Progression of calcium density in the ascending thoracic aorta is inversely associated with incident cardiovascular disease events

Progression of calcium density in the ascending thoracic aorta is inversely associated with... Abstract Aims Little is known regarding the risk of atherosclerotic cardiovascular disease (ASCVD) conferred by changes in the volume and density of ascending thoracic aorta calcium (ATAC) over time. We evaluated changes in ATAC volume and density scores and incident ASCVD events. Methods and results The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of individuals without baseline clinical ASCVD. Ascending thoracic aorta calcium was measured from baseline and follow-up (mean interval 2.4 years) cardiac computed tomography (CT). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) per standard deviation for events after the follow-up exam adjusted for ASCVD risk factors, baseline ATAC and coronary artery calcium (CAC) volume and density, and changes in CAC volume and density. Among 5887 participants, 296 (5.0%) had detectable ATAC at baseline, follow-up, or both exams. A total of 403 events occurred over 9.5 years. An increase in ATAC volume was associated with coronary heart disease (CHD) (HR 1.90, 95% CI 1.14–3.16), ASCVD (HR 1.93, 95% CI 1.26–2.94), and ischaemic stroke (HR 2.14, CI 1.21–3.78). An increase in ATAC density was inversely associated with CHD (HR 0.29, 95% CI 0.14–0.60) and ASCVD (HR 0.42, 95% CI 0.23–0.76), but not stroke (HR 0.61, CI 0.23–1.61). Conclusion Ascending thoracic aorta calcium is uncommon on serial cardiac CT. However, changes in ATAC volume and density are both associated with incident ASCVD events, but in opposite directions. Serial assessments in those with baseline ATAC may provide insight into an individual’s trajectory of ASCVD risk. calcification, calcium density, ascending aorta, atherosclerosis, atherosclerotic cardiovascular disease Introduction Arterial calcification identified on computed tomography (CT) is a marker of subclinical atherosclerosis and is strongly associated with atherosclerotic cardiovascular disease (ASCVD) events. Coronary artery calcium (CAC), in particular, is among the most robust subclinical predictors of ASCVD, with its presence, extent, and density each independently associated with ASCVD risk.1–3 Arterial calcification outside of the coronary arteries is also associated with ASCVD. For instance, calcium in the thoracic aorta is known to be associated with coronary heart disease (CHD), ASCVD, and death.4–6 Recently, the density of calcium in the ascending segment of the thoracic aorta was observed to be inversely associated with ASCVD.7 However, little is known regarding the risk of ASCVD conferred by the progression of calcium in this structure. Changes in the volume and density components of calcium may portend CHD and stroke due to the anatomical continuity and close proximity of the ascending thoracic aorta with both the coronary and carotid arteries. In this study, we evaluated the independent associations of the progression of ascending thoracic aorta calcium (ATAC) with incident CHD, ASCVD, and ischaemic stroke after adjustment for ASCVD risk factors, baseline levels of ATAC and CAC, and CAC progression in a cohort free of clinical ASCVD. Methods MESA study design The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of 6814 individuals aged 45–84 years without known clinical ASCVD at recruitment, enrolled from six field centres (Baltimore, MD; Chicago, IL, USA; Forsyth County, NC, USA; Los Angeles, CA, USA; New York, NY, USA; and St. Paul, MN, USA). Specific ethnic groups enrolled were Non-Hispanic White, African-American, Hispanic, and Chinese. Baseline examinations were conducted from 2000 to 2002. Institutional Review Boards at each participating centre approved the study, and all participants provided written informed consent. Details of the study design have been described previously.8 Medical history and laboratory data for this study were taken from the baseline examination of the cohort. Age, gender, race/ethnicity, and medication use were obtained by self-administered questionnaire. Resting blood pressure was measured three times in the seated position, and the average of the second and third readings was recorded. Total and high-density lipoprotein cholesterol (HDL-C) were measured from blood samples obtained after a 12-h fast. Smoking status was classified as current, former, or never, with current defined as having smoked a cigarette in the last 30 days. Diabetes mellitus was defined as a fasting glucose ≥126 mg/dL or use of hypoglycaemic medications. Age, gender, total cholesterol, HDL-C, systolic blood pressure (SBP), hypertension medication use, current smoking, and diabetes status were used to calculate the American College of Cardiology/American Heart Association 2013 Pooled Cohort ASCVD risk score for each participant.9 CT image acquisition A baseline non-contrast cardiac-gated CT study was performed on all participants of the MESA to evaluate for the presence and extent of CAC.10 An additional CT study was performed on 5888 individuals at a follow-up visit, with the first half of this group receiving the follow-up study between September 2002 and January 2004, and the second half between March 2004 and July 2005, corresponding to an average of 1.6 and 3.2 years after the first CT study, respectively. The nominal slice thickness was 3.0 mm for electron-beam CT and 2.5 mm for four-detector row CT. Scanning centres used an electron-beam CT scanner in Chicago, Los Angeles, and New York field centres and a four-slice multidetector CT system in Baltimore, Forsyth County and St. Paul field centres. Certified technologists scanned all participants over phantoms of known physical calcium concentration, and all studies were read at the Los Angeles Biomedical Research Institute at Harbor-UCLA in Torrance, CA, USA. Calcium in the thoracic aorta was evaluated retrospectively.11 Ascending thoracic aorta calcium was measured in the ascending thoracic aorta from the aortic annulus inferiorly to the pulmonary artery superiorly (Figure 1).4 The aortic arch was not visualized on these scans. Figure 1 View largeDownload slide Ascending thoracic aorta calcium (ATAC). Axial view of the ascending thoracic aorta on cardiac computed tomography (left). Arrow indicates calcification in the ascending thoracic aorta wall. Schematic of the thoracic aorta denoting the ascending segment. Figure 1 View largeDownload slide Ascending thoracic aorta calcium (ATAC). Axial view of the ascending thoracic aorta on cardiac computed tomography (left). Arrow indicates calcification in the ascending thoracic aorta wall. Schematic of the thoracic aorta denoting the ascending segment. Volume and density scoring of calcium Calcified plaque within the vascular territory of interest was identified as attenuation greater than 130 Hounsfield units (HU) with a minimum size of 5.5 mm3 (electron beam CT) or 4.6 mm3 (multidetector CT). The Agatston score was computed by multiplying individual calcified plaque areas by a density factor of 1, 2, 3, or 4, corresponding to the maximum attenuation within each plaque (130–199 HU = 1, 200–299 HU = 2, 300–399 HU = 3, and 400+ HU = 4).12 The Agatston scores for each calcified plaque were then summed to produce the total Agatston score. The volume score was computed by summing the products of all calcified plaque areas (mm2) and multiplying by the CT scan slice thickness (3.0 mm for electron beam CT or 2.5 mm for multidetector CT). For this study, ATAC and CAC density scores were calculated using the method previously described in the MESA, as follows.2 The volume score for each vascular territory was divided by the CT scan slice thickness, resulting in the total area of calcified plaque. This total area was then divided into the total Agatston score, resulting in the density score, which reflects the average density factor of all calcified plaques and is a unitless value that theoretically ranges from 1 to 4. Outcome surveillance Follow-up for incident ASCVD events began at the time of the follow up CT scan and continued until the first ASCVD event, death, loss to follow-up, or December 2013. Details of ASCVD event ascertainment have been previously reported.13 Briefly, participants or their next of kin (if participants were unavailable) were contacted at intervals of 9–12 months by telephone, and trained interviewers inquired about interim hospital admissions, cardiovascular outpatient diagnoses, and death. Medical records and death certificates were requested for verification. Two physicians blinded to the results of the CT scans independently classified events and assigned incidence dates. A mortality and morbidity review committee adjudicated disagreements. Incident outcomes evaluated in this study were hard CHD (myocardial infarction, resuscitated cardiac arrest, or CHD death), hard ASCVD (hard CHD, stroke, or stroke death), and ischaemic stroke (fatal or non-fatal, excluding haemorrhagic and unknown types). End points such as angina and revascularization were not included. For all analyses, events occurring prior to the follow-up CT scan were excluded. Statistical analysis To model ATAC progression, we separated the qualitative association of the change in ATAC status (i.e. presence or absence of ATAC at baseline and follow-up exams) from the quantitative associations of changes in the continuous variables of ATAC volume and density.14 To evaluate the qualitative association, we created a four-category ‘change in status’ variable, defined as follows: no ATAC (volume scores of zero at both baseline and follow-up, reference group), ATAC incidence (volume scores of zero at baseline and greater than zero at follow up), ATAC persistence (volume scores greater than zero at both baseline and follow up), and ATAC regression (volume scores greater than zero at baseline and zero at follow up). For quantitative changes in ATAC, we evaluated the differences in ATAC volume scores and ATAC density scores between the baseline and follow-up scans (delta scores). Baseline and follow-up ATAC volume scores were natural logarithm (ln) transformed [ln(ATAC volume + 1)] to adjust for skewness. The delta scores were divided by the number of years between scans to provide the annualized rate of change in these scores and to adjust for differences in scan intervals. In order to include participants with no density score at the baseline and/or follow-up exams (i.e. those with volume scores of zero) in the multivariable models, baseline and/or delta density scores were substituted with conditional density scores of zero, where applicable. For example, a participant with ATAC incidence would receive conditional baseline and conditional delta density scores of zero. The four-category ‘change in status’ variable was included in the multivariable models to allow for the discontinuity in the associations for the continuous variables introduced by including these participants in the model. This is analogous to the more familiar practice of including a term for smoking status in a model that includes pack-years, which captures the qualitative difference between smokers and non-smokers, and the discontinuity in risk (or means) that may occur when moving from zero to non-zero pack-years.14 Ascending thoracic aorta calcium volume and density scores (both baseline and delta) were centred according to the mean value of each change in status group. The centring of the volume and density scores does not impact the coefficients for the quantitative variables, but allows for the ‘change in status’ variable to be interpretable. For example, the hazard ratio (HR) for the ATAC incidence group is interpreted as the relative hazard of an ‘average incident participant’ (i.e. a participant with no ATAC at baseline and an average volume and density of ATAC at follow up) compared with the reference group of no ATAC at baseline and follow up. Change in CAC status, baseline CAC volume and density scores, and delta CAC volume and density scores were computed in the same manner as ATAC. Descriptive statistics are presented as means ± standard deviations (SDs) for continuous variables and frequencies (%) for categorical variables. A one-way ANOVA was performed with a Tukey post hoc test to evaluate for between group differences in baseline characteristics. Spearman correlation coefficients were calculated between delta volume and delta density values for ATAC and CAC. Cox proportional hazards regression was used to estimate HRs and 95% confidence intervals (CIs) per SD change in the exposure variable for time to CHD, ASCVD, and ischaemic stroke in multivariable models as follows: Model 1: Age, gender, race/ethnicity, change in ATAC status, baseline ATAC volume score, baseline ATAC density score, delta ATAC volume score, and delta ATAC density score. Model 2: Model 1 variables + remaining components of the ASCVD Pooled Cohort Equations Risk Score [total cholesterol, HDL-C, SBP, treatment for hypertension status (yes/no), diabetes status (yes/no) current smoking status (yes/no)], and statin use. Model 3: Model 2 variables + change in CAC status, baseline CAC volume score, baseline CAC density score, delta CAC volume score, and delta CAC density score. In some cases, participants with complete ATAC and CAC regression from baseline to follow up exam had substantial reductions in ATAC and CAC volume. To investigate if this occurrence was a result of a systematic error in the dataset (for instance, slight changes in the field of view between baseline and follow-up CT scan images) that may have skewed our results, we also performed the above analyses after excluding participants with ATAC and/or CAC regression in sensitivity analyses. Analyses were performed using SPSS Statistics version 22.0 (IBM Corporation, Armonk, NY, USA). Statistical significance was defined as a two-tailed P-value of less than 0.05. Results Of the 5888 participants of the MESA cohort receiving serial cardiac CT scans, one was missing ATAC scores, leaving an analytical sample of 5887 participants for this study. The mean time between scans was 2.4 years. Over a mean of 9.5 years after the follow-up scan, 255 CHD events, 403 ASCVD events, and 133 ischaemic strokes occurred. Table 1 summarizes unadjusted characteristics of the study sample stratified by change in ATAC status over time. Ascending thoracic aorta calcium incidence was observed in 109 (1.9%) participants, persistence in 107 (1.8%) participants, regression in 80 (1.3%) participants, and no ATAC at baseline and follow-up exam in 5591 (95.0%) participants. Those with no ATAC were younger, had lower SBP, lower proportions taking antihypertensive and statin medications, and a lower proportion with diabetes compared with the other three ATAC groups. Table 1 Characteristics of participants by change in ATAC status No ATAC (baseline and follow up = 0) ATAC incidence (baseline = 0, follow up > 0) ATAC persistence (baseline and follow up > 0) ATAC regression (baseline > 0, follow up = 0) n (%) 5591 (95.0) 109 (1.9) 107 (1.8) 80 (1.3) Age (years) 61.4 ± 10.0 68.4 ± 8.2* 72 ± 7.4* 69.4 ± 9.1* Female gender 52.6 55.0 40.2* 56.3 Ethnicity  Non-Hispanic White 40.0 43.1 37.4 36.3  Chinese 11.9 9.2 8.4 5.0  African-American 26.5 34.9 29.0 37.5*  Hispanic 21.6 12.8* 25.2 21.3 Clinical characteristics  Total cholesterol (mg/dL) 194 201 200 199  HDL cholesterol (mg/dL) 51 51 49 50  Systolic BP (mmHg) 125 ± 21 136 ± 21* 143 ± 23* 137 ± 24*  Hypertension medication 35.1 54.1* 63.6* 52.5*  Smoking (current) 12.4 13.8 16.0 17.5  Diabetes mellitus 11.4 20.2* 22.4* 16.3  Statin therapy 14.3 29.9* 27.1* 26.3* ASCVD, 10-year CVD risk 12.3 21.2* 29.4* 22.5* Days between CT scans 886 ± 311 873 ± 334 844 ± 314 845 ± 323 Calcium scores  Baseline ATAC volume (mm3) 0 0 293 ± 799* 98 ± 207*  Baseline ATAC density (density-units) 2.93 ± 0.87 2.66 ± 2.82  Delta ATAC volume (mm3/year), mean (range) 0 (0 to 0) 38 (1 to 234)* 42 (−441 to 620)* −48 (−944 to −1)*  Delta ATAC density (density-units/year), mean (range) 0.03 (−1.10 to 1.27) No ATAC (baseline and follow up = 0) ATAC incidence (baseline = 0, follow up > 0) ATAC persistence (baseline and follow up > 0) ATAC regression (baseline > 0, follow up = 0) n (%) 5591 (95.0) 109 (1.9) 107 (1.8) 80 (1.3) Age (years) 61.4 ± 10.0 68.4 ± 8.2* 72 ± 7.4* 69.4 ± 9.1* Female gender 52.6 55.0 40.2* 56.3 Ethnicity  Non-Hispanic White 40.0 43.1 37.4 36.3  Chinese 11.9 9.2 8.4 5.0  African-American 26.5 34.9 29.0 37.5*  Hispanic 21.6 12.8* 25.2 21.3 Clinical characteristics  Total cholesterol (mg/dL) 194 201 200 199  HDL cholesterol (mg/dL) 51 51 49 50  Systolic BP (mmHg) 125 ± 21 136 ± 21* 143 ± 23* 137 ± 24*  Hypertension medication 35.1 54.1* 63.6* 52.5*  Smoking (current) 12.4 13.8 16.0 17.5  Diabetes mellitus 11.4 20.2* 22.4* 16.3  Statin therapy 14.3 29.9* 27.1* 26.3* ASCVD, 10-year CVD risk 12.3 21.2* 29.4* 22.5* Days between CT scans 886 ± 311 873 ± 334 844 ± 314 845 ± 323 Calcium scores  Baseline ATAC volume (mm3) 0 0 293 ± 799* 98 ± 207*  Baseline ATAC density (density-units) 2.93 ± 0.87 2.66 ± 2.82  Delta ATAC volume (mm3/year), mean (range) 0 (0 to 0) 38 (1 to 234)* 42 (−441 to 620)* −48 (−944 to −1)*  Delta ATAC density (density-units/year), mean (range) 0.03 (−1.10 to 1.27) * P-value <0.05 compared with no ATAC value. Values presented are percentages or means ± standard deviations unless specified. ASCVD, atherosclerotic cardiovascular disease risk score; ATAC, ascending thoracic aorta calcium; BP, blood pressure; CAC, coronary artery calcium; CHD, coronary heart disease; CVD, cardiovascular disease; HDL, high-density lipoprotein. Table 1 Characteristics of participants by change in ATAC status No ATAC (baseline and follow up = 0) ATAC incidence (baseline = 0, follow up > 0) ATAC persistence (baseline and follow up > 0) ATAC regression (baseline > 0, follow up = 0) n (%) 5591 (95.0) 109 (1.9) 107 (1.8) 80 (1.3) Age (years) 61.4 ± 10.0 68.4 ± 8.2* 72 ± 7.4* 69.4 ± 9.1* Female gender 52.6 55.0 40.2* 56.3 Ethnicity  Non-Hispanic White 40.0 43.1 37.4 36.3  Chinese 11.9 9.2 8.4 5.0  African-American 26.5 34.9 29.0 37.5*  Hispanic 21.6 12.8* 25.2 21.3 Clinical characteristics  Total cholesterol (mg/dL) 194 201 200 199  HDL cholesterol (mg/dL) 51 51 49 50  Systolic BP (mmHg) 125 ± 21 136 ± 21* 143 ± 23* 137 ± 24*  Hypertension medication 35.1 54.1* 63.6* 52.5*  Smoking (current) 12.4 13.8 16.0 17.5  Diabetes mellitus 11.4 20.2* 22.4* 16.3  Statin therapy 14.3 29.9* 27.1* 26.3* ASCVD, 10-year CVD risk 12.3 21.2* 29.4* 22.5* Days between CT scans 886 ± 311 873 ± 334 844 ± 314 845 ± 323 Calcium scores  Baseline ATAC volume (mm3) 0 0 293 ± 799* 98 ± 207*  Baseline ATAC density (density-units) 2.93 ± 0.87 2.66 ± 2.82  Delta ATAC volume (mm3/year), mean (range) 0 (0 to 0) 38 (1 to 234)* 42 (−441 to 620)* −48 (−944 to −1)*  Delta ATAC density (density-units/year), mean (range) 0.03 (−1.10 to 1.27) No ATAC (baseline and follow up = 0) ATAC incidence (baseline = 0, follow up > 0) ATAC persistence (baseline and follow up > 0) ATAC regression (baseline > 0, follow up = 0) n (%) 5591 (95.0) 109 (1.9) 107 (1.8) 80 (1.3) Age (years) 61.4 ± 10.0 68.4 ± 8.2* 72 ± 7.4* 69.4 ± 9.1* Female gender 52.6 55.0 40.2* 56.3 Ethnicity  Non-Hispanic White 40.0 43.1 37.4 36.3  Chinese 11.9 9.2 8.4 5.0  African-American 26.5 34.9 29.0 37.5*  Hispanic 21.6 12.8* 25.2 21.3 Clinical characteristics  Total cholesterol (mg/dL) 194 201 200 199  HDL cholesterol (mg/dL) 51 51 49 50  Systolic BP (mmHg) 125 ± 21 136 ± 21* 143 ± 23* 137 ± 24*  Hypertension medication 35.1 54.1* 63.6* 52.5*  Smoking (current) 12.4 13.8 16.0 17.5  Diabetes mellitus 11.4 20.2* 22.4* 16.3  Statin therapy 14.3 29.9* 27.1* 26.3* ASCVD, 10-year CVD risk 12.3 21.2* 29.4* 22.5* Days between CT scans 886 ± 311 873 ± 334 844 ± 314 845 ± 323 Calcium scores  Baseline ATAC volume (mm3) 0 0 293 ± 799* 98 ± 207*  Baseline ATAC density (density-units) 2.93 ± 0.87 2.66 ± 2.82  Delta ATAC volume (mm3/year), mean (range) 0 (0 to 0) 38 (1 to 234)* 42 (−441 to 620)* −48 (−944 to −1)*  Delta ATAC density (density-units/year), mean (range) 0.03 (−1.10 to 1.27) * P-value <0.05 compared with no ATAC value. Values presented are percentages or means ± standard deviations unless specified. ASCVD, atherosclerotic cardiovascular disease risk score; ATAC, ascending thoracic aorta calcium; BP, blood pressure; CAC, coronary artery calcium; CHD, coronary heart disease; CVD, cardiovascular disease; HDL, high-density lipoprotein. Supplementary data online, Figure SA shows the distribution of the annual change in the ATAC volume score (delta volume score), with participants with no ATAC at baseline and follow-up (n = 5591) not depicted. Among participants with detectable ATAC at baseline and/or follow up (n = 296), delta volume ranged from −4.98 to 4.25 natural log units, with a median of 0.31 ln-units/year. The SDs for delta volume varied for each change in status category (0.93 ln-units/year for incidence, 0.45 ln-units/year for persistence, and 0.99 ln-units/year for regression). Supplementary data online, Figure SB displays the distribution of the annual change in ATAC density score (delta density score) among those with ATAC present at baseline and follow up (n = 107). Delta density scores ranged from −1.10 to 1.27, with a median of 0.02 density-units/year and a SD of 0.41 density-units/year (for persistence). Supplementary data online, Table SA displays Spearman correlations coefficients between ATAC and CAC scores. There was little to correlation for baseline volume and density scores, as well as delta volume and density scores. Figure 2 depicts the Kaplan–Meier curves demonstrating the survival free from CVD events stratified by level of baseline ATAC volume and density (Panel A), by change in ATAC status over time (Panel B), and by change in ATAC volume and density from baseline (Panel C). Participants with any ATAC at baseline and/or follow-up tended to have a higher risk of CVD events. Participants with higher baseline levels of ATAC volume and increases in ATAC volume over time tended to have a higher risk of CVD events, and participants with higher baseline ATAC density and increases in ATAC density over time tended to have a lower risk, though these associations were not statistically significant. Figure 2 View largeDownload slide The Kaplan–Meier estimates of survival free from incident ASCVD events stratified by ATAC status. (Panel A) stratifies participants by change in ATAC status from baseline to follow-up examination: no ATAC at baseline or follow-up, ATAC incidence, ATAC persistence, and ATAC regression. (Panel B) stratifies participants by baseline level of ATAC volume and density scores, with participants divided above and below the 50th percentile for each score. (Panel C) stratifies participants by change in ATAC volume and density score from baseline to follow-up examination, stratified by whether these scores increased or decreased. Figure 2 View largeDownload slide The Kaplan–Meier estimates of survival free from incident ASCVD events stratified by ATAC status. (Panel A) stratifies participants by change in ATAC status from baseline to follow-up examination: no ATAC at baseline or follow-up, ATAC incidence, ATAC persistence, and ATAC regression. (Panel B) stratifies participants by baseline level of ATAC volume and density scores, with participants divided above and below the 50th percentile for each score. (Panel C) stratifies participants by change in ATAC volume and density score from baseline to follow-up examination, stratified by whether these scores increased or decreased. Table 2 summarizes the associations of ATAC progression with incident CHD in the multivariable-adjusted Cox regression models, with HR reflecting a one SD difference. Baseline ATAC was associated with CHD in all models, including Model 3 (volume HR 2.78, CI 1.46–5.32, P = 0.002; density HR 0.23, CI 0.11–0.49, P < 0.001). There were no significant associations for the qualitative change in ATAC status for ATAC incidence, regression, and persistence when compared with those with no ATAC. However, the quantitative increase in ATAC volume between scans was associated with a higher risk of CHD in Model 3 (HR 1.90, CI 1.14–3.16, P = 0.013). Conversely, an increase in ATAC density between scans was associated with a lower risk of CHD in all models, including Model 3 (HR 0.29, CI 0.14–0.60, P = 0.001). Table 2 Progression of ATAC volume and density and risk of incident CHD Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.66 1.42–4.99 0.002 2.42 1.32–4.46 0.005 2.78 1.46–5.32 0.002 ATAC densityb 0.31 0.15–0.62 0.001 0.31 0.15–0.63 0.001 0.23 0.11–0.49 <0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.56–2.61 0.637 1.02 0.47–2.20 0.969 0.60 0.26–1.44 0.254 ATAC Persistence 1.34 0.69–2.57 0.389 1.01 0.52–1.98 0.972 0.77 0.38–1.59 0.484 ATAC Regression 1.23 0.55–2.77 0.610 1.05 0.46–2.36 0.914 0.86 0.36–2.08 0.742 Change from baseline Delta ATAC volumec 1.58 0.99–2.50 0.053 1.60 1.00–2.55 0.051 1.90 1.14–3.16 0.013 Delta ATAC densityd 0.41 0.21–0.80 0.009 0.39 0.20–0.77 0.007 0.29 0.14–0.60 0.001 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.66 1.42–4.99 0.002 2.42 1.32–4.46 0.005 2.78 1.46–5.32 0.002 ATAC densityb 0.31 0.15–0.62 0.001 0.31 0.15–0.63 0.001 0.23 0.11–0.49 <0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.56–2.61 0.637 1.02 0.47–2.20 0.969 0.60 0.26–1.44 0.254 ATAC Persistence 1.34 0.69–2.57 0.389 1.01 0.52–1.98 0.972 0.77 0.38–1.59 0.484 ATAC Regression 1.23 0.55–2.77 0.610 1.05 0.46–2.36 0.914 0.86 0.36–2.08 0.742 Change from baseline Delta ATAC volumec 1.58 0.99–2.50 0.053 1.60 1.00–2.55 0.051 1.90 1.14–3.16 0.013 Delta ATAC densityd 0.41 0.21–0.80 0.009 0.39 0.20–0.77 0.007 0.29 0.14–0.60 0.001 Model 1 adjusts for age, gender, race/ethnicity, and all the ATAC variables listed. Model 2 adjusts for Model 1 variables and systolic BP, treatment for hypertension, total cholesterol, HDL cholesterol, diabetes, current smoking, and statin use. Model 3 adjusts for Model 2 variables and baseline CAC volume and density, change in CAC status (no CAC, CAC incidence, CAC persistence, CAC regression), and delta CAC volume and density. Coronary heart disease is the composite of myocardial infarction, resuscitated cardiac arrest, and coronary heart disease related death. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group: a per 1.43 (for persistence) and 1.27 (for regression) ln-units; b per 0.87 (for persistence) and 1.06 (for regression) density-units; c per 0.93 (for incidence), 0.45 (for persistence), and 0.99 (for regression) ln-units/year; d per 0.41 density-units/year (for persistence). Bolded text indicates P < 0.05. CI, confidence interval; HR, hazard ratio, ln, natural log, rest of abbreviations per Table 1. Table 2 Progression of ATAC volume and density and risk of incident CHD Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.66 1.42–4.99 0.002 2.42 1.32–4.46 0.005 2.78 1.46–5.32 0.002 ATAC densityb 0.31 0.15–0.62 0.001 0.31 0.15–0.63 0.001 0.23 0.11–0.49 <0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.56–2.61 0.637 1.02 0.47–2.20 0.969 0.60 0.26–1.44 0.254 ATAC Persistence 1.34 0.69–2.57 0.389 1.01 0.52–1.98 0.972 0.77 0.38–1.59 0.484 ATAC Regression 1.23 0.55–2.77 0.610 1.05 0.46–2.36 0.914 0.86 0.36–2.08 0.742 Change from baseline Delta ATAC volumec 1.58 0.99–2.50 0.053 1.60 1.00–2.55 0.051 1.90 1.14–3.16 0.013 Delta ATAC densityd 0.41 0.21–0.80 0.009 0.39 0.20–0.77 0.007 0.29 0.14–0.60 0.001 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.66 1.42–4.99 0.002 2.42 1.32–4.46 0.005 2.78 1.46–5.32 0.002 ATAC densityb 0.31 0.15–0.62 0.001 0.31 0.15–0.63 0.001 0.23 0.11–0.49 <0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.56–2.61 0.637 1.02 0.47–2.20 0.969 0.60 0.26–1.44 0.254 ATAC Persistence 1.34 0.69–2.57 0.389 1.01 0.52–1.98 0.972 0.77 0.38–1.59 0.484 ATAC Regression 1.23 0.55–2.77 0.610 1.05 0.46–2.36 0.914 0.86 0.36–2.08 0.742 Change from baseline Delta ATAC volumec 1.58 0.99–2.50 0.053 1.60 1.00–2.55 0.051 1.90 1.14–3.16 0.013 Delta ATAC densityd 0.41 0.21–0.80 0.009 0.39 0.20–0.77 0.007 0.29 0.14–0.60 0.001 Model 1 adjusts for age, gender, race/ethnicity, and all the ATAC variables listed. Model 2 adjusts for Model 1 variables and systolic BP, treatment for hypertension, total cholesterol, HDL cholesterol, diabetes, current smoking, and statin use. Model 3 adjusts for Model 2 variables and baseline CAC volume and density, change in CAC status (no CAC, CAC incidence, CAC persistence, CAC regression), and delta CAC volume and density. Coronary heart disease is the composite of myocardial infarction, resuscitated cardiac arrest, and coronary heart disease related death. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group: a per 1.43 (for persistence) and 1.27 (for regression) ln-units; b per 0.87 (for persistence) and 1.06 (for regression) density-units; c per 0.93 (for incidence), 0.45 (for persistence), and 0.99 (for regression) ln-units/year; d per 0.41 density-units/year (for persistence). Bolded text indicates P < 0.05. CI, confidence interval; HR, hazard ratio, ln, natural log, rest of abbreviations per Table 1. Table 3 summarizes the associations of ATAC progression with incident ASCVD, with HR again reflecting a 1 SD difference. Baseline ATAC was associated with ASCVD in all models, including Model 3 (volume HR 2.06, CI 1.19–3.55, P = 0.010; density HR 0.33, CI 0.17–0.63, P = 0.001). In comparison to the ‘no ATAC’ group, ATAC persistence had a borderline association in Model 1 (HR 1.66, CI 1.02–2.70, P = 0.043) that was attenuated in Models 2 and 3. Otherwise, there were no significant associations for ATAC incidence and regression. However, an increase in ATAC volume was associated with a higher risk of ASCVD in all models, including Model 3 (HR 1.93, CI 1.26–2.94, P = 0.002), while an increase in ATAC density was associated with a lower risk of ASCVD in all models, including Model 3 (HR 0.42, CI 0.23–0.76, P = 0.004). Table 3 Progression of ATAC volume and density and risk of incident ASCVD events Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.14 1.25–3.64 0.005 1.92 1.15–3.20 0.013 2.06 1.19–3.55 0.010 ATAC densityb 0.41 0.22–0.75 0.004 0.42 0.23–0.78 0.006 0.33 0.17–0.63 0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.65–2.23 0.556 0.92 0.48–1.77 0.810 0.62 0.31–1.26 0.186 ATAC Persistence 1.66 1.02–2.70 0.043 1.27 0.77–2.09 0.348 0.99 0.58–1.68 0.961 ATAC Regression 0.88 0.42–1.85 0.730 0.76 0.36–1.60 0.468 0.65 0.30–1.44 0.291 Change from baseline Delta ATAC volumec 1.59 1.09–2.33 0.017 1.71 1.15–2.54 0.008 1.93 1.26–2.94 0.002 Delta ATAC densityd 0.55 0.31–0.95 0.031 0.52 0.29–0.90 0.021 0.42 0.23–0.76 0.004 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.14 1.25–3.64 0.005 1.92 1.15–3.20 0.013 2.06 1.19–3.55 0.010 ATAC densityb 0.41 0.22–0.75 0.004 0.42 0.23–0.78 0.006 0.33 0.17–0.63 0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.65–2.23 0.556 0.92 0.48–1.77 0.810 0.62 0.31–1.26 0.186 ATAC Persistence 1.66 1.02–2.70 0.043 1.27 0.77–2.09 0.348 0.99 0.58–1.68 0.961 ATAC Regression 0.88 0.42–1.85 0.730 0.76 0.36–1.60 0.468 0.65 0.30–1.44 0.291 Change from baseline Delta ATAC volumec 1.59 1.09–2.33 0.017 1.71 1.15–2.54 0.008 1.93 1.26–2.94 0.002 Delta ATAC densityd 0.55 0.31–0.95 0.031 0.52 0.29–0.90 0.021 0.42 0.23–0.76 0.004 Models 1, 2, and 3, are listed in Table 2. Atherosclerotic cardiovascular disease is the composite of myocardial infarction, resuscitated cardiac arrest, coronary heart disease related death, stroke, and stroke-related death. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group and are listed in Table 2. Bolded text indicates P < 0.05. Abbreviations as per Tables 1 and 2. Table 3 Progression of ATAC volume and density and risk of incident ASCVD events Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.14 1.25–3.64 0.005 1.92 1.15–3.20 0.013 2.06 1.19–3.55 0.010 ATAC densityb 0.41 0.22–0.75 0.004 0.42 0.23–0.78 0.006 0.33 0.17–0.63 0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.65–2.23 0.556 0.92 0.48–1.77 0.810 0.62 0.31–1.26 0.186 ATAC Persistence 1.66 1.02–2.70 0.043 1.27 0.77–2.09 0.348 0.99 0.58–1.68 0.961 ATAC Regression 0.88 0.42–1.85 0.730 0.76 0.36–1.60 0.468 0.65 0.30–1.44 0.291 Change from baseline Delta ATAC volumec 1.59 1.09–2.33 0.017 1.71 1.15–2.54 0.008 1.93 1.26–2.94 0.002 Delta ATAC densityd 0.55 0.31–0.95 0.031 0.52 0.29–0.90 0.021 0.42 0.23–0.76 0.004 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.14 1.25–3.64 0.005 1.92 1.15–3.20 0.013 2.06 1.19–3.55 0.010 ATAC densityb 0.41 0.22–0.75 0.004 0.42 0.23–0.78 0.006 0.33 0.17–0.63 0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.65–2.23 0.556 0.92 0.48–1.77 0.810 0.62 0.31–1.26 0.186 ATAC Persistence 1.66 1.02–2.70 0.043 1.27 0.77–2.09 0.348 0.99 0.58–1.68 0.961 ATAC Regression 0.88 0.42–1.85 0.730 0.76 0.36–1.60 0.468 0.65 0.30–1.44 0.291 Change from baseline Delta ATAC volumec 1.59 1.09–2.33 0.017 1.71 1.15–2.54 0.008 1.93 1.26–2.94 0.002 Delta ATAC densityd 0.55 0.31–0.95 0.031 0.52 0.29–0.90 0.021 0.42 0.23–0.76 0.004 Models 1, 2, and 3, are listed in Table 2. Atherosclerotic cardiovascular disease is the composite of myocardial infarction, resuscitated cardiac arrest, coronary heart disease related death, stroke, and stroke-related death. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group and are listed in Table 2. Bolded text indicates P < 0.05. Abbreviations as per Tables 1 and 2. Table 4 summarizes the associations of ATAC progression with incident ischemic stroke, with HR again reflecting a one SD difference. In all models, the associations of baseline ATAC volume and density, as well as those of ATAC incidence, persistence and regression with stroke were not significant. However, an increase in ATAC volume was associated with a higher risk of stroke in all models, including Model 3 (HR 2.14, CI 1.21–3.78, P = 0.009). The association of an increase in ATAC density with stroke was inverse but not statistically significant in all models, including Model 3 (HR 0.61, CI 0.23–1.61, P = 0.314). Table 4 Progression of ATAC volume and density and risk of incident ischaemic stroke Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 1.59 0.65–3.92 0.313 1.48 0.62–3.52 0.379 1.35 0.53–3.44 0.529 ATAC densityb 0.57 0.22–1.51 0.259 0.58 0.22–1.55 0.276 0.49 0.18–1.39 0.180 Change in ATAC status No ATAC (reference) ATAC incidence 1.64 0.70–3.84 0.252 1.05 0.40–2.75 0.915 0.91 0.34–2.42 0.850 ATAC persistence 1.54 0.68–3.48 0.297 1.09 0.47–2.50 0.842 0.82 0.33–2.03 0.668 ATAC regression 0.89 0.27–2.89 0.839 0.73 0.22–2.41 0.608 0.68 0.20–2.34 0.543 Change from baseline Delta ATAC volumec 1.70 1.03–2.82 0.040 2.08 1.20–3.61 0.009 2.14 1.21–3.78 0.009 Delta ATAC densityd 0.71 0.28–1.78 0.465 0.64 0.25–1.62 0.346 0.61 0.23–1.61 0.314 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 1.59 0.65–3.92 0.313 1.48 0.62–3.52 0.379 1.35 0.53–3.44 0.529 ATAC densityb 0.57 0.22–1.51 0.259 0.58 0.22–1.55 0.276 0.49 0.18–1.39 0.180 Change in ATAC status No ATAC (reference) ATAC incidence 1.64 0.70–3.84 0.252 1.05 0.40–2.75 0.915 0.91 0.34–2.42 0.850 ATAC persistence 1.54 0.68–3.48 0.297 1.09 0.47–2.50 0.842 0.82 0.33–2.03 0.668 ATAC regression 0.89 0.27–2.89 0.839 0.73 0.22–2.41 0.608 0.68 0.20–2.34 0.543 Change from baseline Delta ATAC volumec 1.70 1.03–2.82 0.040 2.08 1.20–3.61 0.009 2.14 1.21–3.78 0.009 Delta ATAC densityd 0.71 0.28–1.78 0.465 0.64 0.25–1.62 0.346 0.61 0.23–1.61 0.314 Models 1, 2, and 3, are listed in Table 2. The ischaemic stroke outcome includes non-fatal and fatal stroke and excludes strokes that were haemorrhagic or unknown in type. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group and are listed in Table 2. Bolded text indicates P < 0.05. Abbreviations as per Tables 1 and 2. Table 4 Progression of ATAC volume and density and risk of incident ischaemic stroke Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 1.59 0.65–3.92 0.313 1.48 0.62–3.52 0.379 1.35 0.53–3.44 0.529 ATAC densityb 0.57 0.22–1.51 0.259 0.58 0.22–1.55 0.276 0.49 0.18–1.39 0.180 Change in ATAC status No ATAC (reference) ATAC incidence 1.64 0.70–3.84 0.252 1.05 0.40–2.75 0.915 0.91 0.34–2.42 0.850 ATAC persistence 1.54 0.68–3.48 0.297 1.09 0.47–2.50 0.842 0.82 0.33–2.03 0.668 ATAC regression 0.89 0.27–2.89 0.839 0.73 0.22–2.41 0.608 0.68 0.20–2.34 0.543 Change from baseline Delta ATAC volumec 1.70 1.03–2.82 0.040 2.08 1.20–3.61 0.009 2.14 1.21–3.78 0.009 Delta ATAC densityd 0.71 0.28–1.78 0.465 0.64 0.25–1.62 0.346 0.61 0.23–1.61 0.314 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 1.59 0.65–3.92 0.313 1.48 0.62–3.52 0.379 1.35 0.53–3.44 0.529 ATAC densityb 0.57 0.22–1.51 0.259 0.58 0.22–1.55 0.276 0.49 0.18–1.39 0.180 Change in ATAC status No ATAC (reference) ATAC incidence 1.64 0.70–3.84 0.252 1.05 0.40–2.75 0.915 0.91 0.34–2.42 0.850 ATAC persistence 1.54 0.68–3.48 0.297 1.09 0.47–2.50 0.842 0.82 0.33–2.03 0.668 ATAC regression 0.89 0.27–2.89 0.839 0.73 0.22–2.41 0.608 0.68 0.20–2.34 0.543 Change from baseline Delta ATAC volumec 1.70 1.03–2.82 0.040 2.08 1.20–3.61 0.009 2.14 1.21–3.78 0.009 Delta ATAC densityd 0.71 0.28–1.78 0.465 0.64 0.25–1.62 0.346 0.61 0.23–1.61 0.314 Models 1, 2, and 3, are listed in Table 2. The ischaemic stroke outcome includes non-fatal and fatal stroke and excludes strokes that were haemorrhagic or unknown in type. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group and are listed in Table 2. Bolded text indicates P < 0.05. Abbreviations as per Tables 1 and 2. Fully-adjusted HR (Model 3) for baseline levels and annualized changes in levels of ATAC volume and density per standard deviation are graphically summarized in Figure 3. In sensitivity analyses that excluded ATAC regression participants, the aforementioned associations were not materially different from the main results in all cases. Figure 3 View largeDownload slide Associations of baseline and annual progression of ATAC volume and density scores with ASCVD events. Volume scores are natural logarithm+1 transformed. Cox proportional hazards models adjust for baseline and delta ATAC volume and density, baseline and delta CAC volume and density, change in ATAC and CAC status category, age, gender, race/ethnicity, and standard ASCVD risk factors (Model 3 in text). Standard deviations vary by ATAC status group (incidence, persistence, and regression; see Table 2 caption). ATAC, ascending thoracic aorta calcium; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CHD, coronary heart disease; SD, standard deviation; MESA, Multi-Ethnic Study of Atherosclerosis Figure 3 View largeDownload slide Associations of baseline and annual progression of ATAC volume and density scores with ASCVD events. Volume scores are natural logarithm+1 transformed. Cox proportional hazards models adjust for baseline and delta ATAC volume and density, baseline and delta CAC volume and density, change in ATAC and CAC status category, age, gender, race/ethnicity, and standard ASCVD risk factors (Model 3 in text). Standard deviations vary by ATAC status group (incidence, persistence, and regression; see Table 2 caption). ATAC, ascending thoracic aorta calcium; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CHD, coronary heart disease; SD, standard deviation; MESA, Multi-Ethnic Study of Atherosclerosis Discussion In this study, we evaluated qualitative and quantitative metrics of ATAC progression and the associated risks of incident CHD, ASCVD, and ischaemic stroke in a cohort free of baseline clinical ASCVD. When controlling for ASCVD risk factors and baseline levels of ATAC volume and density, we observed a significant association between an increase in ATAC volume over time and incident CHD, ASCVD, and ischaemic stroke. We also observed that an increase in ATAC density over time was associated with a lower incidence of CHD and ASCVD. With further adjustment for baseline levels of CAC volume and density and CAC progression, these associations appeared to strengthen slightly or remain unaffected. Qualitative changes in ATAC status (incidence, persistence, and regression) were not associated with adverse outcomes. The findings of this study strengthen our previous observations from the MESA showing baseline levels of ATAC density to be associated with a lower risk of incident CHD after controlling for baseline ASCVD risk factors and CAC.7 This study adds information regarding the dynamic nature of ATAC volume and density over time and provides evidence for an independent link between ATAC and incident CHD and ASCVD. These findings also bolster the possibly protective association of calcium density that was observed for CAC in the MESA, where it was previously shown to be inversely associated with both CHD and ASCVD.2 An implication of these findings is the possibility that reducing ATAC volume and/or increasing ATAC density might reflect a reduction in the risk of future ASCVD events. Whether such changes are simply markers of improvement in overall ASCVD burden, or if such changes are directly tied to reduced risk (perhaps through stabilization of rupture-prone atherosclerotic plaque), is unknown. Additionally, whether risk factor modification and other interventions can affect the trajectory of ATAC volume and density is undetermined. For instance, statin therapies, which are strongly associated with CVD risk reduction, have not been clearly demonstrated to reduce arterial calcification. Rather, studies have suggested that statin use may increase calcification.15,16 Individuals with ATAC were significantly more likely to be on statin therapy in our study, likely as a result of a substantially greater burden of CVD risk factors. Whether can directly contribute to changes in ATAC volume and density merits further investigation. The association of thoracic aorta calcification with ASCVD and stroke has been investigated in prior studies using only a baseline evaluation of the aortic arch and/or the descending thoracic aorta.17,18 However, to our knowledge, this is the first study to find a higher risk of stroke with an increase in ATAC volume over time that was, importantly, independent of baseline CAC and CAC progression. Though the inverse association of increasing ATAC density was not statistically significant, our analysis may have been underpowered given the small number of participants with changes in ATAC density and the small number of strokes that occurred among them. Our findings also lend further support to the assertion that the traditional metric of arterial calcification, the Agatston score, has limitations in that it models calcium density as a hazard, contrary to the inverse association with ASCVD seen in this and other studies from the MESA. This model may be particularly problematic when evaluating changes in the Agatston score, since such changes may reflect changes in volume or density, or a combination of the two. If validated in additional studies, ATAC volume and density assessment may contribute significantly to ASCVD risk assessment among individuals free of clinical ASCVD. While unlikely to be a useful screening test due its low prevalence, the assessment of ATAC in patients undergoing cardiac or diagnostic chest CT can potentially refine CVD risk assessment at no additional radiation risk. For those undergoing serial imaging for a clinical indication, assessing for changes in ATAC volume and density may provide unique insight into a patient’s CVD risk trajectory. Additional research is needed to confirm the findings of this study and explore the potential clinical impact of ATAC assessment. Our study has inherent limitations. We encountered a low prevalence of ATAC in the MESA cohort. Although in line with that seen in other studies (ATAC prevalence <5%),19,20 our study may have been underpowered to show certain associations as a result. The density score reflects the average density factor of all plaques in total, and therefore changes in density on a plaque-by-plaque basis cannot be evaluated. By arbitrarily capping the maximum density factor at four for any attenuation greater than 400 HU, any changes in density that stay above this threshold are obscured, and the inverse association of the density score may be attenuated at higher levels. Nonetheless, despite being a somewhat crude metric, change in ATAC density had a robust association with CVD risk, supporting the hypothesis that arterial calcium density is inversely associated with adverse outcomes. Conclusions Ascending thoracic aorta calcium is an uncommon finding on serial cardiac CT scans in a cohort free of clinical ASCVD at baseline. However, an increase in ATAC volume and a decrease in ATAC density are both independently associated with incident CHD and ASCVD after adjustment for baseline levels of ATAC, CAC, and CAC progression. Ischaemic stroke risk is also higher with increases in ATAC volume. Selective serial assessments of ATAC volume and density in those who have ATAC at baseline may provide further insight into an individual’s trajectory of ASCVD risk beyond CAC assessments. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgements The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Funding This research was supported by T32 HL079891 and the MESA was supported by TR01 HL071739 and contracts N01-HC-95159 through N01-HC-95165 N01-HC-95169 from the National Heart, Lung, and Blood Institute. Conflict of interest: None declared. References 1 Detrano R , Guerci AD , Carr JJ , Bild DE , Burke G , Folsom AR et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups . N Engl J Med 2008 ; 358 : 1336 – 45 . Google Scholar CrossRef Search ADS PubMed 2 Criqui MH , Denenberg JO , Ix JH , McClelland RL , Wassel CL , Rifkin DE et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events . JAMA 2014 ; 311 : 271 – 8 . Google Scholar CrossRef Search ADS PubMed 3 Gepner AD , Young R , Delaney JA , Tattersall MC , Blaha MJ , Post WS et al. Comparison of coronary artery calcium presence, carotid plaque presence, and carotid intima-media thickness for cardiovascular disease prediction in the Multi-Ethnic Study of Atherosclerosis . Circ Cardiovasc Imaging 2015 ; 8 : e002262 . Google Scholar CrossRef Search ADS PubMed 4 Budoff MJ , Nasir K , Katz R , Takasu J , Carr JJ , Wong ND et al. Thoracic aortic calcification and coronary heart disease events: the multi-ethnic study of atherosclerosis (MESA) . Atherosclerosis 2011 ; 215 : 196 – 202 . Google Scholar CrossRef Search ADS PubMed 5 Witteman JC , Kannel WB , Wolf PA , Grobbee DE , Hofman A , D’Agostino RB et al. Aortic calcified plaques and cardiovascular disease (the Framingham Study) . Am J Cardiol 1990 ; 66 : 1060 – 4 . Google Scholar CrossRef Search ADS PubMed 6 Allison MA , Hsi S , Wassel CL , Morgan C , Ix JH , Wright CM et al. Calcified atherosclerosis in different vascular beds and the risk of mortality . Arterioscler Thromb Vasc Biol 2012 ; 32 : 140 – 6 . Google Scholar CrossRef Search ADS PubMed 7 Thomas IC , Forbang N , Allison M , Michos E , Post W , McClelland R et al. Abstract 27: volume and density of calcium in the ascending thoracic aorta, when present, predict incident coronary heart disease beyond coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis . Circulation 2017 ; 135 (Suppl. 1): A27 . 8 Bild DE , Bluemke DA , Burke GL , Detrano R , Diez Roux AV , Folsom AR et al. Multi-Ethnic Study of Atherosclerosis: objectives and design . Am J Epidemiol 2002 ; 156 : 871 – 81 . http://dx.doi.org/10.1093/aje/kwf113 Google Scholar CrossRef Search ADS PubMed 9 Goff DC Jr , Lloyd-Jones DM , Bennett G , Coady S , D’Agostino RB , Gibbons R 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 . Circulation 2014 ; 129 (25 Suppl. 2): S49 – 73 . Google Scholar CrossRef Search ADS PubMed 10 Carr JJ , Nelson JC , Wong ND , McNitt-Gray M , Arad Y , Jacobs DR Jr et al. Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study . Radiology 2005 ; 234 : 35 – 43 . Google Scholar CrossRef Search ADS PubMed 11 Budoff MJ , Takasu J , Katz R , Mao S , Shavelle DM , O’Brien KD et al. Reproducibility of CT measurements of aortic valve calcification, mitral annulus calcification, and aortic wall calcification in the multi-ethnic study of atherosclerosis . Acad Radiol 2006 ; 13 : 166 – 72 . Google Scholar CrossRef Search ADS PubMed 12 Agatston AS , Janowitz WR , Hildner FJ , Zusmer NR , Viamonte M Jr , Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography . J Am Coll Cardiol 1990 ; 15 : 827 – 32 . Google Scholar CrossRef Search ADS PubMed 13 Folsom AR , Kronmal RA , Detrano RC , O’Leary DH , Bild DE , Bluemke DA et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA) . Arch Intern Med 2008 ; 168 : 1333 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Leffondre K , Abrahamowicz M , Siemiatycki J , Rachet B. Modeling smoking history: a comparison of different approaches . Am J Epidemiol 2002 ; 156 : 813 – 23 . Google Scholar CrossRef Search ADS PubMed 15 Puri R , Nicholls SJ , Shao M , Kataoka Y , Uno K , Kapadia SR et al. Impact of statins on serial coronary calcification during atheroma progression and regression . J Am Coll Cardiol 2015 ; 65 : 1273 – 82 . Google Scholar CrossRef Search ADS PubMed 16 Saremi A , Bahn G , Reaven PD. Progression of vascular calcification is increased with statin use in the Veterans Affairs Diabetes Trial (VADT) . Diabetes Care 2012 ; 35 : 2390 – 2 . http://dx.doi.org/10.2337/dc12-0464 Google Scholar CrossRef Search ADS PubMed 17 Hermann DM , Lehmann N , Gronewold J , Bauer M , Mahabadi AA , Weimar C et al. Thoracic aortic calcification is associated with incident stroke in the general population in addition to established risk factors . Eur Heart J Cardiovasc Imaging 2015 ; 16 : 684 – 90 . Google Scholar PubMed 18 Iribarren C , Sidney S , Sternfeld B , Browner WS. Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease . JAMA 2000 ; 283 : 2810 – 5 . Google Scholar CrossRef Search ADS PubMed 19 Itani Y , Watanabe S , Masuda Y. Aortic calcification detected in a mass chest screening program using a mobile helical computed tomography unit. Relationship to risk factors and coronary artery disease . Circ J 2004 ; 68 : 538 – 41 . Google Scholar CrossRef Search ADS PubMed 20 Craiem D , Chironi G , Casciaro ME , Graf S , Simon A , Hendrikse J. Calcifications of the thoracic aorta on extended non-contrast-enhanced cardiac CT . PLoS One 2014 ; 9 : e109584 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Progression of calcium density in the ascending thoracic aorta is inversely associated with incident cardiovascular disease events

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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2047-2404
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10.1093/ehjci/jey007
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Abstract

Abstract Aims Little is known regarding the risk of atherosclerotic cardiovascular disease (ASCVD) conferred by changes in the volume and density of ascending thoracic aorta calcium (ATAC) over time. We evaluated changes in ATAC volume and density scores and incident ASCVD events. Methods and results The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of individuals without baseline clinical ASCVD. Ascending thoracic aorta calcium was measured from baseline and follow-up (mean interval 2.4 years) cardiac computed tomography (CT). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) per standard deviation for events after the follow-up exam adjusted for ASCVD risk factors, baseline ATAC and coronary artery calcium (CAC) volume and density, and changes in CAC volume and density. Among 5887 participants, 296 (5.0%) had detectable ATAC at baseline, follow-up, or both exams. A total of 403 events occurred over 9.5 years. An increase in ATAC volume was associated with coronary heart disease (CHD) (HR 1.90, 95% CI 1.14–3.16), ASCVD (HR 1.93, 95% CI 1.26–2.94), and ischaemic stroke (HR 2.14, CI 1.21–3.78). An increase in ATAC density was inversely associated with CHD (HR 0.29, 95% CI 0.14–0.60) and ASCVD (HR 0.42, 95% CI 0.23–0.76), but not stroke (HR 0.61, CI 0.23–1.61). Conclusion Ascending thoracic aorta calcium is uncommon on serial cardiac CT. However, changes in ATAC volume and density are both associated with incident ASCVD events, but in opposite directions. Serial assessments in those with baseline ATAC may provide insight into an individual’s trajectory of ASCVD risk. calcification, calcium density, ascending aorta, atherosclerosis, atherosclerotic cardiovascular disease Introduction Arterial calcification identified on computed tomography (CT) is a marker of subclinical atherosclerosis and is strongly associated with atherosclerotic cardiovascular disease (ASCVD) events. Coronary artery calcium (CAC), in particular, is among the most robust subclinical predictors of ASCVD, with its presence, extent, and density each independently associated with ASCVD risk.1–3 Arterial calcification outside of the coronary arteries is also associated with ASCVD. For instance, calcium in the thoracic aorta is known to be associated with coronary heart disease (CHD), ASCVD, and death.4–6 Recently, the density of calcium in the ascending segment of the thoracic aorta was observed to be inversely associated with ASCVD.7 However, little is known regarding the risk of ASCVD conferred by the progression of calcium in this structure. Changes in the volume and density components of calcium may portend CHD and stroke due to the anatomical continuity and close proximity of the ascending thoracic aorta with both the coronary and carotid arteries. In this study, we evaluated the independent associations of the progression of ascending thoracic aorta calcium (ATAC) with incident CHD, ASCVD, and ischaemic stroke after adjustment for ASCVD risk factors, baseline levels of ATAC and CAC, and CAC progression in a cohort free of clinical ASCVD. Methods MESA study design The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of 6814 individuals aged 45–84 years without known clinical ASCVD at recruitment, enrolled from six field centres (Baltimore, MD; Chicago, IL, USA; Forsyth County, NC, USA; Los Angeles, CA, USA; New York, NY, USA; and St. Paul, MN, USA). Specific ethnic groups enrolled were Non-Hispanic White, African-American, Hispanic, and Chinese. Baseline examinations were conducted from 2000 to 2002. Institutional Review Boards at each participating centre approved the study, and all participants provided written informed consent. Details of the study design have been described previously.8 Medical history and laboratory data for this study were taken from the baseline examination of the cohort. Age, gender, race/ethnicity, and medication use were obtained by self-administered questionnaire. Resting blood pressure was measured three times in the seated position, and the average of the second and third readings was recorded. Total and high-density lipoprotein cholesterol (HDL-C) were measured from blood samples obtained after a 12-h fast. Smoking status was classified as current, former, or never, with current defined as having smoked a cigarette in the last 30 days. Diabetes mellitus was defined as a fasting glucose ≥126 mg/dL or use of hypoglycaemic medications. Age, gender, total cholesterol, HDL-C, systolic blood pressure (SBP), hypertension medication use, current smoking, and diabetes status were used to calculate the American College of Cardiology/American Heart Association 2013 Pooled Cohort ASCVD risk score for each participant.9 CT image acquisition A baseline non-contrast cardiac-gated CT study was performed on all participants of the MESA to evaluate for the presence and extent of CAC.10 An additional CT study was performed on 5888 individuals at a follow-up visit, with the first half of this group receiving the follow-up study between September 2002 and January 2004, and the second half between March 2004 and July 2005, corresponding to an average of 1.6 and 3.2 years after the first CT study, respectively. The nominal slice thickness was 3.0 mm for electron-beam CT and 2.5 mm for four-detector row CT. Scanning centres used an electron-beam CT scanner in Chicago, Los Angeles, and New York field centres and a four-slice multidetector CT system in Baltimore, Forsyth County and St. Paul field centres. Certified technologists scanned all participants over phantoms of known physical calcium concentration, and all studies were read at the Los Angeles Biomedical Research Institute at Harbor-UCLA in Torrance, CA, USA. Calcium in the thoracic aorta was evaluated retrospectively.11 Ascending thoracic aorta calcium was measured in the ascending thoracic aorta from the aortic annulus inferiorly to the pulmonary artery superiorly (Figure 1).4 The aortic arch was not visualized on these scans. Figure 1 View largeDownload slide Ascending thoracic aorta calcium (ATAC). Axial view of the ascending thoracic aorta on cardiac computed tomography (left). Arrow indicates calcification in the ascending thoracic aorta wall. Schematic of the thoracic aorta denoting the ascending segment. Figure 1 View largeDownload slide Ascending thoracic aorta calcium (ATAC). Axial view of the ascending thoracic aorta on cardiac computed tomography (left). Arrow indicates calcification in the ascending thoracic aorta wall. Schematic of the thoracic aorta denoting the ascending segment. Volume and density scoring of calcium Calcified plaque within the vascular territory of interest was identified as attenuation greater than 130 Hounsfield units (HU) with a minimum size of 5.5 mm3 (electron beam CT) or 4.6 mm3 (multidetector CT). The Agatston score was computed by multiplying individual calcified plaque areas by a density factor of 1, 2, 3, or 4, corresponding to the maximum attenuation within each plaque (130–199 HU = 1, 200–299 HU = 2, 300–399 HU = 3, and 400+ HU = 4).12 The Agatston scores for each calcified plaque were then summed to produce the total Agatston score. The volume score was computed by summing the products of all calcified plaque areas (mm2) and multiplying by the CT scan slice thickness (3.0 mm for electron beam CT or 2.5 mm for multidetector CT). For this study, ATAC and CAC density scores were calculated using the method previously described in the MESA, as follows.2 The volume score for each vascular territory was divided by the CT scan slice thickness, resulting in the total area of calcified plaque. This total area was then divided into the total Agatston score, resulting in the density score, which reflects the average density factor of all calcified plaques and is a unitless value that theoretically ranges from 1 to 4. Outcome surveillance Follow-up for incident ASCVD events began at the time of the follow up CT scan and continued until the first ASCVD event, death, loss to follow-up, or December 2013. Details of ASCVD event ascertainment have been previously reported.13 Briefly, participants or their next of kin (if participants were unavailable) were contacted at intervals of 9–12 months by telephone, and trained interviewers inquired about interim hospital admissions, cardiovascular outpatient diagnoses, and death. Medical records and death certificates were requested for verification. Two physicians blinded to the results of the CT scans independently classified events and assigned incidence dates. A mortality and morbidity review committee adjudicated disagreements. Incident outcomes evaluated in this study were hard CHD (myocardial infarction, resuscitated cardiac arrest, or CHD death), hard ASCVD (hard CHD, stroke, or stroke death), and ischaemic stroke (fatal or non-fatal, excluding haemorrhagic and unknown types). End points such as angina and revascularization were not included. For all analyses, events occurring prior to the follow-up CT scan were excluded. Statistical analysis To model ATAC progression, we separated the qualitative association of the change in ATAC status (i.e. presence or absence of ATAC at baseline and follow-up exams) from the quantitative associations of changes in the continuous variables of ATAC volume and density.14 To evaluate the qualitative association, we created a four-category ‘change in status’ variable, defined as follows: no ATAC (volume scores of zero at both baseline and follow-up, reference group), ATAC incidence (volume scores of zero at baseline and greater than zero at follow up), ATAC persistence (volume scores greater than zero at both baseline and follow up), and ATAC regression (volume scores greater than zero at baseline and zero at follow up). For quantitative changes in ATAC, we evaluated the differences in ATAC volume scores and ATAC density scores between the baseline and follow-up scans (delta scores). Baseline and follow-up ATAC volume scores were natural logarithm (ln) transformed [ln(ATAC volume + 1)] to adjust for skewness. The delta scores were divided by the number of years between scans to provide the annualized rate of change in these scores and to adjust for differences in scan intervals. In order to include participants with no density score at the baseline and/or follow-up exams (i.e. those with volume scores of zero) in the multivariable models, baseline and/or delta density scores were substituted with conditional density scores of zero, where applicable. For example, a participant with ATAC incidence would receive conditional baseline and conditional delta density scores of zero. The four-category ‘change in status’ variable was included in the multivariable models to allow for the discontinuity in the associations for the continuous variables introduced by including these participants in the model. This is analogous to the more familiar practice of including a term for smoking status in a model that includes pack-years, which captures the qualitative difference between smokers and non-smokers, and the discontinuity in risk (or means) that may occur when moving from zero to non-zero pack-years.14 Ascending thoracic aorta calcium volume and density scores (both baseline and delta) were centred according to the mean value of each change in status group. The centring of the volume and density scores does not impact the coefficients for the quantitative variables, but allows for the ‘change in status’ variable to be interpretable. For example, the hazard ratio (HR) for the ATAC incidence group is interpreted as the relative hazard of an ‘average incident participant’ (i.e. a participant with no ATAC at baseline and an average volume and density of ATAC at follow up) compared with the reference group of no ATAC at baseline and follow up. Change in CAC status, baseline CAC volume and density scores, and delta CAC volume and density scores were computed in the same manner as ATAC. Descriptive statistics are presented as means ± standard deviations (SDs) for continuous variables and frequencies (%) for categorical variables. A one-way ANOVA was performed with a Tukey post hoc test to evaluate for between group differences in baseline characteristics. Spearman correlation coefficients were calculated between delta volume and delta density values for ATAC and CAC. Cox proportional hazards regression was used to estimate HRs and 95% confidence intervals (CIs) per SD change in the exposure variable for time to CHD, ASCVD, and ischaemic stroke in multivariable models as follows: Model 1: Age, gender, race/ethnicity, change in ATAC status, baseline ATAC volume score, baseline ATAC density score, delta ATAC volume score, and delta ATAC density score. Model 2: Model 1 variables + remaining components of the ASCVD Pooled Cohort Equations Risk Score [total cholesterol, HDL-C, SBP, treatment for hypertension status (yes/no), diabetes status (yes/no) current smoking status (yes/no)], and statin use. Model 3: Model 2 variables + change in CAC status, baseline CAC volume score, baseline CAC density score, delta CAC volume score, and delta CAC density score. In some cases, participants with complete ATAC and CAC regression from baseline to follow up exam had substantial reductions in ATAC and CAC volume. To investigate if this occurrence was a result of a systematic error in the dataset (for instance, slight changes in the field of view between baseline and follow-up CT scan images) that may have skewed our results, we also performed the above analyses after excluding participants with ATAC and/or CAC regression in sensitivity analyses. Analyses were performed using SPSS Statistics version 22.0 (IBM Corporation, Armonk, NY, USA). Statistical significance was defined as a two-tailed P-value of less than 0.05. Results Of the 5888 participants of the MESA cohort receiving serial cardiac CT scans, one was missing ATAC scores, leaving an analytical sample of 5887 participants for this study. The mean time between scans was 2.4 years. Over a mean of 9.5 years after the follow-up scan, 255 CHD events, 403 ASCVD events, and 133 ischaemic strokes occurred. Table 1 summarizes unadjusted characteristics of the study sample stratified by change in ATAC status over time. Ascending thoracic aorta calcium incidence was observed in 109 (1.9%) participants, persistence in 107 (1.8%) participants, regression in 80 (1.3%) participants, and no ATAC at baseline and follow-up exam in 5591 (95.0%) participants. Those with no ATAC were younger, had lower SBP, lower proportions taking antihypertensive and statin medications, and a lower proportion with diabetes compared with the other three ATAC groups. Table 1 Characteristics of participants by change in ATAC status No ATAC (baseline and follow up = 0) ATAC incidence (baseline = 0, follow up > 0) ATAC persistence (baseline and follow up > 0) ATAC regression (baseline > 0, follow up = 0) n (%) 5591 (95.0) 109 (1.9) 107 (1.8) 80 (1.3) Age (years) 61.4 ± 10.0 68.4 ± 8.2* 72 ± 7.4* 69.4 ± 9.1* Female gender 52.6 55.0 40.2* 56.3 Ethnicity  Non-Hispanic White 40.0 43.1 37.4 36.3  Chinese 11.9 9.2 8.4 5.0  African-American 26.5 34.9 29.0 37.5*  Hispanic 21.6 12.8* 25.2 21.3 Clinical characteristics  Total cholesterol (mg/dL) 194 201 200 199  HDL cholesterol (mg/dL) 51 51 49 50  Systolic BP (mmHg) 125 ± 21 136 ± 21* 143 ± 23* 137 ± 24*  Hypertension medication 35.1 54.1* 63.6* 52.5*  Smoking (current) 12.4 13.8 16.0 17.5  Diabetes mellitus 11.4 20.2* 22.4* 16.3  Statin therapy 14.3 29.9* 27.1* 26.3* ASCVD, 10-year CVD risk 12.3 21.2* 29.4* 22.5* Days between CT scans 886 ± 311 873 ± 334 844 ± 314 845 ± 323 Calcium scores  Baseline ATAC volume (mm3) 0 0 293 ± 799* 98 ± 207*  Baseline ATAC density (density-units) 2.93 ± 0.87 2.66 ± 2.82  Delta ATAC volume (mm3/year), mean (range) 0 (0 to 0) 38 (1 to 234)* 42 (−441 to 620)* −48 (−944 to −1)*  Delta ATAC density (density-units/year), mean (range) 0.03 (−1.10 to 1.27) No ATAC (baseline and follow up = 0) ATAC incidence (baseline = 0, follow up > 0) ATAC persistence (baseline and follow up > 0) ATAC regression (baseline > 0, follow up = 0) n (%) 5591 (95.0) 109 (1.9) 107 (1.8) 80 (1.3) Age (years) 61.4 ± 10.0 68.4 ± 8.2* 72 ± 7.4* 69.4 ± 9.1* Female gender 52.6 55.0 40.2* 56.3 Ethnicity  Non-Hispanic White 40.0 43.1 37.4 36.3  Chinese 11.9 9.2 8.4 5.0  African-American 26.5 34.9 29.0 37.5*  Hispanic 21.6 12.8* 25.2 21.3 Clinical characteristics  Total cholesterol (mg/dL) 194 201 200 199  HDL cholesterol (mg/dL) 51 51 49 50  Systolic BP (mmHg) 125 ± 21 136 ± 21* 143 ± 23* 137 ± 24*  Hypertension medication 35.1 54.1* 63.6* 52.5*  Smoking (current) 12.4 13.8 16.0 17.5  Diabetes mellitus 11.4 20.2* 22.4* 16.3  Statin therapy 14.3 29.9* 27.1* 26.3* ASCVD, 10-year CVD risk 12.3 21.2* 29.4* 22.5* Days between CT scans 886 ± 311 873 ± 334 844 ± 314 845 ± 323 Calcium scores  Baseline ATAC volume (mm3) 0 0 293 ± 799* 98 ± 207*  Baseline ATAC density (density-units) 2.93 ± 0.87 2.66 ± 2.82  Delta ATAC volume (mm3/year), mean (range) 0 (0 to 0) 38 (1 to 234)* 42 (−441 to 620)* −48 (−944 to −1)*  Delta ATAC density (density-units/year), mean (range) 0.03 (−1.10 to 1.27) * P-value <0.05 compared with no ATAC value. Values presented are percentages or means ± standard deviations unless specified. ASCVD, atherosclerotic cardiovascular disease risk score; ATAC, ascending thoracic aorta calcium; BP, blood pressure; CAC, coronary artery calcium; CHD, coronary heart disease; CVD, cardiovascular disease; HDL, high-density lipoprotein. Table 1 Characteristics of participants by change in ATAC status No ATAC (baseline and follow up = 0) ATAC incidence (baseline = 0, follow up > 0) ATAC persistence (baseline and follow up > 0) ATAC regression (baseline > 0, follow up = 0) n (%) 5591 (95.0) 109 (1.9) 107 (1.8) 80 (1.3) Age (years) 61.4 ± 10.0 68.4 ± 8.2* 72 ± 7.4* 69.4 ± 9.1* Female gender 52.6 55.0 40.2* 56.3 Ethnicity  Non-Hispanic White 40.0 43.1 37.4 36.3  Chinese 11.9 9.2 8.4 5.0  African-American 26.5 34.9 29.0 37.5*  Hispanic 21.6 12.8* 25.2 21.3 Clinical characteristics  Total cholesterol (mg/dL) 194 201 200 199  HDL cholesterol (mg/dL) 51 51 49 50  Systolic BP (mmHg) 125 ± 21 136 ± 21* 143 ± 23* 137 ± 24*  Hypertension medication 35.1 54.1* 63.6* 52.5*  Smoking (current) 12.4 13.8 16.0 17.5  Diabetes mellitus 11.4 20.2* 22.4* 16.3  Statin therapy 14.3 29.9* 27.1* 26.3* ASCVD, 10-year CVD risk 12.3 21.2* 29.4* 22.5* Days between CT scans 886 ± 311 873 ± 334 844 ± 314 845 ± 323 Calcium scores  Baseline ATAC volume (mm3) 0 0 293 ± 799* 98 ± 207*  Baseline ATAC density (density-units) 2.93 ± 0.87 2.66 ± 2.82  Delta ATAC volume (mm3/year), mean (range) 0 (0 to 0) 38 (1 to 234)* 42 (−441 to 620)* −48 (−944 to −1)*  Delta ATAC density (density-units/year), mean (range) 0.03 (−1.10 to 1.27) No ATAC (baseline and follow up = 0) ATAC incidence (baseline = 0, follow up > 0) ATAC persistence (baseline and follow up > 0) ATAC regression (baseline > 0, follow up = 0) n (%) 5591 (95.0) 109 (1.9) 107 (1.8) 80 (1.3) Age (years) 61.4 ± 10.0 68.4 ± 8.2* 72 ± 7.4* 69.4 ± 9.1* Female gender 52.6 55.0 40.2* 56.3 Ethnicity  Non-Hispanic White 40.0 43.1 37.4 36.3  Chinese 11.9 9.2 8.4 5.0  African-American 26.5 34.9 29.0 37.5*  Hispanic 21.6 12.8* 25.2 21.3 Clinical characteristics  Total cholesterol (mg/dL) 194 201 200 199  HDL cholesterol (mg/dL) 51 51 49 50  Systolic BP (mmHg) 125 ± 21 136 ± 21* 143 ± 23* 137 ± 24*  Hypertension medication 35.1 54.1* 63.6* 52.5*  Smoking (current) 12.4 13.8 16.0 17.5  Diabetes mellitus 11.4 20.2* 22.4* 16.3  Statin therapy 14.3 29.9* 27.1* 26.3* ASCVD, 10-year CVD risk 12.3 21.2* 29.4* 22.5* Days between CT scans 886 ± 311 873 ± 334 844 ± 314 845 ± 323 Calcium scores  Baseline ATAC volume (mm3) 0 0 293 ± 799* 98 ± 207*  Baseline ATAC density (density-units) 2.93 ± 0.87 2.66 ± 2.82  Delta ATAC volume (mm3/year), mean (range) 0 (0 to 0) 38 (1 to 234)* 42 (−441 to 620)* −48 (−944 to −1)*  Delta ATAC density (density-units/year), mean (range) 0.03 (−1.10 to 1.27) * P-value <0.05 compared with no ATAC value. Values presented are percentages or means ± standard deviations unless specified. ASCVD, atherosclerotic cardiovascular disease risk score; ATAC, ascending thoracic aorta calcium; BP, blood pressure; CAC, coronary artery calcium; CHD, coronary heart disease; CVD, cardiovascular disease; HDL, high-density lipoprotein. Supplementary data online, Figure SA shows the distribution of the annual change in the ATAC volume score (delta volume score), with participants with no ATAC at baseline and follow-up (n = 5591) not depicted. Among participants with detectable ATAC at baseline and/or follow up (n = 296), delta volume ranged from −4.98 to 4.25 natural log units, with a median of 0.31 ln-units/year. The SDs for delta volume varied for each change in status category (0.93 ln-units/year for incidence, 0.45 ln-units/year for persistence, and 0.99 ln-units/year for regression). Supplementary data online, Figure SB displays the distribution of the annual change in ATAC density score (delta density score) among those with ATAC present at baseline and follow up (n = 107). Delta density scores ranged from −1.10 to 1.27, with a median of 0.02 density-units/year and a SD of 0.41 density-units/year (for persistence). Supplementary data online, Table SA displays Spearman correlations coefficients between ATAC and CAC scores. There was little to correlation for baseline volume and density scores, as well as delta volume and density scores. Figure 2 depicts the Kaplan–Meier curves demonstrating the survival free from CVD events stratified by level of baseline ATAC volume and density (Panel A), by change in ATAC status over time (Panel B), and by change in ATAC volume and density from baseline (Panel C). Participants with any ATAC at baseline and/or follow-up tended to have a higher risk of CVD events. Participants with higher baseline levels of ATAC volume and increases in ATAC volume over time tended to have a higher risk of CVD events, and participants with higher baseline ATAC density and increases in ATAC density over time tended to have a lower risk, though these associations were not statistically significant. Figure 2 View largeDownload slide The Kaplan–Meier estimates of survival free from incident ASCVD events stratified by ATAC status. (Panel A) stratifies participants by change in ATAC status from baseline to follow-up examination: no ATAC at baseline or follow-up, ATAC incidence, ATAC persistence, and ATAC regression. (Panel B) stratifies participants by baseline level of ATAC volume and density scores, with participants divided above and below the 50th percentile for each score. (Panel C) stratifies participants by change in ATAC volume and density score from baseline to follow-up examination, stratified by whether these scores increased or decreased. Figure 2 View largeDownload slide The Kaplan–Meier estimates of survival free from incident ASCVD events stratified by ATAC status. (Panel A) stratifies participants by change in ATAC status from baseline to follow-up examination: no ATAC at baseline or follow-up, ATAC incidence, ATAC persistence, and ATAC regression. (Panel B) stratifies participants by baseline level of ATAC volume and density scores, with participants divided above and below the 50th percentile for each score. (Panel C) stratifies participants by change in ATAC volume and density score from baseline to follow-up examination, stratified by whether these scores increased or decreased. Table 2 summarizes the associations of ATAC progression with incident CHD in the multivariable-adjusted Cox regression models, with HR reflecting a one SD difference. Baseline ATAC was associated with CHD in all models, including Model 3 (volume HR 2.78, CI 1.46–5.32, P = 0.002; density HR 0.23, CI 0.11–0.49, P < 0.001). There were no significant associations for the qualitative change in ATAC status for ATAC incidence, regression, and persistence when compared with those with no ATAC. However, the quantitative increase in ATAC volume between scans was associated with a higher risk of CHD in Model 3 (HR 1.90, CI 1.14–3.16, P = 0.013). Conversely, an increase in ATAC density between scans was associated with a lower risk of CHD in all models, including Model 3 (HR 0.29, CI 0.14–0.60, P = 0.001). Table 2 Progression of ATAC volume and density and risk of incident CHD Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.66 1.42–4.99 0.002 2.42 1.32–4.46 0.005 2.78 1.46–5.32 0.002 ATAC densityb 0.31 0.15–0.62 0.001 0.31 0.15–0.63 0.001 0.23 0.11–0.49 <0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.56–2.61 0.637 1.02 0.47–2.20 0.969 0.60 0.26–1.44 0.254 ATAC Persistence 1.34 0.69–2.57 0.389 1.01 0.52–1.98 0.972 0.77 0.38–1.59 0.484 ATAC Regression 1.23 0.55–2.77 0.610 1.05 0.46–2.36 0.914 0.86 0.36–2.08 0.742 Change from baseline Delta ATAC volumec 1.58 0.99–2.50 0.053 1.60 1.00–2.55 0.051 1.90 1.14–3.16 0.013 Delta ATAC densityd 0.41 0.21–0.80 0.009 0.39 0.20–0.77 0.007 0.29 0.14–0.60 0.001 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.66 1.42–4.99 0.002 2.42 1.32–4.46 0.005 2.78 1.46–5.32 0.002 ATAC densityb 0.31 0.15–0.62 0.001 0.31 0.15–0.63 0.001 0.23 0.11–0.49 <0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.56–2.61 0.637 1.02 0.47–2.20 0.969 0.60 0.26–1.44 0.254 ATAC Persistence 1.34 0.69–2.57 0.389 1.01 0.52–1.98 0.972 0.77 0.38–1.59 0.484 ATAC Regression 1.23 0.55–2.77 0.610 1.05 0.46–2.36 0.914 0.86 0.36–2.08 0.742 Change from baseline Delta ATAC volumec 1.58 0.99–2.50 0.053 1.60 1.00–2.55 0.051 1.90 1.14–3.16 0.013 Delta ATAC densityd 0.41 0.21–0.80 0.009 0.39 0.20–0.77 0.007 0.29 0.14–0.60 0.001 Model 1 adjusts for age, gender, race/ethnicity, and all the ATAC variables listed. Model 2 adjusts for Model 1 variables and systolic BP, treatment for hypertension, total cholesterol, HDL cholesterol, diabetes, current smoking, and statin use. Model 3 adjusts for Model 2 variables and baseline CAC volume and density, change in CAC status (no CAC, CAC incidence, CAC persistence, CAC regression), and delta CAC volume and density. Coronary heart disease is the composite of myocardial infarction, resuscitated cardiac arrest, and coronary heart disease related death. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group: a per 1.43 (for persistence) and 1.27 (for regression) ln-units; b per 0.87 (for persistence) and 1.06 (for regression) density-units; c per 0.93 (for incidence), 0.45 (for persistence), and 0.99 (for regression) ln-units/year; d per 0.41 density-units/year (for persistence). Bolded text indicates P < 0.05. CI, confidence interval; HR, hazard ratio, ln, natural log, rest of abbreviations per Table 1. Table 2 Progression of ATAC volume and density and risk of incident CHD Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.66 1.42–4.99 0.002 2.42 1.32–4.46 0.005 2.78 1.46–5.32 0.002 ATAC densityb 0.31 0.15–0.62 0.001 0.31 0.15–0.63 0.001 0.23 0.11–0.49 <0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.56–2.61 0.637 1.02 0.47–2.20 0.969 0.60 0.26–1.44 0.254 ATAC Persistence 1.34 0.69–2.57 0.389 1.01 0.52–1.98 0.972 0.77 0.38–1.59 0.484 ATAC Regression 1.23 0.55–2.77 0.610 1.05 0.46–2.36 0.914 0.86 0.36–2.08 0.742 Change from baseline Delta ATAC volumec 1.58 0.99–2.50 0.053 1.60 1.00–2.55 0.051 1.90 1.14–3.16 0.013 Delta ATAC densityd 0.41 0.21–0.80 0.009 0.39 0.20–0.77 0.007 0.29 0.14–0.60 0.001 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.66 1.42–4.99 0.002 2.42 1.32–4.46 0.005 2.78 1.46–5.32 0.002 ATAC densityb 0.31 0.15–0.62 0.001 0.31 0.15–0.63 0.001 0.23 0.11–0.49 <0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.56–2.61 0.637 1.02 0.47–2.20 0.969 0.60 0.26–1.44 0.254 ATAC Persistence 1.34 0.69–2.57 0.389 1.01 0.52–1.98 0.972 0.77 0.38–1.59 0.484 ATAC Regression 1.23 0.55–2.77 0.610 1.05 0.46–2.36 0.914 0.86 0.36–2.08 0.742 Change from baseline Delta ATAC volumec 1.58 0.99–2.50 0.053 1.60 1.00–2.55 0.051 1.90 1.14–3.16 0.013 Delta ATAC densityd 0.41 0.21–0.80 0.009 0.39 0.20–0.77 0.007 0.29 0.14–0.60 0.001 Model 1 adjusts for age, gender, race/ethnicity, and all the ATAC variables listed. Model 2 adjusts for Model 1 variables and systolic BP, treatment for hypertension, total cholesterol, HDL cholesterol, diabetes, current smoking, and statin use. Model 3 adjusts for Model 2 variables and baseline CAC volume and density, change in CAC status (no CAC, CAC incidence, CAC persistence, CAC regression), and delta CAC volume and density. Coronary heart disease is the composite of myocardial infarction, resuscitated cardiac arrest, and coronary heart disease related death. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group: a per 1.43 (for persistence) and 1.27 (for regression) ln-units; b per 0.87 (for persistence) and 1.06 (for regression) density-units; c per 0.93 (for incidence), 0.45 (for persistence), and 0.99 (for regression) ln-units/year; d per 0.41 density-units/year (for persistence). Bolded text indicates P < 0.05. CI, confidence interval; HR, hazard ratio, ln, natural log, rest of abbreviations per Table 1. Table 3 summarizes the associations of ATAC progression with incident ASCVD, with HR again reflecting a 1 SD difference. Baseline ATAC was associated with ASCVD in all models, including Model 3 (volume HR 2.06, CI 1.19–3.55, P = 0.010; density HR 0.33, CI 0.17–0.63, P = 0.001). In comparison to the ‘no ATAC’ group, ATAC persistence had a borderline association in Model 1 (HR 1.66, CI 1.02–2.70, P = 0.043) that was attenuated in Models 2 and 3. Otherwise, there were no significant associations for ATAC incidence and regression. However, an increase in ATAC volume was associated with a higher risk of ASCVD in all models, including Model 3 (HR 1.93, CI 1.26–2.94, P = 0.002), while an increase in ATAC density was associated with a lower risk of ASCVD in all models, including Model 3 (HR 0.42, CI 0.23–0.76, P = 0.004). Table 3 Progression of ATAC volume and density and risk of incident ASCVD events Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.14 1.25–3.64 0.005 1.92 1.15–3.20 0.013 2.06 1.19–3.55 0.010 ATAC densityb 0.41 0.22–0.75 0.004 0.42 0.23–0.78 0.006 0.33 0.17–0.63 0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.65–2.23 0.556 0.92 0.48–1.77 0.810 0.62 0.31–1.26 0.186 ATAC Persistence 1.66 1.02–2.70 0.043 1.27 0.77–2.09 0.348 0.99 0.58–1.68 0.961 ATAC Regression 0.88 0.42–1.85 0.730 0.76 0.36–1.60 0.468 0.65 0.30–1.44 0.291 Change from baseline Delta ATAC volumec 1.59 1.09–2.33 0.017 1.71 1.15–2.54 0.008 1.93 1.26–2.94 0.002 Delta ATAC densityd 0.55 0.31–0.95 0.031 0.52 0.29–0.90 0.021 0.42 0.23–0.76 0.004 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.14 1.25–3.64 0.005 1.92 1.15–3.20 0.013 2.06 1.19–3.55 0.010 ATAC densityb 0.41 0.22–0.75 0.004 0.42 0.23–0.78 0.006 0.33 0.17–0.63 0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.65–2.23 0.556 0.92 0.48–1.77 0.810 0.62 0.31–1.26 0.186 ATAC Persistence 1.66 1.02–2.70 0.043 1.27 0.77–2.09 0.348 0.99 0.58–1.68 0.961 ATAC Regression 0.88 0.42–1.85 0.730 0.76 0.36–1.60 0.468 0.65 0.30–1.44 0.291 Change from baseline Delta ATAC volumec 1.59 1.09–2.33 0.017 1.71 1.15–2.54 0.008 1.93 1.26–2.94 0.002 Delta ATAC densityd 0.55 0.31–0.95 0.031 0.52 0.29–0.90 0.021 0.42 0.23–0.76 0.004 Models 1, 2, and 3, are listed in Table 2. Atherosclerotic cardiovascular disease is the composite of myocardial infarction, resuscitated cardiac arrest, coronary heart disease related death, stroke, and stroke-related death. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group and are listed in Table 2. Bolded text indicates P < 0.05. Abbreviations as per Tables 1 and 2. Table 3 Progression of ATAC volume and density and risk of incident ASCVD events Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.14 1.25–3.64 0.005 1.92 1.15–3.20 0.013 2.06 1.19–3.55 0.010 ATAC densityb 0.41 0.22–0.75 0.004 0.42 0.23–0.78 0.006 0.33 0.17–0.63 0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.65–2.23 0.556 0.92 0.48–1.77 0.810 0.62 0.31–1.26 0.186 ATAC Persistence 1.66 1.02–2.70 0.043 1.27 0.77–2.09 0.348 0.99 0.58–1.68 0.961 ATAC Regression 0.88 0.42–1.85 0.730 0.76 0.36–1.60 0.468 0.65 0.30–1.44 0.291 Change from baseline Delta ATAC volumec 1.59 1.09–2.33 0.017 1.71 1.15–2.54 0.008 1.93 1.26–2.94 0.002 Delta ATAC densityd 0.55 0.31–0.95 0.031 0.52 0.29–0.90 0.021 0.42 0.23–0.76 0.004 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 2.14 1.25–3.64 0.005 1.92 1.15–3.20 0.013 2.06 1.19–3.55 0.010 ATAC densityb 0.41 0.22–0.75 0.004 0.42 0.23–0.78 0.006 0.33 0.17–0.63 0.001 Change in ATAC status No ATAC (reference) ATAC Incidence 1.20 0.65–2.23 0.556 0.92 0.48–1.77 0.810 0.62 0.31–1.26 0.186 ATAC Persistence 1.66 1.02–2.70 0.043 1.27 0.77–2.09 0.348 0.99 0.58–1.68 0.961 ATAC Regression 0.88 0.42–1.85 0.730 0.76 0.36–1.60 0.468 0.65 0.30–1.44 0.291 Change from baseline Delta ATAC volumec 1.59 1.09–2.33 0.017 1.71 1.15–2.54 0.008 1.93 1.26–2.94 0.002 Delta ATAC densityd 0.55 0.31–0.95 0.031 0.52 0.29–0.90 0.021 0.42 0.23–0.76 0.004 Models 1, 2, and 3, are listed in Table 2. Atherosclerotic cardiovascular disease is the composite of myocardial infarction, resuscitated cardiac arrest, coronary heart disease related death, stroke, and stroke-related death. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group and are listed in Table 2. Bolded text indicates P < 0.05. Abbreviations as per Tables 1 and 2. Table 4 summarizes the associations of ATAC progression with incident ischemic stroke, with HR again reflecting a one SD difference. In all models, the associations of baseline ATAC volume and density, as well as those of ATAC incidence, persistence and regression with stroke were not significant. However, an increase in ATAC volume was associated with a higher risk of stroke in all models, including Model 3 (HR 2.14, CI 1.21–3.78, P = 0.009). The association of an increase in ATAC density with stroke was inverse but not statistically significant in all models, including Model 3 (HR 0.61, CI 0.23–1.61, P = 0.314). Table 4 Progression of ATAC volume and density and risk of incident ischaemic stroke Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 1.59 0.65–3.92 0.313 1.48 0.62–3.52 0.379 1.35 0.53–3.44 0.529 ATAC densityb 0.57 0.22–1.51 0.259 0.58 0.22–1.55 0.276 0.49 0.18–1.39 0.180 Change in ATAC status No ATAC (reference) ATAC incidence 1.64 0.70–3.84 0.252 1.05 0.40–2.75 0.915 0.91 0.34–2.42 0.850 ATAC persistence 1.54 0.68–3.48 0.297 1.09 0.47–2.50 0.842 0.82 0.33–2.03 0.668 ATAC regression 0.89 0.27–2.89 0.839 0.73 0.22–2.41 0.608 0.68 0.20–2.34 0.543 Change from baseline Delta ATAC volumec 1.70 1.03–2.82 0.040 2.08 1.20–3.61 0.009 2.14 1.21–3.78 0.009 Delta ATAC densityd 0.71 0.28–1.78 0.465 0.64 0.25–1.62 0.346 0.61 0.23–1.61 0.314 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 1.59 0.65–3.92 0.313 1.48 0.62–3.52 0.379 1.35 0.53–3.44 0.529 ATAC densityb 0.57 0.22–1.51 0.259 0.58 0.22–1.55 0.276 0.49 0.18–1.39 0.180 Change in ATAC status No ATAC (reference) ATAC incidence 1.64 0.70–3.84 0.252 1.05 0.40–2.75 0.915 0.91 0.34–2.42 0.850 ATAC persistence 1.54 0.68–3.48 0.297 1.09 0.47–2.50 0.842 0.82 0.33–2.03 0.668 ATAC regression 0.89 0.27–2.89 0.839 0.73 0.22–2.41 0.608 0.68 0.20–2.34 0.543 Change from baseline Delta ATAC volumec 1.70 1.03–2.82 0.040 2.08 1.20–3.61 0.009 2.14 1.21–3.78 0.009 Delta ATAC densityd 0.71 0.28–1.78 0.465 0.64 0.25–1.62 0.346 0.61 0.23–1.61 0.314 Models 1, 2, and 3, are listed in Table 2. The ischaemic stroke outcome includes non-fatal and fatal stroke and excludes strokes that were haemorrhagic or unknown in type. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group and are listed in Table 2. Bolded text indicates P < 0.05. Abbreviations as per Tables 1 and 2. Table 4 Progression of ATAC volume and density and risk of incident ischaemic stroke Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 1.59 0.65–3.92 0.313 1.48 0.62–3.52 0.379 1.35 0.53–3.44 0.529 ATAC densityb 0.57 0.22–1.51 0.259 0.58 0.22–1.55 0.276 0.49 0.18–1.39 0.180 Change in ATAC status No ATAC (reference) ATAC incidence 1.64 0.70–3.84 0.252 1.05 0.40–2.75 0.915 0.91 0.34–2.42 0.850 ATAC persistence 1.54 0.68–3.48 0.297 1.09 0.47–2.50 0.842 0.82 0.33–2.03 0.668 ATAC regression 0.89 0.27–2.89 0.839 0.73 0.22–2.41 0.608 0.68 0.20–2.34 0.543 Change from baseline Delta ATAC volumec 1.70 1.03–2.82 0.040 2.08 1.20–3.61 0.009 2.14 1.21–3.78 0.009 Delta ATAC densityd 0.71 0.28–1.78 0.465 0.64 0.25–1.62 0.346 0.61 0.23–1.61 0.314 Model 1 Model 2 Model 3 HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value Baseline level ATAC volumea 1.59 0.65–3.92 0.313 1.48 0.62–3.52 0.379 1.35 0.53–3.44 0.529 ATAC densityb 0.57 0.22–1.51 0.259 0.58 0.22–1.55 0.276 0.49 0.18–1.39 0.180 Change in ATAC status No ATAC (reference) ATAC incidence 1.64 0.70–3.84 0.252 1.05 0.40–2.75 0.915 0.91 0.34–2.42 0.850 ATAC persistence 1.54 0.68–3.48 0.297 1.09 0.47–2.50 0.842 0.82 0.33–2.03 0.668 ATAC regression 0.89 0.27–2.89 0.839 0.73 0.22–2.41 0.608 0.68 0.20–2.34 0.543 Change from baseline Delta ATAC volumec 1.70 1.03–2.82 0.040 2.08 1.20–3.61 0.009 2.14 1.21–3.78 0.009 Delta ATAC densityd 0.71 0.28–1.78 0.465 0.64 0.25–1.62 0.346 0.61 0.23–1.61 0.314 Models 1, 2, and 3, are listed in Table 2. The ischaemic stroke outcome includes non-fatal and fatal stroke and excludes strokes that were haemorrhagic or unknown in type. Hazard ratios for continuous variables are per standard deviation within change in ATAC status group and are listed in Table 2. Bolded text indicates P < 0.05. Abbreviations as per Tables 1 and 2. Fully-adjusted HR (Model 3) for baseline levels and annualized changes in levels of ATAC volume and density per standard deviation are graphically summarized in Figure 3. In sensitivity analyses that excluded ATAC regression participants, the aforementioned associations were not materially different from the main results in all cases. Figure 3 View largeDownload slide Associations of baseline and annual progression of ATAC volume and density scores with ASCVD events. Volume scores are natural logarithm+1 transformed. Cox proportional hazards models adjust for baseline and delta ATAC volume and density, baseline and delta CAC volume and density, change in ATAC and CAC status category, age, gender, race/ethnicity, and standard ASCVD risk factors (Model 3 in text). Standard deviations vary by ATAC status group (incidence, persistence, and regression; see Table 2 caption). ATAC, ascending thoracic aorta calcium; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CHD, coronary heart disease; SD, standard deviation; MESA, Multi-Ethnic Study of Atherosclerosis Figure 3 View largeDownload slide Associations of baseline and annual progression of ATAC volume and density scores with ASCVD events. Volume scores are natural logarithm+1 transformed. Cox proportional hazards models adjust for baseline and delta ATAC volume and density, baseline and delta CAC volume and density, change in ATAC and CAC status category, age, gender, race/ethnicity, and standard ASCVD risk factors (Model 3 in text). Standard deviations vary by ATAC status group (incidence, persistence, and regression; see Table 2 caption). ATAC, ascending thoracic aorta calcium; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CHD, coronary heart disease; SD, standard deviation; MESA, Multi-Ethnic Study of Atherosclerosis Discussion In this study, we evaluated qualitative and quantitative metrics of ATAC progression and the associated risks of incident CHD, ASCVD, and ischaemic stroke in a cohort free of baseline clinical ASCVD. When controlling for ASCVD risk factors and baseline levels of ATAC volume and density, we observed a significant association between an increase in ATAC volume over time and incident CHD, ASCVD, and ischaemic stroke. We also observed that an increase in ATAC density over time was associated with a lower incidence of CHD and ASCVD. With further adjustment for baseline levels of CAC volume and density and CAC progression, these associations appeared to strengthen slightly or remain unaffected. Qualitative changes in ATAC status (incidence, persistence, and regression) were not associated with adverse outcomes. The findings of this study strengthen our previous observations from the MESA showing baseline levels of ATAC density to be associated with a lower risk of incident CHD after controlling for baseline ASCVD risk factors and CAC.7 This study adds information regarding the dynamic nature of ATAC volume and density over time and provides evidence for an independent link between ATAC and incident CHD and ASCVD. These findings also bolster the possibly protective association of calcium density that was observed for CAC in the MESA, where it was previously shown to be inversely associated with both CHD and ASCVD.2 An implication of these findings is the possibility that reducing ATAC volume and/or increasing ATAC density might reflect a reduction in the risk of future ASCVD events. Whether such changes are simply markers of improvement in overall ASCVD burden, or if such changes are directly tied to reduced risk (perhaps through stabilization of rupture-prone atherosclerotic plaque), is unknown. Additionally, whether risk factor modification and other interventions can affect the trajectory of ATAC volume and density is undetermined. For instance, statin therapies, which are strongly associated with CVD risk reduction, have not been clearly demonstrated to reduce arterial calcification. Rather, studies have suggested that statin use may increase calcification.15,16 Individuals with ATAC were significantly more likely to be on statin therapy in our study, likely as a result of a substantially greater burden of CVD risk factors. Whether can directly contribute to changes in ATAC volume and density merits further investigation. The association of thoracic aorta calcification with ASCVD and stroke has been investigated in prior studies using only a baseline evaluation of the aortic arch and/or the descending thoracic aorta.17,18 However, to our knowledge, this is the first study to find a higher risk of stroke with an increase in ATAC volume over time that was, importantly, independent of baseline CAC and CAC progression. Though the inverse association of increasing ATAC density was not statistically significant, our analysis may have been underpowered given the small number of participants with changes in ATAC density and the small number of strokes that occurred among them. Our findings also lend further support to the assertion that the traditional metric of arterial calcification, the Agatston score, has limitations in that it models calcium density as a hazard, contrary to the inverse association with ASCVD seen in this and other studies from the MESA. This model may be particularly problematic when evaluating changes in the Agatston score, since such changes may reflect changes in volume or density, or a combination of the two. If validated in additional studies, ATAC volume and density assessment may contribute significantly to ASCVD risk assessment among individuals free of clinical ASCVD. While unlikely to be a useful screening test due its low prevalence, the assessment of ATAC in patients undergoing cardiac or diagnostic chest CT can potentially refine CVD risk assessment at no additional radiation risk. For those undergoing serial imaging for a clinical indication, assessing for changes in ATAC volume and density may provide unique insight into a patient’s CVD risk trajectory. Additional research is needed to confirm the findings of this study and explore the potential clinical impact of ATAC assessment. Our study has inherent limitations. We encountered a low prevalence of ATAC in the MESA cohort. Although in line with that seen in other studies (ATAC prevalence <5%),19,20 our study may have been underpowered to show certain associations as a result. The density score reflects the average density factor of all plaques in total, and therefore changes in density on a plaque-by-plaque basis cannot be evaluated. By arbitrarily capping the maximum density factor at four for any attenuation greater than 400 HU, any changes in density that stay above this threshold are obscured, and the inverse association of the density score may be attenuated at higher levels. Nonetheless, despite being a somewhat crude metric, change in ATAC density had a robust association with CVD risk, supporting the hypothesis that arterial calcium density is inversely associated with adverse outcomes. Conclusions Ascending thoracic aorta calcium is an uncommon finding on serial cardiac CT scans in a cohort free of clinical ASCVD at baseline. However, an increase in ATAC volume and a decrease in ATAC density are both independently associated with incident CHD and ASCVD after adjustment for baseline levels of ATAC, CAC, and CAC progression. Ischaemic stroke risk is also higher with increases in ATAC volume. Selective serial assessments of ATAC volume and density in those who have ATAC at baseline may provide further insight into an individual’s trajectory of ASCVD risk beyond CAC assessments. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgements The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Funding This research was supported by T32 HL079891 and the MESA was supported by TR01 HL071739 and contracts N01-HC-95159 through N01-HC-95165 N01-HC-95169 from the National Heart, Lung, and Blood Institute. Conflict of interest: None declared. References 1 Detrano R , Guerci AD , Carr JJ , Bild DE , Burke G , Folsom AR et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups . N Engl J Med 2008 ; 358 : 1336 – 45 . Google Scholar CrossRef Search ADS PubMed 2 Criqui MH , Denenberg JO , Ix JH , McClelland RL , Wassel CL , Rifkin DE et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events . JAMA 2014 ; 311 : 271 – 8 . Google Scholar CrossRef Search ADS PubMed 3 Gepner AD , Young R , Delaney JA , Tattersall MC , Blaha MJ , Post WS et al. Comparison of coronary artery calcium presence, carotid plaque presence, and carotid intima-media thickness for cardiovascular disease prediction in the Multi-Ethnic Study of Atherosclerosis . Circ Cardiovasc Imaging 2015 ; 8 : e002262 . Google Scholar CrossRef Search ADS PubMed 4 Budoff MJ , Nasir K , Katz R , Takasu J , Carr JJ , Wong ND et al. Thoracic aortic calcification and coronary heart disease events: the multi-ethnic study of atherosclerosis (MESA) . Atherosclerosis 2011 ; 215 : 196 – 202 . Google Scholar CrossRef Search ADS PubMed 5 Witteman JC , Kannel WB , Wolf PA , Grobbee DE , Hofman A , D’Agostino RB et al. Aortic calcified plaques and cardiovascular disease (the Framingham Study) . Am J Cardiol 1990 ; 66 : 1060 – 4 . Google Scholar CrossRef Search ADS PubMed 6 Allison MA , Hsi S , Wassel CL , Morgan C , Ix JH , Wright CM et al. Calcified atherosclerosis in different vascular beds and the risk of mortality . Arterioscler Thromb Vasc Biol 2012 ; 32 : 140 – 6 . Google Scholar CrossRef Search ADS PubMed 7 Thomas IC , Forbang N , Allison M , Michos E , Post W , McClelland R et al. Abstract 27: volume and density of calcium in the ascending thoracic aorta, when present, predict incident coronary heart disease beyond coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis . Circulation 2017 ; 135 (Suppl. 1): A27 . 8 Bild DE , Bluemke DA , Burke GL , Detrano R , Diez Roux AV , Folsom AR et al. Multi-Ethnic Study of Atherosclerosis: objectives and design . Am J Epidemiol 2002 ; 156 : 871 – 81 . http://dx.doi.org/10.1093/aje/kwf113 Google Scholar CrossRef Search ADS PubMed 9 Goff DC Jr , Lloyd-Jones DM , Bennett G , Coady S , D’Agostino RB , Gibbons R 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 . Circulation 2014 ; 129 (25 Suppl. 2): S49 – 73 . Google Scholar CrossRef Search ADS PubMed 10 Carr JJ , Nelson JC , Wong ND , McNitt-Gray M , Arad Y , Jacobs DR Jr et al. Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study . Radiology 2005 ; 234 : 35 – 43 . Google Scholar CrossRef Search ADS PubMed 11 Budoff MJ , Takasu J , Katz R , Mao S , Shavelle DM , O’Brien KD et al. Reproducibility of CT measurements of aortic valve calcification, mitral annulus calcification, and aortic wall calcification in the multi-ethnic study of atherosclerosis . Acad Radiol 2006 ; 13 : 166 – 72 . Google Scholar CrossRef Search ADS PubMed 12 Agatston AS , Janowitz WR , Hildner FJ , Zusmer NR , Viamonte M Jr , Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography . J Am Coll Cardiol 1990 ; 15 : 827 – 32 . Google Scholar CrossRef Search ADS PubMed 13 Folsom AR , Kronmal RA , Detrano RC , O’Leary DH , Bild DE , Bluemke DA et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA) . Arch Intern Med 2008 ; 168 : 1333 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Leffondre K , Abrahamowicz M , Siemiatycki J , Rachet B. Modeling smoking history: a comparison of different approaches . Am J Epidemiol 2002 ; 156 : 813 – 23 . Google Scholar CrossRef Search ADS PubMed 15 Puri R , Nicholls SJ , Shao M , Kataoka Y , Uno K , Kapadia SR et al. Impact of statins on serial coronary calcification during atheroma progression and regression . J Am Coll Cardiol 2015 ; 65 : 1273 – 82 . Google Scholar CrossRef Search ADS PubMed 16 Saremi A , Bahn G , Reaven PD. Progression of vascular calcification is increased with statin use in the Veterans Affairs Diabetes Trial (VADT) . Diabetes Care 2012 ; 35 : 2390 – 2 . http://dx.doi.org/10.2337/dc12-0464 Google Scholar CrossRef Search ADS PubMed 17 Hermann DM , Lehmann N , Gronewold J , Bauer M , Mahabadi AA , Weimar C et al. Thoracic aortic calcification is associated with incident stroke in the general population in addition to established risk factors . Eur Heart J Cardiovasc Imaging 2015 ; 16 : 684 – 90 . Google Scholar PubMed 18 Iribarren C , Sidney S , Sternfeld B , Browner WS. Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease . JAMA 2000 ; 283 : 2810 – 5 . Google Scholar CrossRef Search ADS PubMed 19 Itani Y , Watanabe S , Masuda Y. Aortic calcification detected in a mass chest screening program using a mobile helical computed tomography unit. Relationship to risk factors and coronary artery disease . Circ J 2004 ; 68 : 538 – 41 . Google Scholar CrossRef Search ADS PubMed 20 Craiem D , Chironi G , Casciaro ME , Graf S , Simon A , Hendrikse J. Calcifications of the thoracic aorta on extended non-contrast-enhanced cardiac CT . PLoS One 2014 ; 9 : e109584 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.

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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Feb 5, 2018

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