Change In Coronary Artery Calcium Research Articles

Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis

BackgroundExposure to metals, a newly recognized risk factor for cardiovascular disease (CVD), could be related to atherosclerosis progression. ObjectivesThe authors hypothesized that higher urinary levels of nonessential (cadmium, tungsten, uranium) and essential (cobalt, copper, zinc) metals previously associated with CVD would be associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of CVD in MESA (Multi-Ethnic Study of Atherosclerosis). MethodsWe analyzed data from 6,418 MESA participants with spot urinary metal levels at baseline (2000-2002) and 1 to 4 repeated, continuous measures of CAC over a 10-year period. We used linear mixed-effect models to assess the association of baseline urinary metal levels with baseline CAC and cumulative change in CAC over a 10-year period. Urinary metals (μg/g creatinine) and CAC were log transformed. Models were adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors. ResultsAt baseline, the median CAC was 6.3 (Q1-Q3: 0.7-58.2). Comparing the highest to lowest quartile of urinary cadmium, CAC levels were 51% (95% CI: 32%, 74%) higher at baseline and 75% (95% CI: 47%, 107%) higher over the 10-year period. For urinary tungsten, uranium, and cobalt, the corresponding CAC levels over the 10-year period were 45% (95% CI: 23%, 71%), 39% (95% CI: 17%, 64%), and 47% (95% CI: 25%, 74%) higher, respectively, with no difference for models with and without adjustment for clinical factors. For copper and zinc, the corresponding estimates dropped from 55% to 33% and from 85% to 57%, respectively, after adjustment for clinical factors. The associations of metals with CAC were comparable in magnitude to those for classical CVD risk factors. ConclusionsExposure to metals was generally associated with extent of coronary calcification at baseline and follow-up. These findings support that metals are associated with the progression of atherosclerosis, potentially providing a novel strategy for the prevention and treatment of atherosclerosis progression.

Progression of Coronary Artery Calcification and Risk of Clinical Events in CKD: The Chronic Renal Insufficiency Cohort Study

Coronary artery calcification (CAC) progresses rapidly in people with chronic kidney disease (CKD) compared with the general population. We studied the association between CAC progression and higher risks of atherosclerotic cardiovascular disease (CVD), congestive heart failure, and all-cause mortality among adults with CKD. Prospective cohort study. & Participants: 1,310 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had at least one CAC scan with no prior history of CVD and with observed or imputed data on changes in CAC over time. Observed or imputed CAC progression, categorized as incident CAC among participants with zero CAC on the baseline scan, or progressive CAC when the baseline scan demonstrated CAC and there was an increase in CAC ≥50 Agatston units per year. Atherosclerotic CVD (myocardial infarction or stroke), congestive heart failure, and all-cause mortality. Cause-specific Cox proportional hazards regression, stratified by presence of CAC at baseline. A total of 545 participants without and 765 with prevalent CAC at baseline were included. During a mean 3.3 years between CAC assessments, 177 (32.5%) participants without baseline CAC developed incident CAC while 270 participants (35.3%) with baseline CAC developed a ≥50 Agatston units per year increase in CAC. After multivariable adjustment, incident CAC was associated with 2.42-fold higher rate of atherosclerotic CVD (95% confidence interval [CI]: 1.23-4.79) and 1.82-fold higher rate of all-cause mortality (95% CI: 1.03-3.22). Progressive CAC (≥50 units per year) was not associated with atherosclerotic CVD (hazard ratio [HR]: 1.42; 95% CI: 0.85-2.35) but was associated with a 1.73-fold higher rate of all-cause mortality (95% CI: 1.31-2.28). Progressive CAC was not associated with incident heart failure. Residual confounding and limited statistical power for some outcomes. Among adults with CKD stages 2-4, CAC progression over a mean 3.3 years was associated with higher risk of atherosclerotic CVD and all-cause mortality. The associations were strongest among participants without CAC at baseline.

Ten-year trajectory of coronary artery calcification and risk of cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis.

Whether and how coronary artery calcium (CAC) progress contributes to cardiovascular outcomes has not been fully elucidated. The aim of this study was to identify different patterns of CAC change and evaluate the associations with different cardiovascular outcomes. Data from the Multi-Ethnic Study of Atherosclerosis study were analyzed. Participants with at least three CT measurements were included. The main study outcome is hard cardiovascular disease (CVD). CAC scores were determined as phantom-adjusted Agatston scores. A group-based trajectory model was used to identify latent groups and estimated the hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional regression models. A total of 3,616 participants were finally enrolled [mean age 60.55 (SD 9.54) years, 47.76% men and 39.30% Caucasian]. Four distinct trajectories in CAC were identified: class 1, low-stable (24.17%); class 2, low-increasing (27.60%); class 3, moderate-increasing (30.56%); and class 4, elevated-increasing (17.67%). During 13.58 (SD 2.25) years of follow-up, 291 cases of hard CVD occurred. The event rates of hard CVD per 1,000 person-years were 2.23 (95% CI 1.53-3.25), 4.60 (95% CI 3.60-5.89), 7.67 (95% CI 6.38-9.21) and 10.37 (95% CI 8.41-12.80) for classes 1-4, respectively. Compared to participants assigned to class 1, the full-adjusted HRs of hard CVD for classes 2-4 were 2.10 (95% CI 1.33-3.01), 3.17 (95% CI 2.07-4.87), and 4.30 (95% CI 2.73-6.78), respectively. The graded positive associations with hard CVD were consistently observed in subgroups of age, sex, and race, with the presence or absence of hypertension or diabetes. By analyzing potential risk factors for distinctive CAC trajectories, risk factors for the onset and progression of CAC could possibly differ: age, male sex, history of hypertension, and diabetes are consistently associated with the low-, moderate-, and elevated-increasing trajectories. However, Caucasian race, cigarette smoking, and a higher body mass index was related only to risk of progression but not to incident CAC. In this multi-ethnic population-based cohort, four unique trajectories in CAC change over a 10-year span were identified. These findings signal an underlying high-risk population and may inspire future studies on risk management.

Association of Lipoprotein(a) with Progression of Coronary Artery Calcification: Retrospective Longitudinal Study.

Atherosclerotic cardiovascular disease (ASCVD) is a major health concern, and lipoprotein(a) (Lp(a)) is an independent risk factor. However, there is limited evidence regarding Lp(a) and the risk of ASCVD in Asian populations. This study aimed to assess the predictive value of changes in coronary artery calcification (CAC) for ASCVD risk associated with Lp(a) level. Participants (n=2,750) were grouped according to their Lp(a) levels, and the association between Lp(a) and CAC progression was examined. CAC progression was defined as the occurrence of incident CAC or a difference ≥2.5 between the square root (√) of baseline and follow-up coronary artery calcium scores (CACSs) (Δ√transformed CACS). To adjust for differences in follow-up periods, Δ√transformed CACS was divided by the follow- up period (in years). Over an average follow-up of 3.07 years, 18.98% of participants experienced CAC progression. Those with disease progression had notably higher Lp(a) levels. Higher Lp(a) tertiles correlated with increased baseline and follow-up CACS, CAC progression (%), and Δ√transformed CACS. Even after adjustment, higher Lp(a) levels were associated with CAC progression. However, annualized Δ√transformed CACS analysis yielded no significant results. This study demonstrated an association between elevated Lp(a) levels and CAC progression in a general population without ASCVD. However, longer-term follow-up studies are needed to obtain meaningful results regarding CAC progression. Further research is necessary to utilize Lp(a) level as a predictor of cardiovascular disease and to establish clinically relevant thresholds specific to the Korean population.

Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification.

Background: Patients receiving dialysis have high cardiovascular risk in part due to extensive vascular calcification. In the CaLIPSO study, infusion of hexasodium fytate (SNF472), the hexasodium salt of inositol hexaphosphate, for 52weeks thrice weekly during hemodialysis significantly reduced progression of coronary artery calcification (CAC). This report examines pharmacokinetic/pharmacodynamic (PK/PD) and exposure-efficacy in CaLIPSO. Methods: We measured hexasodium fytate plasma concentrations (PK) by validated liquid chromatography-mass spectroscopy, and hydroxyapatite crystallization in plasma (PD) by validated spectrophotometry. Analyses included patients evaluable for PK, PD, and CAC change (per-protocol analysis). We developed a simple Emax model for maximum concentration (Cmax) and PD effect, and linear and non-linear Emax models for exposure-efficacy among individual average Cmax and absolute and percent changes in CAC score from baseline to week 52. Results: Among evaluable patients receiving placebo (n = 15), 300mg (n = 20), or 600mg (n = 20), average Cmax across visits was not quantifiable (<0.76μM), 15μM, and 46μM, respectively. These results suggest a more-than-proportional increase, without accumulation, with a Cmax ratio of approximately 3 for the doses administered. Average inhibition of hydroxyapatite crystallization was 15%, 61%, and 75%, respectively, and similar across visits. Simple Emax models described 80% maximal effect at exposures >21.9µM and a plateau in exposure-efficacy above the third quartile of Cmax (≥32µM). Conclusion: Hexasodium fytate has exposure-dependent effects on hydroxyapatite crystallization and progression of cardiovascular calcification. Simple Emax models show robust relations among exposure, inhibition of hydroxyapatite crystallization, and change in CAC volume. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier NCT02966028.

Vascular calcification progression and its association with mineral and bone disorder in kidney transplant recipients

Background The assessment and prevention of vascular calcification (VC) in kidney transplant recipients (KTRs) have not been systematically studied. We aimed to evaluate VC change one year after kidney transplantation (KT) and identify their influencing factors. Methods 95 KTRs (68 males; ages 40.2 ± 10.8 years) were followed one year after KT. Changes in bone mineral density (BMD) and bone metabolism biomarkers were assessed. Coronary artery calcification (CAC) and thoracic aortic calcification (TAC) were measured using 192-slice third-generation dual-source CT. The relationship between bone metabolism indicators and VC and the factors influencing VC were analyzed. Results Postoperative estimated glomerular filtration rate was 79.96 ± 24.18 mL/min*1.73 m2. One year after KT, serum phosphorus, intact parathyroid hormone (iPTH), osteocalcin, type I collagen N-terminal peptide (NTx), type I collagen C-terminal peptide, and BMD decreased, 25-hydroxyvitamin D remained low, and VC increased. Post-CAC and TAC were negatively correlated with pre-femoral neck BMD, and TAC was positively correlated with post-calcium. CAC and TAC change were positively correlated with post-calcium and 25-hydroxyvitamin D. Increased CAC was positively associated with hemodialysis and pre-femoral neck osteopenia. CAC change was positively associated with prediabetes, post-calcium, and pre-CAC and negatively associated with preoperative and postoperative femoral neck BMD, and NTx change. Increased TAC was positively associated with age, prediabetes, preoperative parathyroid hyperplasia/nodule, post-calcium, and post-femoral neck osteopenia. TAC change was positively associated with age, diabetes, pre-triglyceride, pre-TAC, dialysis time, post-calcium and post-iPTH, and negatively associated with post-femoral neck BMD. Conclusions Mineral and bone disorders persisted, and VC progressed after KT, showing a close relationship.

Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study.

Physical activity and exercise training are associated with a lower risk for coronary events. However, cross-sectional studies in middle-aged and older male athletes revealed increased coronary artery calcification (CAC) and atherosclerotic plaques, which were related to the amount and intensity of lifelong exercise. We examined the longitudinal relationship between exercise training characteristics and coronary atherosclerosis. Middle-aged and older men from the MARC-1 (Measuring Athlete's Risk of Cardiovascular Events 1) study were invited for follow-up in MARC-2 (Measuring Athlete's Risk of Cardiovascular Events 2) study. The prevalence and severity of CAC and plaques were determined by coronary computed tomography angiography. The volume (metabolic equivalent of task [MET] hours/week) and intensity (moderate [3 to 6 MET hours/week]; vigorous [6 to 9 MET hours/week]; and very vigorous [≥9 MET hours/week]) of exercise training were quantified during follow-up. Linear and logistic regression analyses were performed to determine the association between exercise volume/intensity and markers of coronary atherosclerosis. We included 289 (age, 54 [50 to 60] years [median (Q1 to Q3)]) of the original 318 MARC-1 participants with a follow-up of 6.3±0.5 years (mean±SD). Participants exercised for 41 (25 to 57) MET hours/week during follow-up, of which 0% (0 to 19%) was at moderate intensity, 44% (0 to 84%) was at vigorous intensity, and 34% (0 to 80%) was at very vigorous intensity. Prevalence of CAC and the median CAC score increased from 52% to 71% and 1 (0 to 32) to 31 (0 to 132), respectively. Exercise volume during follow-up was not associated with changes in CAC or plaque. Vigorous intensity exercise (per 10% increase) was associated with a lesser increase in CAC score (β, -0.05 [-0.09 to -0.01]; P=0.02), whereas very vigorous intensity exercise was associated with a greater increase in CAC score (β, 0.05 [0.01 to 0.09] per 10%; P=0.01). Very vigorous exercise was also associated with increased odds of dichotomized plaque progression (adjusted odds ratio [aOR], 1.09 [1.01 to 1.18] per 10%; aOR, 2.04 [0.93 to 4.15] for highest versus lowest very vigorous intensity tertiles, respectively), and specifically with increased calcified plaques (aOR, 1.07 [1.00 to 1.15] per 10%; aOR, 2.09 [1.09 to 4.00] for highest versus lowest tertile, respectively). Exercise intensity but not volume was associated with progression of coronary atherosclerosis during 6-year follow-up. It is intriguing that very vigorous intensity exercise was associated with greater CAC and calcified plaque progression, whereas vigorous intensity exercise was associated with less CAC progression.

Abstract MP25: Physical Activity And The Progression Of Coronary Artery Calcification

Introduction: High volume endurance physical activity (PA) has been shown to associate with increased clinically relevant coronary artery calcification (CAC) but not mortality. A key issue is whether active individuals with CAC have progression of atherosclerosis in the setting of sustained high levels of PA. Hypothesis: We hypothesized that changes in CAC are not related to corresponding changes in PA volume. Further, we hypothesized the rate of CAC progression to ≥100 Agatston units (AU) does not depend on baseline PA level. Methods: The study included 6,525 men and 2,056 women with ≥2 assessments of PA and CAC (EBT scans (1997-2007) or MDCT scans (2007-2019)). All individuals had at least one follow-up visit (mean=1.8). We used mixed linear regression to relate within-person changes in square-root CAC to changes in PA volume, controlling for between-person effects. We used interval-censored proportional hazards regression to test if progression to CAC≥100 AU was related to baseline PA level: ≥3000, 1500-2999, and &lt;1500 MET·minutes/week (MET·min/wk). Covariates included age, smoking, BMI, glucose, cholesterol, systolic blood pressure, and statin use. In addition, the longitudinal analysis was adjusted for time since baseline, while the time-to-CAC-threshold analysis was adjusted for baseline CAC. Results: Mean baseline age was 50 years in men/51 years in women. Mean time to first follow-up was 4.5 years in men/5.1 years in women. PA levels increased by 100 MET·min/wk in men but were stable in women. Cardiorespiratory fitness was stable between visits. Within person changes in CAC were not associated with changes in PA volume (Table). At baseline, 5285 men and 1948 women had CAC&lt;100 AU; at follow-up, 1127 men and 136 women progressed to CAC≥100 AU. Neither PA ≥3000 nor 1500-2999 MET·min/wk exhibited significant risk of CAC progression versus &lt;1500 MET·min/wk. Estimated hazard ratios were ≤1 for both men and women. Conclusions: These results show no apparent risk of increasing CAC with sustained PA in active individuals.

Abstract 11985: Association of GlycA and Progression of Coronary Artery Calcification: The Multi-Ethnic Study of Atherosclerosis

Background: GlycA, a composite biomarker of systemic inflammation, predicts cardiovascular morbidity and mortality. Despite growing evidence regarding the association of GlycA and CVD, there are no data about the association of GlycA with coronary artery calcium (CAC), a marker of subclinical atherosclerosis. Objective: To investigate the relationship between GlycA levels and progression of CAC. Methods: MESA is a multiethnic cohort study of 6814 men and women aged 45-84 years, free of clinical CVD at baseline. Serum level of GlycA was measured by nuclear magnetic resonance (NMR) spectroscopy at baseline. CAC score was assessed by CT at baseline and follow up using either a cardiac gated electron beam CT scanner or 4-16 detector CT systems. Progression of CAC from baseline was defined as average yearly change in Agatston score &gt;= 3 for CAC 0 to 100 and &gt;=10% for CAC &gt;100. Mean follow up period was 9.6±0.6 years. Multivariate regression analysis was performed adjusting for atherosclerotic risk factors. Results: Cross-sectional mean GlycA level, stratified by race/ethnicity, was higher in those with CAC &gt; 0 compared to no CAC across all race/ethnicity groups and in both men and women (Fig1A). In regression analysis, the progression of annualized CAC was associated with higher baseline GlycA levels (Fig1B). Analysis was stratified due to interaction between GlycA and BMI (Fig2). In multivariable adjusted models, a one unit increase in GlycA was related to 0.23% higher average annual CAC change in normal BMI (p=0.002). In those who were excess weight (BMI &gt;25) one unit increase in GlycA was associated with a 0.04% yearly average CAC change, after adjusting for covariates(p=0.07). Conclusion: Participants with higher baseline GlycA levels have CAC &gt;0 as compared to lower baseline GlycA levels. The annualized progression of CAC is also higher in participants with baseline elevated GlycA levels. This association was statistically significant in participants with normal BMI.

Abstract 11774: Coronary Artery Calcium and All-Cause Mortality

Objectives: Coronary artery calcium (CAC) has been demonstrated as a non-invasive, low-cost means of assessing atherosclerotic burden and risk of major cardiovascular events in asymptomatic individuals. While it has been previously shown that CAC progression predicts all-cause mortality, we sought to further quantify this association by examining a large cohort of individuals over a follow-up period of between 1 to 22 years. Methods: We studied 3,260 persons aged 30 to 89 years who were referred by their primary care physician for CAC measurement, and had a follow-up scan at least 12 months from initial scan. CAC change was evaluated by absolute change between baseline and follow-up scan. Multivariate analyses using Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between CAC progression and death after adjusting for age, gender, race and other risk factors. Participants were considered at risk from the date of exam 1 to the first occurrence of an event of death or lost to follow-up. The occurrence of death across the follow-up period was verified with the National Death Index. Results: The average time between scans was 4.7±3.2 years with an additional average of 9.1±4.0 years of follow-up time. The average age of the cohort was 58.1 ±10.5 years, 70% being male. A total of 164 deaths occurred. A clinical cut point of CAC progression of 100 units was significantly associated with mortality, hazard ratio 1.51 (95% CI 1.10 -2.13) P=0.017, while adjusting for age, gender, race, diabetes mellitus, hypertension, hyperlipidemia, smoking, baseline CAC and family history. Figure 1. Conclusions: CAC progression of greater than 100 units predicts all-cause mortality. This may add clinical value in encouraging close surveillance and aggressive treatment of individuals within this range.

Beta-2-glycoprotein-I IgA antibodies predict coronary plaque progression in rheumatoid arthritis

ObjectivesTo evaluate whether anti-Beta-2-Glycoprotein-I (anti-β2GPI) IgA antibodies associate with progression of coronary atherosclerosis and cardiovascular disease (CVD) events in rheumatoid arthritis (RA). MethodsOne hundred-fifty patients underwent plaque evaluation (total, non-calcified, mixed and calcified) with coronary computed tomography angiography; 101 were re-imaged within 6.9±0.3 years to assess progression. The Framingham-D'Agostino score assessed cardiovascular risk. Coronary artery calcium (CAC) and segment involvement score quantified plaque burden. ResultsAnti-β2GPI IgA were seen in 45 (30%) patients. Despite no link to baseline plaque burden, anti-β2GPI IgA associated with segment involvement score increase (adjusted-RR=1.64 [95%CI 1.02–2.63]), CAC change (adjusted-β=0.33 [95%CI 0.002–0.656]) and developing new extensive or obstructive plaque at follow-up (adjusted-OR=4.24 [95%CI 1.30–13.87]). Adding anti-β2GPI IgA to logistic regression models with conventional risk factors predicting plaque progression outcomes increased Area under the receiver-operator curve and improved Net Reclassification and Integrated Discrimination Improvement indices (all P<0.05). In per-segment analyses, anti-β2GPI IgA predicted mixed plaque formation (adjusted-OR=3.20 [95%CI 1.01–10.09]) and lower likelihood of transition of mixed to calcified plaque (adjusted-OR=0.19 [95%CI 0.04–0.96]). Anti-β2GPI IgA moderated the effect of C-reactive protein on CAC change such that C-reactive protein associated with CAC change (β=0.26 [95%CI 0.14–0.38]) and CVD risk (adjusted-HR=1.89 [95%CI 1.02–3.51]) only in anti-β2GPI IgA positive patients. ConclusionAnti-β2GPI IgA addition to clinical risk models improved prediction accuracy of CAC, plaque progression and transition to extensive/obstructive disease. They associated with new high-risk mixed plaques and delayed healing to calcified lesions. Anti-β2GPI IgA further modified the effect of inflammation on plaque progression and CVD events.

Abstract 12911: Association of Lipoprotein (a) and Coronary Artery Calcification: Prospective Study Assessing Interactions With Other Risk Factors in the Multi-Ethnic Study of Atherosclerosis

Introduction: Elevated plasma lipoprotein (a) [Lp(a)] and coronary artery calcification (CAC) are established cardiovascular disease (CVD) risk factors that correlate with each other. In this study we hypothesized that other CVD risk factors could modify the relationship between baseline Lp(a) levels and CAC change over time. Methods: A total of 5975 participants from the Multi-Ethnic Study of Atherosclerosis were analyzed. All participants were 45-84 years old, free of apparent CVD at baseline and from one of four major ethnic groups (non-Hispanic white, African American, Hispanic American, and Chinese American). We tested for interactions of 24 study variables related to dyslipidemia, diabetes, insulin resistance, hypertension, inflammation and coagulation with baseline Lp(a) on change in CAC volume and density over 9.5 years. Results: Elevated Lp(a) was associated with larger annual absolute increase in CAC volume (3.21 and 4.45 mm 3 /year higher for Lp(a) ≥30 versus &lt;30 mg/dL, and Lp(a) ≥50 versus &lt;50 mg/dL, respectively, both P &lt;0.05), but not in CAC density. The association of elevated Lp(a) with absolute change in CAC volume was more prominent in African Americans and Hispanic Americans, than other ethnic groups ( P for interaction &lt;0.05). After multiple testing correction of 24 study variables, the association of elevated Lp(a) (≥30 mg/dL) with annual absolute change in CAC volume was greater in participants with higher levels of interleukin-2 soluble receptor α, soluble tumor necrosis factor receptor 1 and fibrinogen (change = 15.33, 11.81 and 7.02 mm 3 /year in quartile 4, compared to -3.44, -0.59 and 1.91 mm 3 /year in quartile 1, respectively). A similar trend was seen when expressing Lp(a) ≥50 mg/dL as elevated levels. There were no associations for ln-transformed Lp(a) as a continuous variable, or when assessing the annual relative change in CAC volume and density. Conclusions: Elevated Lp(a) was associated with the progression of CAC volume, especially in participants with higher levels of selected markers of inflammation and coagulation. This study suggests that inflammation and coagulation may modify the relation between Lp(a) and CAC.

Association Between Fasting Glucose Variability in Young Adulthood and the Progression of Coronary Artery Calcification in Middle Age.

To investigate whether intraindividual variability of fasting glucose (FG) in young adulthood is associated with coronary artery calcification (CAC) progression in middle age. We included 2,256 CARDIA (Coronary Artery Risk Development Study in Young Adults) participants with CAC assessment by computed tomography scanner at baseline (2000-2001) and 10 years later (2010-2011). CAC progression was assessed for each individual as the difference of logarithmic CAC scores at follow-up and baseline (log[CAC (follow-up) + 1] - log[CAC (baseline) + 1]). FG variability was defined by the coefficient of variation about the mean FG (FG-CV), the SD of FG (FG-SD), and the average real variability of FG (FG-ARV) during the 10-year follow-up. We investigated the association between FG variability and CAC progression with adjustment for demographics, clinical risk factors, mean FG level, change in FG level, diabetes incidence, and medication use. After multivariable adjustment, 1-SD increment in FG-CV was associated with worse progression of CAC as demonstrated as percent change in CAC, with incident CAC 5.9% (95% CI 1.0, 10.7) and any CAC progression 6.7% (95% CI 2.3, 11.1) during 10 years. Similar findings were also observed in FG-SD and FG-ARV. Higher FG variability during young adulthood was associated with greater CAC progression in middle age, suggesting its value in predicting risk for subclinical coronary artery diseases.

Vitamin D Analogues and Coronary Calcification in CKD Stages 3 and 4: A Randomized Controlled Trial of Calcitriol Versus Paricalcitol

Rationale & ObjectiveMineral and bone disorder in chronic kidney disease (CKD) is associated with progression of coronary artery calcification (CAC). Mineral and bone disorder often is treated with calcitriol and other vitamin D receptor activators, including paricalcitol, agents that may have differential effects on calcium, phosphate, and parathyroid hormone levels. Accordingly, we investigated whether these agents have differential effects on CAC progression in patients with CKD.Study DesignRandomized, double-concealed, 48-week clinical trial.Setting & ParticipantsCKD stage 3 or 4 with secondary hyperparathyroidism with CAC score > 0 and no prior treatment with activated vitamin D.InterventionCalcitriol versus paricalcitol.OutcomesThe primary outcome was log-transformed CAC change. Secondary outcomes included percent change in CAC volume, valvular calcifications, and bone mineral metabolism markers.ResultsAmong 44 individuals randomly assigned, mean age was 65 years and mean estimated glomerular filtration rate was 27 mL/min/1.73 m2. Median CAC score was 140 (IQR, 55-277) Agatston units at baseline. There was no significant difference in CAC progression between treatment arms (P = 0.06). After adjustment for baseline CAC score (log), treatment group remains nonsignificant (P = 0.08). Further adjustment for creatinine level and/or CKD stage did not change the association. In secondary analyses adjusting for dose level of activated vitamin D, treatment group was significant (P = 0.01), and when dose level was also included in the model, the coefficient for individuals in the paricalcitol group was significantly associated with CAC progression (P = 0.02). An interaction term between dosing level and CKD stage was significant at the highest dosing level (P = 0.04).LimitationsPilot single-center study.ConclusionsIn patients with CKD with secondary hyperparathyroidism naive to activated vitamin D therapy, there was no difference in CAC or valvular progression in participants receiving calcitriol compared with paricalcitol during a 48-week period.FundingAbbvie, Inc.Trial RegistrationNCT00752102

P5305Oxidized high-density lipoprotein is associated with progression of coronary artery calcification

Abstract Introduction As a residual cardiovascular risk, high-density lipoprotein (HDL) is of great interest in lipid management. Native HDL has an anti-atherogenic role, while oxidized HDL (oxHDL) has atherogenic property because of reduced anti-inflammatory properties compared with native HDL. Meanwhile, recent studies showed that rapid progression of coronary artery calcification (CAC), a marker of subclinical atherosclerosis, was associated with greater incidence of cardiovascular events. However, the role of oxHDL in the pathogenesis of CAC remains unclear. Purpose The purpose of this study was to examine the association between the annual change in oxHDL and the progression of CAC (Agatston score) in a substudy of prospective multicenter randomized study. Methods In the principal study, patients with a CAC score of 1 to 999 were treated with pitavastatin with/without eicosapentaenoic acid. Measurement of CAC with MDCT and a blood test were performed at baseline and at the 1-year follow-up. The principal study showed 30–40% of annual change in CAC in all patients and no difference in the progression of CAC among treatment groups. In this substudy (n=140), patients were divided into 2 groups: CAC progression (change in Agatston score of &gt;0, n=103) and no CAC progression (n=37). The serum concentration of oxHDL was measured using an antibody against oxidized human apoA-I with ELISA. The difference in oxHDL between patients with hypercholesterolemia and healthy subjects (n=30) was also evaluated. Results OxHDL levels were significantly lower in healthy subjects than in patients with hypercholesterolemia (150 [107–176] and 167 [132–246], respectively; median [25th-75th percentile], U/ml) (p=0.006). The baseline log-transformed oxHDL level was correlated with total cholesterol (r=0.21, p=0.01), HDL-cholesterol (r=0.33, p&lt;0.01), and triglycerides (r=−0.21, p=0.01), but not correlated with age, body mass index, hemoglobinA1c, LDL-cholesterol, serum creatinine, or high-sensitivity C-reactive protein. After treatment, the oxHDL level significantly decreased from 167 (132–246) at baseline to 122 (103–149) (median [25th–75th percentile], U/ml) (p&lt;0.001). The annual change in CAC was significantly positively associated with changes in oxHDL (r=0.17, p=0.04), triglycerides (r=0.17, p=0.04), and hsCRP (r=0.22, p=0.01) but not associated with changes in LDL-C or HDL-C. Multiple logistic analysis demonstrated that the decrease in oxHDL per 10 U/ml was independently associated with CAC progression after adjusting for variables including baseline oxHDL, LDL-cholesterol, Agatston score and current smoking (odds ratio, 0.95; 95% confidence interval, 0.90–0.99; p=0.04). Conclusion The decrease in oxHDL is associated with the attenuation of CAC progression, suggesting that oxHDL is a potential target for preventing atherosclerosis.

The association between progression of coronary artery calcium and colorectal adenoma: A retrospective follow-up study of asymptomatic Koreans.

The potential relationship between coronary artery calcium (CAC) and colorectal adenoma has been widely indicated. This study aimed to investigate the relationship between the risk of colorectal adenoma and CAC progression in asymptomatic Korean adults who underwent serial assessments by colonoscopy and CAC scan.A total of 754 asymptomatic participants, who had undergone serial CAC scans and colonoscopies for screening, were enrolled. Changes in CAC were assessed according to the absolute change between baseline and follow-up results. CAC progression was defined using Multi-Ethnic Study of Atherosclerosis method. Risk for adenoma at follow-up colonoscopy was determined using hazard ratio (HR) by Cox regression. The area under the receiver operating characteristic (ROC) curve was measured.The mean follow-up duration was 3.4 ± 2.5 years. CAC progression was found in 215 participants (28.5%). Participants with adenoma at index colonoscopy showed a higher rate of CAC progression than those without (38.8% vs 23.6%, P < .01). In participants with adenoma at index colonoscopy, CAC progression significantly increased the cumulative risk for adenoma at follow-up colonoscopy (HR = 1.48, 95% confidence interval [CI] 1.06-2.06, log-rank P = .021). In multivariate analysis, male sex (HR = 2.57, 95% CI 1.22-5.42, P = .013), ≥3 adenomas at index colonoscopy (HR = 2.60, 95% CI 1.16-5.85, P = .021), and CAC progression (HR = 2.74, 95% CI 1.48-5.08, P = .001) increased the risk of adenoma at follow-up colonoscopy. In participants without adenoma at index colonoscopy, neither baseline CAC presence nor CAC progression increased the risk of adenoma at follow-up colonoscopy. The interaction between CAC progression and adenoma at index colonoscopy was significant in multivariable model (P = .005). In the ROC analysis, AUC of CAC progression for adenoma at follow-up colonoscopy was 0.625 (95% CI 0.567-0.684, P < .001) in participants with adenoma at index colonoscopy.Participants with CAC progression, who are at high risk of coronary atherosclerosis, may need to be considered for follow-up evaluation of colorectal adenoma, especially those with adenoma at index colonoscopy.

Coronary Artery Calcium From Early Adulthood to Middle Age and Left Ventricular Structure and Function.

Background The relationship of coronary artery calcium (CAC) with adverse cardiac remodeling is not well established. We aimed to study the association of CAC in middle age and change in CAC from early adulthood to middle age with left ventricular (LV) function. Methods CAC score was measured by computed tomography at CARDIA study (Coronary Artery Risk Development in Young Adults) year-15 examination and at year-25 examination (Y25) in 3043 and 3189 participants, respectively. CAC score was assessed as a continuous variable and log-transformed to account for nonlinearity. Change in CAC from year-15 examination to Y25 was evaluated as the absolute difference of log-transformed CAC from year-15 examination to Y25. LV structure and function were evaluated by echocardiography at Y25. Results At Y25, mean age was 50.1±3.6 years, 56.6% women, 52.4% black. In the multivariable analysis at Y25, higher CAC was related to higher LV mass (β=1.218; adjusted P=0.007), higher LV end-diastolic volume (β=0.811; adjusted P=0.007), higher LV end-systolic volume (β=0.350; adjusted P=0.048), higher left atrial volume (β=0.214; adjusted P=0.009), and higher E/e' ratio (β=0.059; adjusted P=0.014). CAC was measured at both year-15 examination and Y25 in 2449 individuals. Higher change in CAC score during follow-up was independently related to higher LV mass index in blacks (β=4.789; adjusted P<0.001), but not in whites (β=1.051; adjusted P=0.283). Conclusions Higher CAC in middle age is associated with higher LV mass and volumes and worse LV diastolic function. Being free of CAC from young adulthood to middle age correlates to better LV function at middle age. Higher change in CAC score during follow-up is independently related to higher LV mass index in blacks.

A Randomized Trial of Magnesium Oxide and Oral Carbon Adsorbent for Coronary Artery Calcification in Predialysis CKD.

Developing strategies for managing coronary artery calcification (CAC) in patients with CKD is an important clinical challenge. Experimental studies have demonstrated that magnesium inhibits vascular calcification, whereas the uremic toxin indoxyl sulfate aggravates it. To assess the efficacy of magnesium oxide (MgO) and/or the oral carbon adsorbent AST-120 for slowing CAC progression in CKD, we conducted a 2-year, open-label, randomized, controlled trial, enrolling patients with stage 3-4 CKD with risk factors for CAC (diabetes mellitus, history of cardiovascular disease, high LDL cholesterol, or smoking). Using a two-by-two factorial design, we randomly assigned patients to an MgO group or a control group, and to an AST-120 group or a control group. The primary outcome was percentage change in CAC score. We terminated the study prematurely after an interim analysis with the first 125 enrolled patients (of whom 96 completed the study) showed that the median change in CAC score was significantly smaller for MgO versus control (11.3% versus 39.5%). The proportion of patients with an annualized percentage change in CAC score of ≥15% was also significantly lower for MgO compared with control (23.9% versus 62.0%). However, MgO did not suppress the progression of thoracic aorta calcification. The MgO group's dropout rate was higher than that of the control group (27% versus 17%), primarily due to diarrhea. The percentage change in CAC score did not differ significantly between the AST-120 and control groups. MgO, but not AST-120, appears to be effective in slowing CAC progression. Larger-scale trials are warranted to confirm these findings.

Effect of bixalomer on coronary artery calcification in hemodialysis patients with hyperphosphatemia: a multi-center, randomized controlled trial

BackgroundCalcium carbonate is a first-line therapy for hyperphosphatemia in hemodialysis patients but is associated with progressive coronary and aortic calcification. Sevelamer compounds are alternatives to calcium-containing phosphate binders as they contain lower calcium levels. The sevelamer compound, bixalomer, is a calcium-free insoluble polymer that has been shown to be effective and safe in comparison with calcium carbonate. We therefore compared the effect of bixalomer vs calcium carbonate on coronary artery calcification in hemodialysis patients with hyperphosphatemia.MethodsIn this open-label, randomized phase IV trial across 23 sites throughout Japan, 85 patients with chronic kidney disease were randomized to bixalomer (n = 44) or calcium carbonate (n = 41) therapy and monitored for 12 months. Bixalomer was administered at a dosage of 1500 mg/day (500 mg three times a day) and calcium carbonate was administered at a dosage of 3000 mg/day (1000 mg three times a day). The primary outcome was the change in coronary artery calcium over time measured using computed tomography. Levels of serum phosphorus, calcium, intact parathyroid hormone, and the occurrence of adverse events were also reported over the course of the study.ResultsThe mean (± standard deviation) changes in coronary artery calcium scores from baseline to 12 months were significantly higher in the calcium carbonate vs bixalomer group (268.6 ± 320.1 vs 126.7 ± 154.8, respectively; between-group difference p = 0.029). At 12 months in the bixalomer group, serum phosphorus and intact parathyroid hormone levels were significantly higher; serum calcium was significantly lower (p < 0.05). The most frequent adverse events were shunt stenosis in the bixalomer group, and shunt stenosis and common cold in the calcium carbonate group. There were no significant between-group differences in adverse drug reaction incidences.ConclusionsThe safety profile of bixalomer was comparable to that of calcium carbonate. Bixalomer further reduced coronary artery calcification, compared with calcium carbonate, in hemodialysis patients with hyperphosphatemia.Trial registrationUMIN/R000015330 Registered 13 February 2014

Decrease in oxidized high-density lipoprotein is associated with slowed progression of coronary artery calcification: Subanalysis of a prospective multicenter study

Background and aimsOxidized high-density lipoprotein (oxHDL) is characterized by reduced anti-inflammatory properties compared with HDL. However, the role of oxHDL in the pathogenesis of coronary artery calcification (CAC), a marker of subclinical atherosclerosis, remains unclear. We prospectively investigated the association between the change in oxHDL and progression of CAC in a substudy of a multicenter study. MethodsIn the principal study, patients with a CAC score of 1–999 were treated with pitavastatin with/without eicosapentaenoic acid. Measurement of CAC with multidetector-row computed tomography and a blood test were performed at baseline and at the 1-year follow-up. In the principal study, the increase in CAC did not differ among treatment groups. In this substudy, patients were divided into two groups: CAC progression (change in Agatston score of >0) and no CAC progression. ResultsIn total, 140 patients were analyzed. The oxHDL level significantly decreased from 167 (132–246) at baseline to 122 (103–149) after treatment (median [25th–75th percentile], U/ml) (p < 0.001). The annual change in CAC was significantly positively associated with changes in oxHDL (r = 0.17, p = 0.04), triglycerides (r = 0.17, p = 0.04), and high-sensitivity C-reactive protein (r = 0.22, p = 0.01) but was not associated with changes in low-density lipoprotein cholesterol or HDL-cholesterol. Multiple logistic analysis demonstrated that the decrease in oxHDL per 10 U/ml was independently associated with CAC progression (odds ratio, 0.95; 95% confidence interval, 0.90–0.99; p = 0.04). ConclusionsThe decrease in oxHDL is associated with the attenuation of CAC progression, suggesting that oxHDL is a potential target for atherosclerosis prevention.