Association between hypercholesterolemia and mortality risk among patients referred for cardiac imaging test: Evidence of a "cholesterol paradox?"

AIM: Some observational studies have observed a lower, rather than higher, mortality rate in association with hypercholesterolemia during follow-up of patients after cardiac stress testing. We aim to assess the relationship of hypercholesterolemia and other CAD risk factors to mortality across a wide spectrum of patients referred for various cardiac tests. METHODS AND RESULTS: We identified four cardiac cohorts: 64,357 patients undergoing coronary artery calcium (CAC) scanning, 10,814 patients undergoing coronary CT angiography (CCTA), 31,411 patients without known CAD undergoing stress/rest single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), and 5051 patients with known CAD undergoing stress/rest SPECT-MPI. Each cohort was followed for all-cause mortality using risk-adjusted Cox models. We pooled the hazard ratios between cohorts with a random effects model. Baseline risk varied markedly among cohorts, from an annualized mortality rate of 0.31%/year in CAC patients to 3.63%/year among SPECT-MPI patients with known CAD. Hypertension, diabetes, and smoking were each associated with increased mortality in each patient cohort (pooled hazard ratio[95% CI]: 1.38[1.33-1.44], 1.88[1.76-2.00], and 1.67[1.48-1.86], respectively). By contrast, hypercholesterolemia was associated with decreased rather than increased mortality (pooled hazard ratio[95% CI]: 0.71[0.58-0.84]). Analysis of serum lipids among 7744 patients undergoing CAC or CCTA scanning revealed an inverse relationship between LDL cholesterol and mortality. CONCLUSIONS: Among a broad spectrum of patients referred for a variety of cardiac tests and ranging from low to high clinical risk, hypercholesterolemia was not associated with increased mortality risk. Our findings suggest that hypercholesterolemia may be sensitive to confounding by other clinical factors and post-test treatment changes in patient populations.

Coronary artery calcium is associated with long-term mortality from lung cancer: Results from the Coronary Artery Calcium Consortium.

BACKGROUND AND AIMS: Coronary artery calcium (CAC) scores have been shown to be associated with CVD and cancer mortality. The use of CAC scores for overall and lung cancer mortality risk prediction for patients in the Coronary Artery Calcium Consortium was analyzed. METHODS: We included 55,943 patients aged 44-84 years without known heart disease from the CAC Consortium. There were 1,088 cancer deaths, among which 231 were lung cancer, identified by death certificates with a mean follow-up of 12.2 ± 3.9 years. Fine-and-Gray competing-risk regression was used for overall and lung cancer-specific mortality, accounting for the competing risk of CVD death and after adjustment for CVD risk factors. Subdistribution hazard ratios (SHR) were reported. RESULTS: The mean age of all patients was 57.1 ± 8.6 years, 34.9% were women, and 89.6% were white. Overall, CAC was strongly associated with cancer mortality. Lung cancer mortality increased with increasing CAC scores, with rates per 1000-person years of 0.2 (95% CI: 0.1-0.3) for CAC = 0 and 0.8 (95% CI: 0.6-1.0) for CAC ≥400. Compared with CAC = 0, hazards were increased for those with CAC ≥400 for lung cancer mortality [SHR: 1.7 (95% CI: 1.2-2.6)], which was driven by women [SHR: 2.3 (95% CI: 1.1-4.8)], but not significantly increased for men. Risks were higher in those with positive smoking history [SHR: 2.2 (95% CI: 1.2-4.2)], with associations driven by women [SHR: 4.0 (95% CI: 1.4-11.5)]. CONCLUSIONS: CAC scores were associated with increased risks for lung cancer mortality, with strongest associations for current and former smokers, especially in women. Used in conjunction with other clinical variables, our data pinpoint a potential synergistic use of CAC scanning beyond CVD risk assessment for identification of high-risk lung cancer screening candidates.

Modeling the Recommended Age for Initiating Coronary Artery Calcium Testing Among At-Risk Young Adults.

BACKGROUND: There are currently no recommendations guiding when best to perform coronary artery calcium (CAC) scanning among young adults to identify those susceptible for developing premature atherosclerosis. OBJECTIVES: The purpose of this study was to determine the ideal age at which a first CAC scan has the highest utility according to atherosclerotic cardiovascular disease (ASCVD) risk factor profile. METHODS: We included 22,346 CAC Consortium participants aged 30-50 years who underwent noncontrast computed tomography. Sex-specific equations were derived from multivariable logistic modeling to estimate the expected probability of CAC >0 according to age and the presence of ASCVD risk factors. RESULTS: Participants were on average 43.5 years of age, 25% were women, and 34% had CAC >0, in whom the median CAC score was 20. Compared with individuals without risk factors, those with diabetes developed CAC 6.4 years earlier on average, whereas smoking, hypertension, dyslipidemia, and a family history of coronary heart disease were individually associated with developing CAC 3.3-4.3 years earlier. Using a testing yield of 25% for detecting CAC >0, the optimal age for a potential first scan would be at 36.8 years (95% CI: 35.5-38.4 years) in men and 50.3 years (95% CI: 48.7-52.1 years) in women with diabetes, and 42.3 years (95% CI: 41.0-43.9 years) in men and 57.6 years (95% CI: 56.0-59.5 years) in women without risk factors. CONCLUSIONS: Our derived risk equations among health-seeking young adults enriched in ASCVD risk factors inform the expected prevalence of CAC >0 and can be used to determine an appropriate age to initiate clinical CAC testing to identify individuals most susceptible for early/premature atherosclerosis.

Predictors of coronary artery calcium among 20-30-year-olds: The Coronary Artery Calcium Consortium.

BACKGROUND AND AIMS: We sought to understand the risk factor correlates of very early coronary artery calcium (CAC), and the potential investigational value of CAC phenotyping in adults aged 20-30 years. METHODS: We studied all participants aged 20-30 years at baseline (N = 373) in the Coronary Artery Calcium Consortium, a large multi-center cohort study of patients aged 18 years or older without known atherosclerotic cardiovascular disease (ASCVD) at baseline, referred for CAC scoring for clinical risk stratification. We described the prevalence of CAC in men and women, the frequency of risk factors by the presence of CAC (CAC = 0 vs CAC >0), and assessed the association between traditional non-demographic CVD risk factors (hypertension, hyperlipidemia, smoking, family history of CHD, and diabetes) and prevalent CAC, using age- and sex-adjusted logistic regression models. RESULTS: The mean age of the study participants was 27.5 ± 2.4 years; 324 (86.9%) had CAC = 0, and 49 (13.1%) had CAC >0. Among the 49 participants with CAC, 38 (77.6%) were men, and median CAC score was low at 4.6. In age- and sex-adjusted models, there was a graded increase in the odds of CAC >0 with increasing traditional cardiovascular disease (CVD) risk factor burden (p = 0.001 for linear trend). Participants with ≥3 traditional risk factors had a statistically significant higher odds of having prevalent CAC (OR 5.57, 95% CI; 1.82-17.03) compared to participants with no risk factors. CONCLUSIONS: Our study demonstrates the non-negligible prevalence of CAC among very high-risk young US adults, reinforcing the critical importance of traditional risk factors in the earliest development of detectable subclinical ASCVD.

Coronary Artery Calcium and the Age-Specific Competing Risk of Cardiovascular Versus Cancer Mortality: The Coronary Artery Calcium Consortium.

BACKGROUND: Coronary artery calcium (CAC) is a guideline recommended cardiovascular disease (CVD) risk stratification tool that increases with age and is associated with non-cardiovascular disease outcomes including cancer. We sought to define the age-specific change in the association between CAC and cause-specific mortality. METHODS: The Coronary Artery Calcium Consortium includes 59,502 asymptomatic patients age 40-75 without known CVD. Age-stratified mortality rates and parametric survival regression modeling was performed to estimate the age-specific CAC score at which CVD and cancer mortality risk were equal. RESULTS: The mean age was 54±8 years (67% men) and there were 2,423 deaths over a mean 12±3 years follow-up. Among individuals with CAC = 0, cancer was the leading cause of death, with low CVD mortality rates for both younger (40-54 years) 0.2/1,000 person-years and older participants (65-75 years) 1.3/1,000 person-years. When CAC ≥400, CVD was consistently the leading cause of death among younger (71% of deaths) and older participants (56% of deaths). The CAC score at which CVD overtook cancer as the leading cause of death increased exponentially with age and was approximately 115 at age 50 and 380 at age 65. CONCLUSIONS: Regardless of age, when CAC = 0 cancer was the leading cause of death and the cardiovascular disease mortality rate was low. Our age-specific estimate for the CAC score at which CVD overtakes cancer mortality allows for a more precise approach to synergistic prediction and prevention strategies for CVD and cancer.

Coronary Artery Calcium as a Synergistic Tool for the Age- and Sex-Specific Risk of Cardiovascular and Cancer Mortality: The Coronary Artery Calcium Consortium.

Background Coronary artery calcium (CAC) is a predictor for the development of cardiovascular disease (CVD) and to a lesser extent cancer. The age- and sex-specific relationship of CAC with CVD and cancer mortality is unknown. Methods and Results Asymptomatic patients aged 40 to 75 years old without known CVD were included from the CAC Consortium. We calculated sex-specific mortality rates per 1000 person-years' follow-up. Using parametric survival regression modeling, we determined the age- and sex-specific CAC score at which the risk of death from CVD and cancer were equal. Among the 59 502 patients included in this analysis, the mean age was 54.9 (±8.5) years, 34% were women, and 89% were white. There were 671 deaths attributable to CVD and 954 deaths attributable to cancer over a mean follow-up of 12±3 years. Among patients with CAC=0, cancer was the leading cause of death, the total mortality rate was low (women, 1.8; men, 1.5), and the CVD mortality rate was exceedingly low for women (0.3) and men (0.3). The age-specific CAC score at which the risk of CVD and cancer mortality were equal had a U-shaped relationship for women, while the relationship was exponential for men. Conclusions The age- and sex-specific relationship of CAC with CVD and cancer mortality differed significantly for women and men. Our age- and sex-specific CAC score provides a more precise estimate and further facilitates the use of CAC as a synergistic tool in strategies for the prediction and prevention of CVD and cancer mortality.

The association of coronary artery calcium score and mortality risk among smokers: The coronary artery calcium consortium.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) and cancer are the two leading causes of death in smokers. Lung cancer screening is recommended in a large proportion of smokers. We examined the implication of coronary artery calcium (CAC) score (quantitative and qualitative) for cardiovascular disease (CVD), coronary heart disease (CHD), and cancer mortality risk prediction among current smokers. METHODS: We included current smokers without known heart disease from the CAC Consortium. Cox regression (for all-cause mortality) and Fine-and-Gray competing-risk regression (for CVD, CHD, and cancer mortality) models, adjusted for traditional CVD risk factors, were used to assess the association between CAC and each mortality outcome, with CAC as a continuous (log2-transformed) or categorical variable (CAC = 0, CAC = 1-99, CAC = 100-399, and CAC ≥400). We used number of vessels with CAC as a surrogate for the qualitative measure of CAC and mortality outcomes. Analyses were repeated for lung cancer screening-eligible population (defined as ever smokers with >30 pack years smoking history) (n = 1,149). Hazard ratios (HR) for all-cause mortality and Subdistribution HRs (sHR) with 95% confidence intervals (CI) were reported. RESULTS: Over a median of 11.9 years (25th-75th percentile: 10.2-13.3) of follow-up, of 5,147 current smokers (mean age 52.5 ± 9.4, 32.4% women) 337 died (102 of CVD, 54 of CHD, and 123 of cancer). A doubling of CAC score was associated with increased HRs of all-cause mortality (1.10 (1.06-1.14)), and sHRs for CVD (1.15 (1.07-1.24)), CHD (1.26 (1.11-1.42)) and cancer mortality (1.06 (1.00-1.13)). Those with CAC ≥400 had increased sHR of CVD (3.55 (1.70-7.41)), CHD (8.80 (2.41-32.10)), and cancer mortality (1.85 (1.07-3.22)), compared with those with CAC = 0. A diffuse CAC pattern significantly increased the risk of all-cause, CVD, and CHD mortality among smokers. Results were consistent for the lung cancer screening-eligible population. CONCLUSIONS: Qualitative and quantitative CAC scores can prognosticate risk of all-cause, CVD, CHD, and cancer mortality beyond traditional risk factors among all smokers as well as those eligible for lung cancer screening.

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

OBJECTIVES: This 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. BACKGROUND: Although CAC is a known predictor of short-term, all-cause mortality, data on long-term and cause-specific mortality are inadequate. METHODS: The 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. RESULTS: During 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. CONCLUSIONS: Across 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.

All-cause and cause-specific mortality in individuals with zero and minimal coronary artery calcium: A long-term, competing risk analysis in the Coronary Artery Calcium Consortium.

BACKGROUND AND AIMS: The long-term associations between zero, minimal coronary artery calcium (CAC) and cause-specific mortality are currently unknown, particularly after accounting for competing risks with other causes of death. METHODS: We evaluated 66,363 individuals from the CAC Consortium (mean age 54 years, 33% women), a multi-center, retrospective cohort study of asymptomatic individuals undergoing CAC scoring for clinical risk assessment. Baseline evaluations occurred between 1991 and 2010. RESULTS: Over a mean of 12 years of follow-up, individuals with CAC = 0 (45% prevalence, mean age 45 years) had stable low rates of coronary heart disease (CHD) death, cardiovascular disease (CVD) death (ranging 0.32 to 0.43 per 1000 person-years), and all-cause death (1.38-1.62 per 1000 person-years). Cancer was the predominant cause of death in this group, yet rates were also very low (0.47-0.79 per 1000 person-years). Compared to CAC = 0, individuals with CAC 1-10 had an increased multivariable-adjusted risk of CVD death only under age 40. Individuals with CAC>10 had multivariable-adjusted increased risks of CHD death, CVD death and all-cause death at all ages, and a higher proportion of CVD deaths. CONCLUSIONS: CAC = 0 is a frequent finding among individuals undergoing CAC scanning for risk assessment and is associated with low rates of all-cause death at 12 years of follow-up. Our results support the emerging consensus that CAC = 0 represents a unique population with favorable all-cause prognosis who may be considered for more flexible treatment goals in primary prevention. Detection of any CAC in young adults could be used to trigger aggressive preventive interventions.

Association between coronary artery calcium and cardiovascular disease as a supporting cause in cancer: The CAC consortium.

BACKGROUND: Identifying cancer patients at high risk of CVD is important for targeting CVD prevention strategies and evaluating chemotherapy options in the context of cardiotoxicity. Coronary artery calcium (CAC), a strong marker of coronary atherosclerosis, is used clinically to enhance risk assessment, yet the value of CAC for assessing risk of CVD complications in cancer is poorly understood. OBJECTIVE: In cases of cancer mortality, to determine the value of CAC for predicting risk of CVD as a supporting cause of death. METHODS: The CAC Consortium is a multi-center cohort of 66,636 asymptomatic adults without CVD who underwent CAC scanning. During a follow-up of 12.5 years, 1129 patients died of cancer and were included in this analysis. The primary outcome was presence of CVD listed as a supporting cause of cancer mortality on official death certificates obtained from the National Death Index. Logistic regression models were used to assess the odds of CVD being listed as a supporting cause of death by CAC. RESULTS: CVD was listed as a supporting cause of death in 306 (27%) cancer mortality cases. Baseline CAC was significantly higher in individuals with CVD-supported mortality. Odds ratios of having CVD-supported death increased by ASCVD risk score category [1.15 (0.81, 1.65) for 5-20% 10-year risk and 1.97 (1.36, 2.89) for ≥20% risk, in reference to <5% 10-year ASCVD risk] and CAC category [1.07 (0.73, 1.57) for CAC 1-99, 1.29 (0.87, 1.93) for CAC 100-399, and 2.14 (1.48, 3.09) for CAC ≥400 relative to CAC 0]. In the CAC ≥400 group, these associations remained significantly elevated after adjustment for traditional CVD risk factors [1.66 (1.08, 2.55)]. A sensitivity analysis using a more specific ASCVD-supported mortality outcome, defined as coronary heart disease, stroke, and peripheral artery disease, demonstrated that adjusted odds of ASCVD-supported cancer mortality were significantly elevated in the CAC ≥400 group relative to CAC 0 [3.09 (1.39, 7.38)]. CONCLUSIONS: In cancer mortality cases, high antecedent CAC predicted risk of having CVD as a supporting cause of death on official death certificates, independently of ASCVD risk score and CVD risk factors. CAC may be useful for identifying cancer patients at high CVD risk who might benefit from more intense preventive cardiovascular therapies.

Role of Coronary Artery Calcium for Stratifying Cardiovascular Risk in Adults With Hypertension.

We examined the utility of coronary artery calcium (CAC) for cardiovascular risk stratification among hypertensive adults, including those fitting eligibility for SPRINT (Systolic Blood Pressure Intervention Trial). Additionally, we used CAC to identify hypertensive adults with cardiovascular disease (CVD) mortality rates equivalent to those observed in SPRINT who may, therefore, benefit from the most intensive blood pressure therapy. Our study population included 16 167 hypertensive patients from the CAC Consortium, among whom 6375 constituted a "SPRINT-like" population. We compared multivariable-adjusted hazard ratios of coronary heart disease and CVD deaths by CAC category (0, 1-99, 100-399, ≥400). Additionally, we generated a CAC-CVD mortality curve for patients aged >50 years to determine what CAC scores were associated with CVD death rates observed in SPRINT. Mean age was 58.1±10.6 years. During a mean follow-up of 11.6±3.6 years, there were 409 CVD deaths and 207 coronary heart disease deaths. Increasing CAC scores were associated with increased coronary heart disease and CVD mortality (coronary heart disease-CAC 100-399: hazard ratio [95% CI] 1.88 [1.04-3.40], CAC ≥400: 4.16 [2.34-7.39]; CVD-CAC 100-399: 1.93 [1.31-2.83], CAC ≥400: 3.51 [2.40-5.13]). A similar increased risk was observed across 10-year atherosclerotic CVD risk categories and in the SPRINT-like population. A CAC score of 220 (confidence range, 165-270) was associated with the CVD mortality rate observed in SPRINT. CAC risk stratifies adults with hypertension, including those who are SPRINT eligible. A CAC score of 220 can identify hypertensive adults with SPRINT-level CVD mortality risk and, therefore, may be reasonable for identifying candidates for aggressive blood pressure therapy.

Coronary artery calcium and the competing long-term risk of cardiovascular vs. cancer mortality: the CAC Consortium.

AIMS: Coronary artery calcium (CAC) is the strongest predictor of cardiovascular disease (CVD), yet is also associated with chronic non-CVD such as cancer. We performed this analysis in order to describe the association of CAC with CVD vs. cancer mortality. METHODS AND RESULTS: The CAC Consortium is comprised of 66 636 scans performed in asymptomatic patients without known CVD. The mean age was 54 ± 11 years and 67% of participants were men. Cause of death was ascertained from death certificates. The association of CAC with cause-specific mortality was calculated using Fine and Gray sub-distribution hazard ratio (SHR) models, which account for competing causes of death. There were 3158 deaths over a median 12 ± 4 years follow-up (37% cancer and 32% CVD). Cancer was the leading cause of death when CAC = 0 (50%) with CVD overtaking cancer when baseline CAC >300. Compared to participants with CAC = 0, the SHR for CVD mortality was 1.44 [95% confidence interval (CI) 1.14-1.81], 2.26 (95% CI 1.76-2.90), and 3.68 (95% CI 2.90-4.67) for patients with CAC 1-99, 100-299, and ≥300, and the SHR for cancer was 1.04 (95% CI 0.88-1.23), 1.19 (95% CI 0.98-1.46), and 1.30 (95% CI 1.07-1.58). CONCLUSION: Cancer was the leading cause of death for patients with baseline CAC = 0, whereas CVD overtook cancer above a threshold of CAC >300. These results argue for a focused approach for patients at the extremes of CAC scoring while suggesting that combined CVD and cancer primary prevention strategies for patients with intermediate CAC scores may significantly decrease mortality from the two leading causes of death.

Rationale and design of the coronary artery calcium consortium: A multicenter cohort study.

BACKGROUND: Although coronary artery calcium (CAC) has been investigated for over two decades, there is very limited data on the association of CAC with cause of death. The CAC Consortium is a large ongoing multi-center observational cohort of individuals who underwent non-contrast cardiac-gated CAC testing and systematic, prospective, long-term follow-up for mortality with ascertainment of cause of death. METHODS: Four participating institutions from three states within the US (California, Minnesota, and Ohio) have contributed individual-level patient data to the CAC Consortium (spanning years 1991-2010). All CAC scans were clinically indicated and physician-referred in patients without a known history of coronary heart disease. Using strict inclusion and exclusion criteria to minimize missing data and to eliminate non-dedicated CAC scans (i.e. concomitant CT angiography), a sharply defined and well-characterized cohort of 66,636 patients was assembled. Mortality status was ascertained using the Social Security Administration Death Master File and a validated algorithm. In addition, death certificates were obtained from the National Death Index and categorized using ICD (International Classification of Diseases) codes into common causes of death. RESULTS: Mean patient age was 54 ± 11 years and the majority were male (67%). Prevalence of CVD risk factors was similar across sites and 55% had a <5% estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Approximately 45% had a Calcium score of 0 and 11% had an Agatston Score ≥400. Over a mean follow-up of 12 ± 4 years, there were 3158 deaths (4.15 per 1000 person-years). The majority of deaths were due to cancer (37%) and CVD (32%). Most CVD deaths were due to CHD (54%) followed by stroke (17%). In general, CAC score distributions were similar across sites, and there were similar cause of death patterns. CONCLUSIONS: The CAC Consortium is large and highly generalizable data set that is uniquely positioned to expand the understanding of CAC as a predictor of mortality risk across the spectrum of disease states, allowing innovative modeling of the competing risks of cardiovascular and non-cardiovascular death.

All-cause mortality in asymptomatic persons with extensive Agatston scores above 1000.

BACKGROUND: Risk assessment in the extensive calcified plaque phenotype has been limited by small sample size. OBJECTIVE: We studied all-cause mortality rates among asymptomatic patients with markedly elevated Agatston scores > 1000. METHODS: We studied a clinical cohort of 44,052 asymptomatic patients referred for coronary calcium scans. Mean follow-up was 5.6 years (range, 1-13 years). All-cause mortality rates were calculated after stratifying by Agatston score (0, 1-1000, 1001-1500, 1500-2000, and >2000). A multivariable Cox regression model adjusting for self-reported traditional risk factors was created to assess the relative mortality hazard of Agatston scores 1001 to 1500, 1501 to 2000, and >2000. With the use of post-estimation modeling, we assessed for the presence of an upper threshold of risk with high Agatston scores. RESULTS: A total of 1593 patients (4% of total population) had Agatston score > 1000. There was a continuous graded decrease in estimated 10-year survival across increasing Agatston score, continuing when Agatston score > 1000 (Agatston score 1001-1500, 78%; Agatston score 1501-2000, 74%; Agatston score > 2000, 51%). After multivariable adjustment, Agatston scores 1001 to 1500, 1501 to 2000, and >2000 were associated with an 8.05-, 7.45-, and 13.26-fold greater mortality risk, respectively, than for Agatston score of 0. Compared with Agatston score 1001 to 1500, Agatston score 1501 to 2000 had a similar all-cause mortality risk, whereas Agatston score > 2000 had an increased relative risk (Agatston score 1501-2000: hazard ratio [HR], 1.01 [95% CI, 0.67-1.51]; Agatston score > 2000: HR, 1.79 [95% CI, 1.30-2.46]). Graphical assessment of the predicted survival model suggests no upper threshold for risk associated with calcified plaque in coronary arteries. CONCLUSION: Increasing calcified plaque in coronary arteries continues to predict a graded decrease in survival among patients with extensive Agatston score > 1000 with no apparent upper threshold.

Mortality rates in smokers and nonsmokers in the presence or absence of coronary artery calcification.

OBJECTIVES: The aim of this study was to further explore the interplay between smoking status, coronary artery calcium (CAC), and all-cause mortality. BACKGROUND: Prior studies have not directly compared the relative prognostic impact of CAC in smokers versus nonsmokers. In particular, although a calcium score of zero (CAC = 0) is a known favorable prognostic marker, whether smokers with CAC = 0 have as good a prognosis as nonsmokers with CAC = 0 is unknown. Given that computed tomography (CT) screening for lung cancer appears effective in smokers, the relative prognostic implications of visualizing any CAC versus no CAC on such screening also deserve study. METHODS: Our study cohort consisted of 44,042 asymptomatic individuals referred for noncontrast cardiac CT (age 54 ± 11 years, 54% men). Subjects were followed for a mean of 5.6 years. The primary endpoint was all-cause mortality. RESULTS: Approximately 14% (n = 6,020) of subjects were active smokers at enrollment. There were 901 deaths (2.05%) overall, with increased mortality in smokers versus nonsmokers (4.3% vs. 1.7%, p < 0.0001). Smoking remained a risk factor for mortality across increasing strata of CAC scores (1 to 100, 101 to 400, and >400). At each stratum of elevated CAC score, mortality in smokers was consistently higher than mortality in nonsmokers from the CAC stratum above. In multivariable analysis within these strata, we found mortality hazard ratios of 3.8 (95% confidence interval [CI]: 2.8 to 5.2), 3.5 (95% CI: 2.6 to 4.9), and 2.7 (95% CI: 2.1 to 3.5), respectively, in smokers compared with nonsmokers. However, among the 19,898 individuals with CAC = 0, the mortality hazard ratio for smokers without CAC was 3.6 (95% CI: 2.3 to 5.7), compared with nonsmokers without CAC. CONCLUSIONS: Smoking is a risk factor for death across the entire spectrum of subclinical coronary atherosclerosis. Smokers with any CAC had significantly higher mortality than smokers without CAC, a finding with implications for smokers undergoing lung cancer CT-based screening. However, the absence of CAC might not be as useful a "negative risk factor" in active smokers, because this group has mortality rates similar to nonsmokers with mild-to-moderate atherosclerosis.

Interplay of coronary artery calcification and traditional risk factors for the prediction of all-cause mortality in asymptomatic individuals.

BACKGROUND: Current guidelines recommend the use of coronary artery calcium (CAC) scoring for intermediate-risk patients; however, the potential role of CAC among individuals who have no risk factors (RFs) is less established. We sought to examine the relationship between the presence and burden of traditional RFs and CAC for the prediction of all-cause mortality. METHODS AND RESULTS: The study cohort consisted of 44,052 consecutive asymptomatic individuals free of known coronary heart disease referred for computed tomography for the assessment of CAC. The following RFs were considered: (1) current cigarette smoking, (2) dyslipidemia, (3) diabetes mellitus, (4) hypertension, and (5) family history of coronary heart disease. Patients were followed for a mean of 5.6 ± 2.6 years for the primary end point of all-cause mortality. Among individuals who had no RF, Cox proportional model adjusted for age and sex identified that increasing CAC scores were associated with 3.00- to 13.38-fold higher mortality risk. The lowest survival rate was observed in those with no CAC and no RF, whereas those with CAC ≥ 400 and ≥3 RFs had the highest all-cause fatality rate. Notably, individuals with no RF and CAC ≥ 400 had a substantially higher mortality rate compared with individuals with ≥3 RFs in the absence of CAC (16.89 versus 2.72 per 1000 person-years). CONCLUSIONS: By highlighting that individuals without RFs but elevated CAC have a substantially higher event rates than those who have multiple RFs but no CAC, these findings challenge the exclusive use of traditional risk assessment algorithms for guiding the intensity of primary prevention therapies.

Potential implications of coronary artery calcium testing for guiding aspirin use among asymptomatic individuals with diabetes.

OBJECTIVE: It is unclear whether coronary artery calcium (CAC) is effective for risk stratifying patients with diabetes in whom treatment decisions are uncertain. RESEARCH DESIGN AND METHODS: Of 44,052 asymptomatic individuals referred for CAC testing, we studied 2,384 individuals with diabetes. Subjects were followed for a mean of 5.6 ± 2.6 years for the end point of all-cause mortality. RESULTS: There were 162 deaths (6.8%) in the population. CAC was a strong predictor of mortality across age-groups (age <50, 50-59, ≥60), sex, and risk factor burden (0 vs. ≥1 additional risk factor). In individuals without a clear indication for aspirin per current guidelines, CAC stratified risk, identifying patients above and below the 10% risk threshold of presumed aspirin benefit. CONCLUSIONS: CAC can help risk stratify individuals with diabetes and may aid in selection of patients who may benefit from therapies such as low-dose aspirin for primary prevention.

Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order amish.

BACKGROUND: Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels. METHODS: To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for coronary artery calcification (CAC) in 1018 of these individuals. RESULTS: From the initial genome-wide association study, a cluster of single nucleotide polymorphisms in the region of the apolipoprotein B-100 gene (APOB) was strongly associated with LDL-C levels (P < 10(-68)). Additional genotyping revealed the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100, which was also strongly associated with LDL-C in the replication sample (P < 10(-36)). The R3500Q carrier frequency, previously reported to be 0.1% to 0.4% in white European individuals, was 12% in the combined sample of 1504 Amish participants, consistent with a founder effect. The mutation was also strongly associated with CAC in both samples (P < 10(-6) in both) and accounted for 26% and 7% of the variation in LDL-C levels and CAC, respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dL higher, a 4.41-fold higher odds (95% confidence interval, 2.69-7.21) of having detectable CAC, and a 9.28-fold higher odds (2.93-29.35) of having extensive CAC (CAC score ≥400). CONCLUSION: The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.

Relation of aortic valve calcium detected by cardiac computed tomography to all-cause mortality.

Aortic valve calcium (AVC) can be quantified on the same computed tomographic scan as coronary artery calcium (CAC). Although CAC is an established predictor of cardiovascular events, limited evidence is available for an independent predictive value for AVC. We studied a cohort of 8,401 asymptomatic subjects (mean age 53 ± 10 years, 69% men), who were free of known coronary heart disease and were undergoing electron beam computed tomography for assessment of subclinical atherosclerosis. The patients were followed for a median of 5 years (range 1 to 7) for the occurrence of mortality from any cause. Multivariate Cox regression models were developed to predict all-cause mortality according to the presence of AVC. A total of 517 patients (6%) had AVC on electron beam computed tomography. During follow-up, 124 patients died (1.5%), for an overall survival rate of 96.1% and 98.7% for those with and without AVC, respectively (hazard ratio 3.39, 95% confidence interval 2.09 to 5.49). After adjustment for age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking, and a family history of premature coronary heart disease, AVC remained a significant predictor of mortality (hazard ratio 1.82, 95% confidence interval 1.11 to 2.98). Likelihood ratio chi-square statistics demonstrated that the addition of AVC contributed significantly to the prediction of mortality in a model adjusted for traditional risk factors (chi-square = 5.03, p = 0.03) as well as traditional risk factors plus the presence of CAC (chi-square = 3.58, p = 0.05). In conclusion, AVC was associated with increased all-cause mortality, independent of the traditional risk factors and the presence of CAC.

Using noncontrast cardiac CT and coronary artery calcification measurements for cardiovascular risk assessment and management in asymptomatic adults.

The presence of mural calcification has, for decades, been recognized as a marker for atheromatous plaque in the coronary arteries and the aorta, but only in the past decade has the application of noncontrast computed tomography (CT) been shown to be a reproducible, safe, and convenient test, which now is available worldwide. However, awareness of coronary artery calcium scanning is insufficient and the practitioner must be aware of the available literature as well as understanding clinical recommendations for applications and interpretation. It is best applied in the medium/intermediate risk, asymptomatic adult regardless of ethnicity across broad age ranges for both men and women; additional prognostic information is also afforded from the calcium distribution in the coronary artery system. Additionally, information can also be derived from the same CT scan regarding heart and aorta size and assessment of the epicardial fat pad (an anatomic marker for the metabolic syndrome). Details of how this test can aid in cardiovascular risk assessment and management in adults are provided.