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

Abstract

Background: Limited attention has been paid to negative cardiovascular disease (CVD) risk markers despite their potential to improve medical decision making. We compared 13 negative risk markers using diagnostic likelihood ratios (DLRs), which model the change in risk for an individual after the result of an additional test.

Methods and results: We examined 6814 participants from the Multi-Ethnic Study of Atherosclerosis. Coronary artery calcium score of 0, carotid intima-media thickness <25th percentile, absence of carotid plaque, brachial flow-mediated dilation >5% change, ankle-brachial index >0.9 and <1.3, high-sensitivity C-reactive protein <2 mg/L, homocysteine <10 µmol/L, N-terminal pro-brain natriuretic peptide <100 pg/mL, no microalbuminuria, no family history of coronary heart disease (any/premature), absence of metabolic syndrome, and healthy lifestyle were compared for all and hard coronary heart disease and all CVD events over the 10-year follow-up. Models were adjusted for traditional CVD risk factors. Among all negative risk markers, coronary artery calcium score of 0 was the strongest, with an adjusted mean DLR of 0.41 (SD, 0.12) for all coronary heart disease and 0.54 (SD, 0.12) for CVD, followed by carotid intima-media thickness <25th percentile (DLR, 0.65 [SD, 0.04] and 0.75 [SD, 0.04], respectively). High-sensitivity C-reactive protein <2 mg/L and normal ankle-brachial index had DLRs >0.80. Among clinical features, absence of any family history of coronary heart disease was the strongest (DLRs, 0.76 [SD, 0.07] and 0.81 [SD, 0.06], respectively). Net reclassification improvement analyses yielded similar findings, with coronary artery calcium score of 0 resulting in the largest, most accurate downward risk reclassification.

Conclusions: Negative results of atherosclerosis-imaging tests, particularly coronary artery calcium score of 0, resulted in the greatest downward shift in estimated CVD risk. These results may help guide discussions on the identification of individuals less likely to receive net benefit from lifelong preventive pharmacotherapy.

Keywords: biomarkers; calcium; cardiac imaging techniques; cardiovascular diseases; risk assessment.

Figure 1

Relationship between pre-test and post-test CVD risk after the knowledge of the negative result of each risk marker. The regression lines display the relationship between the pre-test predicted 10-year ASCVD risk (x axis), and the post-test risk (y axis) after the knowledge of the negative result of each risk marker. A broken back line is displayed as reference (risk shift with no additional testing). Results were obtained by plotting the pre-test and post-test risk based on the DLR of each MESA participant, and then applying a linear fit. CAC indicates coronary artery calcium; CIMT, carotid intima-media thickness; FMD, flow-mediated dilation; ABI, ankle-brachial index; HsCRP, high sensitivity C-reactive protein; BNP, brain natriuretic peptide; and CHD, coronary heart disease.

Figure 2

DLR of CAC=0 for cardiovascular disease events by age and pre-test 10-year atherosclerotic cardiovascular disease risk. Scatterplots of DLR of CAC=0 for CVD events by age (Figure 2A) and pre-test predicted 10-year ASCVD risk (Figure 2B). Best-fit curves (in red) were used to plot the mean DLR for each value of age and pre-test predicted risk. CVD indicates cardiovascular disease; and CAC, coronary artery calcium.

Figure 3

Risk factor-adjusted DLR of negative risk markers for CVD events in four sample patients. Patient A: 50-year-old Chinese American man, non-smoker, SBP 130mmHg (no medication), non-diabetic, HDL 40mg/dL, total cholesterol 170mg/dL. Patient B: 60-year-old White man, smoker, SBP 135mmHg on medication, non-diabetic, HDL 40mg/dL, total cholesterol 200mg/dL. Patient C: 65-year-old Hispanic woman, current smoker, SBP 160mmHg on medication, non-diabetic, HDL 45mg/dL, total cholesterol 220mg/dL. Patient D: 75-year-old African American man, non-smoker, SBP 145mmHg on medication, non-diabetic, HDL 40mg/dL, total cholesterol 230 mg/dL. CAC indicates coronary artery calcium; CIMT, carotid intima-media thickness; FMD, flow-mediated dilation; ABI, ankle-brachial index; HsCRP, high sensitivity C-reactive protein; BNP, brain natriuretic peptide; and CHD, coronary heart disease.