The following are key points to remember from this review of coronary calcium score and cardiovascular (CV) risk:

1. Coronary artery calcium (CAC) is a highly specific feature of coronary atherosclerosis. CAC scoring has emerged as a widely available, consistent, and reproducible means of assessing risk for major CV outcomes, especially when planning primary prevention interventions such as statins and aspirin. CAC testing in asymptomatic populations is cost-effective across a broad range of baseline risks, and has been shown to positively impact patient compliance.
2. Vascular calcification is not simply the result of aging. Ectopic bone production, a common feature of atherosclerosis, is the basis for coronary artery calcification influenced by inflammatory, metabolic, and master transcription factors as well as bone morphogenetic protein.
3. Inflammation, propagated by apolipoproteins and oxidized phospholipids in the artery wall, is instrumental for both development of atherosclerosis and vascular calcification. Oxidative stress may be a key link between inflammation and vascular calcification.
4. Computed tomographic (CT) scanners for CAC scoring are readily available. Scanning can be performed with 10-15 minutes of total room time at about 1 mSv of radiation without the need for contrast agents. Initial studies evaluated the ability of CAC on CT to detect the probability of CAD in symptomatic men and women. In subsequent studies using coronary arteriography, intracoronary ultrasound, and histologic studies from autopsy hearts that were scanned, CAC quantification by scores correlated well with atherosclerotic plaque burden, but there was no association with luminal area.
5. The earliest single-center studies showed an incremental value of CAC for predicting risk compared to traditional risk factors. The incremental value was established in both younger and older persons, diabetics, smokers, and the elderly.
6. Population-based coronary calcium cohort studies were conducted in the United States and Europe. The US MESA (Multi-Ethnic Study of Atherosclerosis) and German HNR (Heinz-Nixdorf Recall [Risk Factors, Evaluation of Coronary Calcium, Lifestyle]) studies had similar design and goals including establishing the normal range of CAC scores (CACS) by age and sex to determine the relationship between CACS, lifestyle, and other known risk factors; and assess to what degree CAC predicted CV events beyond traditional risk factors. The four most common ethnic groups in the United States were included in MESA. CAC was higher in white patients, which was not explained by risk factors alone, yet CAC predicted CV events with similar strength in each ethnic group. The MESA and HNR CACS were similar, as was the ability to predict future CV events despite differences in risk factor profiles. The Rotterdam study group was older and included some persons with previous CV disease (CVD), but also had similar results. In the CARDIA study of young adults, CACS were obtained at follow-up among patients ages 32-46 years, many of whom had a CACS >0, particularly in those with one or more risk factors. Over an approximate 10-year follow-up period, CAC strongly predicted risk beyond traditional risk factors in these young patients. Findings were similar in African American patients in the Jackson Heart Study, and in postmenopausal women in the Women’s Health Initiative.
7. A valuable and useful tool in support of CAC for risk assessment was developed in the MESA study, in which CAC was incorporated into a model using 10-year follow-up data of any coronary heart disease (CHD) outcome. The results were validated in the HNR study. The MESA risk score is available online and incorporates age 45-85 years. It provides 10-year CHD risk with and without the CACS. The weakness is that the present version does not include stroke and all forms of atherosclerotic CVD (ASCVD), as does the American Heart Association/American College of Cardiology guideline for statin therapy.
8. The cost-effectiveness of CAC remains controversial. The most recent summary suggests CAC testing represents a reasonable option to risk-stratify as well as facilitate shared decision making without any significant downstream adverse outcomes, loss of quality of life, and/or increased costs. An example of CAC value is in the ‘low-risk’ men and women with a high-sensitivity C-reactive protein >2 mg/dl and low-density lipoprotein cholesterol (LDL-C) <130 mg/ml participating in the JUPITER trial. Of the eligible patients participating in MESA, 47% had a CACS = 0, whereas 25% had a CACS >100. Using the observed absolute event rates in MESA and the relative risk reduction with 20 mg of rosuvastatin in the JUPITER trial, the 5-year number needed to treat to prevent one CV event varied from 124 for those with a CACS = 0 to 19 for those with a CACS >100. CAC was shown to be of value identifying those expected to derive the most and least benefit from statin therapy in many statin clinical trials, among the elderly, and all patients with dyslipidemia. In MESA, patients with a 10-year ASCVD estimate of 5-7.5%, a range in which the guidelines for statin therapy are not clear, a CACS = 0 was associated with an observed CAC rate of about 1.5%, whereas any calcium score >0 was associated with an actual event rate of at least 7.5%. In MESA persons with an ASCVD risk of 7.5-20%, a CACS = 0 was associated with an event rate of about 4.5%, whereas a CACS >0 was associated with a net benefit of statin therapy by about 10.5%. Using the HNR study, a CACS >400 was associated with a very high coronary and CV event rate in those with and without a statin indication, and should be considered for high-intensity statin dosing. CAC scoring may also be of value for decision about prophylactic aspirin. Using MESA data in nondiabetics, there is a net harm with aspirin when CACS = 0 and net benefit is seen (regardless of risk factors) when CACS is >100. When the 10-year CHD risk is <10%, a CACS <100 does not justify aspirin, but when CHD risk is >10%, a CACS >1 does.
9. CAC progression is associated with a higher risk for myocardial infarction and all-cause mortality. CACS increase by about 20-25% per year and about 20% of subjects with a CACS = 0 progress to CACS >0 in 5 years and increases markedly with age, but less so in women. Analysis of CAC progression did not add benefit to risk prediction models based on the most recent CACS and most recent traditional risk factors. The best CHD prognosis is in patients with a CACS = 0 at baseline and 5 years later. ‘Double zero’ was associated with a 10-year risk of 1.4% followed by new-onset CAC at 5 years of 1.8%. A repeat scan after 5 years appears to be of additional value except for those with a double-zero or high risk because of a CACS >400. (Journal Scan author comment: Unless used to improve compliance with prevention measures, I don’t see value once the patient is considered at high enough risk to warrant maximal prevention therapy).
10. Proposed guideline using 10-year ASCVD risk estimate plus CAC scoring to guide statin therapy:
• <5%: statin is not recommended regardless of CACS.
• 5-7.5%: consider statin; CACS = 0 statin not recommended; CACS >1 consider statin.
• >7.5-20%: recommend statin; CACS = 0 statin not recommended; CACS >0 recommend statin.
• >20%: recommend statin regardless of CACS.
• <5% and >20%: CACS not effective for this population.

Perspective: The suggestion that statin therapy is not recommended when 10-year ASCVD estimate is <5% regardless of CACS ignores a cohort in whom CAC scoring is often considered – that being in pre-45-year-old adults with well characterized premature coronary disease or strokes in the family and risk factors such as low HDL-C, isolated very high LDL-C, and elevated lipoprotein (a).

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Geriatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Computed Tomography, Nuclear Imaging, Smoking, Stress

Keywords: Apolipoproteins, Aspirin, Atherosclerosis, Bone Morphogenetic Proteins, Cholesterol, LDL, Coronary Angiography, Coronary Artery Disease, Cost-Benefit Analysis, C-Reactive Protein, Diabetes Mellitus, Dyslipidemias, Geriatrics, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Inflammation, Life Style, Myocardial Infarction, Oxidative Stress, Phospholipids, Plaque, Atherosclerotic, Primary Prevention, Risk Assessment, Risk Factors, Smoking, Tomography, X-Ray Computed, Vascular Calcification

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