Baseline Coronary Artery Calcium Research Articles

Abstract P174: Kidney Function and Progression of Coronary Artery Calcification in Community-Dwelling Older Adults: The Rancho Bernardo Study

Background: Despite growing evidence for the separate and joint contributions of declining estimated glomerular filtration rate (eGFR) and presence of albuminuria to cardiovascular death, longitudinal studies of the association of these risk factors with coronary artery calcification, a marker of subclinical cardiovascular disease (CVD), are contradictory. Methods: We evaluated 421 community-dwelling men and women (mean age 67 years) without known heart disease who had eGFR estimated by the Modification of Diet in Renal Disease equation and albuminuria assessed by urine albumin/creatinine ratio (ACR) between 1997-99. Coronary artery calcium (CAC) was measured by electron beam computed tomography between 2001-02; 338 participants returned for a repeat scan between 2005-06, a mean of 4.5 (0.5) years later. CAC progression was defined as a difference between the follow-up square-root transformed CAC volume score and the baseline square-root transformed score > 2.5 mm 3 . Results: At baseline, mean eGFR was 78 mL/min/1.73m 2 , median ACR was 10 mg/g. Median total Agatston CAC score was 77 at the baseline scan and 112 at follow-up; 45% (191 of 421) of participants had CAC>100 at baseline and 46% (157 of 338) showed CAC progression. Logistic regression analyses showed no separate or joint association between eGFR or ACR with baseline CAC or with CAC progression. Table 1 shows the odds ratio (95% CI) for CAC progression for each 1 SD decrease in eGFR or increase in ACR. Conclusions: In a cohort of community-dwelling older adults, we found no longitudinal association between eGFR or ACR with CAC progression. This information may enhance our understanding of CAC progression across the spectrum of kidney function in community-dwelling adults without prevalent CVD or kidney disease. 4 Year CAC Progression per 1 SD Decrease in eGFR or Increase in ACR 1997-99 Estimated Glomerular Filtration Rate Urine Albumin/Creatinine Ratio (n=338) (n=292) Covariates Odds Ratio (95% CI) p value Odds Ratio (95% CI) p value Model 1 1.07 (0.86, 1.33) 0.54 0.99 (0.78, 1.26) 0.93 Model 2 1.04 (0.84, 1.30) 0.69 0.97 (0.77, 1.24) 0.82 Model 3 1.06 (0.85, 1.33) 0.57 1.06 (0.82, 1.37) 0.67 Model 4 1.07 (0.85, 1.33) 0.57 1.05 (0.81, 1.36) 0.69 Model 5 1.05 (0.82, 1.36) 0.68 1.06 (0.82, 1.38) 0.66 Model 6 1.10 (0.83, 1.43) 0.53 0.99 (0.75, 1.30) 0.94 Model 1: Unadj; Model 2: Age, time lapse adj; Model 3: Age, time lapse, sex adj; Model 4: Age, timelapse, sex, BMI adj; Model 5: Age, time lapse, sex, BMI and (eGFR or ACR) adj; Model 6: Age, time lapse, sex, BMI, SBP, FPG, HDL and (eGFR or ACR) adj

Prediction of Coronary Artery Calcium Progression in Individuals With Low Framingham Risk Score: The Multi-Ethnic Study of Atherosclerosis

This study sought to determine whether novel markers not involving ionizing radiation could predict coronary artery calcium (CAC) progression in a low-risk population. Increase in CAC scores over time (CAC progression) improves prediction of coronary heart disease (CHD) events. Due to radiation exposure, CAC measurement represents an undesirable method for repeated risk assessment, particularly in individuals with low predicted risk (Framingham Risk Score [FRS] <10%). From 6,814 participants in MESA (Multi-Ethnic Study of Atherosclerosis), 2,620 individuals were classified as low risk for CHD events (FRS <10%) and had follow-up CAC measurement. In addition to traditional risk factors (RFs), various combinations of novel marker models were selected on the basis of data-driven, clinical, or backward stepwise selection techniques. Mean follow-up was 2.5 years. CAC progression occurred in 574 participants (22% overall; 214 of 1,830 with baseline CAC = 0 and 360 of 790 with baseline CAC >0). Addition of various combinations of novel markers to the base model (c statistic = 0.711) revealed improvements in discrimination of approximately only 0.005 each (c statistics 0.7158, 0.7160, and 0.7164) for the best-fit models. All 3 best-fit novel marker models calibrated well but were similar to the base model in predicting individual risk probabilities for CAC progression. The highest prevalence of CAC progression occurred in the highest compared with the lowest probability quartile groups (39.2% to 40.3% vs. 6.4% to 7.1%). In individuals at low predicted risk according to FRS, traditional risk factors predicted CAC progression in the short term with good discrimination and calibration. Prediction improved minimally when various novel markers were added to the model.

Preradiotherapy Calcium Scores of the Coronary Arteries in a Cohort of Women With Early-Stage Breast Cancer: A Comparison With a Cohort of Healthy Women

Breast cancer radiotherapy has been associated with an increased risk of cardiac toxicity. However, no data are available on the probability of developing coronary artery disease (CAD) in breast cancer patients when compared with healthy women. Therefore, baseline coronary artery calcium (CAC) scores, as an accepted tool to predict CAD, were determined and compared with the CAC scores of a healthy, asymptomatic cohort, the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Eighty consecutive patients with ductal carcinoma in situ or infiltrative breast cancer referred for radiotherapy after breast-conserving surgery were included in our study. Their cardiovascular risk profile was registered, and a 64 multislice CT scan was performed. The CAC scores of an unselected (Caucasian only) Radiotherapy Centre West (RCWEST) cohort, as well as of those of a selected (comorbidity and race adjusted) RCWEST cohort, were determined. The scores of both cohorts were compared with those of the female (Caucasian only) MESA cohort. For the unselected RCWEST cohort (n = 62) we found significant (p < .01) higher scores for women in the 55-64 age category compared with those of the MESA cohort. In the selected cohort (n = 55) the CAC scores of the women in the age category 55-64 were significantly (p = .02) higher compared with the MESA cohort. No significant differences were noted in the other age categories. Both cohorts revealed that CAC scores in the 55-64 age category were significantly higher than the CAC scores in the asymptomatic (female) MESA population. These data suggest that breast cancer patients bear a higher risk of developing coronary heart disease before the start of radiotherapy. Therefore, measures to decrease cardiac dose further in breast cancer radiotherapy are even more important.

Abstract 9110: Does Change in Cardiometabolic Risk Factors Relate to Change in Coronary Artery Calcification? Findings from the Multi-Ethnic Study of Atherosclerosis (MESA)

How CVD risk factors impact coronary artery calcification (CAC) remains unclear. Particularly lacking are data describing how change in various risk factor levels relate to change in CAC, which may lead to a greater understanding of these relationships and further inform optimal strategies for CVD prevention and treatment. With data from a multi-ethnic cohort of 4,560 individuals (46.8% men; age M = 61.35) initially free of clinical CVD, this study used latent growth modeling to examine change in specific cardiometabolic risk factors (CRFs; waist circumference, BMI, SBP, DBP, HDL and LDL cholesterol, triglycerides, and fasting glucose) related to change in CAC over an average 4.9 year time period. Data were adjusted for baseline CRF and CAC values, age, race/ethnicity, smoking, family history of CVD, income, and use of antihypertensive, lipid-lowering, and glucose-lowering medications. Men and women were analyzed separately given previously noted differences in clinical CVD development and predictive utility of CRFs. Change in CRFs was not associated with incident CAC among men and women who had undetectable CAC at baseline, or with CAC progression among men who had detectable CAC at baseline. Among women who had detectable CAC at baseline (M = 180.5, SD = 32.4 Agatston units), greater decline (or less progression) in SBP (B = -3.17, p &lt; .05) and DBP (B = -8.56, p &lt; .05), and LDL cholesterol (B = -2.49, p &lt; .05), were each individually associated with greater CAC progression. The associations between change in blood pressure and CAC progression were not independent of change in LDL cholesterol. Medication use appeared to influence these inverse associations, such that women taking antihypertensive and lipid-lowering medications exhibited greater CAC progression despite showing average decreases in respective CRF levels over time. Women not taking such medications did not show these inverse associations. To our knowledge, this is the first study systematically reporting on rates of change in various CRFs related to CAC incidence and progression. Observed inverse associations appear to have been driven by women receiving medications that lowered their initially high risk factor levels but not their increased rate of CAC progression.

The Association of Framingham and Reynolds Risk Scores With Incidence and Progression of Coronary Artery Calcification in MESA (Multi-Ethnic Study of Atherosclerosis)

The purpose of this study was to compare the association of the Framingham risk score (FRS) and Reynolds risk score (RRS) with subclinical atherosclerosis, assessed by incidence and progression of coronary artery calcium (CAC). The comparative effectiveness of competing risk algorithms for identifying subclinical atherosclerosis is unknown. MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective cohort study of 6,814 participants free of baseline cardiovascular disease. All participants underwent risk factor assessment, as well as baseline and follow-up CAC testing. We assessed the performance of the FRS and RRS to predict CAC incidence and progression using relative risk and robust linear regression. The study population included 5,140 individuals (mean age 61 ± 10 years, 47% males, mean follow-up: 3.1 ± 1.3 years). Among 53% of subjects (n = 2,729) with no baseline CAC, 18% (n = 510) developed incident CAC. Both the FRS and RRS were significantly predictive of incident CAC (relative risk: 1.40 [95% confidence interval (CI): 1.29 to 1.52] and 1.41 [95% CI: 1.30 to 1.54] per 5% increase in risk, respectively) and CAC progression (mean CAC score change: 6.92 [95% CI: 5.31 to 8.54] and 6.82 [95% CI: 5.51 to 8.14] per 5% increase). Discordance in risk category classification (<10% or >10% per 10-year coronary heart disease risk) occurred in 13.7%, with only the RRS consistently adding predictive value for incidence and progression of CAC. These subclinical atherosclerosis findings are supported by a coronary heart disease events analysis over a mean follow-up of 5.6 ± 0.7 years. Both the RRS and FRS predict onset and progression of subclinical atherosclerosis. However, the RRS may provide additional predictive information when discordance between the scoring systems exists.

Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub-clinical coronary atherosclerosis

BackgroundEpicardial adipose tissue (EAT), a metabolically active visceral fat depot surrounding the heart, has been implicated in the pathogenesis of coronary artery disease (CAD) through possible paracrine interaction with the coronary arteries. We examined the association of EAT with metabolic syndrome and the prevalence and progression of coronary artery calcium (CAC) burden. MethodsCAC scan was performed in 333 asymptomatic diabetic patients without prior history of CAD (median age 54 years, 62% males), followed by a repeat scan after 2.7±0.3 years. CAC progression was defined as >2.5mm3 increase in square root transformed volumetric CAC scores. EAT and intra-thoracic fat volumes were quantified using a dedicated software (QFAT), and were examined in relation to the metabolic syndrome, baseline CAC scores and CAC progression. ResultsBoth epicardial and intra-thoracic fat were associated with metabolic syndrome after adjustment for conventional cardiovascular risk factors, but the association was attenuated after additional adjustment for body mass index. EAT, but not intra-thoracic fat, showed significant association with baseline CAC scores (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.04–1.22, p=0.04) and CAC progression (OR 1.12, 95% CI 1.05–1.19, p<0.001) after adjustment for conventional measures of obesity and risk factors. ConclusionEAT volume measured on non-contrast CT is an independent marker for the presence and severity of coronary calcium burden and also identifies individuals at increased risk of CAC progression. EAT quantification may thus add to the prognostic value of CAC imaging.

Progression of coronary artery calcification in renal transplant recipients

Cardiovascular disease is the leading cause of mortality among renal transplant recipients. In the general population, coronary artery calcification (CAC) and progression of CAC are predictors of future cardiac risk. We conducted a study to determine the progression of CAC in renal transplant recipients; we also examined the factors associated with progression and the impact of the analytic methods used to determine CAC progression. We used multi-detector computed tomography to examine CAC in 150 prevalent renal transplant recipients, who did not have a documented cardiovascular disease. A baseline and a follow-up scan were performed and changes in CAC scores were evaluated in each patient individually, to calculate the incidence of CAC progression. Multivariate logistic regression analysis was used to evaluate the determinants of CAC progression. Baseline CAC prevalence was 35.3% and the mean CAC score was 60.0 ± 174.8. At follow-up scan that was performed after an average of 2.8 ± 0.4 years, CAC prevalence increased to 64.6% and the mean CAC score to 94.9 ± 245.7. Progression of individual CAC score was found between 28.0 and 38.0%, depending on the method used to define progression. In patients with baseline CAC, median annualized rate of CAC progression was 11.1. Baseline CAC, high triglyceride and bisphosphonate use were the independent determinants of CAC progression. Renal transplantation does not stop or reverse CAC. Progression of CAC is the usual evolution pattern of CAC in renal transplant recipients. Beside baseline CAC, high triglyceride level and bisphosphonate use were associated with progression of CAC.

Prognostic Value of CT Angiography in Patients With Inconclusive Functional Stress Tests

We attempted to determine the prognostic value of coronary computed tomographic angiography (CTA) in patients with inconclusive functional stress tests. Patients with suspected coronary artery disease (CAD) and inconclusive noninvasive cardiac stress tests represent a frequent management challenge. We examined 529 consecutive patients with suspected CAD and prior inconclusive functional stress tests. All patients underwent a coronary CTA scan using a 64-slice multidetector row scanner. CAD severity by coronary CTA was categorized as: 1) no evidence of CAD; 2) nonobstructive coronary plaques (< 30%); 3) mild stenosis (30% to 49%); 4) moderate stenosis (50% to 69%); and 5) severe stenosis (≥ 70%). Patients were also categorized according to a modified Duke prognostic CAD index. Survival analyses were performed using Cox proportional hazards models adjusted for baseline risk factors and coronary artery calcium score. The primary outcome of the study was the combined endpoint of all-cause mortality and nonfatal myocardial infarction. Among patients with inconclusive stress tests, the large majority (69%) did not demonstrate significant CAD by coronary CTA. During a mean follow-up of 30.1 ± 11.1 months, there were 20 (3.8%) deaths and 17 (3.2%) nonfatal myocardial infarctions. Multivariable Cox regression analysis revealed that the presence of increasing degrees of obstructive CAD by CTA was an independent predictor of adverse events (hazard ratio [HR]: 1.66 [95% confidence interval (CI): 1.23 to 2.23], p = 0.001). Indeed, the presence of ≥ 50% coronary stenosis was associated with an increased risk of events (HR: 3.15 [95% CI: 1.26 to 7.89], p = 0.01). Likewise, the Duke prognostic CAD index was also found to be an independent predictor of events (HR: 1.54 [95% CI: 1.20 to 1.97], p = 0.001). Among patients with inconclusive functional stress tests, the noninvasive assessment of CAD severity by coronary CTA has been shown to provide incremental prognostic information beyond the evaluation of traditional risk factors and coronary artery calcium score.

Fetuin-A, coronary artery calcification and outcome in maintenance hemodialysis patients

Previous studies have suggested that serum fetuin-A, a calcification inhibitor, predicts mortality in dialysis patients. This study investigated the relationships between fetuin-A, vascular calcification, and outcome in such patients. 58 patients on maintenance hemodialysis underwent multirow spiral computed tomography to determine baseline coronary artery calcification (CAC) score. Serum fetuin-A was measured repeatedly over time. Time-averaged fetuin-A inversely correlated with age and baseline CAC score. After partial correlation analysis controlling for age, the association between fetuin-A and CAC became insignificant. During the study, 27 of 58 patients died and 26 experienced at least one cardiovascular event. Low fetuin-A was associated with a significant increase in all-cause mortality and the occurrence of a cardiovascular event. The association of fetuin-A with mortality and cardiovascular event remained significant even when adjusting for confounding factors, including age and CAC score. Time-averaged fetuin-A was associated with survival and cardiovascular outcome, independent of vascular calcification.

Impact of Coronary Artery Calcium Scanning on Coronary Risk Factors and Downstream Testing: The EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) Prospective Randomized Trial

We conducted a prospective randomized trial to compare the clinical impact of conventional risk factor modification to that associated with the addition of coronary artery calcium (CAC) scanning.Although CAC scanning predicts cardiac events, its impact on subsequent medical management and coronary artery disease risk is not known.We assigned 2,137 volunteers to groups that either did undergo CAC scanning or did not undergo CAC scanning before risk factor counseling. The primary end point was 4-year change in coronary artery disease risk factors and Framingham Risk Score. We also compared the groups for differences in downstream medical resource utilization.Compared with the no-scan group, the scan group showed a net favorable change in systolic blood pressure (p = 0.02), low-density lipoprotein cholesterol (p = 0.04), and waist circumference for those with increased abdominal girth (p = 0.01), and tendency to weight loss among overweight subjects (p = 0.07). While there was a mean rise in Framingham Risk Score (FRS) in the no-scan group, FRS remained static in the scan group (0.7 ± 5.1 vs. 0.002 ± 4.9, p = 0.003). Within the scan group, increasing baseline CAC score was associated with a dose-response improvement in systolic and diastolic blood pressure (p < 0.001), total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p < 0.001), triglycerides (p < 0.001), weight (p < 0.001), and Framingham Risk Score (p = 0.003). Downstream medical testing and costs in the scan group were comparable to those of the no-scan group, balanced by lower and higher resource utilization for subjects with normal CAC scans and CAC scores ≥400, respectively.Compared with no scanning, randomization to CAC scanning was associated with superior coronary artery disease risk factor control without increasing downstream medical testing. Further study of CAC scanning, including pre-specified treatment recommendations, to assess its impact of cardiovascular outcomes is warranted.

Evolution of coronary artery calcification in patients with chronic kidney disease Stages 3 and 4, with and without diabetes

The purpose of this study was to report the evolution of coronary artery calcification (CAC) in subjects with chronic kidney disease Stages 3 and 4 comparing those with and without diabetes. We previously reported prevalence in the same population. CAC was measured using multi-slice computer tomography. We prospectively followed up 103 patients for 2 years, 49 with diabetes and 54 without diabetes. Demographic, routine biochemistry, calcification inhibitors and bone mineral density data were collected and analysed. Evolution of CAC was defined as those with a difference of ≥ 2.5 U between baseline and final square root CAC scores. There were more progressors in the group with diabetes, 24 compared to 12 in the group without diabetes (P= 0.004). When diabetes was present, CAC progressed equally in men and women. Risk factors for evolution of CAC included age, baseline CAC score and serum phosphate levels. Baseline CAC score, phosphate and body mass index were independent predictors for the increase of CAC score during the study period. Severity of CAC was greater in the diabetes group (median CAC score at baseline in the group with diabetes 154 increased to 258 2 years later, P < 0.001). Evolution of CAC is greater in older patients and those with diabetes, where the gender advantage of being female is lost. Serum phosphate level, despite being within the normal range and virtually no use of phosphate binders, was also a risk factor. Further studies are required to determine the levels of serum phosphate required to minimize cardiovascular risk.

Progression of Coronary Artery Calcium Predicts All-Cause Mortality

This study examined a large cohort to assess whether progression of coronary artery calcium (CAC) was associated with all-cause mortality, and which among 3 different methods to assess CAC progression provided the best estimate of risk. Serial assessment of CAC scores has been proposed as a method to follow progression of coronary artery disease, and it has been suggested that excessive CAC progression may be a useful noninvasive predictor of the patient's risk of future events. However, the optimal method to measure calcium progression has not been well established. The study sample consisted of 4,609 consecutive asymptomatic individuals referred by primary physicians for CAC measurement with electron beam tomography, who underwent repeat screening. Three general statistical approaches were taken: 1) the absolute difference between follow-up and baseline CAC score; 2) percent annualized differences between follow-up and baseline CAC score; and 3) difference between square root of baseline and square root of follow-up CAC score >2.5 (the "SQRT method"). The average interscan time was 3.1 years, and there were 288 deaths. Progression of CAC was significantly associated with mortality regardless of the method used to assess progression (p < 0.0001). After adjusting for baseline score, age, sex, and time between scans, the best CAC progression model to predict mortality was the SQRT method (hazard ratio [HR]: 3.34; 95% confidence interval [CI]: 2.65 to 4.21; p < 0.0001), followed by a >15% yearly increase (HR: 2.98; 95% CI: 2.20 to 4.95; p < 0.0001). Progression was very limited and did not predict mortality in patients with baseline CAC = 0. The CAC progression added incremental value in predicting all-cause mortality over baseline score, time between scans, demographics, and cardiovascular risk factors. Serial assessment may have clinical value in assessing plaque progression and future cardiovascular risk.

Serum Osteoprotegerin Is a Predictor of Progression of Atherosclerosis and Coronary Calcification in Hemodialysis Patients

Background: The aim of this prospective cohort study was to evaluate the progression of coronary artery calcification (CAC), and atherosclerosis in hemodialysis (HD) patients and to relate them to novel biomarkers, i.e. serum osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23). Material and Methods: Forty-seven HD patients were followed up for 30 months or until death. Intima media thickness (CCA-IMT), atherosclerotic plaques and CAC were assessed at baseline and after 30 months. Serum mineral parameters, lipids, OPG and plasma FGF-23 were also measured. Results: At baseline, 70% HD patients presented detectable CAC. The patients without calcification at baseline remained calcification free at 30 months and presented lower serum OPG and FGF-23 than those with CAC. A 64.4% progression of CAC was observed in all patients with CAC at baseline. In parallel, a 13% increase in CCA-IMT was found. Both ΔCAC and ΔCCA-IMT correlated positively with baseline and follow-up serum OPG. The patients who died had significantly higher baseline CAC and serum OPG. Conclusion: The plasma level of OPG could serve as a surrogate marker of progression of atherosclerosis and calcification in patients with end-stage renal disease. Therefore, the serum OPG may be a candidate biomarker of cardiovascular complications and poor outcome among dialysis patients.

Total and Individual Coronary Artery Calcium Scores as Independent Predictors of Mortality in Hemodialysis Patients

Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001–9/2007) survival of 166 MHD patients, aged 53 ± 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1–100, 101–400, and 400+. The 101–400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1–48.1, p = 0.02) and 13.3 (95% CI: 1.3–65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1–21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2–9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1–14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.

Platelet function and relationship to coronary artery disease (CAD) risk in early menopausal women

Risk of CAD increases at menopause and platelets contribute to the etiology of CAD. We hypothesized that individual variation in platelet procoagulant activity at menopause correlates with the extent of CAD as reflected by coronary artery calcification (CAC). We developed several novel and global assays of platelet procoagulant activity: dense (ATP release) and alpha (P‐selectin expression) granule secretion and GPαIIbβ3 fibrinogen‐binding (PAC1 binding) to ADP stimulation, and prostaglandin E1 (PEG1) sensitivity as a surrogate for prostacyclin sensitivity. Platelets were prepared from venous blood collected from women screened for the Kronos Early Estrogen Prevention Study (n=125; mean±SD age=52.5±2.4 years) within 19.4±9.2 months of last menses. Baseline CAC score was determined. Of conventional CAD risk factors, only systolic blood pressure correlated with positive CAC score (n=23). ATP secretion tended to be less in women with positive CAC scores and was negatively correlated with blood glucose (P&lt;0.001). P‐selectin expression and PAC1 binding increased with total cholesterol (P&lt;0.05). PEG1 sensitivity increased with increasing age and waist circumference (P&lt;0.05). These results indicate that platelet functions change with age and in association with conventional risk factors for the disease in women at menopause. Supported by the Kronos Longevity Research Institute and NIH HL90639.

Determinants of Coronary Calcium Conversion Among Patients With a Normal Coronary Calcium Scan: What Is the “Warranty Period” for Remaining Normal?

This study identified the incidence and predictors of conversion of a normal to abnormal coronary artery calcium (CAC) scan during serial CAC scanning over 5 years. Although a normal CAC scan signifies absence of significant atherosclerosis and is used to identify individuals at low clinical risk, the "warranty period" of a normal CAC scan relative to its ability to predict sustained absence of coronary atherosclerosis remains unknown. We assessed frequency of and time to progression, as well as proportional increase of CAC in 422 individuals with normal CAC scan (CAC = 0) undergoing annual CAC scanning for 5 years. Results were compared with those of a referent cohort of 621 individuals with baseline CAC scan (CAC >0). A total of 106 (25.1%) patients with CAC = 0 developed CAC during follow-up at a mean time to conversion of 4.1 +/- 0.9 years. Incidence of conversion to CAC >0 was nonlinear and was highest in the fifth year. In multivariable analysis, progression to CAC >0 was associated with age, diabetes, and smoking (p < 0.01 for all). Among the 621 individuals with baseline CAC >0, only the presence of CAC itself, rather than CAD risk factors, was predictive of CAC progression. Among propensity score-matched individuals with CAC >0 versus CAC = 0, baseline CAC >0 emerged as the strongest predictor of CAC progression (hazard ratio [HR]: 12.50, 95% confidence interval [CI]: 9.31 to 16.77), followed by diabetes (HR: 2.07, 95% CI: 1.47 to 2.90) and smoking (HR: 1.29, 95% CI: 1.02 to 1.63, p < 0.05 for all). Among individuals with CAC = 0, conversion to CAC >0 is nonlinear and occurs at low frequency before 4 years. No clinical factor seems to mandate earlier repeat CAC scanning.

Study design and subject baseline characteristics in the ADVANCE Study: effects of cinacalcet on vascular calcification in haemodialysis patients

The ADVANCE (A Randomized Study to Evaluate the Effects of Cinacalcet plus Low-Dose Vitamin D on Vascular Calcification in Subjects with Chronic Kidney Disease Receiving Haemodialysis) Study objective is to assess the effect of cinacalcet plus low-dose active vitamin D versus flexible dosing of active vitamin D on progression of coronary artery calcification (CAC) in haemodialysis patients. We report the ADVANCE Study design and baseline subject characteristics. ADVANCE is a multinational, multicentre, randomized, open-label study. Adult haemodialysis patients with moderate to severe secondary hyperparathyroidism (intact parathyroid hormone [iPTH] >300 pg/mL or bio-intact PTH >160 pg/mL) and baseline CAC score >or=30 were stratified by CAC score (>or=30-399, >or=400-999, >or=1000) and randomized in a 1:1 ratio to cinacalcet (30-180 mg/day) plus low-dose active vitamin D (cinacalcet group) or flexible dosing of active vitamin D alone (control). The study had three phases: screening, 20-week dose titration and 32-week follow-up. CAC scores obtained by cardiac computed tomography were determined at screening and weeks 28 and 52. The primary end point was percentage change in CAC score from baseline to Week 52. Subjects (n = 360) were randomized to cinacalcet or control. Mean age was 61.5 years, 43% were women, and median dialysis vintage was 36.7 months (range, 2.7-351.5 months). The baseline geometric mean CAC score by the Agatston method was 548.7 (95% confidence interval, 480.5-626.6). Baseline CAC score was independently associated with age, sex, dialysis vintage, diabetes and iPTH. Subjects also had extensive aortic and valvular calcification at baseline. Subjects enrolled in ADVANCE have extensive CAC at baseline. The ADVANCE Study should help determine whether cinacalcet attenuates progression of vascular calcification.

Longitudinal Relationships among Coronary Artery Calcification, Serum Phosphorus, and Kidney Function

Coronary artery calcification (CAC) is common in advanced chronic kidney disease (CKD), yet its onset and time course are uncertain. The study objective was to assess longitudinal relationships among CAC, kidney function, and traditional and putative cardiovascular disease (CVD) risk factors. This is a prospective cohort analysis from the Spokane Heart Study, a long-term observational study of community-dwelling adults who were assessed every 2 yr for CAC (electron-beam computed tomography), CVD risk factors, and laboratory testing. Estimated GFR (eGFR) was determined by the reexpressed Modification of Diet in Renal Disease equation. CAC was present in 28% (245 of 883) at baseline. After 6 yr, new-onset CAC developed in 33% (122 of 371); severity increased from a median CAC score of 38 to 152 in those with baseline CAC. Neither eGFR (101 +/- 34 versus 104 +/- 31 ml/min per 1.73 m(2), respectively) nor serum phosphorus (3.25 +/- 0.49 versus 3.29 +/- 0.48 mg/dl, respectively) differed by CAC presence or absence at baseline; however, multivariate models (generalized estimating equations for incidence and prevalence) revealed that independent predictors of CAC over time were greater baseline CAC scores, higher serum phosphorus levels, lower eGFR levels, and traditional CVD risk factors. Each 1-mg/dl increase in phosphorus imparted odds ratios for CAC of 1.61 (incidence) and 1.54 (prevalence), risks comparable to traditional CVD risk factors. CAC becomes more frequent and severe over time. Higher levels of serum phosphorus and reduced kidney function independently predicted CAC.

Evolution of Coronary Artery Calcifications Following Kidney Transplantation: Relationship with Osteoprotegerin Levels

We prospectively assessed the evolution of coronary artery calcification (CAC) and osteoprotegerin (OPG) levels after renal transplantation (RT). Eighty-three recipients were followed-up prospectively during 1 year. Blood was collected before (baseline) and after RT for determination of mineral metabolism parameters including OPG. CAC was measured by multidetector computed tomography at transplantation (baseline) and 1 year later. Progression of CAC was defined as a difference between the follow-up square-root transformed volume (SRV) and the baseline SRV >or= 2.5. By multivariate analysis, baseline OPG level, age and low LDL levels were significantly associated with baseline CAC. RT was accompanied by mineral metabolism improvement with a decrease of OPG from 955 [395-5652] to 527 [217-1818] pg/mL and parathyroid hormone from 94 [1-550] to 62 [16-410] pg/mL. Thirty-one percent of patients did not exhibit CAC at baseline. CAC diminished in 14.5%, stabilized in 59.2% and progressed in 26.3% of patients. Baseline CAC was associated with progression (OR 2.92 [1.02-8.36]). No significant association was found between OPG and CAC progression despite a higher baseline OPG level in progressors (1046 [456-3285]) vs. non-progressors (899 [396-5952] pg/mL). CAC at baseline, but not 1 year after RT, is independently associated with baseline OPG; posttransplant CAC progression is predicted by baseline CAC score.

Relationship Between Baseline Coronary Calcium Score and Demonstration of Coronary Artery Stenoses During Follow-Up: MESA (Multi-Ethnic Study of Atherosclerosis)

The MESA (Multi-Ethnic Study of Atherosclerosis) is a population-based study of 6,814 men and women. We sought to analyze the relationship between the extent of coronary artery calcium (CAC) at baseline and the severity of coronary stenoses in clinically indicated coronary angiography studies during follow-up. CAC is an established predictor of major cardiovascular events. Yet, the relationship between CAC and the distribution and severity of coronary artery stenoses has not been widely explored. All MESA participants underwent noncontrast enhanced cardiac computed tomography during enrollment to determine baseline CAC. We analyzed 175 consecutive angiography reports from participants who underwent coronary catheterization for clinical indications during a median follow-up period of 18 months. The relationship between baseline CAC and the severity of coronary stenosis detected in coronary angiographies was determined. Baseline Agatston score was 0 in only 7 of 175 (4%) MESA participants who underwent invasive angiography during follow-up. When coronary arteries were studied separately, 13% to 18% of coronary arteries with >or=75% stenosis had 0 calcium mass scores at baseline. There was close association between baseline calcium mass score and the severity of stenosis in each of the coronary arteries (test for trend, p < 0.001). For example, mean calcium mass scores for <50%, 50% to 74%, and >or=75% stenosis in the left anterior descending coronary artery were 105.1 mg, 157.2 mg, and 302.2 mg, respectively (p < 0.001). Finally, there was a direct relationship between the total Agatston Score at baseline and the number of diseased vessels (test for trend, p < 0.001). The majority of patients with clinically indicated coronary angiography during follow-up had detectable coronary calcification at baseline. Although there is a significant relationship between the extent of calcification and mean degree of stenosis in individual coronary vessels, 16% of the coronary arteries with significant stenoses had no calcification at baseline.