The Added Value of Coronary Calcium Score in Predicting Cardiovascular Events in Familial Hypercholesterolemia

JACC Cardiovasc Imaging. 2021 Dec;14(12):2414-2424. doi: 10.1016/j.jcmg.2021.06.011. Epub 2021 Jul 14.


Objectives: This study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH).

Background: Common cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD).

Methods: REFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death.

Results: We included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%.

Conclusions: CAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH.

Keywords: cardiovascular disease; coronary artery calcium; coronary imaging; familial hypercholesterolemia; genetic disease; risk prediction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Atherosclerosis*
  • Calcium
  • Cohort Studies
  • Coronary Artery Disease* / diagnostic imaging
  • Humans
  • Hyperlipoproteinemia Type II* / diagnostic imaging
  • Hyperlipoproteinemia Type II* / genetics
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Risk Assessment
  • Risk Factors
  • Vascular Calcification* / diagnostic imaging


  • Calcium