J Atheroscler Thromb, 2016; 23: 1309-1310. doi: 10.5551/jat.ED058
Editorial
Significance of Small Calcifications in Patients with a Zero Calcium Score Shinichiro Fujimoto Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
See article vol. 23: 1324-1333 Coronary arterial calcium score (CACS) has been considered to be an important index to indicate the severity of coronary atherosclerosis noninvasively. However, even if CACS is 0, it is reported that the presence of coronary atherosclerosis is not always deniable. In a multicenter CORE64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) trial, among 24% of subjects in whom angina pectoris was suspected and coronary CT angiography (CCTA) was performed and CACS was 0, significant stenosis of the coronary artery was detected in 19% 1). In CONFIRM registry with 10,037 symptomatic subjects, the incidence of significant stenosis was 3.5% in the group with a CACS of 0. Compared to the group without significant stenosis, prognosis in the group with significant stenosis was poor even if CACS was 0. Thus, the author concluded that CACS did not give incremental prognostic information to the findings of CCTA 2). In this Journal, Urabe et al. evaluated small calcifications using images with 0.5-mm slices reconstruction and identified small calcifications in 13.6% of 132 subjects whose CACS was 0. They reported that in the group with small calcifications, CCTA revealed a significantly higher incidence of non-calcified/partially calcified plaques or obstructive stenosis 3). In ROC analysis, the presence of small calcifications gave an incremental diagnostic value for detection of patients with non-calcified/partially calcified plaques or any stenosis but not obstructive stenosis which was not significant. From these findings, they concluded Address for correspondence: Shinichiro Fujimoto, Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan E-mail: [email protected] Received: July 23, 2016 Accepted for publication: July 26, 2016
that the evaluation of small calcifications by 0.5-mm slices reconstruction was useful for the differentiation of coronary atherosclerosis presence and CCTA necessity in the group with a CACS of 0. To calculate CACS, calcification is defined as a CT value of 130 HU or more in the coronary artery on plain CT scans with a 3 mm slice thickness, and the CT value is weighted by the area of calcification. A recent development in the CT technique has enabled evaluation with 0.5-mm slice reconstruction without additional radiation exposure. In addition, even in non-obstructive cases, it is reported that the presence of coronary atherosclerosis in CCTA induced significantly worse prognosis than in the normal group 4). Thus, the results of the paper were clinically significant. However, to determine the incidence of the presence of coronary arterial diseases in such studies, it will be necessary to consider the influence of future cardiac event risk and pretest probability on the outcome in the study population. In the study population reported by Urabe et al., the mean Framingham-risk score of them is in the intermediate risk category. On the other hand, subjects are mostly symptomatic patients. According to their study, although the pretest probability for obstructive coronary artery diseases in symptomatic patients is not evaluated, if the pretest probability in the symptomatic patients is intermediate or higher, regardless of CACS, the case would be considered to be an indication of CCTA. Thus, it is considered necessary to conduct further investigations about whether the results are applicable for the stratification of risk in the asymptomatic patients with lowto-intermediate risk, who are the best candidates for CACS evaluation. In addition, the main pathologic conditions underlying acute coronary syndrome are thrombus and occlusion, it is important to identify vulnerable plaques that are associated with a high rate of thrombosis or occlusion. Vulnerable plaque that undergoes rupture accounts for about 60% of these plaques has been designated as thin-capped fibroatheroma and has become one of the most important tar-
Copyright©2016 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
1309
Fujimoto
gets for vulnerable plaque imaging. It is said that these plaques cause ACS regardless of the degree of stenosis, and even in calcified case, the severity is relatively mild 5). It has been reported that such plaques show characteristic features on CCTA such as positive remodeling, low attenuation plaque, spotty calcification and napkin-ring sign. Plaques with such features are reported to become significant predictors of cardiovascular events in the future 6, 7). It is interesting to investigate whether the evaluation of small calcifications by 0.5-mm slice reconstruction gives an incremental diagnostic value to identify such high risk plaques on CCTA. Previously, we found 4.6% high risk plaques on CCTA in the patients with a CACS of 0 and reported that when the subjects were limited to the patients having spotty calcification which could not be detected by CACS, the incidence increased to 9.6% 8). Thus, it was indicated that the evaluation of small calcifications by 0.5-mm slice reconstruction may give an incremental diagnostic value to the patients with a CACS of 0. On the other hand, the prognosis of patients with a CACS of 0 is reported to be favorable 9). It is necessary to study whether the detection of small calcifications gives an incremental prognostic value to the patients with a CACS of 0. Conflict of Interest None. References 1) Gottlieb I, Miller JM, Arbab-Zadeh A, Dewey M, Clouse ME, Sara L, Niinuma H, Bush DE, Paul N, Vavere AL, Texter J, Brinker J, Lima JA, Rochitte CE.. The absence of coronary calcification does not exclude obstructive coronary artery disease or the need for revascularization in patients referred for conventional coronary angiography. J Am Coll Cardiol 2010; 55: 627-634 2) Villines TC, Hulten EA, Shaw LJ, Goyal M, Dunning A, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng VY, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Lin FY, Maffei E, Raff GL, Min JK; CONFIRM Registry Investigators..Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography: results from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An
1310
International Multicenter) registry. J Am Coll Cardiol. 2011; 58: 2533-2540 3) Urabe Y, Yamamoto H, Kitagawa T, Utsunomiya H, Tsushima H, Tatsugami F, Kihara Y. Idenitifying small coronary calcification in non-contrast 0.5mm slice reconstruction to diagnose coronary artery disease in patients with conventional zero coronary calcium score. J Atheroscler Thromb. 2016; 23: 1324-1333 4) Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS; CONFIRM Investigators. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011; 58: 849-860 5) Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation 2004; 108: 1664-1672 6) Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, Naruse H, Ishii J, Hishida H, Wong ND, Virmani R, Kondo T, Ozaki Y, Narula J. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009; 54: 49-57 7) Otsuka K, Fukuda S, Tanaka A, Nakanishi K, Taguchi H, Yoshikawa J, Shimada K, Yoshiyama M. Napkin-ring sign on coronary CT angiography for the prediction of acute coronary syndrome. JACC Cardiovasc Imaging 2013; 6: 448-457 8) Morita H, Fujimoto S, Kondo T, Arai T, Sekine T, Matsutani H, Sano T, Kondo M, Kodama T, Takase S, Narula J. Prevalence of computed tomographic angiography-verified high-risk plaques and significant luminal stenosis in patients with zero coronary calcium score. Int J Cardiol. 2012; 158: 272-278 9) Blaha M, Budoff MJ, Shaw LJ, Khosa F, Rumberger JA, Berman D, Callister T, Raggi P, Blumenthal RS, Nasir K. Absence of coronary artery calcification and all-cause mortality. JACC Cardiovasc Imaging. 2009; 2: 692-700
Editorial
Significance of Small Calcifications in Patients with a Zero Calcium Score Shinichiro Fujimoto Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
See article vol. 23: 1324-1333 Coronary arterial calcium score (CACS) has been considered to be an important index to indicate the severity of coronary atherosclerosis noninvasively. However, even if CACS is 0, it is reported that the presence of coronary atherosclerosis is not always deniable. In a multicenter CORE64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) trial, among 24% of subjects in whom angina pectoris was suspected and coronary CT angiography (CCTA) was performed and CACS was 0, significant stenosis of the coronary artery was detected in 19% 1). In CONFIRM registry with 10,037 symptomatic subjects, the incidence of significant stenosis was 3.5% in the group with a CACS of 0. Compared to the group without significant stenosis, prognosis in the group with significant stenosis was poor even if CACS was 0. Thus, the author concluded that CACS did not give incremental prognostic information to the findings of CCTA 2). In this Journal, Urabe et al. evaluated small calcifications using images with 0.5-mm slices reconstruction and identified small calcifications in 13.6% of 132 subjects whose CACS was 0. They reported that in the group with small calcifications, CCTA revealed a significantly higher incidence of non-calcified/partially calcified plaques or obstructive stenosis 3). In ROC analysis, the presence of small calcifications gave an incremental diagnostic value for detection of patients with non-calcified/partially calcified plaques or any stenosis but not obstructive stenosis which was not significant. From these findings, they concluded Address for correspondence: Shinichiro Fujimoto, Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan E-mail: [email protected] Received: July 23, 2016 Accepted for publication: July 26, 2016
that the evaluation of small calcifications by 0.5-mm slices reconstruction was useful for the differentiation of coronary atherosclerosis presence and CCTA necessity in the group with a CACS of 0. To calculate CACS, calcification is defined as a CT value of 130 HU or more in the coronary artery on plain CT scans with a 3 mm slice thickness, and the CT value is weighted by the area of calcification. A recent development in the CT technique has enabled evaluation with 0.5-mm slice reconstruction without additional radiation exposure. In addition, even in non-obstructive cases, it is reported that the presence of coronary atherosclerosis in CCTA induced significantly worse prognosis than in the normal group 4). Thus, the results of the paper were clinically significant. However, to determine the incidence of the presence of coronary arterial diseases in such studies, it will be necessary to consider the influence of future cardiac event risk and pretest probability on the outcome in the study population. In the study population reported by Urabe et al., the mean Framingham-risk score of them is in the intermediate risk category. On the other hand, subjects are mostly symptomatic patients. According to their study, although the pretest probability for obstructive coronary artery diseases in symptomatic patients is not evaluated, if the pretest probability in the symptomatic patients is intermediate or higher, regardless of CACS, the case would be considered to be an indication of CCTA. Thus, it is considered necessary to conduct further investigations about whether the results are applicable for the stratification of risk in the asymptomatic patients with lowto-intermediate risk, who are the best candidates for CACS evaluation. In addition, the main pathologic conditions underlying acute coronary syndrome are thrombus and occlusion, it is important to identify vulnerable plaques that are associated with a high rate of thrombosis or occlusion. Vulnerable plaque that undergoes rupture accounts for about 60% of these plaques has been designated as thin-capped fibroatheroma and has become one of the most important tar-
Copyright©2016 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
1309
Fujimoto
gets for vulnerable plaque imaging. It is said that these plaques cause ACS regardless of the degree of stenosis, and even in calcified case, the severity is relatively mild 5). It has been reported that such plaques show characteristic features on CCTA such as positive remodeling, low attenuation plaque, spotty calcification and napkin-ring sign. Plaques with such features are reported to become significant predictors of cardiovascular events in the future 6, 7). It is interesting to investigate whether the evaluation of small calcifications by 0.5-mm slice reconstruction gives an incremental diagnostic value to identify such high risk plaques on CCTA. Previously, we found 4.6% high risk plaques on CCTA in the patients with a CACS of 0 and reported that when the subjects were limited to the patients having spotty calcification which could not be detected by CACS, the incidence increased to 9.6% 8). Thus, it was indicated that the evaluation of small calcifications by 0.5-mm slice reconstruction may give an incremental diagnostic value to the patients with a CACS of 0. On the other hand, the prognosis of patients with a CACS of 0 is reported to be favorable 9). It is necessary to study whether the detection of small calcifications gives an incremental prognostic value to the patients with a CACS of 0. Conflict of Interest None. References 1) Gottlieb I, Miller JM, Arbab-Zadeh A, Dewey M, Clouse ME, Sara L, Niinuma H, Bush DE, Paul N, Vavere AL, Texter J, Brinker J, Lima JA, Rochitte CE.. The absence of coronary calcification does not exclude obstructive coronary artery disease or the need for revascularization in patients referred for conventional coronary angiography. J Am Coll Cardiol 2010; 55: 627-634 2) Villines TC, Hulten EA, Shaw LJ, Goyal M, Dunning A, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng VY, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Lin FY, Maffei E, Raff GL, Min JK; CONFIRM Registry Investigators..Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography: results from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An
1310
International Multicenter) registry. J Am Coll Cardiol. 2011; 58: 2533-2540 3) Urabe Y, Yamamoto H, Kitagawa T, Utsunomiya H, Tsushima H, Tatsugami F, Kihara Y. Idenitifying small coronary calcification in non-contrast 0.5mm slice reconstruction to diagnose coronary artery disease in patients with conventional zero coronary calcium score. J Atheroscler Thromb. 2016; 23: 1324-1333 4) Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS; CONFIRM Investigators. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011; 58: 849-860 5) Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation 2004; 108: 1664-1672 6) Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, Naruse H, Ishii J, Hishida H, Wong ND, Virmani R, Kondo T, Ozaki Y, Narula J. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009; 54: 49-57 7) Otsuka K, Fukuda S, Tanaka A, Nakanishi K, Taguchi H, Yoshikawa J, Shimada K, Yoshiyama M. Napkin-ring sign on coronary CT angiography for the prediction of acute coronary syndrome. JACC Cardiovasc Imaging 2013; 6: 448-457 8) Morita H, Fujimoto S, Kondo T, Arai T, Sekine T, Matsutani H, Sano T, Kondo M, Kodama T, Takase S, Narula J. Prevalence of computed tomographic angiography-verified high-risk plaques and significant luminal stenosis in patients with zero coronary calcium score. Int J Cardiol. 2012; 158: 272-278 9) Blaha M, Budoff MJ, Shaw LJ, Khosa F, Rumberger JA, Berman D, Callister T, Raggi P, Blumenthal RS, Nasir K. Absence of coronary artery calcification and all-cause mortality. JACC Cardiovasc Imaging. 2009; 2: 692-700
