Role of Coronary Artery Calcium Score of Zero and Other Negative Risk Markers for Cardiovascular Disease: The Multi-Ethnic Study Of Atherosclerosis (MESA)

The role of coronary artery calcium (CAC) has invoked much debate regarding its utility and role in practice. Furthermore, shared decision-making between providers and patients regarding treatments can be quite challenging and confusing. Current guidelines recommend the selective use of CAC when clinician-patient discussion leads to uncertainty in risk-based treatment decisions.

The MESA (Multi-Ethnic Study of Atherosclerosis) studyhas shown important prognostic implications regarding the use of CAC. In MESA, patients with elevated CAC levels and zero risk factors had significant increases in atherosclerotic cardiovascular disease (ASCVD) risk rates compared to patients with CAC scores of zero and multiple risk factors.1,2 The importance of CAC as a negative risk factor is even greater in this current age in which more and more patients are qualifying for statin therapy based on the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, due to the lower threshold for statin use as compared to the 2001 cholesterol guidelines.

In a MESA sub study, Blaha et al. examined 13 "negative" risk factors (seemingly protective findings) from participants.3 Five of the thirteen negative risk factors were CAC, ankle-brachial index (ABI), carotid intima-media thickness (CIMT), carotid plaque, and brachial-flow mediated dilation (FMD).3 The normal values that were used were CAC of zero,4,5 CIMT ≤25th percentile of the study population,6 FMD of ischemia-induced diameter change ≥5%,7 and ABI of 0.9 to 1.3.8

Based on results of this study, cardiovascular disease (CVD) events were lowest in those with CAC of zero (4.0%) and highest in those with a normal ABI (9.9%).3 Also, those with a CAC of zero had the lowest coronary heart disease (CHD) event proportions.3 Compared to other negative risk markers studied, a zero CAC moved the post-test risk downward the most.3

So, how can we use this information in clinical practice?

As Blaha et al. discuss, the use of negative risk factors can be used in conjunction with conventional ASCVD risk estimates. The consideration of tests such as CAC can correctly place patients in the very low risk group, thus limiting overtreatment with statin and aspirin therapy. However, the use of serial CAC scans is not recommended in clinical practice to assess CAC progression. It is also essential to remember that intermediate risk is defined as a CHD risk of 10-20% by the 2004 National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines. Furthermore, the new 2013 AHA/ACC guidelines no longer use the intermediate risk category.

CAC is considered the most useful tool for CVD risk assessment among current noninvasive modalities.9,10 Sarwar et al. show the role a negative CAC score can have in asymptomatic patients or low-risk patients.5 However, high CAC scores continue to dictate changes in management and zero CAC scores should be used to reinforce decisions towards a less aggressive approach. In addition, many of the ASCVD events in persons with a CAC of zero were strokes, whose etiology is often deemed to be non-atherosclerotic in nature and more likely related to atrial fibrillation and hypertension rather than dyslipidemia.

The addition of CAC to traditional risk factors in the MESA risk score (which can be accessed online at can also more correctly estimate 10-year ASCVD risk.11

It is worth mentioning that the use of negative risk markers was not discussed in the most recent ACC/AHA guidelines. Thus, with results of this multi-ethnic cohort, using a CAC score of zero can inform future guidelines and help with the ever-important clinician-patient risk discussion.


  1. Nasir K, Rubin J, Blaha MJ, et al. Interplay of coronary artery calcification and traditional risk factors for the prediction of all-cause mortality in asymptomatic individuals. Circ Cardiovasc Imaging 2012;5:467–73.
  2. Silverman MG, Blaha MJ, Krumholz HM, et al. Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis. Eur Heart J 2014;35:2232-41.
  3. Blaha MJ, Cainzos-Achirica M, Greenland P, et al. Role of coronary artery calcium score of zero and other negative risk markers for cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2016 Mar;133:849-58.
  4. Hecht HS. A zero coronary artery calcium score: priceless. J Am Coll Cardiol. 2010;55:1118–20.
  5. Sarwar A, Shaw LJ, Shapiro MD, et al. Diagnostic and prognostic value of absence of coronary artery calcification. JACC Cardiovasc Imaging 2009;2:675–88.
  6. Sharma K, Blaha MJ, Blumenthal RS, Musunuru K. Clinical and research applications of carotid intima-media thickness. Am J Cardiol 2009;103:1316–20.
  7. Bots ML, Westerink J, Rabelink TJ, de Koning EJ. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J 2005;26:363–8.
  8. Tison GH, Ndumele CE, Gerstenblith G, Allison MA, Polak JF, Szklo M. Usefulness of baseline obesity to predict development of a high ankle brachial index (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol 2011;107:1386–91.
  9. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59.
  10. Peters SAE, den Ruijter HM, Bots ML, Moons KG. Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review. Heart 2012;98:177–84.
  11. McClelland RL, Jorgensen NW, Budoff M, et al. 10-Year Coronary Heart Disease Risk Prediction Using Coronary Artery Calcium and Traditional Risk Factors: Derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) With Validation in the HNR (Heinz Nixdorf Recall) Study and the DHS (Dallas Heart Study). J Am Coll Cardiol 2015;66:1643-53.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Echocardiography/Ultrasound, Hypertension

Keywords: Ankle Brachial Index, Aspirin, Atherosclerosis, Atrial Fibrillation, Carotid Intima-Media Thickness, Cholesterol, Coronary Artery Disease, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Risk Assessment, Reference Values, Risk Factors, Stroke, Dyslipidemias

< Back to Listings