William Davis, MD, FACC, 1 * Susie Rockway, PhD, CNS, 2 and Mary Kwasny, ScD 3

Transcription

1 American Journal of Therapeutics 16, (2009) Effect of a Combined Therapeutic Approach of Intensive Lipid Management, Omega-3 Fatty Acid Supplementation, and Increased Serum 25 (OH) Vitamin D on Coronary Calcium Scores in Asymptomatic Adults William Davis, MD, FACC, 1 * Susie Rockway, PhD, CNS, 2 and Mary Kwasny, ScD 3 The impact of intensive lipid management, omega-3 fatty acid, and vitamin D3 supplementation on atherosclerotic plaque was assessed through serial computed tomography coronary calcium scoring (CCS). Low-density lipoprotein cholesterol reduction with statin therapy has not been shown to reduce or slow progression of serial CCS in several recent studies, casting doubt on the usefulness of this approach for tracking atherosclerotic progression. In an open-label study, 45 male and female subjects with CCS of $ 50 without symptoms of heart disease were treated with statin therapy, niacin, and omega-3 fatty acid supplementation to achieve low-density lipoprotein cholesterol and triglycerides #60 mg/dl; high-density lipoprotein $60 mg/dl; and vitamin D3 supplementation to achieve serum levels of $50 ng/ml 25(OH) vitamin D, in addition to diet advice. Lipid profiles of subjects were significantly changed as follows: total cholesterol 224%, low-density lipoprotein 241%; triglycerides 242%, high-density lipoprotein +19%, and mean serum 25(OH) vitamin D levels +83%. After a mean of 18 months, 20 subjects experienced decrease in CCS with mean change of 214.5% (range 0% to 264%); 22 subjects experienced no change or slow annual rate of CCS increase of +12% (range 1% 29%). Only 3 subjects experienced annual CCS progression exceeding 29% (44% 71%). Despite wide variation in response, substantial reduction of CCS was achieved in 44% of subjects and slowed plaque growth in 49% of the subjects applying a broad treatment program. Keywords: CT heart scan, calcium score, coronary disease, regression, vitamin D, omega-3 fatty acids INTRODUCTION Coronary calcium scoring (CCS) obtained through computed tomography (CT) heart scanning can be 1 Milwaukee Heart Scan, Milwaukee, WI; 2 Department of Clinical Nutrition; and 3 Department of Community and Mental Health Nursing and Department of Health Systems Management, Rush University Medical Center, Chicago, IL. Financial support: None. Conflicts of interest: None. *Address for correspondence: 2600 North Mayfair Road, Suite 950, Wauwatosa, WI heartprotection@aol.com used as a surrogate measure of total coronary atherosclerotic plaque burden having been validated through correlations with postmortem examination of explanted coronary arteries 1,2 carotid intimal-medial thickness, aortic calcification; ankle brachial index 3,4 ; coronary angiography; and intravascular ultrasound. 5 7 CCS has also been shown to predict coronary events after correction for conventional coronary risk factors and Framingham risk scoring Serial studies using carotid intimal-medial thickness 12 and coronary angiography 13 have shown that progression of atherosclerotic disease burden predicts heightened risk for coronary events, that is, the greater the growth in atherosclerotic plaque burden the greater Ó 2009 Lippincott Williams & Wilkins

2 Effect of Combined Therapeutic Approach on Coronary Calcium Scores in Asymptomatic Adults 327 the likelihood of coronary events. Thus, tracking the burden of coronary atherosclerotic disease may identify persons at greater risk for cardiovascular events. CCS has been shown to increase by 22% 52% per year in patients without treatment. 14 Raggi et al 15 have also shown that greater increases in serial CCS predict higher risk for cardiovascular events compared with those with smaller increases in coronary calcium score. Serial CCS using CT heart scanning has therefore been proposed for tracking progression of atherosclerotic plaque. However, results from several recent trials have raised doubt over whether this surrogate measure of plaque burden responds to cholesterol-reducing efforts and suggest that low-density lipoprotein (LDL) cholesterol reduction alone may be insufficient to arrest or reduce coronary atherosclerotic plaque when measured by CCS. Because few studies have examined the impact of a broader therapeutic approach on plaque, we report our experience in slowing the progression of serial CCS by using a broad treatment approach that extends beyond reduction of LDL cholesterol. METHODS In this retrospective chart review, we reviewed data from 45 consecutive patients with subclinical coronary atherosclerotic plaque identified by CT heart scanning who met our inclusion criteria and presented in the 34-month interval between January 2005 and October The analysis was deemed exempt from formal review by our local institutional review board. All participants were seen in an outpatient private practice cardiology clinic. Treatment goals were to reduce plasma LDL cholesterol to #60 mg/dl, similar to the ASTEROID Trial 16 in which LDL was reduced to 61 mg/dl with rosuvastatin, 40 mg, and resulted in 7% reduction of total atheroma volume by intracoronary ultrasound in a substantial number of participants; increasing high-density lipoprotein (HDL) to $60 mg/dl 17 ; and reducing triglycerides (TG) to #60 mg/dl, a level that predicts maximal reduction of TG-containing lipoproteins. 18 All patients were counseled to consume a high-fiber, low saturated fat, and low glycemic index diet, consistent with the National Cholesterol Education Program Therapeutic Lifestyle Change recommendations. 19 Patients initially supplemented their diet with 2000 IU of vitamin D3 (cholecalciferol per day) and increased as needed to achieve a serum level of 25(OH) vitamin D of ng/ml when assessed at follow-up at 6-month intervals; a range of ,000 mg over-the-counter fish oil softgels (providing a minimum of 180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid per capsule) were supplemented as required to achieve the TG target value. 23 We analyzed pre- and post-plasma lipid values and CCS from patients who followed this program. All subjects underwent initial and final CT heart scans between January 2005 and October 2007 at several sites in the Milwaukee, WI, area. Because of the retrospective design of this analysis, patients were not blinded to their CT heart scan results. Inclusion criteria were as follows: (1) a CT heart scan coronary calcium score (Agatston) of $ 50; (2) plasma lipid, glucose and 25(OH) vitamin D measures within 60 days of an initial enrollment CT heart scan; (3) a follow-up CT heart scan 6 months or more after the initial scan; (4) plasma lipids, glucose, and 25(OH) vitamin D within 60 days of the repeat CT heart scan; and (5) self-reported adherence with the recommended treatment program. Exclusion criteria included prior angioplasty, coronary stents, or coronary bypass surgery, congestive heart failure, and any active symptom attributable to heart disease, active liver disease, renal insufficiency (defined as creatinine. 1.2 mg/dl), or other active systemic illness. CT scans were performed on either an Imatron C-150 electron beam scanner or 16 or 64-slice Philips or Siemens multidetector CT scanners (with pre- and postscans performed on the same devices), with calcium scoring as per the method of Agatston et al. 24 All scoring was performed by trained readers with no knowledge of each subject s participation in this analysis. Annualized rate of change of the calcium score was calculated by applying the following equation based on calculating the rate of return using continuous compound interest: Annual rate of plaque growth ðapgþ ¼ ðscore 2=score 1Þ 1=t 1 Result multiplied by 100 to yield a percent. score 1 represents the first heart scan score, score 2 the second score, and t the amount of time between the 2 scans expressed in years in decimal form. Lipid testing was performed in local clinical laboratories with LDL cholesterol calculated as per the Friedewald equation. Serum 25(OH) vitamin D levels were obtained through assays employing liquid chromatography in tandem with mass spectrometry in local clinical laboratories. Smoking was defined as any smoking within the past year before the beginning of the period of study. Metabolic syndrome was defined according to the criteria set by National Cholesterol Education Program Adult Treatment Panel-III Diabetes was defined American Journal of Therapeutics (2009) 16(4)

3 328 Davis et al as 2 fasting blood sugars of 126 mg/dl or greater, a history of diabetes, or current oral hypoglycemic or insulin use. Hypertension was defined as a history of hypertension, current use of antihypertensive medication, or two seated blood pressures.140/90 mm Hg at the start of the program. Descriptive statistics include counts and percentages for nominal variables and means, SD, and medians for continuous variables. Paired t tests and Wilcoxon Signed Rank tests were used to compare initial lipid values, 25(OH) vitamin D, and CCS with final levels depending on assumptions of normality. The x 2 independent t tests, or Mann Whitney tests were used to compare lipid levels and demographic variables between gender groups. Spearman rank correlation was used to determine if there were any dose effect noticed between outcomes and levels of supplements. A P value,0.05 was considered statistically significant. All analyses were performed using SPSS v15, Chicago, IL. RESULTS Baseline clinical and demographic characteristics of the 45 subjects are provided in Table 1. The mean age was years for 35 men and years for 10 women; all subjects were white. There were no gender differences in the baseline demographics except the initial calcium score, which was significantly higher in men (Mann Whitney P = 0.028). The mean intake of vitamin D3 (cholecalciferol) was IU (median 4000 IU; data not shown). Individual doses of fish oil ranged from 4.0 to 10 g /day, depending on the initial TG levels, and averaged 4.8 g/d with a median value of 4.0 g/d (data not shown). About 77% of men and 100% of women received a statin agent (simvastatin, rosuvastatin, atorvastatin, or lovastatin) in the interval between scans 1 and 2; 83% of men and 80% of women received nicotinic acid (extended-release). About 45% of men and 50% of women received an angiotensin-converting enzyme inhibitor (lisinopril, ramipril) or an angiotensin receptor blocker (losartan, valsartan, candesartan, and olemesartan) for hypertension; 14% of men and 10% of women received a beta-blocker (metoprolol or atenolol). Plasma lipid changes are shown in Table 2 segregated by gender. Combined data from men and women showed significant reductions in total cholesterol (248.6 mg/dl), LDL (245.5 mg/dl), and TG (244.7 mg/dl). HDLs were increased significantly only in the men (P, 0.001), while increases in the women (64 vs 75 mg/dl) did not reach statistical significance, likely because of a lack of statistical power; however, the women averaged an 11- mg increase. Both men and women increased plasma levels of 25(OH) vitamin D significantly, achieving levels of 49.5 and 47.2 ng/ml, respectively, and nearly achieved the target goal of 50 ng/ml. Total CCS was not significantly changed when subjects were grouped together or separated by sex as shown in Table 2. However, when subjects were grouped according to their annual rate of CCS change into 3 clinically relevant subgroups, a different picture emerges. Figure 1 shows the number of subjects (n = 3) who had typical progression, that is, progression at.29% annually, vs those (n = 22) who progressed at a slower rate (,29% annually) vs those subjects (n = 20) who did not progress but showed reduced CCS ranging from 0.3% to 64%. DISCUSSION Unlike previous reports applying a stand-alone hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase Table 1. Baseline clinical and demographic characteristics of the 45 subjects grouped according to gender. Characteristics Male, n = 35 Female, n = 10 Age (yrs)* White (%) BMI (kg/m 2 )* Smoker 2 (6%) 0 Diabetes 1 (3%) 0 Metabolic syndrome 4 (11%) 0 Hypertension 19 (54%) 7 (70%) Initial coronary artery calcium score (633) (327) BMI, body mass index. *Mean 6 SD. Mean 6 SD (median). Gender difference statistically significant Mann Whitney P = American Journal of Therapeutics (2009) 16(4)

4 Effect of Combined Therapeutic Approach on Coronary Calcium Scores in Asymptomatic Adults 329 Table 2. Initial and final plasma lipid values and total calcium score in 45 subjects at baseline and after treatment.* Parameter Initial Final Percent change P value Mean 6 SD (median) Total cholesterol (mg/dl) Male (185) (132) 225,0.001 Female (179) (156) LDL cholesterol (mg/dl) Male (118) (59) 242,0.001 Female (97.5) (73) HDL cholesterol (mg/dl) Male (47) (55) 20,0.001 Female (66.5) (68) TG (mg/dl) Male (94) (51) 243,0.001 Female (84) (41.5) (OH)D (ng/ml) Male (30) (48) 56,0.001 Female (27.5) (47.0) Total calcium score Male (633) (595) Female (327) (354) (OH)D, 25(OH) vitamin D. *All subjects received treatment with statin and/or niacin supplemented with fish oil and vitamin D3. Statistical differences between baseline and final values were determined using Wilcoxon Signed Rank for nonparametric dependent t tests. inhibitor reductase statin approach, 17,25,26 we demonstrate that substantial reduction or slowing of CT CCS progression could be achieved using a more extensive treatment approach. These results suggest that systematic reduction or slowing of CCS is feasible. Although this study was not a randomized, placebo-controlled, prospectively designed trial, the regression seen in many FIGURE 1. Impact of intensive lipid management, omega-3 fatty acid, and vitamin D3 supplement therapy on the rate of coronary atherosclerotic plaque progression. Bar graphs reflect the number of subjects within each category of plaque regression or progression. Changes in CCS were detected by CT CCS at baseline and again at a mean of 18 months. Regression was defined as those with a decrease in CCS and ranged from 0.3% to 64% regression. Slow progression was defined as those with no change or less than 29% annual progression, and progression was defined as those progressing at least 29% annually. of these patients, with reductions in CT coronary calcium score as great as 64%, is noteworthy. With 5% 8% scan-to-scan variability, the dramatic reductions seen in CCS are not likely due to scan variation. 14 Our experience contrasts with that of clinical trials examining effects of statin therapy on rates of CCS progression. The St. Francis Heart Study, a 4-year prospective study of 1005 participants, failed to show any difference between treatment with a combination of alpha-tocopherol, vitamin C, and low- dose atorvastatin (20 mg once daily) vs matched placebos on the rate of progression of CCS (38% vs 36%, respectively, after 2 years). 25 Furthermore, the Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) Trial of 615 hyperlipidemic, postmenopausal women randomized to intensive (atorvastatin 80 mg/d) vs moderate (pravastatin 40 mg/d) statin therapy treated prospectively for 12 months found no difference in the rate of increase of CCS (15.1% and 14.3%, respectively). 26 Likewise, 761 participants receiving open-label statin therapy showed no relationship between LDL cholesterol treatment and rate of plaque progression by serial CT CCS over a 7- year period, though greater HDL cholesterol of $60 mg/dl was associated with less progression, HDL # 40mg/dLassociatedwithgreaterprogression. 17 Most recently, Schmermund et al 27 reported no difference between high- and low- dose atorvastatin on the rate of increase in CCS over 12 months of treatment (27% vs 25%, respectively). No participant in either treatment arm achieved a reduction in score. Our experience suggests that CCS is indeed a modifiable parameter and that slowing and even substantial reduction may be obtained using a broad program of American Journal of Therapeutics (2009) 16(4)

5 330 Davis et al treatment. Given the design of the study, it is not possible to determine which variables were responsible for observed outcomes, that is, reducing atherogenic lipid profiles, addition of niacin, addition of omega-3 fatty acids, dietary manipulations, or supplementation of vitamin D3. Further research is needed to test the impact of these variables in carefully controlled studies. We included vitamin D3 supplementation as part of our standard treatment to correct serum 25(OH) vitamin D levels based on our (unpublished data, Davis WR, March 2008) findings suggesting that vitamin D3 supplementation contributed to improved insulin sensitivity, modestly raised HDL and reduced TG, and reduced C-reactive protein, consistent with several published observations Similar observations have since been made in larger analyses, including that from the National Health and Nutrition Examination Survey, 31 along with emerging evidence of vitamin D3 deficiency as a predictor of greater carotid intimal-medial thickness, also a surrogate measure of atherosclerotic plaque burden 32 and of coronary events. 33,34 It may be possible that supplemental vitamin D3 led to changes in calcium composition of coronary atherosclerotic plaque independent of the noncalcific elements. Further research will be needed to address this potential mechanism. Omega-3 fatty acids from fish oil are included in our program based on data demonstrating their effectiveness for reducing triglycerides, triglyceride-containing lipoproteins, and cardiovascular events. 35,36 Over-thecounter fish oil supplements were used, since the initiation of the program pre-dated the availability of prescription fish oil. Therefore, actual omega-3 fatty acid content was potentially variable and not uniform in our patients. Nonetheless, since we used triglyceride levels as our index of adequacy of omega-3 fatty acid supplementation, this introduced some measure of treatment uniformity. The addition of omega-3 fatty acids facilitated reduction of triglycerides to our target of 60 mg/dl, since statin monotherapy exerts limited triglyceride-reducing effect and would have been unlikely to achieve this level alone. Among the weaknesses of our study was the lack of a control group. Our subjects were all white and highly motivated and willing to make dietary changes and add nutritional supplements and may not be representative of the broader population with a more varied racial and motivational mix. In addition, this group was perhaps healthier than those in other clinical trials because we had few smokers and only a small proportion with metabolic syndrome (n = 4 or 11% males; no females). Although coronary calcium serves as a useful and reliable index of total coronary atherosclerotic plaque American Journal of Therapeutics (2009) 16(4) area in examination of postmortem specimens (with calcium occupying approximately 20% of total plaque area), 1,2 there are no data that would explore whether this relationship holds during treatment. There are data to suggest that atherosclerotic plaque bearing greater calcium burden is less susceptible to change in the face of modification of conventional risk factors when studied using intracoronary ultrasound. 37 However, we are unaware of any data suggesting that vitamin D supplementation used to achieve physiologic levels to completely ameliorate vitamin D deficiency 21,22 has been part of a treatment regimen addressing coronary plaque progression, regression, or composition. It is intriguing to suggest that vitamin D supplementation at levels to achieve plasma levels of 50 ng/ml may prove to be a key factor explaining the reduction in cardiovascular events seen with lipid treatment but not previously reflected by serial CCS. The precise role of CCS in coronary risk determination remains a topic of debate, though the American College of Cardiology Foundation Clinical Expert Consensus Task Force recently updated its consensus statement reflecting a growing acceptance of this technique for specific coronary risk factor subsets. 38 Less well defined is the role of serial CCS in response to risk factor modification, the selective benefits of different risk factor modifying treatments, and how well these manipulations correlate with outcome. As recently suggested by Redberg, 39 the real value of any diagnostic procedure derives not from its ability to give more information but from whether it suggests a better course of treatment than the physician would have recommend anyway. Our findings lend support to the concept that dietary changes and the addition of omega-3 and vitamin D3 supplements to pharmacological therapy targeting LDL cholesterol 60, HDL 60, and TG 60 mg/dl may slow or reduce progression of coronary calcium scores in a substantial proportion of patients. The precise parameters that will be necessary to achieve consistent reductions in coronary calcium scoring have yet to be determined. Whether or not reductions of calcium score will also yield concomitant reduction of coronary events is a tantalizing, but unproven, prospect. REFERENCES 1. Sangiorgi G, Rumberger JA, Severson A, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol. 1998; 31:

6 Effect of Combined Therapeutic Approach on Coronary Calcium Scores in Asymptomatic Adults Rumberger JA, Simons B, Fitzpatrick LA, et al. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area: a histopathologic correlative study. Circulation. 1995;92: Oie HH, Vliegenthart R, Hak AE, et al. The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam Coronary Calcification Study. J Am Coll Cardiol. 2002;39: McDermott MM, Liu K, Criqui MH, et al. Ankle-brachial index and subclinical cardiac and carotid disease: the multi-ethnic study of atherosclerosis. Am J Epidemiol. 2005;162: Baumgart D, Schmermund A, Goerge G, et al. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol. 1997;30: Schmermund A, Baumgart D, Grönemeyer D, et al. Measuring the effect of risk factors on coronary atherosclerosis: coronary calcium score versus angiographic disease severity. J Am Coll Cardiol. 1998;31: Schmermund A, Baumgart D, Adamzik M, et al. Comparison of electron-beam computed tomography and intracoronary ultrasound in detecting calcified and noncalcified plaques in patients with acute coronary syndromes and no or minimal to moderate angiographic coronary artery disease. Am J Cardiol. 1998;81: LaMonte MJ, FitzGerald SJ, Church TS, et al. Coronary artery calcium score and coronary heart disease events in a large cohort of asymptomatic men and women. Am J Epidemiol. 2005;162: Vliegenthart R, Oudkerk M, Song B, et al. Coronary calcification detected by electron-beam computed tomography and myocardial infarction. The Rotterdam Coronary Calcification. Eur Heart J. 2002;23: Arad Y, Spadaro LA, Goodman K, et al. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol. 2000;36: Greenland P, LaBree L, Azen SP, et al. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291: Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med. 1998;128: Waters D, Craven TE, Lesperance J. Prognostic significance of progression of coronary atherosclerosis. Circulation. 1993;87: Budoff MJ. Tracking progression of heart disease with cardiac computed tomography. J Cardiovasc Pharmacol Ther. 2004;9: Raggi P, Callister TA, Shaw LJ. Progression of coronary artery calcium and risk of first myocardial infarction in patients receiving cholesterol-lowering therapy. Arterioscler Thromb Vasc Biol. 2004;24: Nissen SE, Nichols SJ, Sipahi I, et al, for the ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295: Wong ND, Kawakubo M, LaBree L, et al. Relation of coronary calcium progression and control of lipids according to National Cholesterol Education Program guidelines. Am J Cardiol. 2004;94: Otvos J. Measurement of triglyceride-rich lipoproteins by nuclear magnetic resonance spectroscopy. Clin Cardiol. 1999;22 (6 Suppl):II21 II Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel in Adults (Adult Treatment Panel III). JAMA. 2001;285: Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69: Vieth R. Why the optimal requirement for vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid Biochem Mol Biol. 2004;89 90: Holick MF. The vitamin D epidemic and its health consequences. J Nutr. 2005;135:2739S 2748S. 23. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto miocardico. Lancet. 1999; 354: Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15: Arad Y, Spadaro LA, Roth M, et al. Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial. J Am Coll Cardiol. 2005;46: Raggi P, Davidson M, Callister TQ. Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic postmenopausal women: Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES). Circulation. 2005;112: Schmermund A, Achenbach S, Budde T, et al. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial. Circulation. 2006;113: Pittas AG, Harris SS, Stark PC, et al. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care. 2007;30: Major GC, Alarie F, Doré J, et al. Supplementation with calcium + vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein concentrations. Am J Clin Nutr. 2007;85: Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response American Journal of Therapeutics (2009) 16(4)

7 332 Davis et al with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002;95: Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25- hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2007;167: Targher G, Bertolini L, Padovani R, et al. 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Clin Endocrinol (Oxf). 2006;65: Scragg R, Jackson R, Holdaway IM, et al. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol. 1990;19: Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117: Karpe F, Steiner G, Uffelman K, et al. Postprandial lipoproteins and progression of coronary atherosclerosis. Atherosclerosis. 1994;106: Westphal S, Orth M, Ambrosch A, et al. Postprandial chylomicrons and VLDLs in severe hypertriacylglycerolemia are lowered more effectively than are chylomicron remnants after treatment with n-3 fatty acids. Am J Clin Nutr. 2000;71: Nicholls SJ, Tuzcu EM, Wolski K, et al. Coronary artery calcification and changes in atheroma burden in response to established medical therapies. J Am Coll Cardiol. 2007; 49: Greenland P, Bonow RO, Brundage BH, et al. ACCF/ AHA 2007 Clinical Expert Consensus Document on Coronary Artery Calcium Scoring by Computed Tomography in Global Cardiovascular Risk Assessment and in Evaluation of Patients With Chest Pain. A Report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography). Developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. Circulation. 2007;115: Redberg RF. Computed tomographic angiography: more than just a pretty picture? J Am Coll Cardiol. 2007;49: American Journal of Therapeutics (2009) 16(4)