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Thoracic aorta calcification detected by electron beam tomography predicts all-cause mortality
Atherosclerosis 209 (2010) 131–135
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Thoracic aorta calcification detected by electron beam tomography predicts all-cause mortality Raul D. Santos a , John A. Rumberger b , Matthew J. Budoff c , Leslee J. Shaw d , Sarwar H. Orakzai e , Daniel Berman f , Paolo Raggi d , Roger S. Blumenthal g , Khurram Nasir g,h,∗ a
Lipid Clinic Heart Institute – InCor, University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil Princeton Longevity Center, NJ, USA Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA d Division of Cardiology, Emory University, Atlanta, GA, USA e Department of Cardiology, Baylor College of Medicine, St. Luke’s Episcopal Hospital/Texas Heart Institute, Houston, TX, USA f Department of Imaging and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA g Ciccarone Preventive Cardiology Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA h Department of Internal Medicine, Boston Medical Center, Boston, MA, USA b c
a r t i c l e
i n f o
Article history: Received 2 April 2009 Received in revised form 12 August 2009 Accepted 14 August 2009 Available online 21 August 2009 Keywords: Thoracic aorta calcification Coronary calcification Atherosclerosis Risk factors Mortality Electron beam tomography
a b s t r a c t Background: The presence of coronary artery calcium (CAC) is an independent marker of increased risk of cardiovascular disease (CVD) events and mortality. However, the predictive value of thoracic aorta calcification (TAC), which can be additionally identified without further scanning during assessment of CAC, is unknown. Methods: We followed a cohort of 8401 asymptomatic individuals (mean age: 53 ± 10 years, 69% men) undergoing cardiac risk factor evaluation and TAC and CAC testing with electron beam computed tomography. Multivariable Cox proportional hazards models were developed to predict all-cause mortality based on the presence of TAC. Results: During a median follow-up period of 5 years, 124 (1.5%) deaths were observed. Overall survival was 96.9% and 98.9% for those with and without detectable TAC, respectively (p < 0.0001). Compared to those with no TAC, the hazard ratio for mortality in the presence of TAC was 3.25 (95% CI: 2.28–4.65, p < 0.0001) in unadjusted analysis. After adjusting for age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking and family history of premature coronary artery disease, and presence of CAC the relationship remained robust (HR 1.61, 95% CI: 1.10–2.27, p = 0.015). Likelihood ratio 2 statistics demonstrated that the addition of TAC contributed significantly in predicting mortality to traditional risk factors alone (2 = 13.62, p = 0.002) as well as risk factors + CAC (2 = 5.84, p = 0.02) models. Conclusion: In conclusion, the presence of TAC was associated with all-cause mortality in our study; this relationship was independent of conventional CVD risk factors as well as the presence of CAC. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction As part of atherosclerotic development, calcium is deposited in the arterial wall by a process that is histologically similar to bone formation [1]. Strong evidence shows that both coronary artery calcification (CAC) and thoracic aortic calcification (TAC) detected by both chest radiographs and computed tomography (CT) indicate the presence of atherosclerosis and an increased risk of cardiovascular events [2–6]. However, evidence is lacking whether the presence of TAC on CT identifies higher risk indi-
viduals and whether it provides additional information on top of detection and quantification of CAC. This fact is important since additional information about TAC can be easily obtained without further scanning during assessment of CAC with cardiac CT. The primary aim of our study was to assess the predictive value of TAC detected by electron beam tomography (EBT) for all-cause mortality. Secondarily, we were interested in assessing whether this association is independent of coronary heart disease (CHD) risk factors as well as CAC, an established marker of CHD events and mortality. 2. Methods
∗ Corresponding author at: Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA. Tel.: +1 443 413 6350; fax: +1 410 614 9190. E-mail address: [email protected] (K. Nasir). 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.08.025
The study cohort is composed of predominantly white asymptomatic individuals free of known CHD who presented to a single
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R.D. Santos et al. / Atherosclerosis 209 (2010) 131–135
EBT facility in Columbus, Ohio for the assessment of underlying CHD risk from 1999 to 2003. Individuals were referred for screening on the basis of the presence of established risk factors for atherosclerosis and, as such, were not an unselected cohort representative of the general population. All screened individuals provided an informed consent to undergo EBT screening, and our study received the Human Investigations Committee approval. Furthermore, separate approval from the Human Investigations Committee was obtained, along with informed consent, for the patient interviews, collection of data and follow-up, and corroboration of the occurrence of death. 2.1. Risk factor data collection A history of cigarette smoking was considered present if a subject was a current or former smoker. Dyslipidemia was coded as present for any individual self-reporting a history of high total cholesterol, high LDL-cholesterol, low HDL-cholesterol and/or high triglycerides, or current use of lipid-lowering therapy. Patients were considered to have diabetes if they reported using oral hypoglycemic agents, insulin sensitizers, or insulin and were considered to have hypertension if they reported a history of high blood pressure or used antihypertensive medications. Family history of early CHD in parents and siblings was obtained by asking patients whether any member of their immediate family (parents or siblings) had a fatal or non-fatal myocardial infarction and/or coronary revascularization before or after 55 years of age. Body mass index (BMI) was calculated for individuals who provided a self-report of height and weight. Individuals with BMI ≥30 kg/m2 were considered obese. 2.1.1. Coronary and thoracic aorta calcium screening protocol EBT was performed with either a C-100 or C-150 scanner (Imatron® , San Francisco, CA), and images were obtained with 100ms scanning time. The CT section thickness was 3 mm, and, in total, 40 sections were obtained starting at the level of the carina and proceeding to the level of the diaphragm. CT imaging was electrocardiographically triggered at 60–80% of the R–R interval. The same scan series was used for the assessment of thoracic aorta calcification (TAC) and coronary artery calcium (CAC). A calcified lesion was defined as ≥3 contiguous pixels with a peak Hounsfeld (H) attenuation of >130. Presence of TAC was defined as any calcification detected in both ascending and descending thoracic aortas. The CAC scores were calculated with the method described by Agatston et al. [7]. 2.2. Follow-up data collection Epidemiological methods for follow-up included ascertainment of events by individuals blinded to historical and EBT results. Individuals who underwent cardiovascular screening were followed for a median of 5 years (range: 1–7 years). Death from all-causes was the primary endpoint for this registry. The occurrence of death was verified with the Social Security Death Index. 2.3. Statistical methods For comparisons between those with and without TAC, categorical risk factors and CAC score subsets were compared using 2 statistic. Time to death from all-causes was estimated using a Cox proportional hazards model. For the Cox model, univariable and multivariable models were developed and included an evaluation of traditional cardiac risk factors and the presence of TAC. In addition Kaplan Meyer survival curves were also generated according to the presence or absence of TAC.
Specifically, the independent prognostic value of TAC for predicting all-cause mortality was assessed in a hierarchal manner using the following models: Model 1: unadjusted. Model 2: age and gender adjusted. Model 3: age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking and family history of premature CHD adjusted. Model 4: model 3 + CAC. In addition, to determine whether the addition of TAC contributed significantly to the models containing traditional risk factors alone as well as traditional risk factors + CAC scores in predicting all-cause mortality, the likelihood ratio 2 statistic was used. All statistical analyses were performed with STATA version 10.0 (Stata Corp., Austin, Texas, http://www.stata.com). The level of significance was set at p < 0.05 (two-tailed). The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written. 3. Results We followed up a cohort of 8401 asymptomatic individuals without previous manifestation of cardiovascular disease (mean age: 53 ± 10 years, 69% men). The prevalence of cardiac risk factors in our patient cohort was as follows: hyperlipidemia (26%), hypertension (28%), smoking (9%), diabetes (6%), family history of premature CHD (30%), and obesity (25%). Among the 8401 subjects, 35% had no major CHD risk factor, whereas 36%, 20%, and 9% had 1, 2, and 3 major risk factors. Table 1 shows a comparison of subjects with and without detectable TAC. Study participants with TAC were older (p < 0.001), more likely to be females (p = 0.001), have systemic hypertension (p < 0.001), diabetes mellitus (p < 0.001), dyslipidemia (p < 0.001), and a family history of early CHD (p < 0.0001). In our study population TAC was detected in 22% (n = 1877) of study subjects. Overall prevalence of CAC was significantly higher in subjects with TAC (77% vs. 49%, p < 0.0001); in addition higher CAC scores were also observed with the presence of TAC (304 ± 567 vs. 93 ± 302, p < 0.0001). In the absence of CAC (n = 3781), only 11% (n = 424) demonstrated TAC; women were more likely to have TAC (16%) as compared to men (8%) among those with CAC = 0 (p < 0.0001). During the median follow-up of 5 years, 124 (1.5%) all-cause deaths were recorded. Overall survival was 96.9% and 98.9% for those with and without detectable TAC, respectively (p < 0.0001) (Fig. 1). When stratified according to moderate CAC scores (<100 and ≥100), as shown in Fig. 2 the cumulative survival was lower with TAC in both groups. Fig. 3 shows that the lowest event rate was observed in those with CAC <100 and the absence of TAC (1.6 events per 1000 person years), whereas those with CAC ≥100 and detectable TAC had the highest all-fatality rate (9.8 per 1000 person years). Table 1 Clinical characteristics of subjects presenting (TAC+) or not thoracic aortic calcification (TAC−). TAC (−), N = 6524 Age (years) 51 ± 10 Gender (female) (%) 30 Hypertension (%) 25 Diabetes (%) 5 Dyslipidemia (%) 23 Family history of CHD (%) 27 Smoking (%) 8
TAC (+), N = 1877
60 ± 10 34 39 10 35 25 12
p value <0.0001 0.001 <0.0001 <0.0001 <0.0001 0.014 <0.0001
R.D. Santos et al. / Atherosclerosis 209 (2010) 131–135
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Fig. 3. Mortality rate (per 1000 person years) according to thoracic aortic calcification presence (TAC) and CAC <100 and CAC ≥100.
Fig. 1. Cumulative survival for subjects with (TAC+) or without (TAC−) thoracic aortic calcification.
Table 2 shows the hazard ratios (HR) for mortality in the presence of TAC in univariable and multivariable analyses. As compared to those with absent TAC (reference group) risk for mortality with the presence of TAC was approximately 3 times in unadjusted analyses (p < 0.0001). After taking into account age, gender and CHD risk factors the risk was attenuated but remained statistically significant (HR = 1.78, 95% CI: 1.23–2.60, p = 0.002). The relationship
remained robust (HR: 1.61, 95% CI: 1.10–2.27, p = 0.015) when the presence or absence of CAC was added to the multivariate analyses in Table 2 (model 4). On the other hand, when CAC scores categories (0, 1–99, 100–399 and ≥400) were added to the multivariable analyses, TAC demonstrated a strong trend for but did not attain statistical significance with all-cause mortality (HR: 1.45, 95% CI: 0.98–2.16, p = 0.06). Similar results were obtained when CAC was added as a continuous variable (data not shown). Overall likelihood ratio 2 statistics demonstrated that the addition of TAC contributed significantly in predicting mortality to traditional risk factors alone (2 = 13.62, p = 0.002) as well as risk factors + CAC (2 = 5.84 p = 0.02) models. 3.1. TAC and all-cause mortality in women and men In gender specific sub-analyses the HR (95% CI) for all-cause mortality with the presence of TAC was 1.76 (0.83–3.74) for women and 1.76 (1.13–2.72) for men after adjusting for age and CHD risk factors (model 3); the respective hazard ratios after further taking into the presence of CAC (model 4) were 1.61 (0.75–3.44) and 1.60 (1.02–2.52). There was no gender by TAC interaction in the prediction of all-cause mortality. 3.2. TAC and all-cause mortality absence of CAC Among study participants who did not have CAC at baseline (n = 3781, 45%), only 424 (11%) individuals had TAC, and its presence was associated with a hazard ratio of 2.53 (95% CI: 0.99–6.48, p = 0.054) for predicting all-cause mortality in CHD risk adjusted multivariable analyses (model 3). On further stratification according to gender (adjusting for traditional risk factors) in the absence of CAC, the presence of TAC was significantly associated with allcause mortality in women (HR: 4.94, 95% CI: 1.22–19.97, p = 0.02), whereas no such relationship was observed in men (HR: 1.43, 95% CI: 0.31–6.59, p = 0.65). No gender and TAC interaction was found for prediction of all-cause mortality in subjects without detectable CAC.
Table 2 Hazard ratio for all-cause mortality with the presence of thoracic aorta calcification in univariable and multivariable analyses.
Model 1 Model 2 Model 3 Model 4
Fig. 2. Cumulative survival for subjects with (TAC+) or without (TAC−) thoracic aortic calcification according to CAC <100 and CAC ≥100.
Hazard ratio
95% CI
p value
3.25 2.07 1.78 1.61
2.28–4.65 1.43–2.99 1.23–2.60 1.10–2.27
<0.0001 <0.0001 0.002 0.015
Model 1: unadjusted. Model 2: age and gender adjusted. Model 3: age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking and family history of premature CHD adjusted. Model 4: model 3 + presence of CAC.
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4. Discussion After a median 5-year follow-up TAC detected by EBT was associated with all-cause mortality independently of CHD risk factors and CAC in a cohort of men and women without known cardiovascular disease. Our study suggests that detection of TAC in the same scan obtained for CAC assessment without any addition exposure and cost provides prognostic information beyond clinical evaluation of coronary atherosclerosis. The presence of TAC detected by chest X-rays and located in the aortic arch has been associated with an increased risk of CHD in both genders and with stroke in women [4]. Studies have also associated aortic arch TAC detected by chest X-ray with increased cardiovascular death in hemodialysis patients [8] with and without diabetes. Thoracic CT is a more sensitive method to detect TAC than chest X-rays and data from the Multi-Ethnic Study of Atherosclerosis (MESA) study has associated the presence of TAC detected by CT with risk factors like hypertension, smoking, diabetes, dyslipidemia and family history of myocardial infarction in subjects of different ethnicities [9]. The presence of TAC detected by CT has been associated with an increased risk of cardiovascular events and death event in stable angina pectoris patients [10]. The advent of cardiac CT allowed the detection and quantification of CAC, a proven marker of coronary atherosclerosis [3]. Prospective studies have clearly shown that CAC is an independent predictor of myocardial infarction, CHD death and all-cause mortality risk [11–14]. Although the presence and severity of CAC have been clearly established as an indicator of an adverse event, it is still unknown if TAC observed on the same EBT scan performed to detect CAC provides additional prognostic information. Consistent with prior reports, [4,9] subjects with TAC were older, had a greater proportion of females and a higher prevalence of risk factors for atherosclerosis. TAC presence was also associated with a greater prevalence and extent of subclinical coronary atherosclerosis represented by CAC, confirming previous studies in smaller populations showing the association of aortic and coronary calcifications detected by computerized tomography [9,15,16], as well as obstructive coronary plaques detected by invasive coronary angiography [5,17–19]. However, our study is unique and adds to the literature by describing for the first time that the presence of TAC predicts mortality in a large cohort of asymptomatic individuals and this relationship is independent of baseline CHD risk factors and burden of CAC. An important finding was that even in subjects with moderate-to-high CAC scores the presence of TAC was associated with higher death rates suggesting that additional assessment of TAC in non-contrast cardiac scans performed primarily for the assessment of extent of coronary atherosclerosis may provide additional prognostic information. In addition, TAC is readily detected with low-dose ungated chest CT performed for lung cancer and COPD screening and can provide additional information for CHD stratification without additional scanning or burden to participants. Current literature suggests a very low cardiovascular event rate among those with the absence of CAC [11–13]. However, in spite of an excellent prognosis with the absence of CAC, few events do occur in this subgroup. It is not clear whether identification of atherosclerosis in additional vascular beds such as the thoracic aorta will improve further risk stratification in this low risk group. In our study very few individuals without CAC had TAC, who had almost a twofold increase risk of mortality, albeit with a low absolute risk. Although the hazard ratio for predicting all-cause mortality with TAC among those with absent CAC was nearly twofold higher after taking into account the traditional CHD risk factors demonstrating a strong trend, it did not achieve statistical significance. We believe that this may be directly related to a much smaller sample size in this subgroup and to the fact that our study endpoint only included all-cause mortality and we were not able to assess non-fatal cardio-
vascular disease. We have previously demonstrated that women, who are traditionally less likely to have coronary atherosclerosis, have a higher prevalence of TAC even in the absence of CAC [20]. Considering the fact that women are significantly less likely to have CAC, detection of TAC in such scenario may provide the earliest sign of underlying atherosclerotic process and important prognostic information for future risk of adverse events. These findings suggest that beyond the assessment of coronary calcium, additional relevant information can be gained by this study that may be useful in guiding further management. The MESA, which is a prospective study assessing the utility of various information obtained on non-contrast CT currently in progress, will provide more precise information on the additional utility of measuring TAC in predicting cardiovascular events in addition to the assessment of CAC [9]. Although the current study includes a rigorous analysis of the prognostic value of TAC, the majority of patients referred for EBT testing had cardiac risk factors and, as such, were not representative of the general population. A chest CT performed for CAC screening typically excludes the aortic arch and the abdominal aorta; hence our study did not allow us to include these potentially important areas in the estimation of risk. Furthermore, we did not calculate a calcium score for TAC and we limited our assessment to establishing the presence vs. absence of calcification without quantification of the burden of disease in the aorta. We collected patients’ selfreported CHD risk factors. Although Hoff et al. [21] demonstrated a good reliability of self-reported histories, the probability of “residual confounding” cannot be ruled out. In this study we were not able to relate the presence of TAC with the cause of death in the study population. However, nearly three-fourths of all deaths are related to atherosclerosis complications [5,22], and this end point is unaffected by the reporting and misclassification bias potentially introduced by a physician’s filing of a death report [23]. It must be kept in mind that medication type and renal function were not collected in our study, which may affect the association of TAC with mortality. Finally, our study population was mainly Caucasians and the results may not apply to other ethnic groups. Our study findings need to be confirmed in large prospective studies such as the Multi-Ethnic Study of Atherosclerosis, in which all the risk factors are collected as underlying CHD events are recorded. In summary, the presence of TAC in subjects with CAC was independently associated with mortality in a large cohort of physician-referred and self-referred asymptomatic individuals. Detection of TAC may provide supplementary prognostic information in addition to CAC with no extra cost and radiation. The study results need to be verified in prospective population based cohorts such as the Multi-Ethnic Study of Atherosclerosis that takes into account the measured risk factors as well as assess risk in subjects of different ethnicities. References [1] Detrano RC, Wong ND, Tang W, et al. Prognostic significance of cardiac cinefluoroscopy for coronary calcific deposits in asymptomatic high risk subjects. J Am Coll Cardiol 1994;24:354–8. [2] Nasir K, Shaw LJ, Liu ST, et al. Ethnic differences in the prognostic value of coronary artery calcification for all-cause mortality. J Am Coll Cardiol 2007;50:953–60. [3] Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2007;49:378–402. [4] Iribarren C, Sidney S, Sternfeld B, Browner WS. Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease. JAMA 2000;283:2810–5.
R.D. Santos et al. / Atherosclerosis 209 (2010) 131–135 [5] Haberl R, Becker A, Leber A, et al. Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1764 patients. J Am Coll Cardiol 2001;37:451–7. [6] Dávila-Román VG, Barzilai B, Wareing TH, et al. Atherosclerosis of the ascending aorta. Prevalence and role as an independent predictor of cerebrovascular events in cardiac patients. Stroke 1994;25:2010–6. [7] Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–32. [8] Ogawa T, Ishida H, Akamatsu M, et al. Progression of aortic arch calcification and all-cause and cardiovascular mortality in chronic hemodialysis patients. Int Urol Nephrol 2009 [Epub ahead of print]. [9] Takasu J, Katz R, Nasir K, et al. Relationships of thoracic aortic wall calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2008;155:765–71. [10] Eisen A, Tenenbaum A, Koren-Morag N, et al. Calcification of the thoracic aorta as detected by spiral computed tomography among stable angina pectoris patients: association with cardiovascular events and death. Circulation 2008;118:1328–34. [11] Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol 2007;49:1860–70. [12] Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol 2005;46:158–65. [13] Taylor AJ, Bindeman J, Feuerstein I, et al. Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project. J Am Coll Cardiol 2005;46:807–14.
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[14] Detrano R, Hsiai T, Wang S, et al. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 1996;27:285–90. [15] Adler Y, Fisman EZ, Shemesh J, et al. Spiral computed tomography evidence of close correlation between coronary and thoracic aorta calcifications. Atherosclerosis 2004;176:133–8. [16] Odink AE, van der Lugt A, Hofman A, et al. Association between calcification in the coronary arteries, aortic arch and carotid arteries: the Rotterdam Study. Atherosclerosis 2007;193:408–13. [17] Yamamoto H, Shavelle D, Takasu J, et al. Valvular and thoracic aortic calcium as a marker of the extent and severity of angiographic coronary artery disease. Am Heart J 2003;146:153–9. [18] Baumgart D, Schmermund A, Goerge G, et al. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol 1997;30:57– 64. [19] Budoff MJ, Shavelle DM, Lamont DH, et al. Usefulness of electron beam computed tomography scanning for distinguishing ischemic from nonischemic cardiomyopathy. J Am Coll Cardiol 1998;32:1173–8. [20] Nasir K, Roguin A, Sarwar A, Rumberger JA, Blumenthal RS. Gender differences in coronary arteries and thoracic aorta calcification. Arterioscler Thromb Vasc Biol 2007;27:1220–2. [21] Hoff JA, Daviglus ML, Chomka EV, et al. Conventional coronary artery disease risk factors and coronary artery calcium detected by electron beam tomography in 30,908 healthy individuals. Ann Epidemiol 2003;13:163–9. [22] American Heart Association. Heart disease and stroke statistics: 2006 update. Circulation 2006;113:e85–151. [23] Coady SA, Sorlie PD, Cooper LS, et al. Validation of death certificate diagnosis for coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. J Clin Epidemiol 2001;54:40–50.
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Thoracic aorta calcification detected by electron beam tomography predicts all-cause mortality Raul D. Santos a , John A. Rumberger b , Matthew J. Budoff c , Leslee J. Shaw d , Sarwar H. Orakzai e , Daniel Berman f , Paolo Raggi d , Roger S. Blumenthal g , Khurram Nasir g,h,∗ a
Lipid Clinic Heart Institute – InCor, University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil Princeton Longevity Center, NJ, USA Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA d Division of Cardiology, Emory University, Atlanta, GA, USA e Department of Cardiology, Baylor College of Medicine, St. Luke’s Episcopal Hospital/Texas Heart Institute, Houston, TX, USA f Department of Imaging and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA g Ciccarone Preventive Cardiology Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA h Department of Internal Medicine, Boston Medical Center, Boston, MA, USA b c
a r t i c l e
i n f o
Article history: Received 2 April 2009 Received in revised form 12 August 2009 Accepted 14 August 2009 Available online 21 August 2009 Keywords: Thoracic aorta calcification Coronary calcification Atherosclerosis Risk factors Mortality Electron beam tomography
a b s t r a c t Background: The presence of coronary artery calcium (CAC) is an independent marker of increased risk of cardiovascular disease (CVD) events and mortality. However, the predictive value of thoracic aorta calcification (TAC), which can be additionally identified without further scanning during assessment of CAC, is unknown. Methods: We followed a cohort of 8401 asymptomatic individuals (mean age: 53 ± 10 years, 69% men) undergoing cardiac risk factor evaluation and TAC and CAC testing with electron beam computed tomography. Multivariable Cox proportional hazards models were developed to predict all-cause mortality based on the presence of TAC. Results: During a median follow-up period of 5 years, 124 (1.5%) deaths were observed. Overall survival was 96.9% and 98.9% for those with and without detectable TAC, respectively (p < 0.0001). Compared to those with no TAC, the hazard ratio for mortality in the presence of TAC was 3.25 (95% CI: 2.28–4.65, p < 0.0001) in unadjusted analysis. After adjusting for age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking and family history of premature coronary artery disease, and presence of CAC the relationship remained robust (HR 1.61, 95% CI: 1.10–2.27, p = 0.015). Likelihood ratio 2 statistics demonstrated that the addition of TAC contributed significantly in predicting mortality to traditional risk factors alone (2 = 13.62, p = 0.002) as well as risk factors + CAC (2 = 5.84, p = 0.02) models. Conclusion: In conclusion, the presence of TAC was associated with all-cause mortality in our study; this relationship was independent of conventional CVD risk factors as well as the presence of CAC. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction As part of atherosclerotic development, calcium is deposited in the arterial wall by a process that is histologically similar to bone formation [1]. Strong evidence shows that both coronary artery calcification (CAC) and thoracic aortic calcification (TAC) detected by both chest radiographs and computed tomography (CT) indicate the presence of atherosclerosis and an increased risk of cardiovascular events [2–6]. However, evidence is lacking whether the presence of TAC on CT identifies higher risk indi-
viduals and whether it provides additional information on top of detection and quantification of CAC. This fact is important since additional information about TAC can be easily obtained without further scanning during assessment of CAC with cardiac CT. The primary aim of our study was to assess the predictive value of TAC detected by electron beam tomography (EBT) for all-cause mortality. Secondarily, we were interested in assessing whether this association is independent of coronary heart disease (CHD) risk factors as well as CAC, an established marker of CHD events and mortality. 2. Methods
∗ Corresponding author at: Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA. Tel.: +1 443 413 6350; fax: +1 410 614 9190. E-mail address: [email protected] (K. Nasir). 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.08.025
The study cohort is composed of predominantly white asymptomatic individuals free of known CHD who presented to a single
132
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EBT facility in Columbus, Ohio for the assessment of underlying CHD risk from 1999 to 2003. Individuals were referred for screening on the basis of the presence of established risk factors for atherosclerosis and, as such, were not an unselected cohort representative of the general population. All screened individuals provided an informed consent to undergo EBT screening, and our study received the Human Investigations Committee approval. Furthermore, separate approval from the Human Investigations Committee was obtained, along with informed consent, for the patient interviews, collection of data and follow-up, and corroboration of the occurrence of death. 2.1. Risk factor data collection A history of cigarette smoking was considered present if a subject was a current or former smoker. Dyslipidemia was coded as present for any individual self-reporting a history of high total cholesterol, high LDL-cholesterol, low HDL-cholesterol and/or high triglycerides, or current use of lipid-lowering therapy. Patients were considered to have diabetes if they reported using oral hypoglycemic agents, insulin sensitizers, or insulin and were considered to have hypertension if they reported a history of high blood pressure or used antihypertensive medications. Family history of early CHD in parents and siblings was obtained by asking patients whether any member of their immediate family (parents or siblings) had a fatal or non-fatal myocardial infarction and/or coronary revascularization before or after 55 years of age. Body mass index (BMI) was calculated for individuals who provided a self-report of height and weight. Individuals with BMI ≥30 kg/m2 were considered obese. 2.1.1. Coronary and thoracic aorta calcium screening protocol EBT was performed with either a C-100 or C-150 scanner (Imatron® , San Francisco, CA), and images were obtained with 100ms scanning time. The CT section thickness was 3 mm, and, in total, 40 sections were obtained starting at the level of the carina and proceeding to the level of the diaphragm. CT imaging was electrocardiographically triggered at 60–80% of the R–R interval. The same scan series was used for the assessment of thoracic aorta calcification (TAC) and coronary artery calcium (CAC). A calcified lesion was defined as ≥3 contiguous pixels with a peak Hounsfeld (H) attenuation of >130. Presence of TAC was defined as any calcification detected in both ascending and descending thoracic aortas. The CAC scores were calculated with the method described by Agatston et al. [7]. 2.2. Follow-up data collection Epidemiological methods for follow-up included ascertainment of events by individuals blinded to historical and EBT results. Individuals who underwent cardiovascular screening were followed for a median of 5 years (range: 1–7 years). Death from all-causes was the primary endpoint for this registry. The occurrence of death was verified with the Social Security Death Index. 2.3. Statistical methods For comparisons between those with and without TAC, categorical risk factors and CAC score subsets were compared using 2 statistic. Time to death from all-causes was estimated using a Cox proportional hazards model. For the Cox model, univariable and multivariable models were developed and included an evaluation of traditional cardiac risk factors and the presence of TAC. In addition Kaplan Meyer survival curves were also generated according to the presence or absence of TAC.
Specifically, the independent prognostic value of TAC for predicting all-cause mortality was assessed in a hierarchal manner using the following models: Model 1: unadjusted. Model 2: age and gender adjusted. Model 3: age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking and family history of premature CHD adjusted. Model 4: model 3 + CAC. In addition, to determine whether the addition of TAC contributed significantly to the models containing traditional risk factors alone as well as traditional risk factors + CAC scores in predicting all-cause mortality, the likelihood ratio 2 statistic was used. All statistical analyses were performed with STATA version 10.0 (Stata Corp., Austin, Texas, http://www.stata.com). The level of significance was set at p < 0.05 (two-tailed). The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written. 3. Results We followed up a cohort of 8401 asymptomatic individuals without previous manifestation of cardiovascular disease (mean age: 53 ± 10 years, 69% men). The prevalence of cardiac risk factors in our patient cohort was as follows: hyperlipidemia (26%), hypertension (28%), smoking (9%), diabetes (6%), family history of premature CHD (30%), and obesity (25%). Among the 8401 subjects, 35% had no major CHD risk factor, whereas 36%, 20%, and 9% had 1, 2, and 3 major risk factors. Table 1 shows a comparison of subjects with and without detectable TAC. Study participants with TAC were older (p < 0.001), more likely to be females (p = 0.001), have systemic hypertension (p < 0.001), diabetes mellitus (p < 0.001), dyslipidemia (p < 0.001), and a family history of early CHD (p < 0.0001). In our study population TAC was detected in 22% (n = 1877) of study subjects. Overall prevalence of CAC was significantly higher in subjects with TAC (77% vs. 49%, p < 0.0001); in addition higher CAC scores were also observed with the presence of TAC (304 ± 567 vs. 93 ± 302, p < 0.0001). In the absence of CAC (n = 3781), only 11% (n = 424) demonstrated TAC; women were more likely to have TAC (16%) as compared to men (8%) among those with CAC = 0 (p < 0.0001). During the median follow-up of 5 years, 124 (1.5%) all-cause deaths were recorded. Overall survival was 96.9% and 98.9% for those with and without detectable TAC, respectively (p < 0.0001) (Fig. 1). When stratified according to moderate CAC scores (<100 and ≥100), as shown in Fig. 2 the cumulative survival was lower with TAC in both groups. Fig. 3 shows that the lowest event rate was observed in those with CAC <100 and the absence of TAC (1.6 events per 1000 person years), whereas those with CAC ≥100 and detectable TAC had the highest all-fatality rate (9.8 per 1000 person years). Table 1 Clinical characteristics of subjects presenting (TAC+) or not thoracic aortic calcification (TAC−). TAC (−), N = 6524 Age (years) 51 ± 10 Gender (female) (%) 30 Hypertension (%) 25 Diabetes (%) 5 Dyslipidemia (%) 23 Family history of CHD (%) 27 Smoking (%) 8
TAC (+), N = 1877
60 ± 10 34 39 10 35 25 12
p value <0.0001 0.001 <0.0001 <0.0001 <0.0001 0.014 <0.0001
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Fig. 3. Mortality rate (per 1000 person years) according to thoracic aortic calcification presence (TAC) and CAC <100 and CAC ≥100.
Fig. 1. Cumulative survival for subjects with (TAC+) or without (TAC−) thoracic aortic calcification.
Table 2 shows the hazard ratios (HR) for mortality in the presence of TAC in univariable and multivariable analyses. As compared to those with absent TAC (reference group) risk for mortality with the presence of TAC was approximately 3 times in unadjusted analyses (p < 0.0001). After taking into account age, gender and CHD risk factors the risk was attenuated but remained statistically significant (HR = 1.78, 95% CI: 1.23–2.60, p = 0.002). The relationship
remained robust (HR: 1.61, 95% CI: 1.10–2.27, p = 0.015) when the presence or absence of CAC was added to the multivariate analyses in Table 2 (model 4). On the other hand, when CAC scores categories (0, 1–99, 100–399 and ≥400) were added to the multivariable analyses, TAC demonstrated a strong trend for but did not attain statistical significance with all-cause mortality (HR: 1.45, 95% CI: 0.98–2.16, p = 0.06). Similar results were obtained when CAC was added as a continuous variable (data not shown). Overall likelihood ratio 2 statistics demonstrated that the addition of TAC contributed significantly in predicting mortality to traditional risk factors alone (2 = 13.62, p = 0.002) as well as risk factors + CAC (2 = 5.84 p = 0.02) models. 3.1. TAC and all-cause mortality in women and men In gender specific sub-analyses the HR (95% CI) for all-cause mortality with the presence of TAC was 1.76 (0.83–3.74) for women and 1.76 (1.13–2.72) for men after adjusting for age and CHD risk factors (model 3); the respective hazard ratios after further taking into the presence of CAC (model 4) were 1.61 (0.75–3.44) and 1.60 (1.02–2.52). There was no gender by TAC interaction in the prediction of all-cause mortality. 3.2. TAC and all-cause mortality absence of CAC Among study participants who did not have CAC at baseline (n = 3781, 45%), only 424 (11%) individuals had TAC, and its presence was associated with a hazard ratio of 2.53 (95% CI: 0.99–6.48, p = 0.054) for predicting all-cause mortality in CHD risk adjusted multivariable analyses (model 3). On further stratification according to gender (adjusting for traditional risk factors) in the absence of CAC, the presence of TAC was significantly associated with allcause mortality in women (HR: 4.94, 95% CI: 1.22–19.97, p = 0.02), whereas no such relationship was observed in men (HR: 1.43, 95% CI: 0.31–6.59, p = 0.65). No gender and TAC interaction was found for prediction of all-cause mortality in subjects without detectable CAC.
Table 2 Hazard ratio for all-cause mortality with the presence of thoracic aorta calcification in univariable and multivariable analyses.
Model 1 Model 2 Model 3 Model 4
Fig. 2. Cumulative survival for subjects with (TAC+) or without (TAC−) thoracic aortic calcification according to CAC <100 and CAC ≥100.
Hazard ratio
95% CI
p value
3.25 2.07 1.78 1.61
2.28–4.65 1.43–2.99 1.23–2.60 1.10–2.27
<0.0001 <0.0001 0.002 0.015
Model 1: unadjusted. Model 2: age and gender adjusted. Model 3: age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking and family history of premature CHD adjusted. Model 4: model 3 + presence of CAC.
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4. Discussion After a median 5-year follow-up TAC detected by EBT was associated with all-cause mortality independently of CHD risk factors and CAC in a cohort of men and women without known cardiovascular disease. Our study suggests that detection of TAC in the same scan obtained for CAC assessment without any addition exposure and cost provides prognostic information beyond clinical evaluation of coronary atherosclerosis. The presence of TAC detected by chest X-rays and located in the aortic arch has been associated with an increased risk of CHD in both genders and with stroke in women [4]. Studies have also associated aortic arch TAC detected by chest X-ray with increased cardiovascular death in hemodialysis patients [8] with and without diabetes. Thoracic CT is a more sensitive method to detect TAC than chest X-rays and data from the Multi-Ethnic Study of Atherosclerosis (MESA) study has associated the presence of TAC detected by CT with risk factors like hypertension, smoking, diabetes, dyslipidemia and family history of myocardial infarction in subjects of different ethnicities [9]. The presence of TAC detected by CT has been associated with an increased risk of cardiovascular events and death event in stable angina pectoris patients [10]. The advent of cardiac CT allowed the detection and quantification of CAC, a proven marker of coronary atherosclerosis [3]. Prospective studies have clearly shown that CAC is an independent predictor of myocardial infarction, CHD death and all-cause mortality risk [11–14]. Although the presence and severity of CAC have been clearly established as an indicator of an adverse event, it is still unknown if TAC observed on the same EBT scan performed to detect CAC provides additional prognostic information. Consistent with prior reports, [4,9] subjects with TAC were older, had a greater proportion of females and a higher prevalence of risk factors for atherosclerosis. TAC presence was also associated with a greater prevalence and extent of subclinical coronary atherosclerosis represented by CAC, confirming previous studies in smaller populations showing the association of aortic and coronary calcifications detected by computerized tomography [9,15,16], as well as obstructive coronary plaques detected by invasive coronary angiography [5,17–19]. However, our study is unique and adds to the literature by describing for the first time that the presence of TAC predicts mortality in a large cohort of asymptomatic individuals and this relationship is independent of baseline CHD risk factors and burden of CAC. An important finding was that even in subjects with moderate-to-high CAC scores the presence of TAC was associated with higher death rates suggesting that additional assessment of TAC in non-contrast cardiac scans performed primarily for the assessment of extent of coronary atherosclerosis may provide additional prognostic information. In addition, TAC is readily detected with low-dose ungated chest CT performed for lung cancer and COPD screening and can provide additional information for CHD stratification without additional scanning or burden to participants. Current literature suggests a very low cardiovascular event rate among those with the absence of CAC [11–13]. However, in spite of an excellent prognosis with the absence of CAC, few events do occur in this subgroup. It is not clear whether identification of atherosclerosis in additional vascular beds such as the thoracic aorta will improve further risk stratification in this low risk group. In our study very few individuals without CAC had TAC, who had almost a twofold increase risk of mortality, albeit with a low absolute risk. Although the hazard ratio for predicting all-cause mortality with TAC among those with absent CAC was nearly twofold higher after taking into account the traditional CHD risk factors demonstrating a strong trend, it did not achieve statistical significance. We believe that this may be directly related to a much smaller sample size in this subgroup and to the fact that our study endpoint only included all-cause mortality and we were not able to assess non-fatal cardio-
vascular disease. We have previously demonstrated that women, who are traditionally less likely to have coronary atherosclerosis, have a higher prevalence of TAC even in the absence of CAC [20]. Considering the fact that women are significantly less likely to have CAC, detection of TAC in such scenario may provide the earliest sign of underlying atherosclerotic process and important prognostic information for future risk of adverse events. These findings suggest that beyond the assessment of coronary calcium, additional relevant information can be gained by this study that may be useful in guiding further management. The MESA, which is a prospective study assessing the utility of various information obtained on non-contrast CT currently in progress, will provide more precise information on the additional utility of measuring TAC in predicting cardiovascular events in addition to the assessment of CAC [9]. Although the current study includes a rigorous analysis of the prognostic value of TAC, the majority of patients referred for EBT testing had cardiac risk factors and, as such, were not representative of the general population. A chest CT performed for CAC screening typically excludes the aortic arch and the abdominal aorta; hence our study did not allow us to include these potentially important areas in the estimation of risk. Furthermore, we did not calculate a calcium score for TAC and we limited our assessment to establishing the presence vs. absence of calcification without quantification of the burden of disease in the aorta. We collected patients’ selfreported CHD risk factors. Although Hoff et al. [21] demonstrated a good reliability of self-reported histories, the probability of “residual confounding” cannot be ruled out. In this study we were not able to relate the presence of TAC with the cause of death in the study population. However, nearly three-fourths of all deaths are related to atherosclerosis complications [5,22], and this end point is unaffected by the reporting and misclassification bias potentially introduced by a physician’s filing of a death report [23]. It must be kept in mind that medication type and renal function were not collected in our study, which may affect the association of TAC with mortality. Finally, our study population was mainly Caucasians and the results may not apply to other ethnic groups. Our study findings need to be confirmed in large prospective studies such as the Multi-Ethnic Study of Atherosclerosis, in which all the risk factors are collected as underlying CHD events are recorded. In summary, the presence of TAC in subjects with CAC was independently associated with mortality in a large cohort of physician-referred and self-referred asymptomatic individuals. Detection of TAC may provide supplementary prognostic information in addition to CAC with no extra cost and radiation. The study results need to be verified in prospective population based cohorts such as the Multi-Ethnic Study of Atherosclerosis that takes into account the measured risk factors as well as assess risk in subjects of different ethnicities. References [1] Detrano RC, Wong ND, Tang W, et al. Prognostic significance of cardiac cinefluoroscopy for coronary calcific deposits in asymptomatic high risk subjects. J Am Coll Cardiol 1994;24:354–8. [2] Nasir K, Shaw LJ, Liu ST, et al. Ethnic differences in the prognostic value of coronary artery calcification for all-cause mortality. J Am Coll Cardiol 2007;50:953–60. [3] Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2007;49:378–402. [4] Iribarren C, Sidney S, Sternfeld B, Browner WS. Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease. JAMA 2000;283:2810–5.
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