Calcium and Atherosclerosis: The Connection
Naveen L Pereira MD: My name is Naveen L Pereira, Assistant professor of medicine and pharmacology at Mayo Clinic in Rochester, Minnesota. Today we will be discussing the very pertinent and interesting topic of coronary calcium testing, with professor of medicine Dr Iftikkhar Kullo, who has a strong research interest in preventive cardiology, with a focus on using biomarkers for identifying cardiovascular risk. Why is calcium associated with atherosclerosis?
Iftikhar J Kullo, MD: Calcification is part of the inflammation and repair processes that are ubiquitous in atherosclerotic lesions. Calcification occurs early in atherosclerosis, but we are not able to detect it with imaging until it increases in quantity, typically after the age of 40 in men and women. We can detect it with imaging in the later years, but it's present in the very early stages of atherosclerosis.
Dr Pereira: Is CT scanning the most sensitive imaging technology to detect calcium?
Dr Kullo: At this moment, it is the standard test to detect coronary artery calcification. We have seen with histology confirmation that it accurately quantifies the amount of calcification. By quantifying calcium, we get an idea of the extent of atherosclerotic plaque burden, and although it is not a marker of plaque vulnerability, by showing the extent of disease, it gives an insight into the patient's level of risk.
Interpreting the Calcium Score
Dr Pereira: If I order a calcium score, what will I see when I look at the report?
Dr Kullo: Two things must be considered. One is the absolute score, and the other is a percentile for that person's age, sex, and ethnicity. What we consider abnormal is anything above the 75th percentile for age, sex, and ethnicity or an absolute score of 300 (Agatston units), as mentioned in the guidelines. Some people have an issue with that; they would say that any detectable or any calcification score >100 is abnormal.
The scoring is based on the intensity of the calcium signal and the location of the signal. In a sense, it gives the quantity of calcification present.
Dr Pereira: How strong are the data linking calcification identified by CT imaging and actual clinical outcomes?
Dr Kullo: The recent guidelines for risk assessment recommended four modalities for scenarios in which there is uncertainty about the patient's level of risk: coronary calcium, family history, C-reactive protein, and ankle-brachial index. Of those four, the strongest data are for coronary calcification, and it's clear that this is by far the best modality in terms of refining risk estimates when there is uncertainty about the patient's level of risk or when the patient has an intermediate risk score. The data are fairly good; and; in fact, the question we ask is how often this reclassifies individuals when we are assigning risk based on risk calculators. It does this fairly often. In the MESA study, risk was reclassified on the basis of the calcium score 25% of the time; and even more often in the intermediate-risk group, in which nearly half were reclassified. The data are very good that as a marker of adverse outcomes, the calcium score goes above and beyond what we can get from the risk calculators.
Dr Pereira: Not only does it identify atherosclerosis, but it identifies the possibility of adverse cardiovascular events that could occur in that particular person.
Dr Kullo: Exactly, because it suggests the extent of subclinical disease and that, in turn, determines the prognosis in that patient.
Risk and Outcomes: Strength of the Evidence
Dr Pereira: With the incremental value of getting a score by doing coronary calcium imaging, can you integrate risk factors with the coronary calcium score? Would that make it a better predictive tool?
Dr Kullo: That's an excellent question, and we don't know the answer. For example, the guidelines say, "Calculate the risk using the pooled cohort estimator." If you want to do the coronary calcium score, it's not clear how we should integrate that with the pooled cohort estimate. One suggestion is to use the vascular age that you derive from these imaging modalities (calcification or carotid ultrasound), and then use that age instead of the chronological age. The other suggestion has been to use a relative hazard of having an abnormal coronary calcium score. You would multiply the pooled estimate by the relative hazard. If the relative hazard is two times expected, and the patient's risk is 7.5% over 10 years, with a high coronary calcium score, that would essentially double their risk. You would now estimate their risk to be 15%. There are some issues with these, and at this point, we don't know exactly how to integrate coronary calcium score into the baseline of the pooled cohort estimator.
Dr Pereira: What did the guidelines say?
Dr Kullo: The guidelines gave it a level of evidence rating of IIb, which is a pretty good recommendation, although not a flat-out level II. Some of the concerns were that they didn't have enough data for the relationship between excessive coronary calcification and stroke. The new guidelines incorporate stroke as one of the adverse outcomes. They also feel that more data are needed to know whether we can change outcomes with coronary calcium scanning. Trials still need to be done. Second, the degree of reclassification still needs additional data. There are additional concerns, such as cost-effectiveness, and the cost of radiation exposure. Those issues may have tipped it into the IIb category rather than level of evidence II. Many people in the imaging world are somewhat disappointed by that. They had expected this to get a II, preferring that risk estimation be driven by imaging in most people.
Dr Pereira: We have traditionally thought that if someone has higher coronary calcium scores adjusted for age and sex that we should go toward getting a noninvasive stress test, which will translate into ischemia. Is that still generally the approach?
Dr Kullo: That's a very interesting question and, actually, the relationship is not linear; it's quite nonlinear.
Calcium Score 1000 but No Ischemia?
Dr Kullo: I have patients in my practice with coronary calcium scores in excess of 1000; so they are above the 99th percentile. When I image them, even with perfusion or echo stress, they have no inducible ischemia at all.
This is because some of the excess coronary calcium that resides in the arterial wall remodels by what we call Glagovian remodeling; and as a result, the lumen remains relatively nonstenotic, and you don't have any inducible ischemia, at least to the extent you can detect on these imaging modalities. There is not a good linear correlation between the extent of coronary calcification and a positive stress test resulting in inducible ischemia. The patient still has atherosclerosis, however, and is still at higher risk.
Dr Pereira: What do you do with these patients? Would you treat that patient as having a coronary heart disease risk equivalent to the highest-risk category and prescribe moderate intensive statin treatment?
Dr Kullo: If the absolute coronary calcium score is greater than 300, you are almost like a coronary heart disease equivalent. Your risk is 2% per year.
I would treat with aggressive lifestyle modification and all the preventive measures we know to try to control the disease.
Who Should (and Shouldn't) Have a Calcium Score
Dr Pereira: How do you use coronary calcium scores in your practice? There are always some gray areas. Can you illuminate some of those?
Dr Kullo: In my practice, I try to avoid the extremes of age. Typically, I won't order calcium scores in individuals aged less than 40 years. There is some concern that they may have plaque, but it may be softer plaque without that amount of calcium that you could pick it up. You might be lulled into a sense of security. At the other end of the spectrum, I generally won't do calcium scores in older individuals (age >65). I don't find this to be useful, because if you do the pooled cohort estimator, these patients are already at a level of risk at which you have to treat them. So I generally calcium scores in patients aged 41 to 64.
I find it quite useful when I am not certain about a patient's level of risk. If the pooled cohort estimator places the patient at a lower level of risk, but there is a strong family history or the patient is a woman with inflammatory disease (for example, systemic lupus erythematosus or rheumatoid arthritis), or the patient has chronic kidney disease, this is a useful modality.
So there are multiple scenarios in which I find it useful, and family history is probably the most common one. I see many patients who have a family history of early-onset disease, and I am finding this information quite useful to see whether the genetic predisposition actually translates into excessive coronary artery disease burden. In that case, even if the risk calculator puts the patient in a low-risk category, I will certainly treat the patient aggressively.
Dr Pereira: If you are on the fence about committing the patient to life-long statins, it would be useful.
Dr Kullo: Exactly. You are embarking on what could be lifelong therapy with a medication that is not completely free of side effects.
There is an emphasis on shared decision-making in the new guideline. That helps, because when you visually demonstrate to the patient the amount of calcium and plaque burden that is present, it helps the patient make the decision about whether to embark on lifelong therapy.
Dr Pereira: And it might improve compliance too?
Dr Kullo: Exactly. There have been studies[4–6] trying to establish whether showing patients these pictures actually helps motivate them to make lifestyle changes, which otherwise is extremely difficult.
Dr Pereira: Why not just do CT angiography with the calcium scores too?
Dr Kullo: CT angiography is a valuable modality, but its place is more in the emergency room for patients with chest pain. If you are outside the emergency room, you can use it in select situations. It entails more radiation and contrast, and you get good information with just plain coronary calcium scoring in most of the individuals who you see for preventive care in the clinic. CT angiography is valuable, but the applicability of the standard coronary calcium score is much wider.
King Tut's Calcium Score?
Dr Pereira: There is some interesting trivia about coronary calcium from a historical perspective. Can you shed some light on this?
Dr Kullo: In the Egyptian Museum of Antiquity, they CT scanned about 50 mummies, and the surprising finding was that nearly half of them had coronary calcification. The oldest recorded case of coronary artery disease was in a princess who lived about 1500 BC, and she had pretty extensive coronary calcification. They think her age was 45 to 50. This was surprising because we assume that they ate a trans-fat–free diet and were physically active.
Dr Pereira: And ate true organic food.
Dr Kullo: True. There are some theories that perhaps there was more inflammatory burden or some pathogens were responsible, but it does point out that atherosclerosis was present in antiquity, and it's not merely an epidemic of modern times.
Dr Pereira: Thanks, Iftikhar, for these great insights. We hope that our readers will continue to check out future content on Mayo Clinic's page at theheart.org on Medscape.
Cite this: Coronary Calcium Score: Basics and Beyond - Medscape - Apr 13, 2015.