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(Circulation. 1997;96:1477-1481.)
© 1997 American Heart Association, Inc.

Articles

Ethnic Origin and Serum Levels of 1,25-Dihydroxyvitamin D₃ Are Independent Predictors of Coronary Calcium Mass Measured by Electron-Beam Computed Tomography

Terence M. Doherty, BA; Weiyi Tang, MD; Steven Dascalos, BA; Karol E. Watson, MD; Linda L. Demer, MD, PhD; Robert M. Shavelle, PhD; ; Robert C. Detrano, MD, PhD

From the Division of Cardiology, Department of Medicine, Harbor–UCLA Medical Center, and the Saint John's Cardiovascular Research Center (T.M.D., W.T., S.D., R.C.D.), Torrance, Calif; Division of Cardiology (K.E.W., L.L.D.), Department of Medicine, UCLA School of Medicine, Los Angeles, Calif; and Department of Statistics (R.M.S.), University of California, Riverside.

Correspondence to Robert Detrano, MD, PhD, Division of Cardiology, Harbor–UCLA Medical Center, 1124 W Carson St, RB-2, Torrance, CA 90502. E-mail detrano{at}harbor4.humc.edu

	Abstract

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Background Blacks have been found to have lower amounts of coronary calcium as well as higher levels of the osteoregulatory steroid 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] than whites. We sought to determine if racial differences in coronary calcium mass could be explained by differences in serum levels of 1,25(OH)₂D₃.

Methods and Results We evaluated standard coronary risk factors, quantified coronary calcium mass with electron-beam computed tomography (EBCT), and measured serum 1,25(OH)₂D₃ with radioimmunoassay in 283 high-risk subjects (51 [18%] black, 232 [82%] white). Black subjects had lower masses of coronary calcium than whites (14 versus 47 mg; P=.003). Serum 1,25(OH)₂D₃ levels were slightly higher in blacks (41 versus 38 pg/mL; P=.05). Log 1,25(OH)₂D₃ levels were inversely proportional to log-transformed calcium mass (r=-.19; P=.001) in both races. Multivariate linear regression demonstrated that both black race (P=.02) and 1,25(OH)₂D₃ levels (P=.007) contributed inversely and independently to coronary calcium mass. However, an interaction term of racex1,25(OH)₂D₃ did not significantly contribute to coronary calcium mass, indicating that other undetermined factors in addition to 1,25(OH)₂D₃ are responsible for ethnic differences in coronary calcium mass.

Conclusions Both black race and serum levels of 1,25(OH)₂D₃ are independent negative determinants of coronary calcium mass. Nevertheless, diminished amounts of coronary calcium in blacks are not accounted for by higher 1,25(OH)₂D₃ levels.

Key Words: calcium • vitamin D • race • tomography

	Introduction

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On the basis of pathological findings that the presence of coronary arterial calcification indicates concomitant atherosclerotic disease,^{1 2} noninvasive radiographic evaluation has been proposed as a screening tool for the detection of coronary artery disease. However, although the amount of calcification correlates moderately well with the severity of obstructive coronary disease compared with angiography or histopathology,^{3 4} the presence of calcification as well as its sensitivity and specificity in identifying obstructive disease may be influenced by factors such as age^{5 6 7 8 9} and sex.^{6 8 9 10} We have shown that asymptomatic but high-risk black subjects have a significantly lower incidence of coronary calcification than whites despite having a similar risk factor profile¹¹ and higher subsequent numbers of coronary events¹² and thus, presumably, a similar extent of coronary atherosclerotic disease. Might the pathobiological determinants of calcification, then, be different in blacks compared with whites?

Current theory conceptualizes atherosclerotic calcification as an active, regulated process similar to osteogenesis,^{13 14 15} yet the details and possible ethnic differences in this regulation remain unknown. The steroid hormone 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the active metabolite of vitamin D, performs a fundamental role in the biology of mineralized tissues and in the maintenance of calcium homeostasis.^{16 17} Like other steroid hormones, 1,25(OH)₂D₃ exerts its biological effects by binding to intracellular receptors, which results in either stimulation or repression of gene transcription. In bone, the effects of 1,25(OH)₂D₃ are complex and incompletely understood, but 1,25(OH)₂D₃ plays an important role in both the initiation of new bone formation and the stimulation of bone resorption.^{16 18}

In addition to having less coronary calcification,¹¹ blacks have greater bone mass^{19 20 21} and a lower incidence of osteoporosis and hip fractures^{22 23 24} than whites, despite a lower calcium intake²⁵ and a diminished rate of new bone formation.²⁶ These ethnic differences in bone metabolism have been attributed to differences in the vitamin D–endocrine system.^{27 28} Blacks have been shown to have higher serum levels of 1,25(OH)₂D₃ and lower serum levels of 25-hydroxyvitamin D₃ than whites,^{28 29 30 31 32} a result of diminished cutaneous synthesis in black pigmented skin of the precursor to 25-hydroxyvitamin D₃, cholecalciferol, a process that depends on ultraviolet photochemical conversion.^{28 29 32} These considerations led us to investigate the possible role of vitamin D metabolism in the development of coronary arterial calcification in both black and white asymptomatic but high-risk subjects.

	Methods

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Study Sample
The South Bay Heart Watch cohort consisted of 1461 adult subjects at high risk for coronary heart disease who underwent digital subtraction fluoroscopy^{8 33} and standard coronary risk factor determination³⁴ between January 1990 and December 1992. To qualify for enrollment, all subjects were required to have a 5% probability of suffering a coronary heart disease event within 4 years as calculated by use of the Framingham algorithm.³⁴ Two years after initial enrollment, risk factor evaluation, and fluoroscopic assessment of coronary calcification, 1304 of these subjects underwent electron-beam computed tomographic (EBCT) scanning (to quantify coronary calcium mass) and repeat risk factor determination. All risk factor data in this report are derived from the risk factor assessment performed at the time of the EBCT exam. Three hundred thirty-eight subjects, including all of the black subjects (n=51) as well as a random subsample of the white subjects (n=287), underwent fasting phlebotomy for quantification of serum lipoproteins and 1,25(OH)₂D₃. Subjects with hyperparathyroidism, chronic renal failure (serum creatinine >2), or known malignancy were excluded, leaving 283 subjects (51 [18%] black, 232 [82%] white) who were free of these conditions.

EBCT Scans
EBCT studies were obtained by use of an Imatron C-100 computed tomographic scanner, without contrast and with the patient supine. Breath was held at end expiration, exposure time was 100 ms per image slice, and total skin radiation was <6 Gy/scan. Image acquisition was triggered electrocardiographically at the same point in the cardiac cycle during diastole (80% of the RR interval). Transverse image slices of the heart were obtained contiguously beginning 1 cm below the carina and progressing caudally. Before the initiation of this investigation, the EBCT scanner was examined by a radiation physicist and was found to function without interslice gaps or overlaps. A standard calibration phantom^{35 36} was scanned with each subject, allowing calculation of calibrated mass estimates of hydroxyapatite content in each coronary artery and standardized estimation of image noise in each slice. All EBCT scans used a 6-mm image-slice protocol.³⁷

Each scan was examined by a cardiologist experienced in both coronary angiography and EBCT imaging. The area of each pixel was 0.34 mm². A region of interest 66 mm² in area^{35 36} was created that was centered on each focus of coronary calcification, defined as a volume of 8.2 mm³ (four contiguous pixels with a CT number >130 Hounsfield units [HU]³⁸ within the distribution of a coronary artery). The mean and peak CT numbers and the area of the subsets of pixels with a CT number >0 HU within these regions were calculated. The estimated mass of calcium phosphate was calculated for each artery by use of a previously published arterial summation.^{35 36 37}

Demographic Factors
Before EBCT scanning, subjects were interviewed and standard coronary risk factor data were obtained. All risk factor results in this report are based on this assessment rather than that performed 2 years earlier when subjects were initially enrolled in the South Bay Heart Watch study. Ethnicity was determined by asking subjects whether they considered themselves to be black, Asian-American, Native-American, or white. In a separate question, subjects were asked if they considered themselves to be of Hispanic origin or otherwise. Therefore, both Hispanics and non-Hispanics were divided among the four major racial categories listed above. Asian-American and Native-American subjects were excluded.

Risk Factor Evaluation
Evaluations were performed twice, at the time of recruitment and 2 years later within 1 week before EBCT scanning. All risk factor results in the present report are based on the latter assessment.

Family history of coronary heart disease was considered pertinent if a first-degree relative had suffered a myocardial infarction⁸ or had died suddenly before the age of 65 years. Smoking history was assessed by asking each subject if they had ever smoked >10 cigarettes/d for at least 1 year. Diabetes or hypertension was considered present if a subject was receiving dietary or medical therapy or both for these disorders.

Systolic and diastolic blood pressures were measured with a sphygmomanometer in duplicate at 3-minute intervals after the subject was allowed to rest in a sitting position for 5 minutes. Systolic and diastolic measurements differed by 3.4±7.8 and 0.4±0.5 mm Hg, respectively.

Blood samples were drawn after a 12-hour fast from an arm vein with subjects in a sitting position and allowed to coagulate at room temperature. The cholesterol oxidase technique was used to measure total cholesterol levels.

Analysis of 1,25(OH)₂D₃ Levels
Whole blood was collected by venipuncture in the fasting state. The serum was separated by centrifugation and stored at -80°C. Frozen serum samples were transferred to the host site for analysis. Serum concentration of 1,25(OH)₂D₃ was determined by radioimmunoassay (reagents from Nichols Institute). All samples were assayed in duplicate. Any pair that differed by >20% was reassayed. If sufficient serum was not available, the subject was excluded from analysis.

Statistical Analysis
Both 1,25(OH)₂D₃ levels and coronary calcium quantities were found to be distributed nonnormally (signed rank test, P<.001). Therefore, transformations of the form (log₁₀[x+1]) were applied to calcium mass and log₁₀X to 1,25(OH)₂D₃. Pearson correlation was used for all correlation coefficients. Wilcoxon nonparametric tests were used to compare 1,25(OH)₂D₃ levels and coronary calcium masses between groups. Multivariate linear regression was applied to determine predictors of calcium phosphate mass.

	Results

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Demographic and Risk Factor Data
The mean age (±SD) of the subjects was 65±8 years (18% of subjects were black and 82% were white). Table 1 shows the results of risk factor assessment for both black and white subjects performed at the time of EBCT scanning. Blacks were significantly younger than their white counterparts (63±8 versus 66±8 years; P=.01), but no other significant differences were noted for the remaining risk factors of male sex, serum cholesterol, systolic blood pressure, history of diabetes, and history of smoking. The mean calculated Framingham risk³⁴ of a coronary heart disease event was similar in both racial groups (Table 1). Of the 283 subjects, 67 (24%) were taking cholesterol-lowering agents, 90 (32%) were taking aspirin, 31 (11%) were receiving ß-blockade therapy, 151 (53%) were taking other antihypertensive agents, and 92 (32%) were taking vitamin supplements, which might have included vitamin D. There were no significant differences between black and white subjects in consumption of any of these (data not shown).

View this table: [in this window] [in a new window]   Table 1. Coronary Heart Disease Risk Factors and Ethnicity

Correlations
Table 2 shows the Pearson correlation coefficients for log-transformed calcium phosphate mass, log 1,25(OH)₂D₃, and age. Table 3 shows coronary calcium phosphate mass, serum 1,25(OH)₂D₃ levels, and race. Watson et al³⁹ described an inverse and significant correlation (-.18) between log 1,25(OH)₂D₃ and log-transformed calcium phosphate mass. As noted by other investigators,^{7 33 40} there is a strong direct correlation between log-transformed calcium and age.

View this table: [in this window] [in a new window]   Table 2. Pearson Correlation Coefficients

View this table: [in this window] [in a new window]   Table 3. Coronary Calcium Phosphate Mass, Serum 1,25(OH)2D3, and Race

Multivariate Regression
Table 4 shows multivariate linear regression using log-transformed calcium phosphate mass as the dependent variable. Age, risk factors, log 1,25(OH)₂D₃, and race were used as independent candidate variables. This analysis demonstrated that age, race, diabetic history, and log 1,25(OH)₂D₃ were all significantly related to the mass of coronary calcium found in the arteries of the 283 subjects. Both black ethnicity and 1,25(OH)₂D₃ were inversely related to calcium phosphate mass, whereas age and diabetic history were directly related. When this calculation was repeated including an interaction term of racex1,25(OH)₂D₃, this interaction was not statistically significant. This implies that the effect of 1,25(OH)₂D₃ on coronary calcium mass is the same for the two races, as depicted graphically by the similar slopes of the regression lines in the Figure. Thus, higher serum 1,25(OH)₂D₃ predicts lower coronary calcium mass, regardless of race. Blacks have higher serum levels of 1,25(OH)₂D₃ and, as a result, lower quantities of coronary calcium; however, black race in and of itself, independent of serum levels of 1,25(OH)₂D₃, is also associated with lower coronary calcium mass.

View this table: [in this window] [in a new window]   Table 4. Linear Regression Coefficients1

View larger version (23K): [in this window] [in a new window]   Figure 1. The relationship between coronary calcium mass and serum 1,25(OH)2D3 in black () and white () high-risk but asymptomatic subjects. For both races, 1,25(OH)2D3 is inversely related to calcium mass, as indicated by the negative slopes of the regression equations. The similarity of slopes in the regression lines indicates that the relationship between serum 1,25(OH)2D3 and calcium mass is the same for both races. The difference in the y intercepts and the fact that the relationship between coronary calcium mass and 1,25(OH)2D3 is described by distinct regression equations in blacks and whites indicates that although blacks have higher levels of 1,25(OH)2D3 (see "Results"), at any given serum level of 1,25(OH)2D3 blacks tend to have less coronary calcium than whites.

	Discussion

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In this report, we demonstrate an inverse relation between serum levels of 1,25(OH)₂D₃ and coronary calcium mass estimated by EBCT in all subjects irrespective of race, implicating a systemic steroid osteoregulatory factor in the regulation of atherosclerotic calcification and confirming our previous results.³⁹ In addition, our data corroborate, quantify, and extend our previous cinefluoroscopic findings¹¹ that blacks have less coronary calcification than whites. Multivariate linear regression analysis indicates that serum levels of 1,25(OH)₂D₃ and black ethnicity are independently and inversely related to coronary calcium mass. However, racial differences in coronary calcification remain that cannot be attributed solely to quantitative differences in vitamin D metabolism, as demonstrated by the lack of significance of the interaction term of racex1,25(OH)₂D₃ on coronary calcium mass in multivariate regression. Although blacks have less coronary calcium mass and higher serum levels of 1,25(OH)₂D₃ than whites, the relationship between serum levels of 1,25(OH)₂D₃ and coronary calcium mass is the same for both races (as indicated by the similarity of the regression line slopes in the Figure). Therefore, other as-yet-unidentified factors remain that contribute to decreased coronary calcium mass in blacks.

Although we did not directly measure atherosclerosis or coronary artery disease severity, our data cannot readily be explained by postulating less atherosclerosis in blacks. Black and white subjects in our study had similar risk factor profiles and Framingham risk (Table 1 and "Results"); moreover, our black subjects had higher numbers of coronary events during clinical follow-up.^{11 12} Furthermore, in contrast to older studies,^{41 42 43 44 45} more recent postmortem data indicate that there is little difference in the extent of coronary atherosclerosis between blacks and whites,⁴⁶ yet the quantity of coronary calcification is less in blacks than in whites.^{47 48 49} In one study, for example, aortic plaques in whites were calcified 1.6 times more frequently than in blacks with the same types of lesions.⁵⁰ Collectively, these pathological studies suggest that coronary calcium mass in blacks is less than that in whites, and they are consistent with both the EBCT findings reported here and our previous cinefluoroscopic results.¹¹

Our data provide no direct explanation for our findings of less coronary calcium mass in blacks. However, in view of our observation that serum levels of 1,25(OH)₂D₃ are inversely related to calcium mass (Reference 39³⁹ and this report), it is conceivable that ethnic differences in genetic and/or endocrine mechanisms may be contributing factors; data from several sources suggest this possibility. Tentolouris et al⁵¹ reported a familial syndrome of aortic calcification in the absence of aortic or coronary atherosclerosis, suggesting that atherosclerosis and calcification may be genetically distinct yet related processes. More direct evidence implicating genetic determinants for calcification has been obtained recently in a transgenic murine model of atherosclerosis.^{52 53} Several studies have demonstrated racial differences in endocrine factors that affect bone metabolism and that could also affect atherosclerotic calcification. For example, in addition to alterations in the vitamin D–endocrine system,^{27 54} racial differences in levels of growth hormone,⁵⁵ parathyroid hormone,⁵⁴ estrogen,⁵⁶ and testosterone⁵⁷ have been reported. Thus, it seems plausible to speculate that the ethnic differences in coronary calcium reported here as well as previously¹¹ may have at least in part a genetic and/or metabolic basis beyond that attributable to differences in vitamin D metabolism. Further studies are required to elucidate these possibilities.

It is conceivable that some of the coronary calcium we observed was unrelated to atheromatous plaque. Medial calcification of the large arteries unassociated with atherosclerotic disease (Mönckeberg's calcinosis) can be produced in animals by various pharmacological manipulations, including injections or dietary supplementation of large doses of vitamin D.^{58 59 60} Because EBCT is unable to distinguish atherosclerotic calcification from Mönckeberg's medial calcification, we cannot exclude the possibility that some of the calcium we observed was of such nonatherosclerotic origin. However, although medial calcification is observed in peripheral and visceral arteries,⁶¹ available pathological evidence indicates that it occurs only rarely in the coronary arteries.^{1 2 3 62}

Conclusions
Black race and serum levels of 1,25(OH)₂D₃ are independent negative determinants of coronary calcium mass. However, although blacks have higher levels of 1,25(OH)₂D₃ and less coronary calcium mass than whites, the relationship between 1,25(OH)₂D₃ and calcium mass is the same for both races. Diminished quantities of coronary calcium in blacks cannot be accounted for solely by increased 1,25(OH)₂D₃ levels in blacks.

	Acknowledgments

 
This study was supported by NHLBI grants No. 5 RO1 HL-43277-06 and HL-30568, NCRR grant No. MO1 RR 00865, the Kenneth T. and Eileen L. Norris Foundation, and the Saint John's Cardiovascular Research Institute. We would like to extend our gratitude to Bruce H. Brundage, MD, for institutional support and to Ramon M. Valencia for technical and editorial assistance.

Received February 12, 1997; revision received April 2, 1997; accepted April 12, 1997.

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