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Plaque composition and stenosis severity: Is there any hope for plaque regression?
Atherosclerosis 219 (2011) 395–396
Contents lists available at SciVerse ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
Plaque composition and stenosis severity: Is there any hope for plaque regression? Mouaz H. Al-Mallah a,b,∗ , Khurram Nasir c a
Wayne State University, Detroit, MI, United States King Abdul-Aziz Cardiac Center, Riyadh, Saudi Arabia c Yale University, Section of Cardiovascular Medicine, New Haven, CT, United States b
a r t i c l e
i n f o
Article history: Received 11 August 2011 Accepted 12 August 2011 Available online 1 September 2011 Keywords: Coronary CT Plaque sub type Atherosclerosis
Coronary computed tomography angiography (CCTA) has emerged as a sensitive and accurate tool to identify obstructive coronary disease. When applied in patients with intermediate pretest likelihood of coronary disease, it has high sensitivity for obstructive coronary artery disease (CAD) and can be effectively used to rule out coronary artery disease (high negative predictive value [1–3]. In addition, CCTA can CT provides further information regarding plaque and morphology. Atherosclerosis imaging can be performed using contrast-enhanced scans with the highest possible spatial resolution. Compared to coronary angiography, CCTA can detect plaque disruption (ulceration, positively remodeling, low-attenuation) with high sensitivity and specificity [4]. In studies using intravascular ultrasound (IVUS) as the gold standard, CCTA correctly identified 95% of calcified plaques, 83% of non-calcified plaques and 94% of mixed plaques. However, plaque volume estimation by CT shows moderate correlation with IVUS and inter-observer variability is high [5]. In this issue of the journal, Min and colleagues present a subanalysis of the ACCURACY trial, a 16 site multicenter study of patients with suspected CAD who underwent CCTA and coronary angiography [6]. Using the 70% stenosis severity threshold, obstructive plaques were more often mixed (68%) compared to non-calcified (29%) and calcified plaques (4%). This finding is important and interesting. It is worth noting that in this study, the investigators defined
DOI of original article: 10.1016/j.atherosclerosis.2011.05.032. ∗ Corresponding author at: Cardiac Imaging, King Abdul-Aziz Cardiac Center, National Guard Health Affairs, Department Mail Code: 1413, P.O. Box 22490, Riyadh 11426, Saudi Arabia. Tel.: +966 12520088x16035; fax: +16700. E-mail address: [email protected] (M.H. Al-Mallah). 0021-9150/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2011.08.023
non-calcified plaque as >70% noncalcified, calcified plaque as >70% calcified) and mixed plaque as 30–70% noncalcified or calcified. This may be somewhat different than the guidelines suggested definitions of the plaque type. The guidelines note that calcified plaque is the atherosclerotic plaque in which the entire plaque appears as calcium density. Mixed plaque is the partially calcified atherosclerotic plaque in which there are 2 visible plaque components, one of which is calcified. Noncalcified plaque is the atherosclerotic plaque in which the entire plaque is devoid of calcium density. Thus, these findings may have been more dramatic if the above definitions have been used. However, these finding appear to be contradictory to prior findings in which 78 symptomatic patients underwent CCTA and virtual histology IVUS to evaluate plaque burden and plaque composition [7]. There was no evident relation exists between the degree of stenosis and plaque composition or vulnerability, as evaluated noninvasively by CCTA and invasively by IVUS [8]. Also, no differences were observed in fibrotic tissue, fibro-fatty tissue, dense calcium and necrotic core. Thin cap fibroatheroma (considered to represent more vulnerable plaques) were distributed equally across plaques. However, studies that evaluated the correlation between plaque characteristics and ischemia on perfusion imaging always noted that mixed plaque is an independent predictor of ischemia. Thus, it appears that the gold standard used in these studies may have impacted the association between plaque type and hemodynamic significance. An important drawback of the study is that the investigators have limited the evaluation to crude assessment of plaque (calcified, non calcified and mixed). Further research should evaluate whether these obstructive mixed plaques have more often-other
396
M.H. Al-Mallah, K. Nasir / Atherosclerosis 219 (2011) 395–396
signs of increased vulnerability like ulceration and positive remodeling. Vulnerable plaque is associated with positive remodeling, whereas non-vulnerable plaque undergoes negative remodeling [4]. Previous IVUS studies have shown that plaques that show positive remodeling contain “soft” noncalcified plaque with large lipid cores and an active inflammatory process. Outward (or positive) remodeling is strongly associated with future plaque rupture and myocardial infarction, whereas negative remodeling is seen more often in patients with stable angina [4]. 1. What are the clinical implications of these findings? Densely calcified plaques have been shown to reduce the accuracy (and in particular the specificity and negative predictive value of CCTA) [9]. Yet, in this analysis, the authors noted that the calcified plaque is infrequently associated with obstructive disease. It is more often that the less attenuated mixed plaque that is associated with severe obstructive CAD. 2. Plaque composition and potential regression with medical therapy: Is there a relationship? Another important implication, which is on the mind of every clinician who treats patients, is the regression of coronary disease. Improved characterization of the composition of plaque by IVUS and advances in understanding the vascular biology of atherosclerosis, and the development of potent anti-atherosclerotic therapies have shown that atherosclerosis regression may be a realistic goal in some patients [10]. Would a non-calcified or mixed plaque regress more than a calcified plaque is not known at this point, but this may seem biologically plausible. Prior data have shown that statin therapy failed to reduce coronary calcium score. This may be in part due to the fact that the calcium score represents that stable rather than the vulnerable plaque burden. In such a case, findings from this analysis are encouraging. Since most of the obstructive plaques are mixed with anon-calcified component, targeting them by intensive medical therapy for the aim of plaque regression may be appropriate. Whether this reduction is associated with improved outcomes is not known, but some preliminary data suggest that even small plaque regression may be sufficient to produce clinical benefit. 3. Which components of the plaque are most likely to be targets of pharmacotherapy? Multiple studies have attempted to address this important question. However, there has not been a definitive answer yet. Currently there is no data from CCTA to suggest that non-calcified or mixed plaque volume may be reduced by intensive statin therapy. However, IVUS data suggest that intense highly potent statin therapy may reduce plaque volume (Plaque regression). Most of these studies used lipid lowering therapies and in particular statins. Nicholls et al. [11] examined the intravascular ultrasound (IVUS) findings in the REVERSAL and NORMALIZE studies, and determined that the more calcified atheromas were resistant to change, either progression or regression. Conversely, less calcification was a sign of potential for significant changes over time, either progression or regression. The findings suggest that the various components of atheroma respond differently to treatment with medical therapies, and can be used to target plaques that are likely to respond.
Meanwhile it is worth noting that these findings are applicable to stable symptomatic patients. Data from acute coronary syndrome patients have shown that these patients tend to have more low attenuation plaques, which probably represents high plaque ulceration as well as thrombus burden. Pundziute et al. performed 64-slice CT and virtual histology IVUS in patients with ACS or stable angina [12]. They found that non-calcified plaque and mixed plaque were more prevalent in ACS patients, while calcified plaques were more prevalent in stable patients. This analysis also confirms the high accuracy of coronary CTA in the diagnosis of coronary disease; however, it emphasizes the notion that a CCTA has to be appropriately performed and interpreted to provide this high accuracy. In this study, four patients who were noted to have no plaque on CCTA by experienced readers had obstructive CAD on coronary angiography (two patients with 50–69% stenosis and two patients with more than 70% stenosis). These are studies with major artifact and poor contrast enhancement that resulted in major diagnostic inaccuracy. In conclusion, the data presented by Min and colleagues from the ACCURACY study suggest that the mixed plaque is the most often culprit lesion. This provides hope that the non-calcified component of the mixed plaque may be an important target for future potent medical therapeutic agents to help stabilize this plaque and potentially regress it. References [1] Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52(November (21)):1724–32. [2] Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52(December (25)):2135–44. [3] Miller JM, Dewey M, Vavere AL, et al. Coronary CT angiography using 64 detector rows: methods and design of the multi-centre trial CORE-64. Eur Radiol 2009;19(April (4)):816–28. [4] Madder RD, Chinnaiyan KM, Marandici AM, Goldstein JA. Features of disrupted plaques by coronary computed tomographic angiography/clinical perspective. Circ Cardiovasc Imaging 2011;4(March (2)):105–13. [5] Achenbach S, Moselewski F, Ropers D, et al. Detection of calcified and noncalcified coronary atherosclerotic plaque by contrast-enhanced, submillimeter multidetector spiral computed tomography: a segment-based comparison with intravascular ultrasound. Circulation 2004;109(January (1)):14–7. [6] Min JK, Edwardes M, Lin FY, et al. Relationship of coronary artery plaque composition to coronary artery stenosis severity: Results from the prospective multicenter ACCURACY trial. Atherosclerosis 2011;219(December (2)):573–8. [7] van Velzen JE, Schuijf JD, de Graaf FR, et al. Abstract 708: plaque type and composition on multislice computed tomography and virtual histology intravascular ultrasound in relation to the degree of stenosis. Circulation 2009;120(November (120(18 MeetingAbstracts))):S381-b-. [8] Wm. Guy Weigold SA, Achenbach Stephan, Armin Arbab-Zadeh, Berman Daniel, Jeffrey Carr J, Cury Ricardo C, Halliburton Sandra S, McCollough Cynthia H, Taylor Allen J. Standardized medical terminology for cardiac computed tomography: a report of the society of cardiovascular computed tomography. J Cardiovasc Comput Tomogr 2011. [9] Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography. J Am Coll Cardiol 2005;46(August (3)):552–7. [10] Klein LW. Atherosclerosis regression. Vascular remodeling, and plaque stabilization. J Am Coll Cardiol 2007;49(January (2)):271–3. [11] Nicholls SJ, Tuzcu EM, Wolski K, et al. Coronary artery calcification and changes in atheroma burden in response to established medical therapies. J Am Coll Cardiol 2007;49(January (2)):263–70. [12] Pundziute G, Schuijf JD, Jukema JW, et al. Evaluation of plaque characteristics in acute coronary syndromes: non-invasive assessment with multi-slice computed tomography and invasive evaluation with intravascular ultrasound radiofrequency data analysis. Eur Heart J 2008;29(October (19)):2373–81.
Contents lists available at SciVerse ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
Plaque composition and stenosis severity: Is there any hope for plaque regression? Mouaz H. Al-Mallah a,b,∗ , Khurram Nasir c a
Wayne State University, Detroit, MI, United States King Abdul-Aziz Cardiac Center, Riyadh, Saudi Arabia c Yale University, Section of Cardiovascular Medicine, New Haven, CT, United States b
a r t i c l e
i n f o
Article history: Received 11 August 2011 Accepted 12 August 2011 Available online 1 September 2011 Keywords: Coronary CT Plaque sub type Atherosclerosis
Coronary computed tomography angiography (CCTA) has emerged as a sensitive and accurate tool to identify obstructive coronary disease. When applied in patients with intermediate pretest likelihood of coronary disease, it has high sensitivity for obstructive coronary artery disease (CAD) and can be effectively used to rule out coronary artery disease (high negative predictive value [1–3]. In addition, CCTA can CT provides further information regarding plaque and morphology. Atherosclerosis imaging can be performed using contrast-enhanced scans with the highest possible spatial resolution. Compared to coronary angiography, CCTA can detect plaque disruption (ulceration, positively remodeling, low-attenuation) with high sensitivity and specificity [4]. In studies using intravascular ultrasound (IVUS) as the gold standard, CCTA correctly identified 95% of calcified plaques, 83% of non-calcified plaques and 94% of mixed plaques. However, plaque volume estimation by CT shows moderate correlation with IVUS and inter-observer variability is high [5]. In this issue of the journal, Min and colleagues present a subanalysis of the ACCURACY trial, a 16 site multicenter study of patients with suspected CAD who underwent CCTA and coronary angiography [6]. Using the 70% stenosis severity threshold, obstructive plaques were more often mixed (68%) compared to non-calcified (29%) and calcified plaques (4%). This finding is important and interesting. It is worth noting that in this study, the investigators defined
DOI of original article: 10.1016/j.atherosclerosis.2011.05.032. ∗ Corresponding author at: Cardiac Imaging, King Abdul-Aziz Cardiac Center, National Guard Health Affairs, Department Mail Code: 1413, P.O. Box 22490, Riyadh 11426, Saudi Arabia. Tel.: +966 12520088x16035; fax: +16700. E-mail address: [email protected] (M.H. Al-Mallah). 0021-9150/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2011.08.023
non-calcified plaque as >70% noncalcified, calcified plaque as >70% calcified) and mixed plaque as 30–70% noncalcified or calcified. This may be somewhat different than the guidelines suggested definitions of the plaque type. The guidelines note that calcified plaque is the atherosclerotic plaque in which the entire plaque appears as calcium density. Mixed plaque is the partially calcified atherosclerotic plaque in which there are 2 visible plaque components, one of which is calcified. Noncalcified plaque is the atherosclerotic plaque in which the entire plaque is devoid of calcium density. Thus, these findings may have been more dramatic if the above definitions have been used. However, these finding appear to be contradictory to prior findings in which 78 symptomatic patients underwent CCTA and virtual histology IVUS to evaluate plaque burden and plaque composition [7]. There was no evident relation exists between the degree of stenosis and plaque composition or vulnerability, as evaluated noninvasively by CCTA and invasively by IVUS [8]. Also, no differences were observed in fibrotic tissue, fibro-fatty tissue, dense calcium and necrotic core. Thin cap fibroatheroma (considered to represent more vulnerable plaques) were distributed equally across plaques. However, studies that evaluated the correlation between plaque characteristics and ischemia on perfusion imaging always noted that mixed plaque is an independent predictor of ischemia. Thus, it appears that the gold standard used in these studies may have impacted the association between plaque type and hemodynamic significance. An important drawback of the study is that the investigators have limited the evaluation to crude assessment of plaque (calcified, non calcified and mixed). Further research should evaluate whether these obstructive mixed plaques have more often-other
396
M.H. Al-Mallah, K. Nasir / Atherosclerosis 219 (2011) 395–396
signs of increased vulnerability like ulceration and positive remodeling. Vulnerable plaque is associated with positive remodeling, whereas non-vulnerable plaque undergoes negative remodeling [4]. Previous IVUS studies have shown that plaques that show positive remodeling contain “soft” noncalcified plaque with large lipid cores and an active inflammatory process. Outward (or positive) remodeling is strongly associated with future plaque rupture and myocardial infarction, whereas negative remodeling is seen more often in patients with stable angina [4]. 1. What are the clinical implications of these findings? Densely calcified plaques have been shown to reduce the accuracy (and in particular the specificity and negative predictive value of CCTA) [9]. Yet, in this analysis, the authors noted that the calcified plaque is infrequently associated with obstructive disease. It is more often that the less attenuated mixed plaque that is associated with severe obstructive CAD. 2. Plaque composition and potential regression with medical therapy: Is there a relationship? Another important implication, which is on the mind of every clinician who treats patients, is the regression of coronary disease. Improved characterization of the composition of plaque by IVUS and advances in understanding the vascular biology of atherosclerosis, and the development of potent anti-atherosclerotic therapies have shown that atherosclerosis regression may be a realistic goal in some patients [10]. Would a non-calcified or mixed plaque regress more than a calcified plaque is not known at this point, but this may seem biologically plausible. Prior data have shown that statin therapy failed to reduce coronary calcium score. This may be in part due to the fact that the calcium score represents that stable rather than the vulnerable plaque burden. In such a case, findings from this analysis are encouraging. Since most of the obstructive plaques are mixed with anon-calcified component, targeting them by intensive medical therapy for the aim of plaque regression may be appropriate. Whether this reduction is associated with improved outcomes is not known, but some preliminary data suggest that even small plaque regression may be sufficient to produce clinical benefit. 3. Which components of the plaque are most likely to be targets of pharmacotherapy? Multiple studies have attempted to address this important question. However, there has not been a definitive answer yet. Currently there is no data from CCTA to suggest that non-calcified or mixed plaque volume may be reduced by intensive statin therapy. However, IVUS data suggest that intense highly potent statin therapy may reduce plaque volume (Plaque regression). Most of these studies used lipid lowering therapies and in particular statins. Nicholls et al. [11] examined the intravascular ultrasound (IVUS) findings in the REVERSAL and NORMALIZE studies, and determined that the more calcified atheromas were resistant to change, either progression or regression. Conversely, less calcification was a sign of potential for significant changes over time, either progression or regression. The findings suggest that the various components of atheroma respond differently to treatment with medical therapies, and can be used to target plaques that are likely to respond.
Meanwhile it is worth noting that these findings are applicable to stable symptomatic patients. Data from acute coronary syndrome patients have shown that these patients tend to have more low attenuation plaques, which probably represents high plaque ulceration as well as thrombus burden. Pundziute et al. performed 64-slice CT and virtual histology IVUS in patients with ACS or stable angina [12]. They found that non-calcified plaque and mixed plaque were more prevalent in ACS patients, while calcified plaques were more prevalent in stable patients. This analysis also confirms the high accuracy of coronary CTA in the diagnosis of coronary disease; however, it emphasizes the notion that a CCTA has to be appropriately performed and interpreted to provide this high accuracy. In this study, four patients who were noted to have no plaque on CCTA by experienced readers had obstructive CAD on coronary angiography (two patients with 50–69% stenosis and two patients with more than 70% stenosis). These are studies with major artifact and poor contrast enhancement that resulted in major diagnostic inaccuracy. In conclusion, the data presented by Min and colleagues from the ACCURACY study suggest that the mixed plaque is the most often culprit lesion. This provides hope that the non-calcified component of the mixed plaque may be an important target for future potent medical therapeutic agents to help stabilize this plaque and potentially regress it. References [1] Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52(November (21)):1724–32. [2] Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52(December (25)):2135–44. [3] Miller JM, Dewey M, Vavere AL, et al. Coronary CT angiography using 64 detector rows: methods and design of the multi-centre trial CORE-64. Eur Radiol 2009;19(April (4)):816–28. [4] Madder RD, Chinnaiyan KM, Marandici AM, Goldstein JA. Features of disrupted plaques by coronary computed tomographic angiography/clinical perspective. Circ Cardiovasc Imaging 2011;4(March (2)):105–13. [5] Achenbach S, Moselewski F, Ropers D, et al. Detection of calcified and noncalcified coronary atherosclerotic plaque by contrast-enhanced, submillimeter multidetector spiral computed tomography: a segment-based comparison with intravascular ultrasound. Circulation 2004;109(January (1)):14–7. [6] Min JK, Edwardes M, Lin FY, et al. Relationship of coronary artery plaque composition to coronary artery stenosis severity: Results from the prospective multicenter ACCURACY trial. Atherosclerosis 2011;219(December (2)):573–8. [7] van Velzen JE, Schuijf JD, de Graaf FR, et al. Abstract 708: plaque type and composition on multislice computed tomography and virtual histology intravascular ultrasound in relation to the degree of stenosis. Circulation 2009;120(November (120(18 MeetingAbstracts))):S381-b-. [8] Wm. Guy Weigold SA, Achenbach Stephan, Armin Arbab-Zadeh, Berman Daniel, Jeffrey Carr J, Cury Ricardo C, Halliburton Sandra S, McCollough Cynthia H, Taylor Allen J. Standardized medical terminology for cardiac computed tomography: a report of the society of cardiovascular computed tomography. J Cardiovasc Comput Tomogr 2011. [9] Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography. J Am Coll Cardiol 2005;46(August (3)):552–7. [10] Klein LW. Atherosclerosis regression. Vascular remodeling, and plaque stabilization. J Am Coll Cardiol 2007;49(January (2)):271–3. [11] Nicholls SJ, Tuzcu EM, Wolski K, et al. Coronary artery calcification and changes in atheroma burden in response to established medical therapies. J Am Coll Cardiol 2007;49(January (2)):263–70. [12] Pundziute G, Schuijf JD, Jukema JW, et al. Evaluation of plaque characteristics in acute coronary syndromes: non-invasive assessment with multi-slice computed tomography and invasive evaluation with intravascular ultrasound radiofrequency data analysis. Eur Heart J 2008;29(October (19)):2373–81.