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Predictive value of CT coronary artery calcium scanning for coronary heart disease in asymptomatic subjects with diabetes mellitus

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Predictive value of CT coronary artery calcium scanning for coronary heart disease in asymptomatic subjects with diabetes mellitus

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Content INFORMATION TO U SERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. ProQuest Information and Learning 300 North Zeeb Road, Ann Arbor, M l 48106-1346 USA 800-521-0600 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. R eproduced with permission of the copyright owner. Further reproduction prohibited without permission. PREDICTIVE VALUE OF CT CORONARY ARTERY CALCIUM SCANNING FOR CORONARY HEART DISEASE IN ASYMPTOMATIC SUBJECTS WITH DIABETES MELLITUS by Wenchun Qu A Thesis Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment o f the Requirements for the Degree MASTER OF SCIENCE (APPLIED BIOSTATISTICS AND EPIDEMIOLOGY) December 2001 Copyright 2001 Wenchun Qu Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 1411036 _ ___ ® UMI UMI Microform 1411036 Copyright 2002 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O.Box 1346 Ann Arbor, Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UNIVERSITY OF SOUTHERN CALIFORNIA The Graduate School University Park LOS ANGELES, CALIFORNIA 90089 1695 This thesis, w ritten b y \ } J E M £ K u N Q t M U nder the direction o f h. Thesis Com m ittee, an d approved b y a il its members, has been p resen ted to and accepted b y The Graduate School, in partial fu lfillm en t o f requirem ents fo r th e degree o f I N e u t e r Q{ Scifcvxie &ate _ 12 - 17-2001 THESIS COMMITTEE Chiirperson r, s Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGMENTS We are grateful to Dr. Robert Drtrano o f Harbor-UCLA Department of Cardiology for allowing us access to their records of South Bay Heart Watch (SBHW). We also thank Youhanna Ibrahim for interviewing study subjects and for abstraction and management of data from SBHW records. I w ould like to express my gratitude to Dr. Stanley Azen. Dr. Robert Detrano, Dr. Wendy Mack, Dr. Thuy Le. and Terence Doherty for their helpful comments, suggestions and editing throughout the course o f my research and in the preparation o f this manuscript. Special thanks also go to Dr. Stanley Azen for his inspiration and guidance throughout my graduate education and the preparation of this thesis. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ACKNOW LEDGMENTS ii LIST OF TABLES iv LIST OF FIGURES v ABSTRACT vi INTRODUCTION 1 METHODS 3 Subjects and Study Design 3 Procedures and Laboratory Methods 4 Evaluation o f Study Endpoints 4 Statistical Analysis 6 RESULTS 8 Descriptive Statistics 8 Bivariate Risk Group Analyses 10 Stratified Risk Group Analyses 11 Robustness o f Findings 13 DISCUSSION 15 BIBLIOGRAPHY 20 REFERENCES 24 iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES Table Table . Baseline Characteristics o f Diabetics and Non-Diabetic Subjects . Comparison of Incidence Rates for Study Endpoints between Diabetics and Non-diabetic Subjects Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES Figure la. Relative risks o f nonfatal MI or coronary death associated with diabetes status and calcium score risk groups. Figure lb. Relative risks o f nonfatal MI. coronary death. PTCA, CABG. or stroke associated with diabetes status and calcium score risk groups. Figure 2a. Relative risks o f nonfatal MI or coronary death associated with calcium score risk groups. Figure 2b. Relative risks o f nonfatal MI. coronary death. PTCA, CABG, or stroke associated with calcium score risk groups. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ABSTRACT Subjects with diabetes mellitus (DM ) suffer high rates o f coronary heart disease (CHD) events. To examine the association between coronary artery calcium (CAC) and the increased risk o f CHD events in subjects with DM. diabetic and non diabetic subjects underwent risk factor screening, computed tomography for baseline CAC. and were followed clinically for 5.5 + 1.3 years. Cox regression analyses of the CHD bivariate risk relationship of diabetes status and CAC risk groups demonstrated a) for non-diabetics an increasing risk of either endpoint with increasing CAC (p < 0.05). and b) for diabetics an even greater risk o f either endpoint with increasing CAC (p < 0.05). Analysis conducted separately for non diabetics and diabetics indicated that CAC risk groups were significantly associated with either endpoint in non-diabetics (p < 0.05). but not in diabetics. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INTRODUCTION Individuals with diabetes mellitus (DM) suffer a disproportionately higher rate o f coronary heart disease (CHD) events. While microvascular complications o f DM such as retinopathy, nephropathy, and neuropathy adversely affect quality o f life and contribute to morbidity from DM, m acrovascular complications are o f particular concern, since most death associated with DM results directly from myocardial infarction (MI), stroke, and sudden coronary death (1). The age-adjusted relative risk o f CHD death for those with DM is triple that o f the general population (2,3), and those with DM fare poorly after a CHD event such as MI (4), with or without coronary revascularization (5). To compound the problem, standard coronary risk factors do not appear to carry the same significance in those with DM compared to those without DM (6,7), making risk stratification and prevention a difficult and imprecise task. Accurate prospective identification o f those diabetics destined to suffer a CHD event might allow better targeting o f risk reduction efforts and thereby improve clinical outcomes, and could also result in more cost-effective use o f health care expenditures. Pathologic studies have demonstrated a strong correlation between the presence o f coronary calcium and the amount o f atheromatous plaque (8). Computed tomography (CT) is a non-invasive test which estimates coronary atherosclerotic burden, by measuring the extent o f coronary artery calcium (9). Furthermore, CT I Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. calcium scanning predicts subsequent CHD events (9,10). However, no study to date has examined the predictive accuracy o f calcium m easurem ent in persons with DM. The South Bay Heart Watch (SBHW ) is a prospective cohort study designed to test the value o f radiographically detectable coronary calcification for predicting CHD outcomes in high-risk asymptomatic patients. This investigation utilizes data obtained from the SBHW cohort to determine whether CT coronary calcium assessment might be a useful noninvasive means to prospectively distinguish those diabetics who will suffer a CHD event from those who w ill not. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. M ETHODS Subjects and Study Design The study design o f the SBHW has been previously described (11-15). Briefly, the SBHW cohort is comprised o f respondents to a community-based mailing campaign o f letters o f invitation to participate in a research project during the period o f December 1990 and December 1992. The cohort consists o f 1461 asymptomatic subjects > 45 years old with multiple cardiac risk factors (> 10% 8- year risk o f developing coronary heart disease by Framingham risk equation) and without evidence o f coronary heart disease at the tim e o f enrollment. Thirty months after enrollment, 1312 surviving subjects underwent a second medical and risk-factor evaluation including phlebotomy concurrent with CT examinations for coronary calcification. Subjects with ECG evidence o f infarction or a clinical history o f infarction, revascularization or typical angina were excluded. Subjects were classified as having diabetes if the participant had a history o f being on diet or medication for diabetes mellitus, w'ere diagnosed with diabetes during a hospital admission, or had a random blood sugar o f at least 200 mg/dl at the time or recruitment into the cohort. All subjects gave informed consent at the time o f recruitment and again at the time o f repeat risk factor assessment and CT scanning. The Harbor UCLA Research and Education Institute Human Subjects Committee approved this study. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Procedures and Laboratory Methods CT scans were performed within 2 ± 2 days after risk-factor evaluation using an Imatron C-100 scanner. The acquisition protocol consisted o f standardized 6-mm image slices (16) obtained at 80% o f the RR interval during breathold. All subjects were scanned over a bone mineral density phantom (Image Analysis, Columbia Kentucky). All scans were interpreted by a single cardiologist blinded to all clinical outcome and serologic data. The scoring software used was the same as that used for the Multi-Ethnic Study o f Atherosclerosis (MESA). This includes a pixel adjustment which uses the formula: new pixel value = (old pixel value - intercept)/slope, where slope and intercept refer to the results o f a least-squares linear fit relating standard radiographic densities to the measured mean CT numbers in the calibration phantom scanned under the subjects. The coronary calcium score was calculated according to the method o f Agatston (17). Evaluation of Study Endpoints Subjects were contacted every year for 7 years after CT examinations. At that time, coronary heart disease was assessed using questions concerning intervening hospital admissions. Medical records were obtained and reviewed for any hospitalization related to a complaint o f chest discomfort, dyspnea, vascular or cardiac problems or admissions for major cardiac or non-cardiac surgeries. We considered a follow-up attempt successful when surviving subjects either returned to the clinic or completed a telephone interview and all relevant medical records were 4 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. obtained. For deceased subjects, we defined successful follow-up as the procurement o f relevant medical records, transcribed conversation with the next o f kin, death certificate or autopsy report. A committee o f three board-certified cardiologists reviewed medical records and transcripts o f conversations with next o f kin, without knowledge o f other data and applied majority rule to determine the occurrence o f the primary end points myocardial infarction or coronary death. Secondary endpoints o f coronary revascularization with either coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PTCA) as well as stroke were likewise ascertained. We defined myocardial infarction (MI) as the presence o f two o f the following three factors: a) prolonged chest pain prompting hospital admission, b) diagnostic evolutionary ECG changes, and c) elevation o f serum creatine kinase to twice the upper limits o f normal or a positive serum creatine kinase MB fraction or Troponin. The research team confirmed all deaths with transcriptions of conversations with next o f kin, medical records or death certificates. The committee reviewing medical records considered coronary heart disease death to have occurred if the death a) was proved to be due to coronary atherosclerosis by autopsy, b) occurred within 1 hour after the onset o f prolonged severe chest pain, and occurred suddenly in a subject for whom there was no other known cause, or c) occurred during hospital 5 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. admission for acute myocardial infarction. The committee considered stroke to be present if there was a persistent neurological deficit (> 48 hours) with corroborative imaging evidence by computed tom ography or magnetic resonance imaging. Coronary revascularization with either coronary artery bypass surgery or percutaneous coronary intervention was ascertained by review o f operative and cardiac catheterization reports. Statistical Analysis Two study endpoints were defined. The primary' endpoint was the occurrence o f nonfatal MI or coronary death; the secondary' endpoint was the occurrence o f nonfatal MI, coronary death, PTCA, CABG or stroke. Baseline characteristics were com pared between diabetic and non-diabetic groups using independent Student t-tests or Wilcoxon rank sum tests for continuous variables (depending on the normality o f the distributions) and chi-square tests for discrete variables. Baseline factors found to be significantly different between the groups, as well as factors recognized as risk factors for cardiac events, were used as covariates in subsequent analyses. Cox regression analyses were utilized to estimate the covariate-adjusted hazard rate ratios o f the calcium score risk groups for each o f the study endpoints. Calcium score risk groups were determ ined according to tertiles o f the distribution o f calcium scores using the subgroup o f non-diabetic subjects without any coronary event (i.e., the secondary endpoint). Cox regression analyses were initially 6 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. conducted for 6 risk groups defined by a) diabetes status (non-diabetic, diabetic) and b) calcium score risk groups (low, medium, high). In addition, Cox regression analyses were also utilized to evaluate the interaction o f diabetes status with the calcium score risk groups. If significant interactions were found, Cox regression analyses were then conducted separately for non-diabetics and diabetics to determine the prognostic utility o f the 3 calcium score risk groups within each subgroup o f study participants. Finally, to evaluate the robustness o f the findings, analyses were repeated for calcium score risk groups determined according to tertiles o f the distribution o f calcium scores using the full cohort (diabetics and non-diabetics) without any coronary event. All analyses were conducted at the 0.05 significance level, and utilized SAS (Cary, North Carolina). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. RESULTS Descriptive Statistics O f the 1312 subjects in the study cohort with CT scans, 1157 (88.2%) were males and 155 (11.8%) were females; 269 (20%) suffered from diabetes and 1043 (80%) were diabetes-free. The average age was 65 years (range = 47 to 90 years). Table 1 contrasts baseline characteristics between diabetic and non-diabetic subjects. Proportionately more non-diabetic subjects were males and current alcohol drinkers (p < 0.0001). No significant differences were found for age, smoking status, and exercise (p > 0.05). Diabetic subjects had significantly greater body mass indices, systolic blood pressure, and triglyceride levels (p < 0.005), whereas non diabetic subjects had significantly higher levels o f total cholesterol and HDL- cholesterol (p < 0.005). The coronary calcium score for diabetic subjects was statistically significantly greater than that for non-diabetic subjects (p < 0.0001). Based on these results, all subsequent analyses controlled for the following risk factors: age, gender, body mass index, smoking status, alcohol consumption, exercise, systolic blood pressure, cholesterol, HDL-cholesterol, and triglyceride levels. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 1. Baseline Characteristics o f Diabetics and N on-D iabetic Subjects. Characteristic Non-diabetics* (n = 1043) Diabetics* (n = 269) P-valuet Gender: M ale 939 (90.0% )’ 218 (81.0% ) <0.0001 Age (years) 6 5 .2 (7 .8 )" 65.9 (7.4) 0.18 Body Mass Index 27.4 (4.5) 28.8 (4.9) <0.0001 Sm oking History Current sm oker 284 (27.2% ) 6S (25.3% ) 0.41 Form er sm oker 535 (51.3% ) 150(55.8% ) N on-sm oker 224(21.5% ) 51 (19.0% ) Alcohol Usage 656(63.7% ) 104 (38.8% ) <0.0001 Exercise Regularly 676 (68.6% ) 1 7 0(63.1% ) 0.66 Systolic BP (mm Hg) 141.0(19.8) 145.1 (21.3) 0.003 Cholesterol (m g d L ) 231.7(41.4) 2 2 0 .7 (5 0 .1 ) 0.0002 HDL-Cholesterol 46.2(15.6) 4 0 .6 (1 4 .1 ) <0.0001 Triglycerides (m g dL) 171.7(124.9) 2 1 5 .0 (2 2 0 .5 ) <0.0001 Calcium Score 4 7.7(0.00, 254.2) 104.7 (9 .4 , 433.3) <0.0001 * Discrete variables expressed as frequency (percent), continuous variables expressed as m ean (SD). Calcium score expressed as median (25th, 75th quartile range) t Statistical testing utilized two-sam ple t-tests (for continuous variables), chi-square tests ( for discrete variables), and the VVilcoxon rank sum test for the calcium score. T able 2. C o m p a riso n o f Incidence R ates for S tudy E n d p o in ts b e tw e e n D iabetics and N o n -d iab e tic Subjects. Endpoint* Study Group Incidence rate (% ) Relative Risk* 95% Cl P-valuet Primary Non-Diabetics 54/1043 (5.1% ) 1.00 — — Diabetics 36/269 (13.4% ) 2.10 1.33- <0.0001 Secondary Non-Diabetics 105/1043(10.1% ) 1.00 — — Diabetics 52/269 (19.3% ) 1.56 1.09- <0.0001 * The prim ary endpoint was the occurrence o f nonfatal MI o r coronary death; the secondary endpoint was the occurrence o f nonfatal MI, coronary death, PTC A , CABG or stroke. t Cox regression analyses, controlling for age, gender, body m ass index, smoking status, exercise, alcohol consumption, systolic blood pressure, cholesterol, HDL-cholesterol, and triglycerides. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. There were a total o f 90 primary events (54 in the non-diabetic group, 36 in the diabetic group), and 157 secondary events (105 in the non-diabetic group, 52 in the diabetic group). Table 2 contrasts the between-group incidence rates for the primary and secondary endpoints. After adjusting for risk-factor covariates, statistically significant differences between diabetics and non-diabetics were found for both study endpoints (p < 0.001). The incidence rate for the prim ary endpoint for diabetic vs. non-diabetic subjects w ras 13.4% vs. 5.1% (relative risk = 2.10, 95% confidence interval = 1.33 - 3.30). The incidence rate for the secondary endpoint for diabetic vs. non-diabetic subjects was 19.3% vs. 10.1% (relative risk = 1.56, 95% confidence interval = 1.09 - 2.22). Bivariate Risk Group Analyses Based on the group o f non-diabetic subjects without any coronary event (secondary endpoint), risk groups for the calcium scores were defined by tertiles as: low (< 2.8), medium (2.8 to 123.9), and high (> 123.9). Figures la and lb presents the risk-factor adjusted RRs for the primary and secondary endpoints according to bivariate risk groups defined by calcium score risk groups and diabetes status. Relative to the low-risk group baseline category (low calcium score and non diabetic), there was increasing risk o f the primary endpoint (Figure la) for non diabetics in the high calcium score group (RR = 2.9, p = 0.006). For diabetics, this risk increased linearly across calcium score risk groups (RR = 3.2, 4.6 and 5.0 for low, medium and high calcium score risk groups, respectively, all p < 0.05). For the 10 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. secondary endpoint (Figure lb), relative to the baseline category, there was increasing risk o f the secondary endpoint for non-diabetics for both the medium and high calcium score groups (RR = 2.0 and 3.6, p < 0.02). For diabetics, this risk increased linearly across the medium and high calcium score risk groups (RR = 3.9 and 5.1 for medium and high calcium score risk groups, both p < 0.001). Stratified Risk Group Analyses Multivariate Cox regression analysis for the entire cohort (diabetic and non diabetic groups) demonstrated a significant interaction between diabetes status and the calcium score (p < 0.01 for the primary endpoint, p = 0.06 for the secondary endpoint). These findings justify conducting stratified analyses separately for non diabetics and for diabetics in order to evaluate the risk relationships across calcium score risk groups. Figure 2a presents for the non-diabetic and diabetic groups the risk-factor adjusted RR’s for the primary endpoint across calcium score risk groups. For the non-diabetic group, after adjusting for baseline risk factors, the high calcium score risk group was significantly associated with the primary endpoint (RR = 3.1, p = 0.004). In contrast, the calcium score risk groups were not significantly related to the prim ary endpoint for the diabetic group (R R ’s < 1.5, all p > 0.46). Figure 2b presents for the non-diabetic and diabetic groups the risk-factor adjusted relative risks for the secondary endpoint across calcium score risk groups. After adjusting for baseline risk factors, the medium and high calcium score risk 11 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. F ig u re la. R elativ e risks o f n o n fa ta l M I o r co ronary d e a th a s so c ia te d w ith d ia b e te s sta tu s an d ca lc iu m sc o re risk g ro u p s: low (< 2.8), m e d iu m (2 .8 to 123.9), a n d h ig h (> 123.9). Diabetic Non-diabetic Calcium Score F ig u re lb. R elative risks o f n o n fata l M I, co ro n ary death, P T C A , C A B G , o r stro k e asso cia te d w ith d ia b e te s sta tu s an d calcium sc o re ris k gro u p s: low (< 2.8), m ed iu m (2.8 to 123.9), an d h igh (> 123.9). F<nn Calcium Score 1 2 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. group were significantly associated with the secondary endpoint for the non-diabetic group (RR = 2.0, p = 0.03 and RR = 3.7, p < 0.0001, respectively). In contrast, the calcium score risk groups w ere not significantly related to the secondary endpoint for the diabetic group (RR < 1.84, p > 0.17). R o b u s tn e s s o f F in d in g s To evaluate the robustness of the findings, statistical analyses were redone for calcium score risk groups determined according to tertiles o f the distribution of calcium scores using the full cohort. Risk groups were: low (< 4.1), medium (4.1 to 150.4), and high (> 150.4). Relative risk relationships were similar. For the primary endpoint, the RR’s for the original vs. the alternative calcium score risk groups in non-diabetics were: medium (R R = 1.1 vs. 1.3) and high (RR = 3.2 vs. 3.3). For non-diabetics, the relationships were: medium (RR = 1.1 vs. 1.1), high (RR = 1.9 vs. 1.5). For the secondary endpoint, the RR’s for the original vs. the alternative calcium score risk groups in non-diabetics were: medium (RR = 2.0 vs. 2.3) and high (RR = 3.4 vs. 4.0). For non-diabetics, the relationships were: medium (RR = 1.4 vs. 1.4), high (RR = 1.6 vs. 1.8). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. F ig u re 2a. R elative risk s o f n o n fa ta l M I o r co ronary d ea th a s so c ia te d w ith calcium score risk groups: lo w (< 2.8), m ed iu m (2.8 to 1 23.9), an d h ig h (> 123.9), stratified by d ia b ete s sta tu s. Diabetic Calcium Score F ig u re 2b. R elative risks o f n o n fa ta l M I, c o ro n a ry death, P T C A , C A B G , o r stroke asso ciated w ith c a lc iu m sc o re risk groups: low (< 2 .8 ), m e d iu m (2.8 to 123.9), an d high (> 123.9), stratified by d iab etes sta tu s. Diabetic Non-diabetic Calcium Score Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DISCUSSION DM is a major global health concern, and most death and disability associated with DM results from macrovascular disease (1). The pathobiologic substrate for these is coronary atherosclerosis, which can be identified with a high degree o f sensitivity by radiographic detection o f coronary calcium deposits (8,9). O ur investigation sought to determine whether coronary calcium assessm ent with CT might be useful to prospectively identify those with DM who w ere destined to have a CHD event. If so, these individuals could be targeted for aggressive preventive measures, and the enormous fiscal burden o f DM might then be more cost- effectively directed. We report here seven-year clinical follow-up on a prospective cohort comparing subjects with DM and those without DM who underwent CHD risk factor assessment and calcium scanning with electron beam CT on enrollment. We found that CT calcium scores were significantly greater in those with compared to those without DM (p < 0.0001). Subjects with DM suffered clinical events at roughly twice the rate as those without DM for both prim ary (death, MI) and secondary (death, MI, revascularization, CVA) endpoints. A fter adjusting for the effects o f coronary risk factors, coronary calcium score was significantly associated with the occurrence o f both primary and secondary endpoints in subjects without DM. However, in diabetic subjects, there was no significant relationship observed between baseline CT calcium scores and the subsequent occurrence o f either primary Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. or secondary endpoints. Our analysis o f the interaction term dem onstrates that the prognostic power o f CT calcium scores is less in those with DM. Determ ination of relative risks after readjusting the tertile cut points using the entire cohort yielded similar results, indicating the robustness o f our findings. In part, our results appear consistent with current understanding o f the pathobiology o f atherosclerosis, thought to be accelerated in the m etabolic milieu o f diabetes. Consistent with this notion, our subjects with DM had roughly twice as much coronary calcium as those without DM, and suffered adverse clinical endpoints roughly twice as frequently. O ur findings o f increased prevalence o f coronary calcium in diabetic subjects are in accordance with the recently reported findings o f a smaller retrospective observational study (18). It is probable that atherosclerosis progressed more rapidly in those with DM, and the amount o f coronary calcium would be expected to change accordingly. But while this may in part account for the high event rate we observed in diabetics, it does not explain why the relationship between CT calcium score and events was not significant in subjects w ith DM. Accelerated atherogenesis in DM does not appear to be sim ply a result o f elevated glucose, dyslipidemia, hypertension, and obesity, though these certainly contribute (6,7). There are indications that in those with DM, the course o f atherosclerosis is particularly malignant, however the reasons why this is so remain obscure. Recent studies have suggested that enhanced inflam m atory signaling mediated by advanced glycation endproducts (AGEs) and related ligands through 16 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. cell-surface receptors may importantly accelerate atherogenesis in DM, whether glucose levels are controlled or not (19-21). Co-morbid conditions associated with DM are also likely to exert some negative influence. We did not assess the effects o f microvascular complications; therefore the impact o f such co-morbidities on our results cannot be determined. Further studies are necessary to elucidate these complex interrelationships. It is possible that some o f the calcium in our diabetic subjects was not associated with atherosclerosis. Calcification o f the arterial media has long been known to be highly prevalent in those with DM (22). This type o f calcium deposition (M onckeberg’s calcinosis) is thought to be distinct from the mostly intimal calcification seen in the setting o f atherosclerosis, frequently occurs in arteries without intimal plaque, and is most often noted in the peripheral and visceral arteries. Medial calcification has not been reported to occur in the coronary arteries, but since CT cannot distinguish medial from intimal calcification, we cannot rule out the possibility that some o f the calcification we observed in our diabetic subjects was o f this type. However, in a prospective study with 7 years’ follow-up, Mehto and colleagues found that medial calcification o f the femoral artery in diabetics was a predictor o f cardiovascular and CHD mortality and morbidity independently o f CHD risk factors and regardless of glycemic control (23). Therefore, it seems reasonable to expect that any possible medial calcification o f the coronary arteries in our diabetic subjects would similarly be expected to strengthen, rather than weaken, the relationship between calcium and outcome. 17 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. It is also conceivable that there were differences in the relative proportions of specific plaque components other than calcium in our diabetic and non-diabetic subjects, and this might at least in part explain our finding. In recent years, it has been revealed that plaque disruption is the proximate cause o f the great proportion of CHD events (24-26). The propensity o f plaques to rupture is unrelated to the extent o f luminal narrowing, but appears instead to be determined more by the specific features o f plaque composition (27). In DM, coronary arterial compensatory remodeling (28) and distensibility (29) are impaired, and a study o f coronary atherectom y specimens found that diabetic patients plaques had more lipid, greater macrophage infiltration, and more frequent overlying thrombus compared to patients without DM (30). We suggest that our results might be most consistent with the notion that DM somehow alters plaque composition in such a way that it is rendered less stable. Calcium is one plaque component that has been hypothesized to render plaques more stable (9,31); it could be that the relative proportion o f calcium compared to total plaque was similar, but the relative proportions o f other features such as lipid pools that could tend to destabilize plaques might have been increased in diabetic subjects. However, our study did not evaluate plaque composition or stability directly, and thus this notion remains speculative. Some investigators have suggested that CT calcium scanning in asymptomatic populations is justified, however the benefit o f such an approach is controversial (8,9,32). Our findings here demonstrate a significant relationship 18 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. between CT calcium score and subsequent events, however that relationship is significantly different and o f lesser magnitude in those individuals with DM. Since after adjusting for the effects o f coronary risk factors we found no significant relationship between calcium score and either prim ary or secondary endpoints in diabetics, we conclude that CT coronary calcium scanning in subjects with DM for the purpose o f coronary risk stratification will not yield clinically beneficial prognostic data. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. BIBLIOGRAPHY 1. Haffner SM. Coronary heart disease in patients w ith diabetes. N Engl J Med. 2000 6;342:1040-1042. 2. Haffner SN, Lehto S, Ronnemma T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without myocardial infarction. N Engl J Med. 1998;339:229-234. 3. Sowers JR, Epstein M. Risk factors for arterial disease in diabetes: hypertension. In: Tooke JE, ed. Diabetic Angiopathy. London, UK: Arnold Publishers; 1000:45-63. 4. Paty BW. Managing myocardial infarction in the diabetic patient. Endocrinol Metab Clin North Am. 2000;29:831-842. 5. Brooks RC, Detre KM. Clinical trials o f revascularization therapy in diabetics. Curr Opin Cardiol. 2000;15:287-292. 6. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetes in the Framingham population: sixteen-year follow-up study. Diabetes. 1974;23:105-111. 7. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors and 12-year cardiovascular m ortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;263:2335-2340. 8. Detrano RC, Doherty TM, Davies MJ, Stary HC. Predicting coronary events with coronary calcium: pathophysiologic and clinical problems. Curr Probl Cardiol. 2000;25:374-402. 9. O'Rourke RA, Brundage BH, Froelicher VF, Greenland P, Grundy SM, Hachamovitch R, et al. American College of Cardiology/American Heart Association Expert Consensus document on electron-beam computed tomography for the diagnosis and prognosis o f coronary artery disease. Circulation. 2000; 102:126-140. 10. O'Malley PG, Taylor AJ, Jackson JL, et al. Prognostic value of coronary electron-beam computed tom ography for coronary heart disease events in asymptomatic populations. Am J Cardiol. 2000;85:945-8. 20 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 11. Detrano RC, Wong ND, Doherty TM, Shavelle RM, Tang W, Ginzton LE, Budoff MJ, Narahara KA. Coronary calcium does not accurately predict near-term future coronary events in high-risk adults. Circulation. 1999;99:2633-2638. 12. Detrano RC, Wong ND, French WJ, Tang W, Georgiou D, Young E, Brezden OS, Doherty TM , Brundage BH. Prevalence o f fluoroscopic coronary calcific deposits in high-risk asymptomatic persons. Am Heart J. 1994;127:1526-1532. 13. Detrano RC, Wong ND, Tang W, French WJ, Georgiou D, Young E, Brezden OS, Doherty TM , Narahara KA, Brundage BH. Prognostic significance o f cardiac cinefluoroscopy for coronary calcific deposits in asymptomatic high risk subjects. J Am Coll Cardiol. 1994;24:354-358. 14. Detrano RC, Wong ND, Doherty TM, Shavelle R. Prognostic significance of coronary calcific deposits in asymptomatic high-risk subjects. Am J Med. 1997;102:344-349. 15. Secci A, Wong N, Tang W, Wang S, Doherty T, Detrano R. Electron beam computed tomographic coronary calcium as a predictor o f coronary events: comparison o f two protocols. Circulation. 1997;96:1122-1129. 16. Wang S, et al. Detection o f coronary calcification with electron beam computed tomography: evaluation o f inter-examination reproducibility and comparison o f three image acquisition protocols. Am Heart J. 1996; 132:550- 558. 17. Agatston AS, et al. Quantification o f coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827-832. 18. Schmidt AM, Hofmann M, Taguchi A, Yan SD, Stem DM. RAGE: a multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation. Semin Thromb Hemost. 2000;26:485-493. 19. Schurgin S, Rich S, M azzone T. Increased prevalence o f significant coronary artery calcification in patients with diabetes. Diabetes Care. 2001 Feb;24(2):335-8. 20. Schmidt AM, Stem DM. RAGE: a new target for the prevention and treatment o f the vascular and inflammatory complications o f diabetes. Trends Endocrinol Metab. 2000; 11:368-375. 21 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 21. Schmidt AM. Yan SD. Stem DM. The dark side o f glucose. Nat Med. 1995;1:1002-1004. 22. Edmonds ME. Medial arterial calcification and diabetes mellitus. Z Kardiol. 2000:89 Suppl 2:101-104. 23. Mehto S, Niskanen L. Suhonen M. Ronnemaa T. Laakso M. Medial artery calcification. A neglected harbinger of cardiovascular complications in non insulin-dependent diabetes mellitus. Arterioscler Thromb Vase Biol. 1996;16:978-983. 24. Fuster V. Fayad ZA. Badimon JJ. Acute coronary syndromes: biology. Lancet. 1999:353 Suppl 2:SII5-S119. 25. Davies MJ. Going from im mutable to mutable atherosclerotic plaques. Am J Cardiol. 2001 ;88(Suppl 4):2F-9F. 26. Felton CV. Crook D. Davies MJ. Oliver MF. Relation o f plaque lipid composition and morphology to the stability o f human aortic plaques. Arterioscler Thromb Vase Biol. 1997:17:1337-1345. 27. Davies MJ. The composition o f coronary-artery plaques. N Engl J Med. 1997:336:1312-1314. 28. Vavuranakis M. Stefanadis C. Toutouzas K, Pitsavos C. Spanos V, Toutouzas P. Impaired compensatory coronary artery enlargement in atherosclerosis contributes to the development o f coronary artery stenosis in diabetic patients. An in vivo intravascular ultrasound study. Eur Heart J. 1997:18:1090-1094. 29. Vavuranakis M. Stefanadis C, Triandaphyllidi E, Toutouzas K, Toutouzas P. Coronary artery distensibility in diabetic patients with simultaneous measurements o f luminal area and intracoronary pressure: Evidence o f impaired reactivity to nitroglycerin. J Am Coll Cardiol. 1999;34:1075-1081. 30. Moreno PR, Murcia AM, Palacios IF, Leon MN, Bemardi VH, Fuster V, Fallon JT. Coronary com position and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus. Circulation. 2000:102:2180- 2184. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 31. Doherty TM. Detrano RC. Mautner SL. Mautner GC, Shavelle R. Coronary calcium: The good, the bad. and the uncertain. Am Heart J. 1999; 137:806- 814. 32. Taylor AJ. O'Malley PG. Self-referral o f patients for electron-beam computed tomography to screen for coronary artery disease. N Engl J M ed. 1998:339:2018-2020. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES Agatston AS. et al. Quantification o f coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827-832. Brooks RC. Detre KM. Clinical trials o f revascularization therapy in diabetics. Curr Opin Cardiol. 2000;15:287-292. Davies MJ. Going from immutable to mutable atherosclerotic plaques. Am J Cardiol. 2001 ;88(Suppl 4):2F-9F. Davies MJ. The composition o f coronary-artery plaques. N Engl J Med. 1997:336:1312-1314. Detrano RC. Doherty TM. Davies MJ, Starv HC. Predicting coronary events with coronary calcium: pathophysiologic and clinical problems. Curr Probl Cardiol. 2000;25:374-402. Detrano RC, Wong ND, Doherty TM, Shavelle R. Prognostic significance of coronary calcific deposits in asymptomatic high-risk subjects. Am J Med. 1997:102:344-349. Detrano RC, Wong ND. Doherty TM. Shavelle RM, Tang W, Ginzton LE, Budoff MJ. Narahara KA. Coronary calcium does not accurately predict near-term future coronary events in high-risk adults. Circulation. 1999;99:2633-2638. Detrano RC, Wong ND, French WJ, Tang W, Georgiou D, Young E, Brezden OS, Doherty TM. Brundage BH. Prevalence o f fluoroscopic coronary calcific deposits in high-risk asymptomatic persons. Am Heart J. 1994;127:1526-1532. Detrano RC, Wong ND. Tang W, French WJ. Georgiou D, Young E, Brezden OS, Doherty TM, Narahara KA, Brundage BH. Prognostic significance o f cardiac cinefluoroscopy for coronary calcific deposits in asymptomatic high risk subjects. J Am Coll Cardiol. 1994;24:354-358. Doherty TM. Detrano RC, M autner SL, M autner GC, Shavelle R. Coronary calcium: The good, the bad, and the uncertain. Am Heart J. 1999;137:806-814. Edmonds ME. Medial arterial calcification and diabetes mellitus. Z Kardiol. 2000;89 Suppl 2:101-104. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Felton CV. Crook D, Davies MJ, Oliver MF. Relation o f plaque lipid composition and morphology to the stability o f human aortic plaques. Arterioscler Thromb Vase Biol. 1997;17:1337-1345. Fuster V, Fayad ZA. Badimon J J. Acute coronary syndromes: biology. Lancet. 1999:353 Suppl 2:SI15-S 119. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetes in the Framingham population: sixteen-year follow-up study. Diabetes. 1974:23:105-111. Haffner SM. Coronary heart disease in patients with diabetes. N Engl J Med. 2000 6:342:1040-1042. Haffner SN. Lehto S. Ronnemma T. Pyorala K. Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without myocardial infarction. N Engl J Med. 1998:339:229-234. Mehto S. Niskanen L, Suhonen M. Ronnemaa T, Laakso M. Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin- dependent diabetes mellitus. Arterioscler Thromb Vase Biol. 1996;16:978-983. Moreno PR. Murcia AM. Palacios IF, Leon MN, Bemardi VH, Fuster V, Fallon JT. Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus. Circulation. 2000:102:2180-2184. O'M alley PG. Taylor AJ, Jackson JL. et al. Prognostic value o f coronary electron- beam computed tomography for coronary heart disease events in asymptomatic populations. Am J Cardiol. 2000;85:945-8. O'Rourke RA. Brundage BH, Froelicher VF, Greenland P, Grundy SM, Hachamovitch R. et al. American College o f Cardiology/American Heart Association Expert Consensus document on electron-beam computed tomography for the diagnosis and prognosis o f coronary artery disease. Circulation. 2000;102:126-140. Paty BW. Managing myocardial infarction in the diabetic patient. Endocrinol Metab Clin North Am. 2000:29:831-842. Schmidt AM, Hofmann M, Taguchi A. Yan SD. Stem DM. RAGE: a multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation. Semin Thromb Hemost. 2000;26:485-493. 25 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Schmidt AM, Stem DM. RAGE: a new target for the prevention and treatment of the vascular and inflammatory complications o f diabetes. Trends Endocrinol Metab. 2000:11:368-375. Schmidt AM, Yan SD, Stem DM. The dark side o f glucose. Nat Med. 1995; 1:1002- 1004. Schurgin S, Rich S. M azzone T. Increased prevalence o f significant coronary artery calcification in patients w ith diabetes. Diabetes Care. 2001 Feb;24(2):335-8. Secci A, Wong N, Tang W. Wang S. Doherty T. Detrano R. Electron beam computed tomographic coronary calcium as a predictor o f coronary events: comparison o f two protocols. Circulation. 1997:96:1122-1129. Sowers JR, Epstein M. Risk factors for arterial disease in diabetes: hypertension. In: Tooke JE, ed. Diabetic Angiopathy. London, UK: Arnold Publishers; 1000:45-63. Stamler J, Vaccaro O. N eaton JD, Wentworth D. Diabetes, other risk factors and 12- year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;263:2335-2340. Taylor AJ, O'Malley PG. Self-referral o f patients for electron-beam computed tomography to screen for coronary artery disease. N Engl J Med. 1998:339:2018- 2020. Vavuranakis M, Stefanadis C, Toutouzas K, Pitsavos C, Spanos V, Toutouzas P. Impaired compensatory coronary artery enlargement in atherosclerosis contributes to the development o f coronary artery stenosis in diabetic patients. An in vivo intravascuiar ultrasound study. Eur Heart J. 1997:18:1090-1094. Vavuranakis M, Stefanadis C, Triandaphyllidi E, Toutouzas K, Toutouzas P. Coronary artery distensibility in diabetic patients with simultaneous measurements o f luminal area and intracoronary pressure: Evidence o f impaired reactivity to nitroglycerin. J Am Coll Cardiol. 1999;34:1075-1081. Wang S, et al. Detection o f coronary calcification with electron beam computed tomography: evaluation o f inter-examination reproducibility and comparison o f three image acquisition protocols. Am Heart J. 1996;132:550-558. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

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Creator Qu, Wenchun (author)

Core Title Predictive value of CT coronary artery calcium scanning for coronary heart disease in asymptomatic subjects with diabetes mellitus

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag biology, biostatistics,health sciences, public health,health sciences, radiology,OAI-PMH Harvest

Language English

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Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-292382

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Legacy Identifier 1411036.pdf

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Document Type Thesis

Rights Qu, Wenchun

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...

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