Coronary Artery Calcification

Etiology

Calcification can occur in the tunica intima or tunica media layers of blood vessels. Medial calcification causes peripheral arterial disease and is associated with renal failure, hypercalcemia, hyperphosphatemia, and hyperparathyroidism. Intimal calcification is associated with coronary artery disease and atherosclerosis and is the focus of this review.[4]

Atherosclerosis is thought to start from initial lipid deposition on the endothelium of a vessel. Macrophages invade the lipid core of the plaque, which may become necrotic. CAC is thought to be initiated by apoptosis of smooth muscles that have migrated to the tunica intima from the tunica media. In addition to smooth muscle cell apoptosis, macrophage apoptosis produces larger foci of calcification.[4] Microcalcifications occur in the deeper layer of the necrotic core near the internal elastic lamina. Coalescence of microcalcifications leads to the formation of calcium fragments and speckles. As the process advances, the calcification encroaches on the matrix, resulting in calcified sheets or plates. These sheets can fracture, forming calcium nodules. The calcium nodules contribute to the distortion of the endothelial lining and can contribute to acute luminal thrombosis. Calcified nodules contribute to 2% to 7% of coronary artery thrombosis.[3]

Calcification and necrosis of the lipid core can occur independently. If the necrotic core increases, a thin-cap fibroatheroma may form and is prone to rupture. In healed plaque ruptures and fibrocalcific plaques, calcification increases disproportionately more than the necrotic core areas.[4] 

Epidemiology

The presence of coronary artery calcification is age and gender dependent. This calcification is present in 90% of men and 67% of women older than 70. This is attributed to the protective effect of estrogen in premenopausal women. The Women's Health Initiative demonstrated a lower mean CAC in the estrogen-treated group than the placebo group.[4] Additionally, CAC is 3 times higher in postmenopausal women than premenopausal women. In an autopsy study of victims of sudden cardiac death, the extent of calcification was higher in men than women up to the sixth decade of life, but the difference was not significant after the seventh decade.[4][5][6]

There is growing evidence of racial differences in CAC and clinical outcomes. In the Multi-Ethnic Study of Atherosclerosis, after adjustment for traditional risk factors, there was a statistically significant difference in CAC across four ethnicities (Whites, African Americans, Hispanics, and Chinese). Whites had the highest CAC, followed in descending order by Chinese, Hispanics, and African Americans. The results were consistent across both sexes.[7]

Patients with diabetes mellitus tend to have higher CAC, which predicts adverse clinical outcomes. Higher HbA1C is associated with both incident and progressive CAC.[8] Other factors associated with an increased risk of CAC are metabolic syndrome, dyslipidemia, tobacco use, hypertension, chronic kidney disease, and a high baseline C-reactive protein level.[9]

Pathophysiology

It is well-known that coronary calcification causes reduced myocardial perfusion, abnormal vasomotor response, and overall impaired vascular compliance. Several theories have been proposed regarding CAC, including calcium-phosphorus imbalance, apoptotic bodies, induction of bone formation, and migration of vascular smooth muscle cells. Calcification in the coronary arteries can occur as early as the second decade of life, immediately after fatty streak formation. Laboratory analysis of lesions of young adults has demonstrated aggregation of crystalline calcium among lipid particles. Furthermore, calcific deposits are found in greater quantities in older adults and complex lesions.[10][11][12] 

While previously thought to be age-related degeneration, aortic stenosis may also result from some of the same processes related to atherosclerotic calcification and inflammatory cytokines. Aortic stenosis can cause additional cardiac stress and adverse cardiac events.[2]

CAC is hypothesized to be a protective mechanism to strengthen atherosclerotic plaques, as calcified areas are less likely to rupture. Plaques with calcified caps are less prone to rupture than unstable plaques with a necrotic lipid core.[13]

The primary question is whether calcification promotes plaque stability or instability. However, there is no single answer, as calcification characteristics—such as type, location, volume, density, and size—all affect clinical outcomes. In general, spotty or speckled calcification is associated with plaque instability, and heavy calcification corresponds with overall plaque burden; it is thought that plaque burden correlates with overall CAD.[4][14] 

Histopathology

Histologically, there is a progression of CAC starting from microcalcifications as small as 0.5 to 15 micrometers, which are thought to originate from smooth muscle apoptosis. The microcalcifications progress to larger punctuate and fragmented lesions, which become sheets of calcium deposits measuring more than 3 millimeters. The sheets of calcium can break off into nodules, forming intraluminal thromboses.[4]

History and Physical

Although coronary artery calcification has no specific clinical manifestations, it has significant prognostic implications. This calcification can independently predict future cardiovascular events and reclassify patients into more accurate and clinically relevant categories.

Evaluation

Diagnostic Methods for Measuring Coronary Artery Calcification

Computed tomography: The detection of CAC via CT scan was made possible in the 1980s after the development of the electron-beam CT (EBCT) scanner. This was due to the significantly superior speed of the CT scanner, allowing the detection of CAC despite heart motion. The development of the multislice detector CT scan (MDCT) has allowed even faster acquisition of images. MDCT is used more commonly than EBCT due to increased accuracy and image quality.[15][16] Newer developments in cardiac CT angiography can also show characteristics such as plaque volume and density.

The evaluation of coronary artery calcium scoring via CT offers a fast, reproducible, and relatively inexpensive modality to determine the extent and presence of coronary calcification. It does not require IV access or specific patient preparation. Scans are typically obtained with prospective electrocardiogram triggering during diastole. After imaging is acquired, the extent of calcification is quantified using the Agatston score. The Agatston score is obtained by multiplying the area of calcification by the corresponding density factor as follows:

• 130-199 HU: 1
• 200-299 HU: 2
• 300-399 HU: 3
• 400+ HU: 4

For example, for a calcification area measuring 8 mm² and a HU of 400, the Agatston score will be 8x4 = 32. The score is obtained using a slice thickness of 2.5 to 3 mm. The Agatston score is the most validated method of CAC quantification. The total CAC is calculated by summing individual calcification speck scores. Other methods of CAC quantification include calcium volume score, visual assessment, calcium density score, calcium mass score, and segment involvement score. 

Currently, the American College of Cardiology/American Heart Association gives class IIa indication for coronary CTA in asymptomatic patients with intermediate-risk (10-20%) of cardiac events over 10 years based on the Framingham risk score, as well as for asymptomatic individuals 40 years and older with diabetes mellitus. CAC measurement is generally not recommended for patients at low (<10%) or high (>20%) 10-year risk of cardiac events based on the Framingham risk score.

The following definitions have been used to quantify coronary artery calcium score and coronary plaque burden

• 0: No identifiable disease
• 1 to 99: Mild disease 
• 100 to 399: Moderate disease
• Greater than 400: Severe Disease

Although the presence of CAC can help predict the presence or absence of coronary artery stenosis, it is generally a better marker for the extent of coronary atherosclerosis rather than the degree of stenosis. In early atherosclerosis, there is a compensatory enlargement of the arteries to accommodate the plaque. Therefore, although extensive plaque burden may be present, there may not be any clinically relevant stenosis. Severe coronary calcification (Agatston score >1000) is associated with advanced obstructive coronary disease.

CAC may also be found incidentally on CT scans performed for other indications. The presence and extent of CAC should be reported on all noncontrast CT chest scans. Non-gated scans usually do not have a slice thickness of 2.5 to 3 mm, and hence, formal Agatston scoring may not be possible. However, there is a good correlation between the gated Agatston score and the non-gated ordinal scores used.[17]

The effective radiation exposure with EBCT is approximately 0.7 to 1.0 mSv in men and 0.9 to 1.3 mSv in women. MDCT has a slightly higher radiation dose of 1.0 to 1.5 mSv in men and 1.1 to 1.9 mSv in women. To place this in context, the average annual background radiation in the United States is 3.0 to 3.6 mSv.

In asymptomatic patients, a zero Agatston score is the most powerful 'negative predictive risk factor' compared to a normal level of hs-CRP, or lack of carotid plaque.[18]

Chest radiography: Coronary calcification is not easily detected in routine chest radiography. Although chest radiography is inexpensive, it has very poor sensitivity in detecting CAC, so is not recommended.

Practical Use of Diagnostic Testing

The gold standard for imaging cardiac vasculature is cardiac catheterization, an invasive procedure using percutaneous access to inject dye for visualization and possible stent deployment. Using noninvasive testing to stratify patients who need catheterization is an area of current research. Functional stress tests (FST) are noninvasive methods to evaluate stable chest pain; these modalities include exercise stress testing, stress echocardiography, nuclear single-photon emission computerized tomography (SPECT), and positron emission testing (PET). These tests have a sensitivity and specificity of 70% to 90%, resulting in many unnecessary referrals for invasive cardiovascular testing. About two-thirds of cardiac catheterization will find nonobstructive CAD.[14] The other primary method to noninvasively image coronary arteries is coronary computed tomographic angiography (CTA). 

Coronary artery calcium is mostly evaluated by non-contrast, electrocardiographic (ECG)-gated cardiac electron beam computerized tomography (EBCT) or multislice detector computed tomography (MDCT). A coronary calcium score is associated with plaque burden; however, it is not a marker of plaque vulnerability. Nonetheless, it gives an insight into the patient’s level of cardiovascular disease risk and helps guide interventions or prevent coronary artery disease.[19][20][21]

The PROMISE trial is a randomized control trial assigning patients with stable chest pain and suspected coronary artery disease into FST and CTA groups. The primary outcome of all-cause mortality, myocardial infarction, unstable angina, or major complications from a cardiovascular procedure was similar between the two groups. The CTA group had a higher rate of cardiac catheterization than the functional group but lower rates of nonobstructive CAD. Therefore, a low pretest probability combined with a negative CTA has a high negative predictive value for CAD.[22] Although both the functional testing and CTA groups overall had similar rates of major adverse cardiac events, in subgroup analysis, patients with diabetes had significantly fewer events in the CTA group than those randomized to FST. This is likely due to different symptom presentations and suggests that in patients with diabetes and stable angina, CTA should be the initial test.[23]

Another large randomized control trial, SCOT-HEART, also addressed the utility of CTA, but in this study, CTA was performed after FST. SCOT-HEART also demonstrated the safety and efficacy of CTA, and results suggest a trend toward reducing major cardiac events with both CTA and FST compared to FST alone.[22]

The benefit of CTA over FST is that CTA is an anatomical study and can directly visualize the coronary vessels. Both the PROMISE and SCOT-HEART showed that after 5-year follow-up, nonobstructive lesions were associated with as many adverse cardiac events as obstructive lesions, but a CTA negative for calcification maintained its negative predictive value.[14] As noted above, there are certain characteristics of coronary calcifications considered high risk, including plaque stenosis greater than 70%, thin-cap fibroatheromas, and plaques with a large necrotic lipid core. Although overall adverse cardiac events were not significantly associated with high-risk plaques, there was a positive association in the subgroups of younger patients and women.[24]

Treatment / Management

The overall incidence of adverse cardiac events is lower than expected in most large-scale studies. This is thought to be due to aggressively treating the risk factors of study patients, such as blood pressure, lipids, and smoking. Controlling diabetes and chronic kidney disease is also important.

Use of CAC in primary prevention of atherosclerotic cardiovascular diseases. The clinical practice guidelines have recognized the utility of CAC in the primary prevention of atherosclerotic disease. A positive CAC score can be used to help guide decisions about statin use. If the CAC is 0 and smoking, diabetes, and a family history of premature CAD are absent, then no statin therapy is indicated. For patients with CAC 1-99, initiation of a statin is indicated if they are older than 55. For patients with CAC 1-99 but aged less than 55, statins can be held, and the patient can be reassessed for candidacy in 3-5 years. For patients with a CAC of greater than 100, initiation of statin is recommended.[25] Aspirin may be useful in primary prevention for patients younger than 70 and with CAC greater than 100.[26] Serial CAC testing to assess treatment efficacy is not recommended.  

Coronary artery calcification in coronary intervention: There have been advances in the treatment of coronary artery calcification. Intravascular lithotripsy (IVL) for the modification of severe coronary artery calcification was seen in the Disrupt CAD III study.[27] In addition, the presence of CAC makes a percutaneous coronary intervention during cardiac catheterization more challenging. Techniques that can be utilized during cardiac catheterization in addition to drug-eluting or bare metal stent placement include rotational, orbital, or laser atherectomy, as well as cutting balloons.[28][29][30](B3)

Differential Diagnosis

The differential diagnosis of CAC includes artifacts that can appear as calcification, such as increased background noise misinterpreted as microcalcifications, pericardial calcification near the epicardial vessels, movement-related noise, and perhaps most significantly, tunica media calcification, which can be misinterpreted as intimal calcification but has a different etiology and prognosis. 

Prognosis

Coronary artery calcification in several large observational studies has been shown to predict future cardiovascular events. Furthermore, when added to commonly used risk prediction models, CAC significantly improves risk prediction and stratification compared to other biomarkers. It can accurately classify patients into low-risk and high-risk categories. Patients have an extremely low risk of cardiovascular disease and events if they have no coronary calcification detected (CAC score of 0).

For example, in patients classified as low risk due to risk factors present or Framingham risk score, a CAC of 100 indicated an estimated 10-year all-CHD event rate of nearly 10%. However, in the same high-risk patients, a CAC score of 0 is associated with a 10-year all-CHD event risk of only 3%. Asymptomatic patients who are in the intermediate-risk category most commonly undergo CAC scoring due to guideline recommendations. A CAC score of greater than 400 is associated with worsened clinical outcomes. This illustrates the ability of coronary artery calcification scoring to help reclassify the risk of many patients and estimate future cardiovascular events.

Complications

Complications of CAC are stenosis leading to decreased coronary blood flow, angina, and myocardial infarction. Stratifying patients for cardiac catheterization through functional testing or coronary CTA is based on the likelihood of having a vascular lesion amenable to intervention based on size, location, and appearance. Stenosis greater than 50% of an epicardial vessel or 50% in the left anterior descending artery is generally considered hemodynamically significant. The risks of extensive testing for CAC can lead to unnecessary cardiac catheterizations with associated risks of bleeding, infection, artery dissection, and coronary vasospasm.