osteopontin, Gremlin, Noggin, and uncarboxylated Matrix Gla Protein (MGP), the progressive mineralization that generates macro-calcification that stabilizes the plaque and prevents additional inflammation [5,12,16].

Clinical Manifestations
There are no specific clinical indications for carotid artery calcification. On the other side, this phenomenon is sometimes misconstrued as a proxy for atherosclerosis, leading to clinical indications being misinterpreted as atherosclerosis issues. Because it can be a marker of luminal stenosis, arterial calcification is associated with ischemic symptoms. Signs and symptoms arise when an artery is highly stenotic or completely occluded. The most common signs and symptoms include bumps, amaurosis fugax, contralateral weakness or numbness of an extremity or face, with significant sparing of the forehead, dysarthria, aphasia, transient ischemic attack (TIA), or ischemic stroke.

Symptomatic vs Asymptomatic Carotid Artery Plaques
Shaalan et al. used Spiral CT to measure the percent plaque calcification area and performed an assessment of carotid plaque calcification. They discovered that asymptomatic patients had two times more plaque calcification area than symptomatic patients (48% +/-19% versus 24% +/-20%; P0.05) [20]. Shaalan et al. concluded that higher carotid artery plaque calcification is associated with plaque stability and could serve as a quantitative measure for cerebrovascular ischemia event risk based on this and other findings throughout their investigation [20]. Hunt et al. found that patients with calcified carotid plaques had fewer symptoms of stroke and transient ischemic attack (P = 0.042) than patients with non-calcified carotid plaques [21].
Shi et al. recently discovered that asymptomatic patients exhibited plaque calcification areas that were two times larger than symptomatic patients [2,22]. Intraplaque bleeding and ulceration were frequently found in plaques with a greater calcification volume and numerous calcifications. Multiple calcifications may trigger a stronger inflammatory response, increasing the risk of the plaque becoming ulcerated and hemorrhagic, according to one theory. While the authors acknowledged that plaque calcification and plaque stability are linked, they were skeptical about the information's utility in forecasting future cerebrovascular accidents [2,[23][24][25][26]. Asymptomatic carotid plaques are more calcified than symptomatic plaques, according to Wu et al., and extracranial carotid plaque calcification is linked to plaque stability [5]. They also disclosed a study that used carotid-femoral pulse wave velocity and 24-hour ambulatory pulse pressure to quantify arterial stiffness. There was increased stiffness in major cerebral arteries in patients without stroke and with asymptomatic intracranial atherosclerosis, according to this study [27].
According to the findings from the various sources, calcified carotid artery plaques may be more stable than non-calcified carotid artery plaques. The findings of Fisher et al. and Wu et al., on the other hand, are in opposition to this [5,28]. Patients who were asymptomatic were compared to patients who had stroke symptoms ipsilateral or contralateral to the plaque by Fisher et al.. They discovered that asymptomatic, ipsilateral symptomatic, and contralateral symptomatic patients all had similar plaque calcification averages (16%, and 15%, respectively; P0.001), leading them to conclude that the extent of carotid plaque calcification had no relation to symptoms [28].

Stroke and Transient Ischemic Attack
There was a decreased incidence of stroke and TIA in patients with carotid plaques composed of large calcific granules, compared to those without calcification (P = 0.021) and large calcifications were inversely related to plaque rupture [2,21]. Hunt et al. also found that 52 out of the 142 patients who had a TIA or stroke, 65% (n = 34) did not have any carotid plaque calcification, while 35% (n = 18) had a calcified plaque (P < 0.042) [21]. In contrast, Golüke et al. found that intimal and medial intracranial carotid artery calcifications were significantly associated with stroke [adjusted odds ratio (OR) 1.84, 1.88, and 2.88, respectively], and the severity of calcification in both intimal and medial layers also had significant associations with stroke and myocardial infarction [29]. Furthermore, a Korean study involving 445 patients determined that higher carotid siphon calcification scores were associated with higher rates of lacunar infarction [5,30].
Several studies correlated carotid artery calcifications and cardiovascular disease. Dominant intimal calcifications were significantly associated with myocardial infarction (adjusted OR 2.27 and 4.45, respectively) [29]. Patients with carotid plaques composed of large sheets of calcium were more likely to have coronary artery disease (P < 0.0333) [21]. Shaalan et al. concluded that there was no difference between the prevalence of atherosclerotic risk factors between symptomatic and asymptomatic groups, except for hypercholesterolemia, which had a higher prevalence in the group with symptomatic carotid artery plaques (36% vs 26%; P < 0.05) [20].
Other well-researched clinical manifestations associated with intracranial carotid artery calcification include deep cerebral microbleeds and white matter hyperintensities, as described by Wu et al.. cognitive decline and dementia are well studied as proposed clinical manifestations of carotid artery calcification. Suggested mechanisms relate to decreased cerebral blood flow regulation leading to cognitive deficits. Chu et al. described a significant negative correlation between carotid artery calcification scores and cognition (R = -0.359, P < 0.001), in a study of 102 patients with confirmed carotid artery calcification using color doppler ultrasound, multi-detector row spiral CT angiography, and MRI scanning [31]. Furthermore, a crosssectional study of 2,414 non-demented people in the Rotterdam Study, followed by a subsequent longitudinal study, both demonstrated a cognitive decline in individuals with larger intracranial carotid artery calcification volume [5,8,32].

Diagnostic methods
Diagnostic techniques for carotid artery calcification have advanced in sophistication over time. Improved diagnostic tools aid in the early detection of potentially life-threatening disorders as well as clinical decision-making. Although duplex ultrasonography (DUS) is often the first diagnostic test indicated for carotid artery stenosis evaluation, confirmatory imaging modalities such as magnetic resonance angiography (MRA) or computed tomography angiography (CTA) is currently used. These diagnostic tests are used to guide therapeutic measures, such as procedure planning. Another regularly scheduled screening technique that has been shown to detect calcified atheromas in the carotid artery is panoramic radiography. The frequency of confirmed accidental carotid artery calcification identified on panoramic radiography ranges from 2% to 5%. [33]. Duplex ultrasound is frequently performed after this test, and the results are validated with computed tomography angiography or magnetic resonance angiography. More advanced imaging technologies, including optical coherence tomography (OCT), photoacoustic tomography, and infrared thermography, have been developed to characterize plaques [34]. PET-CT imaging using (18)F-Sodium Fluoride was originally developed to detect calcifying metastases, but it is currently utilized to detect and quantify microcalcification in atherosclerotic plaques. Its relationship with cardiovascular risk factors makes it a helpful noninvasive approach for determining the amount and severity of carotid artery calcification [35][36][37].

Duplex Ultrasound (DUS)
Duplex ultrasonography (DUS) is one of the most used and well recommended initial diagnostic tests for carotid artery disease since it is non-invasive, low-cost, and accurate. It enables for direct visualization of vessel shape as well as flow measurement. It has a sensitivity of 86.4 for 50% stenosis and 92.1 for 100% stenosis, as well as a specificity of 90.1 for 50% stenosis and 89.5 for 100% stenosis [33]. DUS cannot tell the difference between high-grade stenosis and total occlusion, which is a disadvantage [38].

Computed Tomography Angiography (CTA) and Magnetic Resonance Angiography (MRA)
The use of intravenously supplied iodine contrast medium and complete vascular visualization to diagnose carotid artery disease using Computed Tomography Angiography (CTA) allows for the assessment of stenotic degree. This diagnostic modality allows for plaque composition characterization and calcification score computation in the carotid artery. CTA has a sensitivity of 89 for 50% stenosis and 99% for 99% stenosis, according to Anderson et al. [39]. The specificity reported was 91% for 50% stenosis and 99% for 100% stenosis [39]. CTA was proven to be nearly 100% accurate for total blockage and stenosis between 0 and 29% [39]. CTA and magnetic resonance angiography (MRA) are both sensitive, but CTA has a greater specificity [34]. The requirement for intravenous contrast injection and radiation exposure are both disadvantages of CTA [38]. MRA is a non-invasive way of detecting stenotic vessels that can be utilized with or without contrast. Similarly, to DUS, MRA may exaggerate the degree of stenosis; consequently, combining DUS and MRA is more accurate than doing either test alone [38].

PET-CT imaging with (18)F-Sodium Fluoride
PET-CT imaging with (18)F-Sodium Fluoride (18F-NaF) is a molecular imaging technique that uses an 18 Fluoride-labeled sodium fluoride radiotracer to detect areas of necrotic inflammation and metabolic activity in atherosclerotic plaques. Derlin et al. found a significantly significant connection (r = 0.85; P0.0001) between the occurrence and amount of artery wall calcification and 18F-sodium fluoride absorption [36]. When compared to other PET radiotracers, 18F-sodium is cleared from circulation faster, has no superfluous soft-tissue uptake, and has significantly higher absorption in important artery walls than 18F-FDG [16,[35][36][37]. Because CT scans can only identify large areas of calcification, they are more likely to overlook newer and smaller calcifications. With the help of x-ray attenuation, 18F-NaF was able to detect microcalcifications not evident on CT [35][36][37]40]. There was also a statistically significant relationship between tracer uptake in the common carotid arteries and cardiovascular risk variables such as age, male sex, hypertension, hypercholesterolemia, and cumulative smoking exposure (P0.0001) [35][36][37][41][42][43][44][45].

Optical Coherence Tomography (OCT)
The highest resolution of any intravascular imaging method is optical coherence tomography (OCT), which can be used to classify the volume of calcification. This enables the visualization of plaque shape, calcification features, and potential vulnerability in more detail. It is extremely sensitive and specific for assessing carotid artery calcification [34]. An intravascular OCT catheter was used to see the artery wall, and the imaging results were consistent with those obtained from histological inspection. When OCT was first employed during carotid artery stenting, it successfully detected fibrocalcific carotid plaque disruption, thrombosis, and plaque protrusion in 17 individuals [34]. After angioplasty and stenting, OCT has been successfully used to detect possible stenting problems such as plaque ulceration and thrombus development. However, because of its invasiveness, further research is needed before it may be used more widely [34,46].

Medical Management
The goal of medical care in individuals with carotid atherosclerotic disease is to reduce the number of cerebrovascular episodes. Chimowitz et al. observed that patients who underwent a stenting surgery with intensive medical therapy had a 20.0% one-year rate of stroke or death, compared to 12.2% in patients who received aggressive medical management alone (P = 0.009) [47]. They determined that medical care alone was superior to medical management combined with percutaneous angioplasty and stenting in terms of lowering the risk of stroke [47].
Risk factor adjustment, antithrombotic treatment, and statin medication are all recommended for optimal management. Regardless of symptoms or stenosis severity, this is suggested for all individuals with carotid stenosis [48][49][50].
Modification of risk factors can include the following: 1) A systolic blood pressure target of 140/90 mmHg, 2) LDL cholesterol reduction, 3) smoking cessation and 4) moderate to vigorous-intensity aerobic physical exercise of at least 40 minutes per day, three to four days per week [38,48,50]. Clinicians should prescribe a low, moderate, or high-intensity statin depending on the patient's 10-year risk of atherosclerotic cardiovascular disease [38,48]. Aspirin 325 mg per day and an antiplatelet medication are used as antithrombotic treatment [38,47].

Carotid Endarterectomy and Carotid Stenting
Carotid endarterectomy is a treatment that is performed to reduce the risk of TIA and stroke in those who have carotid atherosclerosis. A qualified surgeon should execute the surgery, which involves accessing the common and/or internal carotid arteries via the sternocleidomastoid muscle and removing atheromatous plaque material [51]. Plaque clearance should improve cerebrovascular perfusion by increasing the luminal size. Even though the technique has been used for decades, the inherent dangers of the surgery need clinicians and patients to carefully weigh the benefits and risks before opting to undergo it. The North American Symptomatic Carotid Endarterectomy Trials (NASCET) and the Asymptomatic Carotid Artery Stenosis (ACAS) trials for endarterectomy were conducted in 1987, and the current treatment recommendations and indications for endarterectomy are based on these trials [49,[51][52]. Carotid endarterectomy (CEA) is advised for symptomatic patients (those who have had a TIA or stroke in the past) if carotid stenosis is 50% or greater, and it must be conducted soon after the onset of symptoms to be useful [51]. CEA is suggested for carotid stenosis of 70% or greater in asymptomatic patients [49,51].
The current standard endovascular therapy intervention for carotid atherosclerotic disease is carotid stenting [48,53]. For patients who are unable to undergo endarterectomy, stenting is an option [48]. There are several carotid vascular access and stent implantation techniques available, each with its own set of risks and benefits [48]. Stenting can be done percutaneously with a transfemoral approach or by a tiny incision in the neck with a transcarotid technique [48]. Patients aged 80 and up have a higher chance of negative outcomes after transfemoral stenting, however, this is not the case with the transcarotid method [48,54]. Several strategies are employed to prevent embolic stroke during the stenting procedure, however, there is no conclusive evidence that one method is better than the others [48].
Muller et al. conducted a systematic review that compared the safety and efficacy of stenting versus carotid endarterectomy in 5,396 participants with symptomatic and asymptomatic carotid artery stenosis. The primary outcome was death or stroke occurring up to 30 days after treatment. Up to 30 days after stenting, there was a significantly increased risk of death or stroke [OR 1.70, 95% confidence interval (CI) 1.31 to 2.19; P 0.0001). [54]. Data from six of the trials revealed that participants over the age of 70 were twice as likely to die or have a stroke up to 30 days after stenting (OR=2.23, 95 % CI 1.61 to 3.08; P0.0007) [54]. However, after four years of follow-up data, it was determined that stenting and endarterectomy were equally effective in the long term in preventing recurrent stroke [54]. CAC risk factors vary depending on whether the calcification is intimal or medial dominant. There were 37 studies used in this review ( Table 1).

Risk factors, pathogenesis, clinical manifestations, diagnostic techniques and management of carotid artery calcification
Author Country Study

Conclusions
Carotid artery calcification is important in clinical practice because stenosis leads to high morbidity and mortality. The pathophysiology of CAC is an immediate inflammatory response that results in microcalcifications. Microcalcifications cause plaque instability, while macrocalcification causes plaque stabilization. Medial calcification is linked to calcium-phosphate imbalance and diabetes and chronic renal disease. These two calcifications have distinct risk factors, indicating a distinct etiology. Some studies show that increasing plaque calcification results in stenosis with minimal or no symptoms. Carotid artery calcification as a cerebrovascular risk indicator is still debated. Several methods exist to identify and characterize carotid plaque severity and shape. The initial ultrasound imaging study is quick and inexpensive. PET-CT imaging with (18)F-Sodium Fluoride (18F-NaF) is a newer technique that can detect new microcalcifications.
Anticoagulants, statins, and lowering risk factors are used to treat carotid stenosis. Following medical management alone was found to be inferior in several studies. Patients over 70 were twice as likely to die or have a stroke 30 days after carotid stenting. Long-term, stenting is riskier than endarterectomy. However, both stenting and endarterectomy are effective in preventing strokes.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.