Metabolic Syndrome, Diabetes, and Incidence and Progression of Coronary Calcium: The Multiethnic Study of Atherosclerosis (MESA)

Abstract

Objectives

The purpose of the study was to examine and compare the incidence and progression of coronary artery calcium (CAC) among persons with metabolic syndrome (MetS) and diabetes mellitus (DM), compared to those with neither condition.

Background

MetS and DM are associated with subclinical atherosclerosis as evidenced by coronary artery calcium (CAC).

Methods

The Multiethnic Study of Atherosclerosis included 6,814 African-American, Asian, Caucasian, and Hispanic adults aged 45–84 free of cardiovascular disease at baseline. 5,662 subjects (51% female, mean age 61.0 ± 10.3 years) received baseline and follow-up (mean 2.4 years) cardiac CT scans. We compared the incidence of CAC in 2,927 subjects without CAC at baseline and progression of CAC in 2,735 subjects with CAC at baseline in those with MetS without DM (25.2%), DM without MetS (3.5%), or both DM and MetS (9.0%), compared to neither MetS nor DM (58%). Progression of CAC was also examined in relation to coronary heart disease events over an additional 4.9 years.

Results

Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals) for incident CAC were 1.7 (1.4–2.0), 1.9 (1.4–2.4), and 1.8 (1.4–2.2) (all p<0.01) and absolute differences in mean progression (volume score) were 7.8 (4.0–11.6; p<0.01), 11.6 (2.7–20.5; p<0.05), and 22.6 (17.2–27.9; p<0.01) for those with MetS without DM, DM without MetS, and both DM and MetS, respectively. Similar findings were seen in analysis using Agatston calcium score. In addition, progression predicted CHD events in those with MetS without DM (adjusted hazard ratio 4.1, 95% CI=2.0–8.5, p<0.01) and DM (4.9 [1.3–18.4], p<0.05) among those in highest tertile of CAC increase vs. no increase).

Conclusions

Individuals with MetS and DM have a greater incidence and absolute progression of CAC compared to individuals without these conditions, with progression also predicting CHD events in those with MetS and DM.

Introduction

Metabolic syndrome (MetS) and diabetes (DM) predict coronary heart disease (CHD) events and mortality.^1–3 Subclinical atherosclerosis as evidenced by coronary artery calcium (CAC)^4–9 and carotid intimal medial thickeness^10–11 is increased in MetS and DM, but no study has compared the incidence and progression of CAC across these conditions. Progression of CAC may be clinically important since persons experiencing CHD events have greater progression of CAC¹² and recently progression of CAC has been shown to predict all-cause mortality.¹³ The population-based Multiethnic Study of Atherosclerosis (MESA) has demonstrated most standard CHD risk factors to be associated with the incidence and progression of CAC.¹⁴

In this report, we compared in MESA the incidence and progression of CAC among persons with MetS (but no DM) and DM (with and without MetS) relative to those with neither condition. Our hypothesis was that MetS would be associated with future development and progression of CAC greater than those without MetS, but less than those with DM.

Methods

Study Population and Definitions

The design of MESA, a prospective epidemiologic study of the prevalence, risk factors and progression of subclinical cardiovascular disease (CVD) has been previously published.¹⁵ Briefly, 6,814 participants aged 45–84 free of clinical CVD, identified as White, African-American, Hispanic, or Chinese, were recruited from six U.S. communities (Forsyth County, NC, Northern Manhattan and the Bronx, NY, Baltimore City and Baltimore County, MD, St. Paul, MN, Chicago, IL, and Los Angeles County, CA) in 2000–2002. Recruitment included lists of residents, dwellings, telephone exchanges, lists of Medicare beneficiaries, and referrals by participants. Similar numbers of men and women were recruited according to pre-specified age and race/ethnicity quotas. All participants gave informed consent, and the study protocol was approved by the Institutional Review Board at each site.

This report includes 5,662 subjects with both baseline (Exam 1) and follow-up (at Exam 2 or 3) CT scans, available data to define DM or MetS, and with no incident CHD event occurring between baseline and follow-up CT. This resulted in excluding 1,056 subjects who did not have follow-up scans (or were out of protocol), 26 with incomplete data to define DM or MetS, and 70 who had an intervening CHD event. Diabetes was defined as a fasting glucose ≥7.0 mmol/l (126 mg/dl), or if on insulin or oral hypoglycemic medications. Among non-diabetics, MetS was defined to be present if ≥3 of the following were present: 1) abdominal obesity based on waist circumference >88cm (35 in) for women and >102 cm (40 in) for men, 2) HDL-cholesterol <1.0 mmol/l (40 mg/dl) for men or <1.3 mmol/l (50 mg/dl) for women, 3) fasting triglycerides ≥1.7 mmol/l (150 mg/dl), 4) blood pressure of ≥130mmHg systolic or ≥85 diastolic, or on treatment, or 5) impaired fasting glucose defined as a fasting glucose of 5.55–6.99 mmol/l (100–125 mg/dl), based on the American Heart Association / National Heart, Lung, and Blood Institute definition.¹⁶

Measurement of Coronary Artery Calcium

CAC was measured by electron-beam (3 sites) or multi-detector (3 sites) computed tomography. Participants were scanned twice consecutively and scans were read by a trained physician-reader at a centralized reading center (Los Angeles Biomedical Research Institute, Torrance, CA). The methodology for acquisition and interpretation of the scans has been published.¹⁷ Calcium volume scores¹⁷ and Agatston scores¹⁸ were based on averaging results from each scan and adjusted using a standard calcium phantom (scanned with the participant) to calibrate X-ray attenuation between measurements conducted on different machines.¹⁹ Detectable calcium was defined as a CAC score >0. A second scan was performed on half the cohort (randomly selected) at a second exam (September, 2002–January, 2004) and on the other half at a third exam (March, 2004–July, 2005), averaging 1.6 and 3.2 years after the first scan, respectively (average 2.4 years between). The distribution of CAC in MESA at baseline by age, gender and race has been published previously.²⁰

Examination Data and Covariates

Information on demographics, smoking, medical conditions, and family history was obtained by questionnaire. Height, weight, total and high density lipoprotein-cholesterol, triglycerides, and fasting glucose levels were determined. Resting blood pressure was measured three times, with the average of the last two measurements used in analysis. Use of cholesterol, blood pressure, and diabetes medications was determined by questionnaire and from medication containers.¹⁵

Follow-up for Coronary Heart Disease (CHD) Events

The cohort was followed for incident CHD events for a mean of 4.9 ± 1.3 years following the second scan. At intervals of 9–12 months, a telephone interviewer inquired about interim hospital admissions, cardiovascular diagnoses, and deaths. An adjudication committee received copies of all death certificates and medical records for hospitalizations and outpatient cardiovascular diagnoses and conducted next-of-kin interviews. Two physicians independently classified and assigned incidence dates. For disagreements, a full mortality and morbidity review committee made the final classification. We followed participants for occurrence of all CHD endpoints which included myocardial infarction, angina, resuscitated cardiac arrest, or CHD death. CHD death was based on review of hospital records and interviews with families. The reviewers were blinded to CT scan and MRI results and used pre-specified criteria.

Statistical Analysis

Subjects were classified as having: 1) neither MetS nor DM, 2) MetS without DM, 3) DM without MetS, and 4) DM with MetS. The first two groups were also classified by number of MetS risk factors (0, 1, 2, 3, and 4–5). To assess bivariate associations between these groups, risk factors, and CAC score/volume measures, the Chi-square test (for categorical covariates) or an F-test from analysis of variance (for continuous covariates) was used. Incident CAC was defined among those without baseline CAC (n=2,918) as those who developed detectable CAC at the follow-up scan. Absolute progression of CAC was defined among those with CAC at baseline (n=2,729) as the difference between the CAC volume score on follow-up (CAC_FU) and that at baseline (CAC_BL).¹⁴ We used relative risk regression²¹ to obtain asymptotically unbiased estimates of the relative risk (RR) of incident CAC among those free of CAC at baseline. This involved modeling the probability of incident CAC score as an exponential function of risk factors (including each MetS / DM classification relative to the reference group) and performing nonlinear least squares estimation. To account for misspecification of the variance, we computed model-robust (Huber-White) standard errors. To estimate the absolute progression of CAC among those with detectable CAC at baseline, we used robust linear regression, downweighting the influence of participants with very large progression to increase model robustness. We also present our findings as relative progression, defined as the median annualized percent change in CAC from baseline to follow-up scan. Our analyses also adjusted for time between scans, age, gender, ethnicity, baseline total cholesterol, lipid-lowering medication use, smoking status, and family history of myocardial infarction. Adjusting for the time between scans in a progression model of the absolute change in CAC implicitly standardizes CAC change with respect to time and is equivalent to directly modeling the annualized absolute CAC change. Absolute progression analyses (but not relative progression) were additionally adjusted for the scanner pair used at baseline and follow-up to account for scanner changes over time. As a sensitivity analysis, we also performed progression analyses additionally adjusted for baseline calcium volume score. We also investigated the independent contribution of each MetS component to predicting the incidence or progression of CAC, we evaluated incidence and progression models that included each of the five separate MetS components in the model together, and to examine if the composite of MetS / DM still predicted incidence and progression of CAC after accounting for the individual MetS components, we added this in a final model. Finally, Cox proportional hazards regression was used to examine the relation of progression of CAC to the incidence of total CHD events within each disease group separately. All statistical analyses were performed using SAS version 9.1²².

Results

Overall, 5,662 subjects were included (51% female, mean age 61.0 ± 10.3 years); 3,528 (62.3%) had neither MetS nor DM, 1,426 (25.2%) had MetS without DM, 198 (3.5%) had DM without MetS, and 510 (9.0%) had both MetS and DM. Subjects excluded (n=70) because of intervening CHD events between baseline and follow-up scans were more likely to have both MetS and DM (23%) and less likely to have neither condition (40%); also, 31% had MetS (without DM) and 6% had DM without MetS. Scanners used for the initial and followup scan were electron beam CT (n=2,854, 50.4%), multidetector (n=2,630, 46.4%) and the remainder were electron beam-multidetector (n=180, 3.2%). Table 1 shows the distribution of demographic and clinical risk factors and calcium scores by the four category MetS/DM classification. Systolic and diastolic blood pressure, triglycerides, and waist circumference were highest and HDL-C lowest in those with MetS, and fasting glucose levels were highest in those with DM (all p<0.01). The prevalence of CAC ranged from 44% to 62% by MetS/DM classification (p<0.01). Among those with CAC, baseline volume score was highest in those with DM. The unadjusted incidence of CAC increased progressively by according to MetS/DM status (Figure 1). Among men with DM and women with DM plus MetS, incidence of CAC was highest. Incidence was unexpectedly low, however, in women with DM but without MetS (although uncertain because of a low sample size).

Table 1.

Baseline Risk Factor Distributions and Baseline and Follow-up Coronary Calcium Volume and Scores by Metabolic Syndrome and Diabetes Grouping

	Exposure
Factor	No MetS/No DM (n=3,528, 62.3%)	MetS/No DM (n=1,426, 25.2%)	No MetS/DM (n=198, 3.5%)	Both MetS/DM (n=510, 9.0%)
Age (years)*	61.0 (10.3)	62.6 (9.9)	64.3 (9.6)	63.9 (9.4)
Female (%)*	51.3	58.8	31.8	53.1
Ethnicity (%)*
Caucasian	43.2	40.1	19.7	20.6
Chinese-American	12.9	9.6	17.2	9.6
African-American	25.8	24.9	38.4	37.1
Hispanic	18.2	25.4	24.8	32.8
Current Smoker (%)	12.1	13.0	13.6	12.6
Family History of MI (%)*	38.6	43.4	30.3	40.6
Fasting glucose, mg/dl *	86.9 (8.6)1	95.2 (11.9)1	133.2 (53.0)1	152.0 (52.4)1
Triglycerides, mg/dl *	104.1 (57.5)1	181.7 (88.5)1	99.7 (49.2)1	184.1 (152.8)1
Systolic BP (mmHg) *	121.7 (20.2)	133.1 (20.2)	126.4 (18.8)	133.7 (21.6)
Diastolic BP (mmHg) *	71.1 (10.0)	73.9 (10.4)	71.9 (10.2)	71.6 (10.2)
Waist circum. (cm) *	93.6 (13.3)	105.5 (12.4)	95.7 (11.8)	108.0 (13.6)
HDL – cholesterol, mg/dl *	55.2 (14.9)	42.9 (10.0)	53.5 (13.6)	43.8 (11.7)
Total cholesterol, mg/dl *	194.3 (33.3)	196.6 (37.5)	184.5 (33.1)	189.9 (40.7)
Prevalence of Calcium (%)*	43.9	53.4	57.1	61.6
Baseline Volume Score (all subjects n=5662), mean+SD*	84.5 ± 261.4	107.3 ± 281.6	193.2 ± 477.1	171.4 ± 364.2
Follow-up Volume Score (all subjects n=5662), mean+SD*	112.0 ± 318.7	150.3 ± 358.3	282.9 ± 609.2	257.6 ± 512.4
Baseline Volume Score (baseline CAC>0, n=2735), mean+SD*	192.6 ± 367.5	201.0 ± 360.4	338.6 ± 592.3	278.4 ± 431.0
Follow-up Volume Score (baseline CAC>0 n=2735), mean+SD*	253.9 ± 442.5	279.8 ± 452.4	493.7 ± 740.4	416.6 ± 600.8
Baseline Agatston Score (all subjects n=5662), mean+SD*	106.7 ± 334.6	138.5 ± 365.4	244.9 ± 608.3	221.0 ± 469.6
Follow-up Agatston Score (all subjects n=5662), Mean+SD*	143.9 ± 414.2	196.1 ± 468.2	362.9 ± 784.7	337.7 ± 674.9
Baseline Agatston Score (baseline CAC>0, n=2735), mean+SD*	243.3 ± 471.3	259.5 ± 467.9	429.1 ± 755.7	359.0 ± 555.8
Follow-up Agatston Score (baseline CAC>0 n=2735), mean+SD*	326.5 ± 576.1	365.2 ± 591.2	633.5 ± 954.4	546.3 ± 791.9

¹Tests for association done on mean of log-transformed data. Among analyses in those with CAC>0, disease group sample sizes are 1547, 761, 113, and 314 for those with neither MetS/DM, MetS without DM, DM without MetS, and DM plus MetS, respectively.

^*p<0.001 across groups; MetS = metabolic syndrome, DM = diabetes mellitus, BP = blood pressure, HDL = high density lipoprotein, MI = myocardial infarction, CAC = coronary artery calcium.

Figure 1.

Incidence of Coronary Artery Calcium (CAC) (per 100 person years) according to Metabolic Syndrome (MetS) and Diabetes (DM) Status, by Gender, among persons without baseline CAC.

Table 2 shows the adjusted relative risks (RRs) for incident CAC for the four and seven category MetS/DM classifications. Compared to those with neither MetS nor DM, those with MetS (without DM) and those with DM (regardless of the presence of MetS) had a greater incidence of CAC. In gender-stratified analyses, results were generally similar to the overall group, except for those with DM (without MetS) where findings were not significant for women. In analyses stratified by ethnicity (results not shown), the RR for incident CAC was significantly greater for those with both DM and MetS among Chinese (RR=3.7, p<0.05), Hispanics (RR=2.2, p<0.01), and African-Americans (RR=1.8, p<0.05) and was also greater for those with MetS without DM in all ethnic groups (RR’s 1.7–2.1, p<0.05 to p<0.01). Only in African-Americans was incident CAC was significantly greater (RR of 2.1, p<0.05) for those with DM (without MetS) compared to those with neither MetS nor DM. When examining CAC incidence by number of MetS risk factors, compared to those with no MetS risk factors, those with as few as 2 MetS risk factors had an increased incidence of CAC (RR=1.5, p<0.05), with an increases to RR’s of 2.0 or greater in those with 3 or 4–5 MetS risk factors, DM without MetS, or both DM and MetS (p<0.01 overall), with stronger associations seen in women.

Table 2.

Relative Risk Regression for Incidence of CAC among Persons without CAC at Baseline (n=2,927) by Metabolic Syndrome and Diabetes Grouping and by Number of Metabolic Syndrome Risk Factors: Incidence and Risk Ratio Estimates by Gender

		Overall		Female		Male
Exposure	N	Adjusted RR (95% CI)1	N	Adjusted RR (95% CI)1	N	Adjusted RR (95% CI)1
Both Diabetes and MetS	196	2.0 (1.5, 2.8)†	130	2.0 (1.3, 3)†	66	2.0 (1.2, 3.2)†
Diabetic and No MetS	85	1.6 (1.0, 2.6)*	35	0.8 (0.2, 2.5)	50	2.0 (1.2, 3.4) †
MetS and Non-Diabetic	661	1.8 (1.5, 2.2) †	456	1.9 (1.4, 2.4) †	205	1.7 (1.2, 2.4) †
Neither MetS nor Diabetes	1976	1.0	1209	1.0	767	1.0
Exposure	N	Adjusted RR (95% CI)1	N	Adjusted RR (95% CI)1	N	Adjusted RR (95% CI)1
Both Diabetes and MetS	196	2.6 (1.7, 3.9) †	130	3.1 (1.7, 5.7) †	66	2.2 (1.2, 3.9) †
Diabetic and No MetS	85	2.1 (1.2, 3.5) †	35	1.2 (0.3, 4)	50	2.4 (1.3, 4.3) †
4–5 MetS risk factors	216	2.2 (1.5, 3.3) †	155	2.8 (1.6, 5.1) †	61	1.6 (0.8, 3)
3 MetS risk factors	445	2.3 (1.6, 3.3) †	301	2.8 (1.6, 4.8) †	144	2 (1.3, 3.3) †
2 MetS risk factors	688	1.5 (1.1, 2.1)*	454	1.8 (1.1, 3.1)*	234	1.2 (0.7, 1.9)
1 MetS risk factors	741	1.2 (0.9, 1.7)	451	1.4 (0.8, 2.4)	290	1.1 (0.7, 1.8)
No MetS risk factors	547	1.0	304	1.0	243	1.0

^*p<0.05,

^†p<0.01 compared reference group of Neither MetS nor Diabetes, or No MetS risk factors; 9 observations were missing covariates so are not reflected in these analyses.

Estimates adjusted for Age, Gender (except in gender-stratified analyses), Ethnicity, Time Between Scans, Smoking Status, Total Cholesterol, Lipid Lowering Meds Use, Family History of MI, and Scanner Pair. MetS = metabolic syndrome, CAC = coronary artery calcium, MI = myocardial infarction, RR = relative risk, CI = confidence interval

Among those with baseline CAC, progression of CAC (median annualized percent change in CAC) also increased directly according to MetS/DM status (Figure 2). Robust linear regression (Table 3) showed those with both MetS and DM as well as those with DM but no MetS to have the greatest progression of CAC, and those with MetS but not DM to have an intermediate level of progression. Women with DM and no MetS and men with both DM and MetS had the greatest degree of progression of CAC. Among each individual ethnic group, progression of CAC was greatest in those with both MetS and DM (mean adjusted volume score differences of 15.3 to 27.1, p<0.01, compared to those with neither MetS/DM), being highest in Caucasians (23.4) and African-Americans (27.1). Of other MetS/DM groups, only DM without MetS in African-Americans (31.7, p<0.01) and Chinese (17.5, p<0.05) and MetS without DM in Caucasians (11.0, p<0.01) had progression significantly greater than those with neither MetS/DM. In analyses by number of MetS risk factors (Table 4), compared to those with 0 MetS risk factors, progression was greater only for those with ≥3 MetS risk factors, DM, or both DM and MetS The greatest increases were seen for those with DM with MetS, although in gender-stratified analyses this was the case for men, but not women where DM without MetS had the greatest progression. Results presented according to Agatston score showed similar findings with the expected greater magnitude of differences due to absolute Agatston scores being higher than volume scores.

Figure 2.

Progression of Coronary Artery Calcium (CAC)(Mean Unadjusted Absolute Change in Volume Score) according to Metabolic Syndrome and Diabetes (DM) Status, by Gender, among Persons without baseline CAC.

Table 3.

Multivariable Analysis of Absolute Progression of Coronary Calcium by Metabolic Syndrome / Diabetes Status among Persons with CAC at baseline (n=2,729)

			All		Female		Male
			Robust Difference in Mean Progression		Robust Difference in Mean Progression		Robust Difference in Mean Progression
Score	Exposure	N	(95% CI)	N	(95% CI)	N	(95% CI)
Agatston Score	Both	314	29.3 (21.8, 36.7)†	141	20.8 (11.7, 29.8)†	173	35.4 (24.0, 46.8)†
	Diabetic and No MetS	113	25.0 (13.5, 36.5)†	28	38.6 (20.4, 56.8)†	85	21.9 (6.4, 37.4)†
	MetS and Non-Diabetic	758	8.2 (3.0, 13.5)†	379	3.6 (−2.6, 9.8)	379	15.4 (7.2, 23.7)†
	Neither MetS nor Diabetes	1544	0.0 (0.0, 0.0)	596	0.0 (0.0, 0.0)	948	0.0 (0.0, 0.0)
Volume Score	Both	314	22.4 (16.9, 27.9)†	141	16.3 (9.4, 23.2)†	173	26.6 (18.3, 34.9)†
	Diabetic and No MetS	113	16.7 (8.1, 25.2)†	28	26.4 (12.5, 40.4)†	85	14.2 (3.0, 25.5)*
	MetS and Non-Diabetic	758	7.4 (3.5, 11.3)†	379	5.2 (0.5, 10.0)*	379	10.8 (4.8, 16.8)†
	Neither MetS nor Diabetes	1544	0.0 (0.0, 0.0)	596	0.0 (0.0, 0.0)	948	0.0 (0.0, 0.0)

Adjusted for Age, Gender (except in gender-stratified analyses), Ethnicity, Time Between Scans, Smoking Status, Total Cholesterol, Lipid Lowering Meds Use, Family History of MI, and Scanner Pair.

^*p<0.05,

^†p<0.01 compared to Neither MetS nor Diabetes; 7 observations were missing covariates so are not reflected in these analyses.

Relative Risk Regression adjusted for Age, Gender (except in gender-stratified analyses), Ethnicity, Time Between Scans, Smoking Status, Total Cholesterol, Lipid Lowering Meds Use, Family History of MI, and Scanner Pair; Reference group comprises those with neither MetS nor Diabetes. MetS = metabolic syndrome, MI = myocardial infarction, CI = confidence interval

Table 4.

Multivariable Analysis of Absolute Progression of Coronary Calcium By Number of Metabolic Syndrome Risk Factors / Diabetes Status Among Persons with CAC at Baseline (n=2,729)

			All		Female		Male
			Robust Difference in Mean Progression		Robust Difference in Mean Progression		Robust Difference in Mean Progression
Score	Exposure	N	(95% CI)	N	(95% CI)	N	(95% CI)
Agatston Score	Both	314	32.4 (22.5, 42.2) †	141	20.8 (7.9, 33.6) †	173	38.8 (24.3, 53.3) †
	Diabetic and No MetS	113	28.0 (14.8, 41.1) †	28	38.5 (18.5, 58.6) †	85	25.3 (7.4, 43.2) †
	4–5 MetS risks	294	12.9 (3.1, 22.8)*	159	5.7 (−6.7, 18.0)	135	23.0 (7.7, 38.2) †
	3 MetS risks	464	10.5 (1.5, 19.4)*	220	4.3 (−7.5, 16.0)	244	16.8 (3.7, 29.9)*
	2 MetS risks	650	5.9 (−2.5, 14.4)	292	4.5 (−6.8, 15.7)	358	4.5 (−7.7, 16.6)
	1 MetS risk	613	1.6 (−6.9, 10.0)	217	−2.1 (−13.6, 9.5)	396	4.2 (−7.8, 16.2)
	0 MetS risks	281	0.0 (0.0, 0.0)	87	0.0 (0.0, 0.0)	194	0.0 (0.0, 0.0)
Volume Score	Both	314	23.7 (16.3, 31.0) †	141	18.5 (8.5, 28.5) †	173	26.9 (16.3, 37.4) †
	Diabetic and No MetS	113	17.9 (8.1, 27.7) †	28	28.9 (13.3, 44.5) †	85	14.6 (1.5, 27.6)*
	4–5 MetS risks	294	10.9 (3.5, 18.2) †	159	10.1 (0.5, 19.7)*	135	14.6 (3.5, 25.7) †
	3 MetS risks	464	7.5 (0.8, 14.1)*	220	6.4 (−2.7, 15.5)	244	9.5 (−0.0, 19.1)
	2 MetS risks	650	3.9 (−2.4, 10.1)	292	5.8 (−3.0, 14.6)	358	1.2 (−7.7, 10.0)
	1 MetS risk	613	−1.0 (−7.3, 5.3)	217	−0.4 (−9.4, 8.6)	396	−0.3 (−9.0, 8.4)
	0 MetS risks	281	0.0 (0.0, 0.0)	87	0.0 (0.0, 0.0)	194	0.0 (0.0, 0.0)

^*p<0.05,

^†p<0.01 compared to 0 MetS risk factors; 7 observations were missing covariates so are not reflected in these analyses.

Relative Risk Regression adjusted for Age, Gender (except in gender-stratified analyses), Ethnicity, Time Between Scans, Smoking Status, Total Cholesterol, Lipid Lowering Meds Use, Family History of MI, and Scanner. Reference group comprises those with 0 MetS risk factors. MetS = metabolic syndrome, MI = myocardial infarction, CI = confidence interval

When additionally adjusting for baseline volume score, our findings regarding progression of CAC were not substantially affected and remained statistically significant. Mean differences (compared to those with neither MetS nor DM) in volume score change were 6.2 (3.0–9.4) for those with MetS without DM, 13.4 (6.5–20.4) for those with DM without MetS, and 14.6 (10.1–19.1) for those with DM and MetS (all p<0.01).

We also evaluated the relation of individual MetS components to the incidence and progression of CAC. With all components in the model simultaneously, only increased waist circumference (adjusted RR=1.4, p<0.001) and increased glucose (adjusted RR=1.25, p<0.01) predicted CAC incidence. Progression of CAC was driven most strongly by elevated glucose (volume score change of 10.7, p<0.001) and blood pressure (volume score change of 5.8, p<0.05)

When examining the relation of CAC progression to total CHD events in each disease group, total CHD events per 1000 person years increased progressively according to extent of change in volume score in those with neither MetS nor DM, those with MetS and no DM and those with both MetS and DM (Figure 3). Corresponding hazard ratios, adjusted for age, gender, ethnicity, and risk factors, compared to those with no or negative change were increased in those in the 2^nd and 3^rd tertiles of positive CAC change were 2.3 (1.0–4.9), p<0.05 and 4.1 (2.0–8.5), p<0.01, respectively, in those with MetS and no DM and 4.0 (1.1–14.9), p<0.05 and 4.9 (1.3–18.4), p<0.05, respectively, in those with both MetS and DM; after additional adjustment for baseline CAC, these estimates were similar: 2.3 (1.1–5.0), p<0.05 and 3.5 (1.6–7.3), p<0.01, respectively in those with MetS and no DM and 3.9 (1.0–14.8), p<0.05 and 4.0 (0.95–16.0), p=n.s., respectively, in those with both MetS and DM.

Figure 3.

Coronary Heart Disease (CHD) Event Rates (per 1000 person years) according to Tertile of CAC Progression by Presence of Metabolic Syndrome (MetS) and Diabetes (DM). Data are not shown for persons with DM without MetS because of an insufficient number of CHD events.

Discussion

In the Multiethnic Study of Atherosclerosis, persons with MetS or DM have a greater incidence and progression of CAC compared to those without MetS; those with MetS (without DM) have an intermediate incidence and progression. Also, impaired fasting glucose¹⁸, insulin resistance²³ and DM^24–25 have been shown in smaller or selected cohorts to relate to progression of CAC, and in those with DM, a glycated hemoglobin ≥7% predicted progression of CAC.²⁶ Progression of CAC has also been shown to predict total mortality over baseline risk factors and CAC.¹³ We also found in our study increased progression of CAC in persons with MetS and DM to predict future CHD events.

Important to understanding the relationship of MetS and DM to progression of CAC is the baseline calcium score, a strong predictor of CAC progression.^{23, 27} Since MetS is associated with an intermediate level and DM the highest level of CAC, one might expect a similar pattern for progression. While baseline CAC could be considered a confounder, it can also be considered part of the causal pathway between risk factors such as MetS and DM and the progression of CAC. Such persons likely had more rapid progression of CAC to begin with and continued to show greater future progression, hence including baseline CAC in the model could condition out the effects that variables of interest (in this case MetS and DM) may have up to baseline.¹⁴ In our study, however, secondary analyses additionally adjusted for baseline calcium volume showed only a slight attenuation of our findings, which remained largely significant.

In addition, the choice of the scale for continuous progression (e.g. absolute versus relative change) and the failure to account for outlying progressors may markedly influence the results obtained.¹⁴ Similar to Kronmal¹⁴, we use absolute progression as our primary outcome and account for outlying progressors using robust regression modeling techniques which limits the influence of outlying observations (e.g. fast progressors).

Strengths of MESA include its large sample size, ethnic diversity, and community-based recruitment. The prospective design allows for assessment of baseline factors including MetS and DM in relation to development and progression of CAC, as well as the evaluation of progression of CAC in relation to subsequent CHD events. In addition, MESA had standardized protocols for scanning and interpretation of scans. Importantly, our estimate of progression of CAC was based only on the change between two scans done an average of about 2 years apart, from which progression was then annualized; however, this assumes a linear relation of progression with time, which may or may not be the case, hence results could be different had more measures been available and/or if the time between scans was greater. Also, exclusion of a small number of individuals (n=70) who had intervening CHD events may have influenced the results; such persons were more likely to have DM and MetS, progression of CAC, as well as CHD events, so our findings relating progression to events could have been underestimated (thus conservative); however, our intention was to look at the natural progression of CAC not interrupted by CHD events, thus we kept our group homogenous by excluding such individuals. As there is controversy of which definition may be most appropriate, or even whether MetS should be considered a syndrome^28–30, our findings may have differed had other definitions for MetS been used.

Persons with both MetS and DM have the greatest incidence and degree of progression of CAC; those with MetS without DM have an incidence and degree of progression of CAC intermediate between those with DM and without these conditions. Moreover, in those with MetS or DM, progression predicts future CHD event risk.

ABBREVIATIONS

BP

blood pressure

CAC

Coronary artery calcium

CT

Computed tomography

CHD

Coronary heart disease

CVD

Cardiovascular disease

DM

Diabetes mellitus

HDL

High density lipoprotein

MESA

Multiethnic Study of Atherosclerosis

MetS

Metabolic syndrome

MI

Myocardial infarction

RR

Relative risk

SD

Standard deviation