Atherosclerotic cardiovascular disease (ASCVD) risk prediction is the cornerstone of decision-making strategies for the prevention of ASCVD.1Arnett D.K. Blumenthal R.S. Albert M.A. et al.2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.,2Grundy S.M. Stone N.J. Bailey A.L. et al.2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Whereas guideline recommendations for ASCVD risk prediction are still largely based on the measurement of traditional ASCVD risk factors, there are well-established limitations to this approach, and other predictors of ASCVD risk are needed to better personalize ASCVD risk prediction. Accordingly, the most recent American College of Cardiology/American Heart Association guidelines place added emphasis on refining risk beyond traditional ASCVD risk factors. Coronary artery calcium (CAC), which is a measure of an individual’s subclinical burden of coronary atherosclerosis obtained by non–contrast-enhanced cardiac computed tomography, is strongly associated with increased ASCVD beyond traditional ASCVD risk factors3Nasir K. Bittencourt M.S. Blaha M.J. et al.Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association Cholesterol Management Guidelines: MESA (Multi-Ethnic Study of Atherosclerosis).; notably, the 2019 American College of Cardiology/American Heart Association primary prevention guidelines provide a IIa recommendation to perform CAC scoring when there is uncertainty among patients with a calculated borderline to intermediate 10-year ASCVD risk (7.5% to 1Arnett D.K. Blumenthal R.S. Albert M.A. et al.2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. A higher level of cardiorespiratory fitness (CRF) or exercise capacity is also strongly associated with a lower ASCVD risk and all-cause mortality, and indeed, the 2016 American Heart Association Cardiorespiratory Fitness Scientific Statement emphasizes that CRF is a stronger risk factor for incident ASCVD and all-cause mortality than traditional risk factors.4Ross R. Blair S.N. Arena R. et al.Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American Heart Association., 5Kodama S. Saito K. Tanaka S. et al.Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women A meta-analysis., 6Laukkanen J.A. Isiozor N.M. Kunutsor S.K. Objectively assessed cardiorespiratory fitness and all-cause mortality risk: an updated meta-analysis of 37 cohort studies involving 2,258,029 participants. In addition to their improvement in ASCVD risk prediction, CAC and CRF tests are widely accessible, relatively low cost, and simple to perform. However, only a small number of studies have examined how the concomitant measurement of both CAC and CRF may improve ASCVD risk prediction.In this issue of Mayo Clinic Proceedings, Ahmed et al7Ahmed A.I. Saad J.M. Han Y. et al.Prognostic interplay between coronary artery calcium scoring and cardiorespiratory fitness: the CAC-FIT study. examine whether the measurement of both CAC and CRF together can improve risk stratification for incident major adverse cardiovascular events (MACE), defined as all-cause death, nonfatal myocardial infarction, late revascularization, or hospital admission for heart failure. This study cohort included a total of 1932 patients who had a clinically indicated CAC scan and clinically indicated exercise stress test between January 2015 and September 2021. Approximately half of patients had exercise testing before their CAC scan and vice versa, with a median of 27 days between the 2 tests. Exercise capacity or CRF was defined on the basis of peak metabolic equivalents (METs) derived from symptom-limited treadmill stress testing performed with the Bruce protocol, the most commonly performed protocol in routine clinical practice. Ascertainment of MACE after testing was obtained through electronic health record review and International Classification of Diseases, Ninth Revision and Tenth Revision code search, which was then adjudicated by cardiologists blinded to the CAC and exercise testing results. Both CAC and CRF independently improved ASCVD risk stratification beyond traditional cardiovascular disease risk factors. In addition, CAC score provided additional risk stratification within fitness groups, and prediction models that included both CAC and CRF had the best prediction for MACE. There was no statistical interaction between CAC and CRF, suggesting that the 2 predict risk independently of each other.Patients with the lowest exercise capacity (8Radford N.B. DeFina L.F. Leonard D. et al.Cardiorespiratory fitness, coronary artery calcium, and cardiovascular disease events in a cohort of generally healthy middle-age men: results from the Cooper Center Longitudinal Study. Conversely, exercise testing appears to have the largest improvement in ASCVD risk estimation among persons with moderate to high CAC scores, with observed event rates approximately 50% lower for patients with moderate to high CRF compared with low CRF. However, whereas patients with a moderate or high CAC score had significant improvement in risk estimation based on their exercise capacity, those patients with a moderate to high exercise capacity and CAC score of 400 or higher still had an absolute event rate consistent with high ASCVD risk and are therefore likely to benefit from preventive pharmacotherapy, such as statin therapy.A major strength of CAC and exercise capacity/CRF is that they serve as integrated measures of an individual’s cardiovascular disease risk and overall health status. Indeed, beyond cardiovascular disease outcomes, higher CAC scores and lower CRF are associated with increased total mortality and non–cardiovascular disease outcomes, such as cancers.9Cardiorespiratory fitness as predictor of cancer mortality: a systematic review and meta-analysis., 10Whetton S.P. Al Rifai M. Dardari Z. et al.Coronary artery calcium and the competing long-term risk of cardiovascular vs. cancer mortality: the CAC Consortium., 11Blaha M.J. Feldman D.I. Nasir K. Coronary artery calcium and physical fitness—the two best predictors of long-term survival. However, CAC and CRF also effectively integrate different and complementary physiologic information. For example, CAC integrates an individual’s duration and intensity of exposure to risk factors along with an individual’s genetic susceptibility to subclinical atherosclerosis. Exercise capacity is dependent on multiple organ systems—including the heart, lungs, skeletal muscles, and nervous system—and genetics, lifestyle, and exercise training.12Lavie C.J. Arena R. Kamisnski L.A. Making the case to measure and improve cardiorespiratory fitness in routine clinical practice. It also serves as a robust measure of an individual’s frailty. Therefore, it makes intuitive sense that these 2 measures of ASCVD risk can together improve risk prediction beyond either measurement alone.It is noteworthy that although this study categorized patients into 3 CRF groups, the primary results focus on a comparison of patients with low CRF and those with moderate to high CRF. In addition, only 8.4% of patients (n=162) had a low exercise capacity, whereas 54% had a high exercise capacity (≥10 METs), and the absolute number of MACE was relatively low, occurring among only 66 patients during the mean follow-up of 32 months. Accordingly, there are very wide 95% CI ratios for the event rate estimates among patients with low CRF, and the limited number of events precluded investigation of the individual outcomes within the composite MACE definition. In addition, although a number of studies have noted a paradoxical increase in CAC among individuals who perform extreme levels of physical activity and very high CRF but low associated rate of ASCVD, the results presented in this manuscript do not provide sufficient granularity in exercise capacity/CRF to further examine this relationship.13Defina L.F. Radford N.B. Barlow C.E. et al.Association of all-cause and cardiovascular mortality with high levels of physical activity and concurrent coronary artery calcification., 14Lavie C.J. Hecht H.F. Wisloff U. Extreme physical activity may increase coronary calcification, but fitness still prevails., 15Lavie C.J. Wisloff U. Blumenthal R.S. Extreme physical activity and coronary artery calcification—running heavily and safely with “hearts of stone.”.In addition, the cohort is relatively young, with a median age of 56 years, with 42% women and a high prevalence of traditional ASCVD risk factors. Accordingly, although the authors do not present estimated 10-year ASCVD risk, this study cohort appears representative of what we would expect for middle-aged persons with intermediate ASCVD risk. One of the primary indications for ordering CAC testing is to determine the potential benefit of statin therapy or intensification of statin therapy. However, in this study, 65% of patients were already prescribed a statin, which was likely to be low- or moderate-intensity statin for most patients based on the median low-density lipoprotein cholesterol level of 106 mg/dL. Although the authors did not specifically examine patients receiving statin therapy as a subgroup, these findings showing the utility of CAC for risk stratification among this cohort with a high proportion of patients receiving statin therapy provide further evidence to support the potential utility of CAC scoring among individuals already receiving statin therapy.16Osei A.D. Mirbolouk M. Berman D. et al.Prognostic value of coronary artery calcium score, area, and density among individuals on statin therapy vs. non-users: the Coronary Artery Calcium Consortium.,17Orringer C.E. Blaha M.J. Blankstein R. et al.The National Lipid Association scientific statement on coronary artery calcium scoring to guide preventive strategies for ASCVD risk reduction. In addition, whereas 62% of patients in this study were referred for risk assessment and presumably asymptomatic, 38% had chest pain or dyspnea prompting cardiovascular testing. However, sensitivity analyses showed similar results across multiple subgroups including asymptomatic patients.

Overall, this study provides further evidence supporting that the complementary information obtained from CAC testing and exercise stress testing/CRF assessment improves ASCVD risk prediction. Whereas CAC improved risk stratification of patients with both low and moderate to high CRF, it appears to be especially useful among persons with low levels of CRF. Conversely, exercise testing appears to have the largest improvement in ASCVD risk estimation among persons with moderate to high CAC scores, although those patients still had an absolute event rate likely to benefit from statin therapy. These large observed differences in event rates by exercise capacity/CRF demonstrate heterogeneity within CAC score groups, and they highlight the need for further research to determine whether an improvement in exercise capacity/CRF among persons with a positive CAC score is associated with a reduction in ASCVD risk.

Potential Competing Interests

The authors report no competing interests.

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J Clin Lipidol. 15: 33-60Article InfoFootnotes

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DOI: https://doi.org/10.1016/j.mayocp.2022.05.027

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