Coronary Artery Calcium to Improve the Efficiency of Randomized Controlled Trials in Primary Cardiovascular Prevention

ObjectivesThis study sought to assess the value, in terms of sample size and cost, of using the coronary artery calcium (CAC) score to enrich the study population of primary prevention randomized controlled trials (RCTs) with participants at high absolute risk of atherosclerotic cardiovascular disease (ASCVD) events.BackgroundThe feasibility of RCTs assessing the efficacy of novel add-on therapies for primary prevention among high-risk individuals treated with statins may be limited by sample size and cost.MethodsWe evaluated 3,075 statin-naive participants from the MESA (Multi-Ethnic Study of Atherosclerosis) with estimated 10-year ASCVD risk of ≥7.5%. CAC of >100, CAC of >400, high sensitivity C-reactive protein levels of >2 and >3 mg/l, ankle-brachial index of <0.9, and triglyceride levels of >175 mg/dl were each evaluated as enrichment criteria on top of estimated ASCVD risk of ≥7.5%, ≥10%, ≥15% and ≥20%. For each criterion, using the observed 5-year incidence of CVD, we projected the incidence of CVD assuming a 28% relative risk reduction with high-intensity statin therapy and after addition of novel therapy with additive relative risk reductions of 15% and 25%. Sample size and cost of a hypothetical primary prevention 5-year RCT of a novel therapy on top of statins versus statins alone were then computed by using the projected incidences. Yearly costs per included participant of $6,000 to $9,000 and of $500/$600 per screened nonparticipant were assumed.ResultsCAC of >400, present in 15% to 23% participants, consistently identified the subgroups with highest 5-year incident events and outperformed the other features yielding the smallest projected sample size, ranging 33% to 58% lower than using risk estimations alone for participant selection. CAC of >400 also yielded the lowest projected RCT costs, at least $40 million lower than using risk estimations alone. CAC of >100 showed the second-best performance in most scenarios.ConclusionsHigh CAC scores used as study entry criteria can improve the efficiency and feasibility of primary prevention RCTs evaluating the incremental efficacy of novel add-on therapies.     

Warranty Period of a Calcium Score of Zero: Comprehensive Analysis From MESA

ObjectivesThis study sought to quantify and model conversion of a normal coronary artery calcium (CAC) scan to an abnormal CAC scan.BackgroundAlthough the absence of CAC is associated with excellent prognosis, progression to CAC >0 confers increased risk. The time interval for repeated scanning remains poorly defined.MethodsThis study included 3,116 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) with baseline CAC = 0 and follow-up scans over 10 years after baseline. Prevalence of incident CAC, defined by thresholds of CAC >0, CAC >10, or CAC >100, was calculated and time to progression was derived from a Weibull parametric survival model. Warranty periods were modeled as a function of sex, race/ethnicity, cardiovascular risk, and desired yield of repeated CAC testing. Further analysis was performed of the proportion of coronary events occurring in participants with baseline CAC = 0 that preceded and followed repeated CAC testing at different time intervals.ResultsMean participants’ age was 58 ± 9 years, with 63% women, and mean 10-year cardiovascular risk of 14%. Prevalence of CAC >0, CAC >10, and CAC >100 was 53%, 36%, and 8%, respectively, at 10 years. Using a 25% testing yield (number needed to scan [NNS] = 4), the estimated warranty period of CAC >0 varied from 3 to 7 years depending on sex and race/ethnicity. Approximately 15% of participants progressed to CAC >10 in 5 to 8 years, whereas 10-year progression to CAC >100 was rare. Presence of diabetes was associated with significantly shorter warranty period, whereas family history and smoking had small effects. A total of 19% of all 10-year coronary events occurred in CAC = 0 prior to performance of a subsequent scan at 3 to 5 years, whereas detection of new CAC >0 preceded 55% of future events and identified individuals at 3-fold higher risk of coronary events.ConclusionsIn a large population of individuals with baseline CAC = 0, study data provide a robust estimation of the CAC = 0 warranty period, considering progression to CAC >0, CAC >10, and CAC >100 and its impact on missed versus detectable 10-year coronary heart disease events. Beyond age, sex, race/ethnicity, diabetes also has a significant impact on the warranty period. The study suggests that evidence-based guidance would be to consider rescanning in 3 to 7 years depending on individual demographics and risk profile.     

The Added Value of Coronary Calcium Score in Predicting Cardiovascular Events in Familial Hypercholesterolemia

ObjectivesThis study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH).BackgroundCommon cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD).MethodsREFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death.ResultsWe included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%.ConclusionsCAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH.     

Impacto de los tratamientos hipolipemiantes en los resultados cardiovasculares según la puntuación de calcio coronario. Revisión sistemática y metanálisis

Introduction and objectivesCoronary artery calcium (CAC) score improves the accuracy of risk stratification for atherosclerotic cardiovascular disease (ASCVD) events compared with traditional cardiovascular risk factors. We evaluated the interaction of coronary atherosclerotic burden as determined by the CAC score with the prognostic benefit of lipid-lowering therapies in the primary prevention setting.MethodsWe reviewed the MEDLINE, EMBASE, and Cochrane databases for studies including individuals without a previous ASCVD event who underwent CAC score assessment and for whom lipid-lowering therapy status stratified by CAC values was available. The primary outcome was ASCVD. The pooled effect of lipid-lowering therapy on outcomes stratified by CAC groups (0, 1-100, > 100) was evaluated using a random effects model.ResultsFive studies (1 randomized, 2 prospective cohort, 2 retrospective) were included encompassing 35 640 individuals (female 38.1%) with a median age of 62.2 [range, 49.6-68.9] years, low-density lipoprotein cholesterol level of 128 (114-146) mg/dL, and follow-up of 4.3 (2.3-11.1) years. ASCVD occurrence increased steadily across growing CAC strata, both in patients with and without lipid-lowering therapy. Comparing patients with (34.9%) and without (65.1%) treatment exposure, lipid-lowering therapy was associated with reduced occurrence of ASCVD in patients with CAC > 100 (OR, 0.70; 95%CI, 0.53-0.92), but not in patients with CAC 1-100 or CAC 0. Results were consistent when only adjusted data were pooled.ConclusionsAmong individuals without a previous ASCVD, a CAC score > 100 identifies individuals most likely to benefit from lipid-lowering therapy, while undetectable CAC suggests no treatment benefit.Full English text available from:www.revespcardiol.org/en     

Mean Versus Peak Coronary Calcium Density on Non-Contrast CT: Calcium Scoring and ASCVD Risk Prediction

ObjectivesThis study sought to assess the relationship between mean vs peak calcified plaque density and their impact on calculating coronary artery calcium (CAC) scores and to compare the corresponding differential prediction of atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD) mortality.BackgroundThe Agatston CAC score is quantified per lesion as the product of plaque area and a 4-level categorical peak calcium density factor. However, mean calcium density may more accurately measure the heterogenous mixture of lipid-rich, fibrous, and calcified plaque reflective of ASCVD risk.MethodsWe included 10,373 individuals from the CAC Consortium who had CAC >0 and per-vessel measurements of peak calcium density factor and mean calcium density. Area under the curve and continuous net reclassification improvement analyses were performed for CHD and ASCVD mortality to compare the predictive abilities of mean calcium density vs peak calcium density factor when calculating the Agatston CAC score.ResultsParticipants were on average 53.4 years of age, 24.4% were women, and the median CAC score was 68 Agatston units. The average values for mean calcium density and peak calcium density factor were 210 ± 50 HU and 3.1 ± 0.5, respectively. Individuals younger than 50 years of age and/or those with a total plaque area <100 mm² had the largest differences between the peak and mean density measures. Among persons with CAC 1-99, the use of mean calcium density resulted in a larger improvement in ASCVD mortality net reclassification improvement (NRI) (NRI = 0.49; P < 0.001 vs. NRI = 0.18; P = 0.08) and CHD mortality discrimination (Δ area under the curve (AUC) = +0.169 vs +0.036; P < 0.001) compared with peak calcium density factor. Neither peak nor mean calcium density improved mortality prediction at CAC scores >100.ConclusionMean and peak calcium density may differentially describe plaque composition early in the atherosclerotic process. Mean calcium density performs better than peak calcium density factor when combined with plaque area for ASCVD mortality prediction among persons with Agatston CAC 1-99.     

Discordance Between Coronary Artery Calcium Area and Density Predicts Long-Term Atherosclerotic Cardiovascular Disease Risk

BackgroundCoronary artery calcium (CAC) is commonly quantified as the product of 2 generally correlated measures: plaque area and calcium density.ObjectivesThe authors sought to determine whether discordance between calcium area and density has long-term prognostic importance in atherosclerotic cardiovascular disease (ASCVD) risk.MethodsThe authors studied 10,373 primary prevention participants from the CAC Consortium with CAC >0. Based on their median values, calcium area and mean calcium density were divided into 4 mutually exclusive concordant/discordant groups. Cox proportional hazards regression assessed the association of calcium area/density groups with ASCVD mortality over a median of 11.7 years, adjusting for traditional risk factors and the Agatston CAC score.ResultsThe mean age was 56.7 years, and 24% were female. The prevalence of plaque discordance was 19% (9% low calcium area/high calcium density, 10% high calcium area/low calcium density). Female sex (odds ratio [OR]: 1.48 [95% CI: 1.27-1.74]) and body mass index (OR: 0.81 [95% CI: 0.76-0.87], per 5 kg/m² higher) were significantly associated with high calcium density discordance, whereas diabetes (OR: 2.23 [95% CI: 1.85-3.19]) was most strongly associated with discordantly low calcium density. Compared to those with low calcium area/low calcium density, individuals with low calcium area/high calcium density had a 71% lower risk of ASCVD death (HR: 0.29 [95% CI: 0.09-0.95]).ConclusionsFor a given CAC score, high calcium density relative to plaque area confers lower long-term ASCVD risk, likely serving as an imaging marker of biological resilience for lesion vulnerability. Additional research is needed to define a robust definition of calcium area/density discordance for routine clinical risk prediction.     

Coronary Artery Calcium for Risk Stratification of Sudden Cardiac Death: The Coronary Artery Calcium Consortium

BackgroundCoronary artery calcium (CAC) is a marker of plaque burden. Whether CAC improves risk stratification for incident sudden cardiac death (SCD) beyond atherosclerotic cardiovascular disease (ASCVD) risk factors is unknown.ObjectivesSCD is a common initial manifestation of coronary heart disease (CHD); however, SCD risk prediction remains elusive.MethodsThe authors studied 66,636 primary prevention patients from the CAC Consortium. Multivariable competing risks regression and C-statistics were used to assess the association between CAC and SCD, adjusting for demographics and traditional risk factors.ResultsThe mean age was 54.4 years, 33% were women, 11% were of non-White ethnicity, and 55% had CAC >0. A total of 211 SCD events (0.3%) were observed during a median follow-up of 10.6 years, 91% occurring among those with baseline CAC >0. Compared with CAC = 0, there was a stepwise higher risk (P trend < 0.001) in SCD for CAC 100 to 399 (subdistribution hazard ratio [SHR]: 2.8; 95% CI: 1.6-5.0), CAC 400 to 999 (SHR: 4.0; 95% CI: 2.2-7.3), and CAC >1,000 (SHR: 4.9; 95% CI: 2.6-9.9). CAC provided incremental improvements in the C-statistic for the prediction of SCD among individuals with a 10-year risk <7.5% (ΔC-statistic = +0.046; P = 0.02) and 7.5% to 20% (ΔC-statistic = +0.069; P = 0.003), which were larger when compared with persons with a 10-year risk >20% (ΔC-statistic = +0.01; P = 0.54).ConclusionsHigher CAC burden strongly associates with incident SCD beyond traditional risk factors, particularly among primary prevention patients with low-intermediate risk. SCD risk stratification can be useful in the early stages of CHD through the measurement of CAC, identifying patients most likely to benefit from further downstream testing.     

Machine Learning Adds to Clinical and CAC Assessments in Predicting 10-Year CHD and CVD Deaths

ObjectivesThe aim of this study was to evaluate whether machine learning (ML) of noncontrast computed tomographic (CT) and clinical variables improves the prediction of atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD) deaths compared with coronary artery calcium (CAC) Agatston scoring and clinical data.BackgroundThe CAC score provides a measure of the global burden of coronary atherosclerosis, and its long-term prognostic utility has been consistently shown to have incremental value over clinical risk assessment. However, current approaches fail to integrate all available CT and clinical variables for comprehensive risk assessment.MethodsThe study included data from 66,636 asymptomatic subjects (mean age 54 ± 11 years, 67% men) without established ASCVD undergoing CAC scanning and followed for cardiovascular disease (CVD) and CHD deaths at 10 years. Clinical risk assessment incorporated the ASCVD risk score. For ML, an ensemble boosting approach was used to fit a predictive classifier for outcomes, followed by automated feature selection using information gain ratio. The model-building process incorporated all available clinical and CT data, including the CAC score; the number, volume, and density of CAC plaques; and extracoronary scores; comprising a total of 77 variables. The overall proposed model (ML all) was evaluated using a 10-fold cross-validation framework on the population data and area under the curve (AUC) as metrics. The prediction performance was also compared with 2 traditional scores (ASCVD risk and CAC score) and 2 additional models that were trained using all the clinical data (ML clinical) and CT variables (ML CT).ResultsThe AUC by ML all (0.845) for predicting CVD death was superior compared with those obtained by ASCVD risk alone (0.821), CAC score alone (0.781), and ML CT alone (0.804) (p < 0.001 for all). Similarly, for predicting CHD death, AUC by ML all (0.860) was superior to the other analyses (0.835 for ASCVD risk, 0.816 for CAC, and 0.827 for ML CT; p < 0.001).ConclusionsThe comprehensive ML model was superior to ASCVD risk, CAC score, and an ML model fitted using CT variables alone in the prediction of both CVD and CHD death.     

Coronary Atherosclerosis in an Asymptomatic U.S. Population: Miami Heart Study at Baptist Health South Florida

BackgroundThe burden of total coronary plaque, plaque subtypes, and high-risk plaque features was unknown in asymptomatic individuals from the general U.S. primary prevention population.ObjectivesIn a large, asymptomatic U.S. cohort evaluated using coronary computed tomography angiography (CCTA), we aimed to assess the burden of total coronary plaque, plaque subtypes, and high-risk plaque features; the interplay between CCTA findings and coronary artery calcium (CAC) scores; and identify independent predictors of coronary plaque.MethodsCross-sectional analysis in the MiHeart (Miami Heart Study), a cohort of 2,359 asymptomatic individuals from the Greater Miami Area (mean age 53 years, 50% women, 47% Hispanic/Latino, 43% non-Hispanic White). We estimated the burden of CAC (=0, >0 to <100, ≥100), CCTA-based plaque features (any plaque, stenosis ≥50%, ≥70%, high-risk features), and their interplay.ResultsOverall, 58% participants had CAC = 0, 28% CAC >0 to <100, and 13% CAC ≥100. A total of 49% participants had plaque on the CCTA, including 16% among those with CAC = 0. Overall, 6% participants had coronary stenosis ≥50% (12% among those with coronary plaque), 1.8% had stenosis ≥70% (3.7% among those with plaque), and 7% had at least 1 coronary plaque with ≥1 high-risk feature (13.8% among those with plaque). Only 0.8% participants with CAC = 0 had stenosis ≥50%, 0.1% stenosis ≥70%, and 2.3% plaque with high-risk features. In logistic regression models, independent predictors of coronary plaque and high-risk plaque were older age, male sex, tobacco use, diabetes, overweight, and obesity. Male sex, overweight, and obesity were independent predictors of plaque if CAC = 0.ConclusionsThe Miami Heart Study confirms substantial prevalence of coronary plaque in asymptomatic individuals. Overall, 49% of participants had coronary plaque, 6% had stenosis ≥50%, and 7% had plaques with at least 1 high-risk feature. These proportions were 16%, 0.8%, and 2.3%, respectively, among those with CAC = 0. Longitudinal follow-up will shed further light on the prognostic implications of these findings in asymptomatic individuals.     

Coronary Atherosclerosis,Cardiac Troponin,and Interleukin-6 in Patients With Chest Pain: The PROMISE Trial Results

BackgroundIncreased inflammation and myocardial injury can be observed in the absence of myocardial infarction or obstructive coronary artery disease (CAD).ObjectivesThe authors determined whether biomarkers of inflammation and myocardial injury—interleukin (IL)-6 and high-sensitivity cardiac troponin (hs-cTn)—were associated with the presence and extent of CAD and were independent predictors of major adverse cardiovascular events (MACEs) in stable chest pain.MethodsUsing participants from the PROMISE trial, the authors measured hs-cTn I and IL-6 concentrations and analyzed computed tomography angiography (CTA) images in the core laboratory for CAD characteristics: significant stenosis (≥70%), high-risk plaque (HRP), Coronary Artery Disease Reporting and Data System (CAD-RADS) categories, segment involvement score (SIS), and coronary artery calcium (CAC) score. The primary endpoint was a composite MACE (death, myocardial infarction, or unstable angina).ResultsThe authors included 1,796 participants (age 60.2 ± 8.0 years; 47.5% men, median follow-up 25 months). In multivariable linear regression adjusted for atherosclerotic cardiovascular disease (ASCVD) risk, hs-cTn was associated with HRP, stenosis, CAD-RADS, and SIS. IL-6 was only associated with stenosis and CAD-RADS. hs-cTn above median (1.5 ng/L) was associated with MACEs in univariable analysis (HR: 2.1 [95% CI: 1.3-3.6]; P = 0.006), but not in multivariable analysis adjusted for ASCVD and CAD. IL-6 above median (1.8 ng/L) was associated with MACEs in multivariable analysis adjusted for ASCVD and HRP (HR: 1.9 [95% CI: 1.1-3.3]; P = 0.03), CAC (HR: 1.9 [95% CI: 1.0-3.4]; P = 0.04), and SIS (HR: 1.8 [95% CI: 1.0-3.2]; P = 0.04), but not for stenosis or CAD-RADS. In participants with nonobstructive CAD (stenosis 1%-69%), the presence of both hs-cTn and IL-6 above median was strongly associated with MACEs (HR: 2.5-2.7 after adjustment for CAD characteristics).ConclusionsConcentrations of hs-cTn and IL-6 were associated with CAD characteristics and MACEs, indicating that myocardial injury and inflammation may each contribute to pathways in CAD pathophysiology. This association was most pronounced among participants with nonobstructive CAD representing an opportunity to tailor treatment in this at-risk group. (PROspective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550)     

Stress-Only Adenosine CMR Improves Diagnostic Yield in Stable Symptomatic Patients With Coronary Artery Calcium

ObjectivesThis study assessed whether adenosine stress-only perfusion cardiac magnetic resonance (CMR) following a positive coronary artery calcium (CAC) score improved the diagnostic yield of invasive coronary angiography (CAG) in patients with stable chest pain. The study also established the association between positive CAC scores and stress-induced myocardial ischemia.BackgroundThe diagnostic yield of catheterization among patients with suspected coronary artery disease (CAD) is low. Improved patient selection and diagnostic testing are necessary. The CAC score can minimize unnecessary diagnostic testing, and in low-risk patients, normal CMR results have a high negative predictive value. Less comprehensive protocols may be sufficient to guide further work-up.MethodsA total of 642 consecutive patients (mean age: 63 years; 50% women) with stable chest pain and CAC scores of >0 who were referred for CMR were enrolled. Patients with a perfusion defect were subsequently examined by CAG. Patients were followed up for 1 year. Outcome was obstructive CAD.ResultsObstructive CAD was present in 12% of patients. For CAD diagnosis, the sensitivity of adenosine CMR was 90.9% (95% confidence interval [CI]: 88.7 to 93.1), specificity was 98.7% (95% CI: 97.9 to 99.6), positive predictive value was 92.0% (95% CI: 89.8 to 94.1), and negative predictive value was 98.6% (95% CI: 97.6 to 99.5). A CAC score between 0.1 and 100 without typical angina was associated with obstructive CAD in only 3% of patients. Patients with nonanginal chest pain and a CAC score ≥400 had obstructive CAD (16%).ConclusionsStress-only adenosine CMR had high diagnostic accuracy and served as an efficient gatekeeper to CAG in stable patients with a CAC score >0. Patients with CAC scores between 0.1 and 100 could be deferred from further testing in the absence of clinical features that suggested high risk. However, in patients with CAC score ≥400, functional testing should be indicated, regardless of the type of chest pain.     

Coronary Artery Calcium Versus Pooled Cohort Equations Score for Primary Prevention Guidance: Randomized Feasibility Trial

ObjectivesThis study sought to determine the feasibility of performing an extensive randomized outcomes trial comparing a coronary artery calcium (CAC)- versus a pooled cohort equations (PCE) risk score–based strategy for initiating statin therapy for primary atherosclerotic cardiovascular disease (ASCVD) prevention.BackgroundStatin therapy is standard for the primary prevention of ASCVD in subjects at increased risk. National guidelines recommend using the American College of Cardiology/American Heart Association PCE risk score to guide a statin recommendation. Whether guidance by a CAC score is equivalent or superior is unknown.MethodsCorCal (Effectiveness of a Proactive Cardiovascular Primary Prevention Strategy, With or Without the Use of Coronary Calcium Screening, in Preventing Future Major Adverse Cardiac Events) was a randomized trial consenting 601 patients without known ASCVD, diabetes, or prior statin therapy recruited from primary care clinics and randomized to CAC- (n = 302) or PCE guidance (n = 299) of statin initiation for primary prevention. Enrolled subjects and their physicians made final treatment decisions. Primary outcomes compared the proportion of statin recommendations received and subject adherence over 1 year between CAC- and PCE-arm subjects. Modeled medical costs, adverse effects, and low-density lipoprotein–cholesterol (LDL-C) were additional measures of interest.ResultsSubjects were well matched, and 540 (89.9%) completed entry testing and received a protocol-based recommendation. A statin was recommended in 101 (35.9%) CAC-arm and 124 (47.9%) PCE-arm subjects (P = 0.005). Compared to PCE-based recommendations, CAC-arm subjects were reclassified from statin to no statin in 36.0% and from no statin to statin in 5.6% of cases, resulting in a total reclassification of 20.6%. Physicians accepted the study-dictated recommendation to start a statin in 88.1% of CAC-arm vs 75.0% of PCE-arm subjects (P = 0.01). Patient-reported adherence to this recommendation at 3 months was 62.2% vs 42.2%, respectively (P = 0.009). At 1 year, statin adherence remained superior, LDL-C levels were lower, estimated costs were similar or reduced in CAC subjects, and few events occurred.ConclusionsCAC guidance may be a more efficient, personalized, cost-effective, and motivating approach to statin initiation and maintenance in primary prevention. This feasibility phase of CorCal should be regarded as hypothesis-generating with respect to cardiovascular outcomes, which is being addressed in a large, longer-term outcomes trial. (Effectiveness of a Proactive Cardiovascular Primary Prevention Strategy, With or Without the Use of Coronary Calcium Screening, in Preventing Future Major Adverse Cardiac Events [CorCal]; NCT03439267)     

Deep Learning of Coronary Calcium Scores From PET/CT Attenuation Maps Accurately Predicts Adverse Cardiovascular Events

BackgroundAssessment of coronary artery calcium (CAC) by computed tomographic (CT) imaging provides an accurate measure of atherosclerotic burden. CAC is also visible in computed tomographic attenuation correction (CTAC) scans, always acquired with cardiac positron emission tomographic (PET) imaging.ObjectivesThe aim of this study was to develop a deep-learning (DL) model capable of fully automated CAC definition from PET CTAC scans.MethodsThe novel DL model, originally developed for video applications, was adapted to rapidly quantify CAC. The model was trained using 9,543 expert-annotated CT scans and was tested in 4,331 patients from an external cohort undergoing PET/CT imaging with major adverse cardiac events (MACEs) (follow-up 4.3 years), including same-day paired electrocardiographically gated CAC scans available in 2,737 patients. MACE risk stratification in 4 CAC score categories (0, 1-100, 101-400, and >400) was analyzed and CAC scores derived from electrocardiographically gated CT scans (standard scores) by expert observers were compared with automatic DL scores from CTAC scans.ResultsAutomatic DL scoring required <6 seconds per scan. DL CTAC scores provided stepwise increase in the risk for MACE across the CAC score categories (HR up to 3.2; P < 0.001). Net reclassification improvement of standard CAC scores over DL CTAC scores was nonsignificant (−0.02; 95% CI: −0.11 to 0.07). The negative predictive values for MACE of zero CAC with standard (85%) and DL CTAC (83%) CAC scores were similar (P = 0.19).ConclusionsDL CTAC scores predict cardiovascular risk similarly to standard CAC scores quantified manually by experienced operators from dedicated electrocardiographically gated CAC scans and can be obtained almost instantly, with no changes to PET/CT scanning protocol.     

Triglycerides and Residual Atherosclerotic Risk

BackgroundEven when low-density lipoprotein-cholesterol (LDL-C) levels are lower than guideline thresholds, a residual risk of atherosclerosis remains. It is unknown whether triglyceride (TG) levels are associated with subclinical atherosclerosis and vascular inflammation regardless of LDL-C.ObjectivesThis study sought to assess the association between serum TG levels and early atherosclerosis and vascular inflammation in apparently healthy individuals.MethodsAn observational, longitudinal, and prospective cohort study, including 3,754 middle-aged individuals with low to moderate cardiovascular risk from the PESA (Progression of Early Subclinical Atherosclerosis) study who were consecutively recruited between June 2010 and February 2014, was conducted. Peripheral atherosclerotic plaques were assessed by 2-dimensional vascular ultrasound, and coronary artery calcification (CAC) was assessed by noncontrast computed tomography, whereas vascular inflammation was assessed by fluorine-18 fluorodeoxyglucose uptake on positron emission tomography.ResultsAtherosclerotic plaques and CAC were observed in 58.0% and 16.8% of participants, respectively, whereas vascular inflammation was evident in 46.7% of evaluated participants. After multivariate adjustment, TG levels ≥150 mg/dl showed an association with subclinical noncoronary atherosclerosis (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.08 to 1.68; p = 0.008). This association was significant for groups with high LDL-C (OR: 1.42; 95% CI: 1.11 to 1.80; p = 0.005) and normal LDL-C (OR: 1.85; 95% CI: 1.08 to 3.18; p = 0.008). No association was found between TG level and CAC score. TG levels ≥150 mg/dl were significantly associated with the presence of arterial inflammation (OR: 2.09; 95% CI: 1.29 to 3.40; p = 0.003).ConclusionsIn individuals with low to moderate cardiovascular risk, hypertriglyceridemia was associated with subclinical atherosclerosis and vascular inflammation, even in participants with normal LDL-C levels. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318)     

Risk Stratification With the Use of Coronary Computed Tomographic Angiography in Patients With Nonobstructive Coronary Artery Disease

ObjectivesThe purpose of this study was to develop a risk prediction model for patients with nonobstructive CAD.BackgroundAmong stable chest pain patients, most cardiovascular (CV) events occur in those with nonobstructive coronary artery disease (CAD). Thus, developing tailored risk prediction approaches in this group of patients, including CV risk factors and CAD characteristics, is needed.MethodsIn PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) computed tomographic angiography patients, a core laboratory assessed prevalence of CAD (nonobstructive 1% to 49% left main or 1% to 69% stenosis any coronary artery), degree of stenosis (minimal: 1% to 29%; mild: 30% to 49%; or moderate: 50% to 69%), high-risk plaque (HRP) features (positive remodeling, low-attenuation plaque, and napkin-ring sign), segment involvement score (SIS), and coronary artery calcium (CAC). The primary end point was an adjudicated composite of unstable angina pectoris, nonfatal myocardial infarction, and death. Cox regression analysis determined independent predictors in nonobstructive CAD.ResultsOf 2,890 patients (age 61.7 years, 46% women) with any CAD, 90.4% (n = 2,614) had nonobstructive CAD (mean age 61.6 yrs, 46% women, atherosclerotic cardiovascular disease [ASCVD] risk 16.2%). Composite events were independently predicted by ASCVD risk (hazard ratio [HR]: 1.03; p = 0.001), degree of stenosis (30% to 69%; HR: 1.91; p = 0.011), and presence of ≥2 HRP features (HR: 2.40; p = 0.008). Addition of ≥2 HRP features to: 1) ASCVD and CAC; 2) ASCVD and SIS; or 3) ASCVD and degree of stenosis resulted in a statistically significant improvement in model fit (p = 0.0036; p = 0.0176; and p = 0.0318; respectively). Patients with ASCVD ≥7.5%, any HRP, and mild/moderate stenosis had significantly higher event rates than those who did not meet those criteria (3.0% vs. 6.2%; p = 0.007).ConclusionsAdvanced coronary plaque features have incremental value over total plaque burden for the discrimination of clinical events in low-risk stable chest pain patients with nonobstructive CAD. This may be a first step to improve prevention in this cohort with the highest absolute risk for CV events.     

Dyslipidemia and coronary artery calcium: From association to development of a risk-prediction nomogram

Background and aimsThe associations between dyslipidemia and coronary artery calcium (CAC) are controversial. We investigated their cross-sectional relationships and developed a predictive scoring system for prognostically significant coronary calcification (PSCC).Methods and resultsThis study evaluated the lipid profiles and the CAC score (CACS) measured through multidetector computed tomography (MDCT) among Taiwanese adult patients in a tertiary hospital between 2011 and 2016. Patients with CACS higher than 100 were classified as having PSCC. Dyslipidemia for each lipid component was defined based on the clinical cutoffs or the use of the lipid-lowering agents. Multivariable logistic regression was used to assess the association between dyslipidemia and PSCC and the model performance was assessed using calibration plot, discrimination, and a decision curve analysis.Of the 3586 eligible patients, 364 (10.2%) had PSCC. Increased age, male sex, higher body mass index (BMI), and higher level of triglyceride (TG) were associated with PSCC. The adjusted odds ratios (95% confidence intervals) of PSCC was 1.15 (0.90–1.47) for dyslipidemia defined by total cholesterol (TC) ≥200 mg/dL, 1.06 (0.83–1.35) for low-density-lipoprotein-cholesterol (LDL-C) ≥130 mg/dL, and 1.36 (1.06–1.75) for TG ≥ 200 mg/dL. The positive association between TG ≥ 200 mg/dL and PSCC was not modified by sex. Incorporating hypertriglyceridemia did not significantly improve the predictive performance of the base model comprising of age, sex, BMI, smoking, hypertension, diabetes, estimated glomerular filtration rate, and fasting glucose.ConclusionsHypertriglyceridemia was significantly associated with the prevalent odds of PSCC. Our proposed predictive model may be a useful screening tool for PSCC.     

Interplay of Risk Factors and Coronary Artery Calcium for CHD Risk in Young Patients

ObjectivesThe aim of this study was to examine prevalence, predictors, and impact of coronary artery calcium (CAC) across different risk factor burdens on the prevalence of obstructive coronary artery disease (CAD) and future coronary heart disease (CHD) risk in young patients.BackgroundThe interplay of risk factors and CAC for predicting CHD in young patients aged ≤45 years is not clear.MethodsThe study included 3,691 symptomatic patients (18-45 years of age) from the WDHR (Western Denmark Heart Registry) undergoing coronary computed tomographic angiography. CHD events were myocardial infarction and late revascularization.ResultsDuring a median of 4.1 years of follow-up, 57 first-time CHD events occurred. In total, 3,180 patients (86.1%) had CAC = 0 and 511 patients (13.9%) had CAC >0. Presence of CAC increased with number of risk factors (odds ratio: 4.5 [95% CI: 2.7-7.3] in patients with >3 vs 0 risk factors). The prevalence of obstructive CAD at baseline and the rate of future CHD events increased in a stepwise manner with both higher CAC and number of risk factors. The CHD event rate was lowest at 0.5 (95% CI: 0.1-3.6) per 1,000 person-years in patients with 0 risk factors and CAC = 0. Among patients with >3 risk factors, the event rate was 3.1 (95% CI: 1.0-9.7) in patients with CAC = 0 compared with 36.3 (95% CI: 17.3-76.1) in patients with CAC >10.ConclusionsIn young patients, there is a strong interplay between CAC and risk factors for predicting the presence of obstructive CAD and for future CHD risk. In the presence of risk factors, even a low CAC score is a high-risk marker. These results demonstrate the importance of assessing risk factors and CAC simultaneously when assessing risk in young patients.     

Relationship Between Coronary Artery Calcium and Atherosclerosis Progression Among Patients With Suspected Coronary Artery Disease

BackgroundAmong symptomatic patients, it remains unclear whether a coronary artery calcium (CAC) score alone is sufficient or misses a sizeable burden and progressive risk associated with obstructive and nonobstructive atherosclerotic plaque.ObjectivesAmong patients with low to high CAC scores, our aims were to quantify co-occurring obstructive and nonobstructive noncalcified plaque and serial progression of atherosclerotic plaque volume.MethodsA total of 698 symptomatic patients with suspected coronary artery disease (CAD) underwent serial coronary computed tomographic angiography (CTA) performed 3.5 to 4.0 years apart. Atherosclerotic plaque was quantified, including by compositional subgroups. Obstructive CAD was defined as ≥50% stenosis. Multivariate linear regression models were used to measure atherosclerotic plaque progression by CAC scores. Cox proportional hazard models estimated CAD event risk (median of 10.7 years of follow-up).ResultsAcross baseline CAC scores from 0 to ≥400, total plaque volume ranged from 30.4 to 522.4 mm³ (P < 0.001) and the prevalence of obstructive CAD increased from 1.4% to 49.1% (P < 0.001). Of those with a 0 CAC score, 97.9% of total plaque was noncalcified. Among patients with baseline CAC <100, nonobstructive CAD was prevalent (40% and 89% in CAC scores of 0 and 1-99), with plaque largely being noncalcified. On the follow-up coronary CTA, volumetric plaque growth (P < 0.001) and the development of new or worsening stenosis (P < 0.001) occurred more among patients with baseline CAC ≥100. Progression varied compositionally by baseline CAC scores. Patients with no CAC had disproportionate growth in noncalcified plaque, and for every 1 mm³ increase in calcified plaque, there was a 5.5 mm³ increase in noncalcified plaque volume. By comparison, patients with CAC scores of ≥400 exhibited disproportionate growth in calcified plaque with a volumetric increase 15.7-fold that of noncalcified plaque. There was a graded increase in CAD event risk by the CAC with rates from 3.3% for no CAC to 21.9% for CAC ≥400 (P < 0.001).ConclusionsCAC imperfectly characterizes atherosclerotic disease burden, but its subgroups exhibit pathogenic patterns of early to advanced disease progression and stratify long-term prognostic risk.     

Predicting Long-Term Absence of Coronary Artery Calcium in Metabolic Syndrome and Diabetes: The MESA Study

ObjectivesThe purpose of this study was to identify predictors of healthy arterial aging (long-term coronary artery calcification [CAC] of 0) among individuals with metabolic syndrome (MetS) or type 2 diabetes (T2D), which may improve primary prevention strategies.BackgroundIndividuals with MetS or T2D have a heterogeneously increased risk of atherosclerotic cardiovascular disease and not all have a high-intermediate risk.MethodsWe included 574 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) with MetS or T2D who had CAC=0 at baseline and a repeat CAC scan 10 years later. Multivariable logistic regression assessed the association of traditional and novel atherosclerotic cardiovascular disease risk factors and the MetS severity score (based on the 5 MetS criteria) with healthy arterial aging.ResultsThe mean age of participants was 58.9 years, 67% were women, 422 participants had MetS, and 152 had T2D. The proportion with long-term CAC=0 was similar for MetS (42%) and T2D (44%). A younger age was the only individual low/normal traditional risk factor associated with an increased likelihood of long-term CAC=0 (odds ratio [OR]: 1.50; 95% confidence interval [CI]: 1.22 to 1.85 per 10-years younger). The strongest associations of nontraditional risk factors were observed for an absence of thoracic calcification (OR: 2.42; 95% CI: 1.24 to 4.72), absence of carotid plaque (OR: 1.81; 95% CI: 1.25 to 2.61), and among persons with a high sensitivity troponin <3 ng/ml (OR: 1.55; 95% CI: 1.01 to 2.38). In addition, persons with the lowest quartile MetS severity score had a substantially higher odds of healthy long-term CAC=0 (OR: 2.71; 95% CI: 1.27 to 5.76).ConclusionSMore than 40% of adults with MetS or T2D and baseline CAC=0 had long-term absence of CAC, which was most strongly associated with an absence of extracoronary atherosclerosis and a low MetS score. An optimal overall cardiovascular profile appears to be more important than an ideal value of any individual risk factor to maintain healthy arterial aging.     

Interplay of Coronary Artery Calcium and Risk Factors for Predicting CVD/CHD Mortality: The CAC Consortium

ObjectivesThis study sought to evaluate the association and burden of coronary artery calcium (CAC) with long-term, cause-specific mortality across the spectrum of baseline risk.BackgroundAlthough CAC is a known predictor of short-term, all-cause mortality, data on long-term and cause-specific mortality are inadequate.MethodsThe CAC Consortium cohort is a multicenter cohort of 66,636 participants without coronary heart disease (CHD) who underwent CAC testing. The following risk factors (RFs) were considered: 1) current cigarette smoking; 2) dyslipidemia; 3) diabetes mellitus; 4) hypertension; and 5) family history of CHD.ResultsDuring the 12.5-years median follow-up, 3,158 (4.7%) deaths occurred; 32% were cardiovascular disease (CVD) deaths. Participants with CAC scores ≥400 had a significantly increased risk for CHD and CVD mortality (hazard ratio [HR]: 5.44; 95% confidence interval [CI]: 3.88 to 7.62; and HR: 4.15; 95% CI: 3.29 to 5.22, respectively) compared with CAC of 0. Participants with ≥3 RFs had a smaller increased risk for CHD and CVD mortality (HR: 2.09; 95% CI: 1.52 to 2.85; and HR: 1.84; 95% CI: 1.46 to 2.31, respectively) compared with those without RFs. Across RF strata, CAC added prognostic information. For example, participants without RFs but with CAC ≥400 had significantly higher all-cause, non-CVD, CVD, and CHD mortality rates compared with participants with ≥3 RFs and CAC of 0.ConclusionsAcross the spectrum of RF burden, a higher CAC score was strongly associated with long-term, all-cause mortality and a greater proportion of deaths due to CVD and CHD. Absence of CAC identified people with a low risk over 12 years of follow-up, with most deaths being non-CVD in nature, regardless of RF burden.