The coronary artery calcium (CAC) score has emerged over the past two decades from an area of research to an important clinical marker of cardiovascular risk.^1-3 CAC scores are fast, noninvasive, and fairly inexpensive; they provide valuable prognostic information in assessing atherosclerotic cardiovascular disease (ASCVD) risk.^4,5 While the evidence supporting the relationship of CAC to assess risk for coronary heart disease has grown, its association with cardiac structure and function has remained relatively unexplored in large cohort studies.

CAC Scores and Risk Prediction

Of particular clinical significance, CAC scoring provides a window into true ASCVD risk and provides additive prognostic information to the 2013 ASCVD risk score.^6,7 Not only is it the case that at high levels CAC are associated with a significantly higher risk than the pooled cohort equation estimate (PCE), but the absence of CAC (CAC=0) is the strongest negative predictor for ASCVD in near-to-medium term (5 to 10 year) patient follow-up.^8,9 Further studies have demonstrated that this prognostic effect remains important on long-term follow-up; patients with CAC=0 exhibit a significantly reduced CVD event rate even as compared to patients with low levels (CAC 1-10) patients, with CAC acting a better predictor of long-term than intermediate-term events.⁹

From a clinical standpoint, CAC has become a valuable tool in shared decision-making with patients.¹⁰ The presence of CAC may strongly influence the decision to initiate statin therapy, while its absence provides a strong rationale not to start pharmacotherapy or to pursue further diagnostic work-up for cardiac risk assessment in the short-term.^11,12 This is highlighted in greater detail in the recent 2018 American College of Cardiology/American Heart Association Guideline on the Management of Blood Cholesterol, with brief recommendations below (Table 1):¹³

Table 1: CAC in Intermediate 10-year ASCVD Risk Patients without Diabetes Mellitus

CAC=0	No statin therapy unless current smoking or possibly diabetes Reassess in 5-10 years
CAC 1-99	Favor starting statin therapy Particular consideration if > age 55 years
CAC ≥100	Start moderate or high intensity statin therapy

Coronary Artery Calcium and Ventricular Remodeling

Despite a strong association with ASCVD risk, the relationship of CAC to reduced cardiac function and remodeling is more nuanced. Prior studies have associated elevated CAC with adverse cardiac remodeling, such as increased left ventricular mass; however, these studies have been limited in scope or utilized younger adult patient cohorts with very low median CAC.^14,15 Recent work by Yared and colleagues has helped elucidate further the relationship between CAC and left ventricular structure over time, opening new avenues for the importance of CAC outside the arterial lumen.¹⁶

The association of coronary artery disease to changes in left ventricular function and remodeling has extended beyond subclinical ASCVD, non-obstructive disease, or obstructive disease.^17-19 Indeed, CAC has also previously been associated with increased left ventricular mass.¹⁴ The underpinnings of this relationship, particularly with respect to left ventricular function and remodeling, have not been well described.

Within the broader Coronary Artery Risk Development in Young Adults (CARDIA) study, Yared and colleagues sought to investigate this question. They studied a population of 2,449 participants across four sites who had CAC scores ten years apart – years 15 and 25 of the study overall – with echocardiography performed alongside the second CAC assessment. Upon follow-up assessment, higher CAC was associated with increased left ventricular mass (β=1.218, p=0.007), end diastolic volume (β=0.811, p=0.007), end systolic volume (β=0.350, p=0.048), elevated E/e' ratio (β=0.059, p=0.014), and higher left atrial volume (β=0.214, p=0.009). There was no clear difference in left ventricular (LV) ejection fraction (p=0.071), though this trended toward significance.

The authors suggest that this association may be secondary to increased atherosclerosis, as noted by elevated CAC, leading to silent ischemia and subsequent elevated filling pressures.¹⁶ If true, this complements previous data on the relationship between elevated CAC and clinical cardiovascular events, now highlighting such a relationship at the subacute level and noted via precursors to left ventricular remodeling. Continued research investigating later advancement to signs of heart failure with preserved ejection fraction and whether CAC remains a risk factor independent of overall plaque burden is required to solidify this data.

Perhaps the key finding of this study is that patients without CAC at both assessments exhibited lower left ventricular strain (p=0.001), end diastolic volume (p<0.001), end systolic volume (p<0.001), left ventricular mass (p<0.001), and lower left atrial volumes (p=0.003) as compared to those with a progression from CAC=0 at initial assessment to follow-up. This lends further credibility to the prognostic power of persistently absent and very minimal CAC, already well-established with respect to clinical cardiovascular events and extends its importance to left ventricular remodeling.^11,20 As the cohort studied was of middle age and the remodeling changes found were largely precursors for systolic and/or diastolic dysfunction, the degree to which this effect carries on as protective against incident heart failure will be an interesting question going forward.

When adjusted for baseline ASCVD risk factors, change in risk over 10 years, and chronic risk factors, higher left ventricular mass index remained significantly associated with progression of CAC between measurements. This change in CAC between assessments, however, was associated with a higher left ventricular mass only in black participants (p<0.001), with no such similar relationship exhibited in white participants (p<0.283). The etiology behind this difference is unclear; as this was a biracial cohort, further data is required to explore if this distinction exists in other demographic groups.¹⁴

Notably 2,282 participants had CAC=0 at the time of echo follow-up, and 1,721 exhibited no CAC in both measurements. Given an initial 2,449 participants, this indicates that the number of patients with measurable CAC was relatively small.

Conclusion

In a large middle-aged cohort followed longitudinally for changes in CAC score as well as LV function and size, the authors show that CAC is associated with worsening outcomes on subclinical measures of maladaptive LV measures. These results highlight the impact of CAC on LV function and adverse cardiac remodeling.

Further, the study lends continued support to the prognostic power of absent CAC, highlighting lower markers of subacute systolic and diastolic dysfunction in those with zero or minimal CAC score. The degree to which this carries over to a reduction in incident heart failure, however, remains to be seen.

It is also worth noting the small number of patients in the cohort with measurable CAC, suggesting that the population where such change does eventually become clinically relevant may be small, and likely not be visible upon near term follow-up. Regardless, Yared and colleagues lay out a novel path for the importance of CAC beyond purely atherosclerotic vascular disease risk. As a result, avenues for the study of CAC continue to grow, providing clinicians with additional guidance for global cardiovascular disease risk prediction.

References

1. Wayhs R, Zelinger A, Raggi P. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol 2002;39:225-30.
2. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:1336-45.
3. Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events. J Am Coll Cardiol 2005;46:158-65.
4. Pletcher MJ, Tice JA, Pignone M, Browner WS. Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis. Arch Intern Med 2004;164:1285-92.
5. Roberts ET, Horne A, Martin SS, et al. Cost-effectiveness of coronary artery calcium testing for coronary heart and cardiovascular disease risk prediction to guide statin allocation: the Multi-Ethnic Study of Atherosclerosis (MESA). PLoS One 2015;10:e0116377.
6. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 2004;291:210-15.
7. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol 2007;49:1860-70.
8. 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. Circulation 2016;133:849-58.
9. Nakanishi R, Li D, Blaha MJ, et al. All-cause mortality by age and gender based on coronary artery calcium scores. Eur Heart J Cardiovasc Imaging 2016;17:1305-14.
10. Hecht HS, Shaw LJ, Chandrashekhar Y, Narula J. Coronary artery calcium and shared decision making. JACC Cardiovasc Imaging 2016;9:637-39.
11. Joshi PH, Blaha MJ, Budoff MJ, et al. The 10-year prognostic value of zero and minimal CAC. JACC Cardiovascular Imaging 2017;10:957-58.
12. Michos ED, Blaha MJ, Blumenthal RS. Use of the coronary artery calcium score in discussion of initiation of statin therapy in primary prevention. Mayo Clinic Proc 2017;92:1831-41.
13. Grundy SM, Stone NJ, Bailey AL, 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. J Am Coll Cardiol 2019:73:3158-3209.
14. Tong W, Lima JA, Lai H, Celentano DD, Dai S, Lai S. Relation of coronary artery calcium to left ventricular mass in African-Americans. Am J Cardiol 2004;93:490-92.
15. Gardin JM, Iribarren C, Detrano RC, et al. Relation of echocardiographic left ventricular mass, geometry and wall stress, and left atrial dimension to coronary calcium in young adults (the CARDIA study). Am J Cardiol 2005;95:626-29.
16. Yared GS, Moreira HT, Ambale-Venkatesh B, et al. Coronary artery calcium from early adulthood to middle age and left ventricular structure and function. Circ Cardiovasc Imaging 2019;12:e009228.
17. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397-402.
18. Lin FY, Zemedkun M, Dunning A, et al. Extent and severity of coronary artery disease by coronary CT angiography is associated with elevated left ventricular diastolic pressures and worsening diastolic function. J Cardiovasc Comput Tomogr 2013;7:289-96.
19. Fernandes VR, Polak JF, Edvardsen T, et al. Subclinical atherosclerosis and incipient regional myocardial dysfunction in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2006;47:2420-28.
20. Lakshmanan SB, M.J. Something old predicting something new. Circ Cardiovasc Imaging 2019;12;e009320.

Keywords: Dyslipidemias, Risk Factors, Ventricular Remodeling, Ventricular Function, Left, Follow-Up Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Vessels, American Heart Association, Atrial Fibrillation, Cardiovascular Diseases, Stroke Volume, Diastole, Risk Assessment, Atherosclerosis, Echocardiography, Heart Failure, Diabetes Mellitus, Coronary Disease, Decision Making, Cholesterol

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