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Usefulness of coronary artery calcium for detecting significant coronary artery disease in asymptomatic individuals
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Revista Clínica Española www.elsevier.es/rce
ORIGINAL ARTICLE
Usefulness of coronary artery calcium for detecting significant coronary artery disease in asymptomatic individuals夽 M. Descalzob,c,∗ , R. Vidal-Péreza , R. Letab,c , X. Alomarb , G. Pons-Lladób,c , F. Carrerasb,c a
Servicio de Cardiología, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain Unidad de Imagen, Clínica Creu Blanca, Barcelona, Spain c Unidad de Imagen Cardiaca, Servicio de Cardiología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain b
Received 14 November 2013; accepted 10 January 2014
KEYWORDS Asymptomatic; Subclinical coronary artery disease; Cardiovascular risk stratification; Agatston coronary calcium score; Noninvasive coronary angiography; Multidetector computed tomography
Abstract Objectives: To confirm the value of the coronary artery calcium (CAC) score as an indicator of significant coronary artery disease (CAD) in the asymptomatic Spanish population, using noninvasive coronary angiography by multidetector computed tomography (MDCT). Methods: This was a retrospective study of 232 asymptomatic individuals, referred for a cardiovascular health checkup that included CAC and MDCT. Results: Participants’ mean age was 54.6 years (SD ± 12.8); 73.3% of them were men. The mean CAC value was 117.8 (SD ± 277). The individuals with arterial hypertension, diabetes mellitus, smoking and 3 or more risk factors had significantly greater CAC scores. Some 16.4% of the participants were in the ≥75th percentile population for CAC. The MDCT identified 148 individuals (63.8%) with CAD; the coronary lesions were not significant in 116 individuals (50%) and were significant (>50% stenosis) in 32 (13.8%). The participants with diabetes, smoking and ≥3 risk vascular factors had a greater prevalence of significant stenosis. The individuals with >50% stenosis had higher CAC values (352.5 vs. 1; p < .0001), and those in the ≥75th percentile had a high percentage of significant lesions (57.9% vs. 5.2%; p < .0001). The predictors of significant CAD were a CAC score >300 (OR = 10.9; 95% CI 3.35---35.8; p = .0001), belonging to the ≥75th percentile (OR = 5.65; 95% CI 1.78---17.93; p = .03) and having 3 or more vascular risk factors (OR = 4.19; 95% CI 1.44---12.14; p = .008). Conclusion: CAC quantification is an effective method for determining the extent and magnitude of CAD and delimiting the predictive capacity of traditional risk factors. © 2013 Elsevier Espa˜ na, S.L. All rights reserved.
夽 Please cite this article as: Descalzo M, Vidal-Pérez R, Leta R, Alomar X, Pons-Lladó G, Carreras F. Utilidad del calcio arterial coronario para detectar enfermedad arterial coronaria significativa en sujetos asintomáticos. Rev Clin Esp. 2014. http://dx.doi.org/10.1016/j.rce.2014.01.005 ∗ Corresponding author. E-mail address: [email protected] (M. Descalzo).
2254-8874/$ – see front matter © 2013 Elsevier Espa˜ na, S.L. All rights reserved.
RCENG-896; No. of Pages 7
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PALABRAS CLAVE Asintomático; Enfermedad coronaria subclínica; Estratificación de riesgo cardiovascular; Score Agatston de calcio coronario; Coronariografía no invasiva; Tomografía computarizada multidetector
Utilidad del calcio arterial coronario para detectar enfermedad arterial coronaria significativa en sujetos asintomáticos Resumen Objetivos: Confirmar el valor de la puntuación o score del calcio arterial coronario (CAC) como indicador de enfermedad arterial coronaria (EAC) significativa en población espa˜ nola asintomática, mediante coronariografía no invasiva por tomografía computarizada multidetector (TCMD). Métodos: Estudio retrospectivo de 232 individuos asintomáticos, remitidos para un chequeo de salud cardiovascular que incluyó CAC y TCMD. Resultados: La edad media de los sujetos estudiados fue de 54,6 a˜ nos (DE: 12,8; 73,3% varones). El valor medio del CAC fue de 117,8 (DE: 277). Los individuos con hipertensión arterial, diabetes mellitus, tabaquismo y con ≥3 factores de riesgo mostraron un CAC significativamente mayor. Un 16,4% de los sujetos se encontraban en el percentil poblacional ≥75 de CAC. La TCMD identificó a 148 individuos (63,8%) con EAC, siendo las lesiones coronarias no significativas en 116 individuos (50%) y significativas (estenosis > 50%) en 32 (13,8%). Los sujetos con diabetes, tabaquismo y ≥3 factores de riesgo vascular mostraron una mayor prevalencia de estenosis significativa. Los individuos con estenosis > 50% presentaron valores de CAC superiores (352,5 vs. 1; p < 0,0001) y los de percentil ≥75 presentaron un alto porcentaje de lesiones (57,9 vs. 5,2%; p < 0,0001). Como variables predictoras de EAC significativa destacaron el CAC > 300 (OR = 10,9; IC95%: 3,35-35,8; p = 0,0001), ocupar un percentil ≥75 (OR = 5,65; IC95%: 1,78-17,93; p = 0,03) y la agrupación de ≥3 factores de riesgo vascular (OR = 4,19; IC95%: 1,44-12,14; p = 0,008). Conclusión: La cuantificación del CAC es un método eficaz para determinar la extensión y magnitud de la EAC y delimitar la capacidad predictiva de los factores de riesgo tradicionales. © 2013 Elsevier Espa˜ na, S.L. Todos los derechos reservados.
Background Coronary artery disease (CAD) remains the leading cause of death in Western industrialized countries despite the results of prevention strategies.1 Given that approximately 50% of deaths from a coronary origin occur in asymptomatic patients, the early detection of individuals at risk of cardiovascular events is crucial for establishing an adequate prevention of CAD.2 The most frequently used stratification tools are cardiovascular risk scales such as the Framingham Risk Score and the European Systematic Coronary Risk Evaluation (SCORE).3,4 These risk scales have proven useful when applied to population groups but result in a limited estimation of individual risk.5 It is known that the conventional risk stratification models would not have identified up to 40% of patients with a myocardial infarction.6 Therefore, there is increasing interest in identifying more precise risk prediction strategies, apart from the traditional risk factors. The presence of coronary artery calcium (CAC) was demonstrated more than 15 years ago to be a sensitive marker for atherosclerosis, even in subclinical stages.7 Subsequent meta-analyses confirmed the clear association of CAC, its magnitude and progression with the clinical prognosis of CAD.8---10 This analysis further showed the added predictive value of incorporating CAC into traditional stratification scales.11 These findings make the CAC score (CACS) a potential tool for improving vascular risk stratification and are particularly useful for the intermediate-risk population.12
The objective of the current study was to analyze the CACS as an indicator of significant CAD in an asymptomatic Spanish population, using noninvasive coronarography with multidetector computed tomography (MDCT) as a reference technique.
Methods Population selection The study comprised a retrospective series of 232 consecutive, asymptomatic individuals, without evidence of CAD, referred for a MDCT in the context of a health checkup. The patients were studied between the years 2004 and 2008. Majority of the studies were conducted in the context of a company health checkup or comprised people who wanted an assessment of their own cardiovascular situation. The following were considered inclusion criteria: absence of heart disease, absence of angina and symptoms that might correspond to an anginal equivalent. The following were considered exclusion criteria: allergy to iodinated contrast media, nondialyzed renal insufficiency with a glomerular filtration rate <30 mL/min and a body mass index >40 kg/m2 . All participants consented to the MDCT procedure after reading and signing the informed consent. The cardiovascular risk factors considered for this study were gathered from the participants’ previous clinical history.
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Usefulness of coronary artery calcium
What we know Determining coronary calcium levels through noninvasive techniques such as multidetector computed tomography is a useful procedure for establishing the diagnosis of coronary artery disease. However, we do not know its sensitivity and specificity for a Spanish population of asymptomatic patients.
What this article provides In a university hospital in Barcelona and with a sample of 232 asymptomatic patients (73% men) who visited for a health checkup, 64% had coronary atherosclerotic disease (14% with significant coronary lesions [stenosis in an arterial lumen, >50%]). The predictors of coronary artery disease were (a) a coronary calcium score >300; (b) being above the 75th percentile for coronary calcium content and (c) having 3 or more vascular risk factors. Multidetector computed tomography was useful for detecting coronary artery disease in patients with high vascular risk. The Editors
Coronary multidetector computed tomography The CAC and MDCT protocols used for this study have been described in previous publications.11 The protocols also included the acquisition of noncontrast images (coronary calcium study) and a second acquisition with the concomitant administration of iodinated contrast media (noninvasive coronarography).
Coronary calcium study The imaging study was conducted on a first-generation Toshiba® Aquilion 64 CT scanner (Toshiba Corporation, Medical Systems, Otawara, Japan) with 64 detectors. The study protocol started with performing a topogram to determine the limits of acquisition of cardiac volume, which are generally delimited by the carina, trachea and diaphragm. The parameters of the administered radiation were adjusted in a conventional manner with respect to the morphological characteristics of each patient: X-rays of 120 kV, with a tube current between 250 and 400 mA. The CAC study was performed according to the modified Agatston protocol.12
Noninvasive coronarography The acquisition of cardiac volume images was performed using a continuous helical technique, throughout the entire cardiac cycle, with a slice thickness of 0.5 mm; an electrocardiogram was simultaneously recorded. Nitroglycerine was administered sublingually to all participants. Patients with a heart rate >70 beats per minute were treated
3 intravenously with a beta-blocker (5---15 mg metoprolol), when not contraindicated. An infusion pump in the cephalic vein was used to deliver iodinated contrast media in order to enhance the coronary arterial tree. A total of 80---100 mL of Iobitridol (Xenetix® ) was administered at a concentration of 350 mg/mL at an infusion rate of 5---6 mL/s. The adjustment between contrast media administration and image acquisition was performed automatically using a bolus-tracking system, which detected the arrival of the contrast media in the region of interest situated within the ascending aorta. After the acquisition, the images were reconstructed with an interval of 0.3 mm and with a temporal resolution of approximately 80 ms, resulting in a cardiac volume comprising 350---400 anatomical sections.
Analysis of coronary multidetector tomography data - Coronary artery calcium score (CACS): Coronary calcium was quantified on a workstation with specialized software (Vitrea2® , Vital images, Plymouth, MN, USA). CAC areas were identified as dense regions in the coronary artery that exceeded a threshold of 130 Hounsfield units (HU). The Agatston CACS was also quantified13 for each patient as well as the population percentile for age and gender corresponding to this CACS.14 - Coronary multidetector tomography: The coronary anatomical study was conducted using maximum intensity projections, multiplanar (curved plane and transverse axis) reconstruction and 3-D volume rendering. Coronary segmentation followed a 17-segment model in accordance with the modified classification of the American Heart Association.15 Two expert observers (one with more than 10 years of experience and the other with 4 years of experience) reached a consensus and determined (a) the capacity for image interpretation and (b) the presence and magnitude of coronary stenotic lesions. Lesions were considered significant if they were visually estimated to be larger than 50%, using as reference the contrasted area of the vessel lumen in the segments neighboring the stenosis.
Statistical analysis The quantitative variables with a normal distribution were expressed as mean ± standard deviation (SD), variables with an asymmetric distribution were expressed as median (with interquartile range) and categorical variables were expressed as frequency (percentage). The differences between quartiles for the various clinical variables were analyzed using an analysis of variance (ANOVA), the Mann---Whitney U test (for the continuous variables) and Pearson’s chi-squared test (for the categorical variables). The multivariate analysis to determine the independent predictors of significant CAC for MDCT was performed using a logistic regression model. Statistical significance was set at p < .05. The statistical analysis was performed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA) and MedCalc for Windows version 9.2.1.0 (MedCalc Software, Mariakerke, Belgium).
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Study population characteristics.
Risk factors
n = 232
Age Gender distribution, men (%) Hypertension (%) Dyslipidemia (%) Smoking (%) Diabetes (%) Family history of CAD (%) ≥3 vascular risk factors (%)
54.6 170 78 107 89 23 26 45
(DE: 12.8) (73.3%) (36.6%) (46.1%) (38.4%) (9.9%) (11.2%) (19.4%)
Abbreviations: CAD, premature coronary artery disease; SD, standard deviation.
Results The details of the 232 individuals involved in the present study are listed in Table 1.
Coronary artery calcium score and coronary artery calcium population percentile The mean CACS was 117.8 (±277), with scores ranging from 0 to 2137 (144.6 [±312] for men and 44.4 [±117] for women; p = .014). Ninety-three cases (40.1%) had a complete lack of CAC, while 32 individuals (13.8%) had CACS >300. The participants with hypertension had significantly higher CACS values than the participants with no hypertension (median CACS, 32 [1---242] vs. 1 [0---29]; p = .0001), those with diabetes (median 189 [4---555.2] vs. 3 [0---54.7]; p = .0001) and those who smoked (median 7 [0---170.2] vs. 3 [0---53.5]; p = .029). There were no significant differences between the patients with dyslipidemia and those without dyslipidemia. The individuals with ≥3 vascular risk factors had higher CACS values (median 45 [1.75---389.7] vs. 2 [0---53.5]; p = .0001). A total of 38 individuals (16.4%) fell above the 75th population percentile for their CACS adjusted for age and gender.
Multidetector coronary computer tomography An MDCT coronary angiography was successfully performed and interpreted for all patients in this series. A total of 148 individuals (63.8%) were identified with differing magnitudes of CAD, while 84 (36.2%) had no signs of CAD. Of the individuals with CAD, 116 (50%) had no significant lesions (luminal stenosis <50%), and 32 (13.8%) had significant
Table 2
0.75
Sensitivity
Table 1
Area under the curve ROC, 0.9458
0.50
0.25
0.00 0.50
0.25
0.75
1.00
1 - Specificity
Figure 1 Sensitivity and specificity of coronary calcium determination for the diagnosis of coronary artery disease by multidetector computed tomography.
lesions (luminal stenosis >50%). Among the patients with significant CAD, 11 (34.4%) had 1 diseased vessel, 8 (25%) had 2 diseased vessels, and 13 (45.6%) had 3 diseased vessels. We observed no significant coronary trunk disease in any of the patients in this series. The relationship between the vascular risk factors and the presence of significant coronary stenosis was evaluated using MDCT (Table 2). Diabetes, smoking and having 3 or more vascular risk factors were associated with a higher percentage of CAD cases by MDCT.
Coronary artery calcium score vs. multidetector coronary computer tomography Individuals with >50% stenosis presented significantly higher CACS values than those with no significant lesions (median 352.5 [220.5---707] vs. 1 [0---28]; p < .0001). A significantly increased number of >50% stenoses were found in individuals with CACS >300 compared with the number found in individuals with CACS <300 (65.6% vs. 5.5%; p < .0001) (Table 3). Similarly, patients within or above the 75th percentile of CAC had an increased percentage of significant lesions (57.9% vs. 5.2%; p < .0001). However, 2.1% of the patients with CACS <10 (n = 48) presented significant CAD. None of the individuals lacking coronary calcium (n = 93; CACS = 0) had significant lesions. The overall diagnostic accuracy of CACS for predicting significant CAD had an area under the receiver operating curve of 0.95 (95% CI: 0.92---0.98) (Fig. 1). With a CACS cutoff of 300, the sensitivity, specificity and positive and negative predictive values for predicting significant CAD were 65.6%
Significant stenosis according to risk factors.
Risk factors
>50% stenosis
<50% stenosis
p-Value
Hypertension (%) Dyslipidemia (%) Smoking (%) Diabetes (%) Family history of CAD (%) ≥3 vascular risk factors (%)
20.5 17.8 21.3 43.5 11.5 37.8
10.4 10.4 9.1 10.5 14.1 8.0
.056 .15 .015 .0001 .95 .0001
Abbreviation: CAD, premature coronary artery disease.
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Table 3 Relationship between the coronary calcium score determined with multidetector computed tomography and the presence of significant coronary stenosis. Coronary arterial calcium 0 1---10 11---100 101---300 >300 a
<50% coronary stenosisn = 200 (%) 93 47 34 15 11
>50% coronary stenosisn = 32 (%)
(100) (97.9)a (94.4) (65.2) (34.4)
0 1 2 8 21
(0) (2.1) (5.6) (34.8) (65.6)
Percentage of patients for each category of coronary arterial calcium.
(95% CI: 46.8---81.4), 94.5% (95% CI: 90.4---97.2), 65.5% (95% CI: 50.5---78.1) and 94.5% (95% CI: 91.4---96.5), respectively.
Predictors of significant CAD In the multivariate analysis, the presence of a CACS >300, a value in the ≥75th CACS percentile and the coexistence of ≥3 vascular risk factors were all shown to be independent predictors for the presence of significant CAD (Table 4).
Discussion This study revealed a high prevalence of asymptomatic CAD (63%), detected by MDCT, and symptomatic CAD (13.8%). These results agree with those reported by our group in a separate study conducted using a different patient set.16 We observed varying levels of CAC in 60% of the individuals; 13.8% of our study population had CACS >300. The presence of 3 or more vascular risk factors and a high CACS were independent markers of significant CAD (Table 4), although the predictive ability of the latter was clearly superior. High CACS can, therefore, be an attractive tool for adding value to traditional risk scales. The relevance of these findings emphasizes the aforementioned need to refine the traditional cardiovascular risk stratification scales. Moreover, there have been no other studies with Spanish populations that have recorded CAD prevalence data and CAC risk stratification strategies for asymptomatic individuals. The mean CAC values of our sample were similar to those published by Becker et al.17 (who studied a population at intermediate to high risk) and higher than those reported by other authors.18,19 This discrepancy could be explained by the presence of a certain selection bias in our population compared with other studies that focused on the general population. The presence of asymptomatic individuals with significant CAD was 13.8% for our study. A study by Romeo et al.
Table 4
conducted in an asymptomatic population showed a higher rate (27%) of significant CAD than our study; however, their study was restricted to a group of high-risk asymptomatic subjects.20 Moreover, Choi et al.18 found a 5% prevalence of significant CAD for a group of 1000 individuals from South Korea, highlighting the variability associated with the different characteristics of the study population. The multivariate analysis showed that the independent predictors for the detection of significant CAD by MDCT were a CACS >300, a CACS in the 75th percentile (or higher) and the presence of 3 or more risk factors. Within the parameters obtained by MDCT, the one with the greatest potential for predicting a stenosis >50% was a CACS >300. There are numerous studies that directly relate the presence, magnitude and extent of coronary calcifications with coronary atherosclerosis.21 When present in large amounts, coronary calcifications have been associated with a high probability of significant stenotic lesions and increased mortality.15,22,23 These findings have favored the inclusion of CACS in American and European guidelines24,25 as a screening method for the asymptomatic population at lowintermediate to intermediate risk. Some authors, however, question this strategy based upon the observation that the majority of individuals presenting with acute coronary syndromes or unstable angina show noncalcified or minimally calcified lesions.26 These authors also argue that most of the vulnerable lesions are small, not significant and not visible with angiography.27,28 It is notable that in our series, 2.12% of the patients with CACS <10 had a stenosis >50%. A number of studies have shown that despite the high negative predictive value of CACS for coronary events, low CACS (including 0 for individual cases) does not exclude the existence of obstructive CAD.29,30 This fact, along with the introduction of the latest generation of MDCT equipment that can use radiation doses below 1 mSv,31 opens the debate on whether to replace the quantification of coronary calcium (as a surrogate marker for CAD) with the direct visualization of coronary lesions using the latest-generation noninvasive MDCT angiography.
Predictors of significant coronary arterial disease.
Variables
Odds ratio
95% CI
p-Value
≥3 vascular risk factors CACS >300 75th percentile of CACS
4.193 10.954 5.657
1.44---12.14 3.35---35.82 1.78---17.935
.008 .0001 .003
Abbreviation: CACS, coronary artery calcium score.
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6 A recent subanalysis of asymptomatic individuals in the CONFIRM study29 revealed that both CACS and MDCT significantly improved the prognostic capacity of traditional risk factors for predicting all-cause mortality and combined events. Moreover, CACS had a greater incremental prognostic value in the predictive model, with little additional contribution from MDCT. It should be noted that this study, although large in scale, is an open registry and that the actions of the clinicians when presented with the results of the MDCT were not reported. It has been suggested that changes in the therapeutic conduct resulting from the anatomical information provided by the MDCT might influence the prognostic impact.30 Incorporating the measurement of CAC into algorithms of cardiovascular risk prediction for low-intermediate to intermediate risk populations might represent a suitable future strategy. There is a need, however, for more large-scale randomized studies with long-term follow-up to evaluate the role of noninvasive coronary angiography by MDCT for the identification of vulnerable patients and unstable plaques as well as its prognostic impact.31,32 Moreover, a low CAC score means that the presence of significant coronary stenosis is unlikely, while a CAC score >300 can be used as a screening strategy for selecting patients for noninvasive coronary angiography. The limitations of this study should be mentioned. It is retrospective in nature and has a certain patient selection bias. This bias is most likely caused by the probability that a high percentage of individuals who request a checkup are not at very low risk for coronary heart disease, a situation that is repeated systematically in most published studies with these characteristics.
Conclusions The quantification of CAC by MDCT is an effective method for determining the extent and magnitude of CAD as well as for defining the predictive capacity of traditional risk factors. A CAC score >300 or occupying the ≥75th population percentile is associated with a high prevalence of significant CAD.
Conflicts of interest
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The authors declare that they have no conflicts of interest.
Acknowledgements
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The authors thank Toshiba Medical Systems, Spain, for the technical support provided during the implementation of the studies.
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ORIGINAL ARTICLE
Usefulness of coronary artery calcium for detecting significant coronary artery disease in asymptomatic individuals夽 M. Descalzob,c,∗ , R. Vidal-Péreza , R. Letab,c , X. Alomarb , G. Pons-Lladób,c , F. Carrerasb,c a
Servicio de Cardiología, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain Unidad de Imagen, Clínica Creu Blanca, Barcelona, Spain c Unidad de Imagen Cardiaca, Servicio de Cardiología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain b
Received 14 November 2013; accepted 10 January 2014
KEYWORDS Asymptomatic; Subclinical coronary artery disease; Cardiovascular risk stratification; Agatston coronary calcium score; Noninvasive coronary angiography; Multidetector computed tomography
Abstract Objectives: To confirm the value of the coronary artery calcium (CAC) score as an indicator of significant coronary artery disease (CAD) in the asymptomatic Spanish population, using noninvasive coronary angiography by multidetector computed tomography (MDCT). Methods: This was a retrospective study of 232 asymptomatic individuals, referred for a cardiovascular health checkup that included CAC and MDCT. Results: Participants’ mean age was 54.6 years (SD ± 12.8); 73.3% of them were men. The mean CAC value was 117.8 (SD ± 277). The individuals with arterial hypertension, diabetes mellitus, smoking and 3 or more risk factors had significantly greater CAC scores. Some 16.4% of the participants were in the ≥75th percentile population for CAC. The MDCT identified 148 individuals (63.8%) with CAD; the coronary lesions were not significant in 116 individuals (50%) and were significant (>50% stenosis) in 32 (13.8%). The participants with diabetes, smoking and ≥3 risk vascular factors had a greater prevalence of significant stenosis. The individuals with >50% stenosis had higher CAC values (352.5 vs. 1; p < .0001), and those in the ≥75th percentile had a high percentage of significant lesions (57.9% vs. 5.2%; p < .0001). The predictors of significant CAD were a CAC score >300 (OR = 10.9; 95% CI 3.35---35.8; p = .0001), belonging to the ≥75th percentile (OR = 5.65; 95% CI 1.78---17.93; p = .03) and having 3 or more vascular risk factors (OR = 4.19; 95% CI 1.44---12.14; p = .008). Conclusion: CAC quantification is an effective method for determining the extent and magnitude of CAD and delimiting the predictive capacity of traditional risk factors. © 2013 Elsevier Espa˜ na, S.L. All rights reserved.
夽 Please cite this article as: Descalzo M, Vidal-Pérez R, Leta R, Alomar X, Pons-Lladó G, Carreras F. Utilidad del calcio arterial coronario para detectar enfermedad arterial coronaria significativa en sujetos asintomáticos. Rev Clin Esp. 2014. http://dx.doi.org/10.1016/j.rce.2014.01.005 ∗ Corresponding author. E-mail address: [email protected] (M. Descalzo).
2254-8874/$ – see front matter © 2013 Elsevier Espa˜ na, S.L. All rights reserved.
RCENG-896; No. of Pages 7
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PALABRAS CLAVE Asintomático; Enfermedad coronaria subclínica; Estratificación de riesgo cardiovascular; Score Agatston de calcio coronario; Coronariografía no invasiva; Tomografía computarizada multidetector
Utilidad del calcio arterial coronario para detectar enfermedad arterial coronaria significativa en sujetos asintomáticos Resumen Objetivos: Confirmar el valor de la puntuación o score del calcio arterial coronario (CAC) como indicador de enfermedad arterial coronaria (EAC) significativa en población espa˜ nola asintomática, mediante coronariografía no invasiva por tomografía computarizada multidetector (TCMD). Métodos: Estudio retrospectivo de 232 individuos asintomáticos, remitidos para un chequeo de salud cardiovascular que incluyó CAC y TCMD. Resultados: La edad media de los sujetos estudiados fue de 54,6 a˜ nos (DE: 12,8; 73,3% varones). El valor medio del CAC fue de 117,8 (DE: 277). Los individuos con hipertensión arterial, diabetes mellitus, tabaquismo y con ≥3 factores de riesgo mostraron un CAC significativamente mayor. Un 16,4% de los sujetos se encontraban en el percentil poblacional ≥75 de CAC. La TCMD identificó a 148 individuos (63,8%) con EAC, siendo las lesiones coronarias no significativas en 116 individuos (50%) y significativas (estenosis > 50%) en 32 (13,8%). Los sujetos con diabetes, tabaquismo y ≥3 factores de riesgo vascular mostraron una mayor prevalencia de estenosis significativa. Los individuos con estenosis > 50% presentaron valores de CAC superiores (352,5 vs. 1; p < 0,0001) y los de percentil ≥75 presentaron un alto porcentaje de lesiones (57,9 vs. 5,2%; p < 0,0001). Como variables predictoras de EAC significativa destacaron el CAC > 300 (OR = 10,9; IC95%: 3,35-35,8; p = 0,0001), ocupar un percentil ≥75 (OR = 5,65; IC95%: 1,78-17,93; p = 0,03) y la agrupación de ≥3 factores de riesgo vascular (OR = 4,19; IC95%: 1,44-12,14; p = 0,008). Conclusión: La cuantificación del CAC es un método eficaz para determinar la extensión y magnitud de la EAC y delimitar la capacidad predictiva de los factores de riesgo tradicionales. © 2013 Elsevier Espa˜ na, S.L. Todos los derechos reservados.
Background Coronary artery disease (CAD) remains the leading cause of death in Western industrialized countries despite the results of prevention strategies.1 Given that approximately 50% of deaths from a coronary origin occur in asymptomatic patients, the early detection of individuals at risk of cardiovascular events is crucial for establishing an adequate prevention of CAD.2 The most frequently used stratification tools are cardiovascular risk scales such as the Framingham Risk Score and the European Systematic Coronary Risk Evaluation (SCORE).3,4 These risk scales have proven useful when applied to population groups but result in a limited estimation of individual risk.5 It is known that the conventional risk stratification models would not have identified up to 40% of patients with a myocardial infarction.6 Therefore, there is increasing interest in identifying more precise risk prediction strategies, apart from the traditional risk factors. The presence of coronary artery calcium (CAC) was demonstrated more than 15 years ago to be a sensitive marker for atherosclerosis, even in subclinical stages.7 Subsequent meta-analyses confirmed the clear association of CAC, its magnitude and progression with the clinical prognosis of CAD.8---10 This analysis further showed the added predictive value of incorporating CAC into traditional stratification scales.11 These findings make the CAC score (CACS) a potential tool for improving vascular risk stratification and are particularly useful for the intermediate-risk population.12
The objective of the current study was to analyze the CACS as an indicator of significant CAD in an asymptomatic Spanish population, using noninvasive coronarography with multidetector computed tomography (MDCT) as a reference technique.
Methods Population selection The study comprised a retrospective series of 232 consecutive, asymptomatic individuals, without evidence of CAD, referred for a MDCT in the context of a health checkup. The patients were studied between the years 2004 and 2008. Majority of the studies were conducted in the context of a company health checkup or comprised people who wanted an assessment of their own cardiovascular situation. The following were considered inclusion criteria: absence of heart disease, absence of angina and symptoms that might correspond to an anginal equivalent. The following were considered exclusion criteria: allergy to iodinated contrast media, nondialyzed renal insufficiency with a glomerular filtration rate <30 mL/min and a body mass index >40 kg/m2 . All participants consented to the MDCT procedure after reading and signing the informed consent. The cardiovascular risk factors considered for this study were gathered from the participants’ previous clinical history.
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Usefulness of coronary artery calcium
What we know Determining coronary calcium levels through noninvasive techniques such as multidetector computed tomography is a useful procedure for establishing the diagnosis of coronary artery disease. However, we do not know its sensitivity and specificity for a Spanish population of asymptomatic patients.
What this article provides In a university hospital in Barcelona and with a sample of 232 asymptomatic patients (73% men) who visited for a health checkup, 64% had coronary atherosclerotic disease (14% with significant coronary lesions [stenosis in an arterial lumen, >50%]). The predictors of coronary artery disease were (a) a coronary calcium score >300; (b) being above the 75th percentile for coronary calcium content and (c) having 3 or more vascular risk factors. Multidetector computed tomography was useful for detecting coronary artery disease in patients with high vascular risk. The Editors
Coronary multidetector computed tomography The CAC and MDCT protocols used for this study have been described in previous publications.11 The protocols also included the acquisition of noncontrast images (coronary calcium study) and a second acquisition with the concomitant administration of iodinated contrast media (noninvasive coronarography).
Coronary calcium study The imaging study was conducted on a first-generation Toshiba® Aquilion 64 CT scanner (Toshiba Corporation, Medical Systems, Otawara, Japan) with 64 detectors. The study protocol started with performing a topogram to determine the limits of acquisition of cardiac volume, which are generally delimited by the carina, trachea and diaphragm. The parameters of the administered radiation were adjusted in a conventional manner with respect to the morphological characteristics of each patient: X-rays of 120 kV, with a tube current between 250 and 400 mA. The CAC study was performed according to the modified Agatston protocol.12
Noninvasive coronarography The acquisition of cardiac volume images was performed using a continuous helical technique, throughout the entire cardiac cycle, with a slice thickness of 0.5 mm; an electrocardiogram was simultaneously recorded. Nitroglycerine was administered sublingually to all participants. Patients with a heart rate >70 beats per minute were treated
3 intravenously with a beta-blocker (5---15 mg metoprolol), when not contraindicated. An infusion pump in the cephalic vein was used to deliver iodinated contrast media in order to enhance the coronary arterial tree. A total of 80---100 mL of Iobitridol (Xenetix® ) was administered at a concentration of 350 mg/mL at an infusion rate of 5---6 mL/s. The adjustment between contrast media administration and image acquisition was performed automatically using a bolus-tracking system, which detected the arrival of the contrast media in the region of interest situated within the ascending aorta. After the acquisition, the images were reconstructed with an interval of 0.3 mm and with a temporal resolution of approximately 80 ms, resulting in a cardiac volume comprising 350---400 anatomical sections.
Analysis of coronary multidetector tomography data - Coronary artery calcium score (CACS): Coronary calcium was quantified on a workstation with specialized software (Vitrea2® , Vital images, Plymouth, MN, USA). CAC areas were identified as dense regions in the coronary artery that exceeded a threshold of 130 Hounsfield units (HU). The Agatston CACS was also quantified13 for each patient as well as the population percentile for age and gender corresponding to this CACS.14 - Coronary multidetector tomography: The coronary anatomical study was conducted using maximum intensity projections, multiplanar (curved plane and transverse axis) reconstruction and 3-D volume rendering. Coronary segmentation followed a 17-segment model in accordance with the modified classification of the American Heart Association.15 Two expert observers (one with more than 10 years of experience and the other with 4 years of experience) reached a consensus and determined (a) the capacity for image interpretation and (b) the presence and magnitude of coronary stenotic lesions. Lesions were considered significant if they were visually estimated to be larger than 50%, using as reference the contrasted area of the vessel lumen in the segments neighboring the stenosis.
Statistical analysis The quantitative variables with a normal distribution were expressed as mean ± standard deviation (SD), variables with an asymmetric distribution were expressed as median (with interquartile range) and categorical variables were expressed as frequency (percentage). The differences between quartiles for the various clinical variables were analyzed using an analysis of variance (ANOVA), the Mann---Whitney U test (for the continuous variables) and Pearson’s chi-squared test (for the categorical variables). The multivariate analysis to determine the independent predictors of significant CAC for MDCT was performed using a logistic regression model. Statistical significance was set at p < .05. The statistical analysis was performed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA) and MedCalc for Windows version 9.2.1.0 (MedCalc Software, Mariakerke, Belgium).
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Study population characteristics.
Risk factors
n = 232
Age Gender distribution, men (%) Hypertension (%) Dyslipidemia (%) Smoking (%) Diabetes (%) Family history of CAD (%) ≥3 vascular risk factors (%)
54.6 170 78 107 89 23 26 45
(DE: 12.8) (73.3%) (36.6%) (46.1%) (38.4%) (9.9%) (11.2%) (19.4%)
Abbreviations: CAD, premature coronary artery disease; SD, standard deviation.
Results The details of the 232 individuals involved in the present study are listed in Table 1.
Coronary artery calcium score and coronary artery calcium population percentile The mean CACS was 117.8 (±277), with scores ranging from 0 to 2137 (144.6 [±312] for men and 44.4 [±117] for women; p = .014). Ninety-three cases (40.1%) had a complete lack of CAC, while 32 individuals (13.8%) had CACS >300. The participants with hypertension had significantly higher CACS values than the participants with no hypertension (median CACS, 32 [1---242] vs. 1 [0---29]; p = .0001), those with diabetes (median 189 [4---555.2] vs. 3 [0---54.7]; p = .0001) and those who smoked (median 7 [0---170.2] vs. 3 [0---53.5]; p = .029). There were no significant differences between the patients with dyslipidemia and those without dyslipidemia. The individuals with ≥3 vascular risk factors had higher CACS values (median 45 [1.75---389.7] vs. 2 [0---53.5]; p = .0001). A total of 38 individuals (16.4%) fell above the 75th population percentile for their CACS adjusted for age and gender.
Multidetector coronary computer tomography An MDCT coronary angiography was successfully performed and interpreted for all patients in this series. A total of 148 individuals (63.8%) were identified with differing magnitudes of CAD, while 84 (36.2%) had no signs of CAD. Of the individuals with CAD, 116 (50%) had no significant lesions (luminal stenosis <50%), and 32 (13.8%) had significant
Table 2
0.75
Sensitivity
Table 1
Area under the curve ROC, 0.9458
0.50
0.25
0.00 0.50
0.25
0.75
1.00
1 - Specificity
Figure 1 Sensitivity and specificity of coronary calcium determination for the diagnosis of coronary artery disease by multidetector computed tomography.
lesions (luminal stenosis >50%). Among the patients with significant CAD, 11 (34.4%) had 1 diseased vessel, 8 (25%) had 2 diseased vessels, and 13 (45.6%) had 3 diseased vessels. We observed no significant coronary trunk disease in any of the patients in this series. The relationship between the vascular risk factors and the presence of significant coronary stenosis was evaluated using MDCT (Table 2). Diabetes, smoking and having 3 or more vascular risk factors were associated with a higher percentage of CAD cases by MDCT.
Coronary artery calcium score vs. multidetector coronary computer tomography Individuals with >50% stenosis presented significantly higher CACS values than those with no significant lesions (median 352.5 [220.5---707] vs. 1 [0---28]; p < .0001). A significantly increased number of >50% stenoses were found in individuals with CACS >300 compared with the number found in individuals with CACS <300 (65.6% vs. 5.5%; p < .0001) (Table 3). Similarly, patients within or above the 75th percentile of CAC had an increased percentage of significant lesions (57.9% vs. 5.2%; p < .0001). However, 2.1% of the patients with CACS <10 (n = 48) presented significant CAD. None of the individuals lacking coronary calcium (n = 93; CACS = 0) had significant lesions. The overall diagnostic accuracy of CACS for predicting significant CAD had an area under the receiver operating curve of 0.95 (95% CI: 0.92---0.98) (Fig. 1). With a CACS cutoff of 300, the sensitivity, specificity and positive and negative predictive values for predicting significant CAD were 65.6%
Significant stenosis according to risk factors.
Risk factors
>50% stenosis
<50% stenosis
p-Value
Hypertension (%) Dyslipidemia (%) Smoking (%) Diabetes (%) Family history of CAD (%) ≥3 vascular risk factors (%)
20.5 17.8 21.3 43.5 11.5 37.8
10.4 10.4 9.1 10.5 14.1 8.0
.056 .15 .015 .0001 .95 .0001
Abbreviation: CAD, premature coronary artery disease.
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Table 3 Relationship between the coronary calcium score determined with multidetector computed tomography and the presence of significant coronary stenosis. Coronary arterial calcium 0 1---10 11---100 101---300 >300 a
<50% coronary stenosisn = 200 (%) 93 47 34 15 11
>50% coronary stenosisn = 32 (%)
(100) (97.9)a (94.4) (65.2) (34.4)
0 1 2 8 21
(0) (2.1) (5.6) (34.8) (65.6)
Percentage of patients for each category of coronary arterial calcium.
(95% CI: 46.8---81.4), 94.5% (95% CI: 90.4---97.2), 65.5% (95% CI: 50.5---78.1) and 94.5% (95% CI: 91.4---96.5), respectively.
Predictors of significant CAD In the multivariate analysis, the presence of a CACS >300, a value in the ≥75th CACS percentile and the coexistence of ≥3 vascular risk factors were all shown to be independent predictors for the presence of significant CAD (Table 4).
Discussion This study revealed a high prevalence of asymptomatic CAD (63%), detected by MDCT, and symptomatic CAD (13.8%). These results agree with those reported by our group in a separate study conducted using a different patient set.16 We observed varying levels of CAC in 60% of the individuals; 13.8% of our study population had CACS >300. The presence of 3 or more vascular risk factors and a high CACS were independent markers of significant CAD (Table 4), although the predictive ability of the latter was clearly superior. High CACS can, therefore, be an attractive tool for adding value to traditional risk scales. The relevance of these findings emphasizes the aforementioned need to refine the traditional cardiovascular risk stratification scales. Moreover, there have been no other studies with Spanish populations that have recorded CAD prevalence data and CAC risk stratification strategies for asymptomatic individuals. The mean CAC values of our sample were similar to those published by Becker et al.17 (who studied a population at intermediate to high risk) and higher than those reported by other authors.18,19 This discrepancy could be explained by the presence of a certain selection bias in our population compared with other studies that focused on the general population. The presence of asymptomatic individuals with significant CAD was 13.8% for our study. A study by Romeo et al.
Table 4
conducted in an asymptomatic population showed a higher rate (27%) of significant CAD than our study; however, their study was restricted to a group of high-risk asymptomatic subjects.20 Moreover, Choi et al.18 found a 5% prevalence of significant CAD for a group of 1000 individuals from South Korea, highlighting the variability associated with the different characteristics of the study population. The multivariate analysis showed that the independent predictors for the detection of significant CAD by MDCT were a CACS >300, a CACS in the 75th percentile (or higher) and the presence of 3 or more risk factors. Within the parameters obtained by MDCT, the one with the greatest potential for predicting a stenosis >50% was a CACS >300. There are numerous studies that directly relate the presence, magnitude and extent of coronary calcifications with coronary atherosclerosis.21 When present in large amounts, coronary calcifications have been associated with a high probability of significant stenotic lesions and increased mortality.15,22,23 These findings have favored the inclusion of CACS in American and European guidelines24,25 as a screening method for the asymptomatic population at lowintermediate to intermediate risk. Some authors, however, question this strategy based upon the observation that the majority of individuals presenting with acute coronary syndromes or unstable angina show noncalcified or minimally calcified lesions.26 These authors also argue that most of the vulnerable lesions are small, not significant and not visible with angiography.27,28 It is notable that in our series, 2.12% of the patients with CACS <10 had a stenosis >50%. A number of studies have shown that despite the high negative predictive value of CACS for coronary events, low CACS (including 0 for individual cases) does not exclude the existence of obstructive CAD.29,30 This fact, along with the introduction of the latest generation of MDCT equipment that can use radiation doses below 1 mSv,31 opens the debate on whether to replace the quantification of coronary calcium (as a surrogate marker for CAD) with the direct visualization of coronary lesions using the latest-generation noninvasive MDCT angiography.
Predictors of significant coronary arterial disease.
Variables
Odds ratio
95% CI
p-Value
≥3 vascular risk factors CACS >300 75th percentile of CACS
4.193 10.954 5.657
1.44---12.14 3.35---35.82 1.78---17.935
.008 .0001 .003
Abbreviation: CACS, coronary artery calcium score.
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6 A recent subanalysis of asymptomatic individuals in the CONFIRM study29 revealed that both CACS and MDCT significantly improved the prognostic capacity of traditional risk factors for predicting all-cause mortality and combined events. Moreover, CACS had a greater incremental prognostic value in the predictive model, with little additional contribution from MDCT. It should be noted that this study, although large in scale, is an open registry and that the actions of the clinicians when presented with the results of the MDCT were not reported. It has been suggested that changes in the therapeutic conduct resulting from the anatomical information provided by the MDCT might influence the prognostic impact.30 Incorporating the measurement of CAC into algorithms of cardiovascular risk prediction for low-intermediate to intermediate risk populations might represent a suitable future strategy. There is a need, however, for more large-scale randomized studies with long-term follow-up to evaluate the role of noninvasive coronary angiography by MDCT for the identification of vulnerable patients and unstable plaques as well as its prognostic impact.31,32 Moreover, a low CAC score means that the presence of significant coronary stenosis is unlikely, while a CAC score >300 can be used as a screening strategy for selecting patients for noninvasive coronary angiography. The limitations of this study should be mentioned. It is retrospective in nature and has a certain patient selection bias. This bias is most likely caused by the probability that a high percentage of individuals who request a checkup are not at very low risk for coronary heart disease, a situation that is repeated systematically in most published studies with these characteristics.
Conclusions The quantification of CAC by MDCT is an effective method for determining the extent and magnitude of CAD as well as for defining the predictive capacity of traditional risk factors. A CAC score >300 or occupying the ≥75th population percentile is associated with a high prevalence of significant CAD.
Conflicts of interest
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The authors declare that they have no conflicts of interest.
Acknowledgements
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The authors thank Toshiba Medical Systems, Spain, for the technical support provided during the implementation of the studies.
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