- Email: [email protected]
Not All Body Fat Weighs Equally in the Acceleration of Coronary Artery Disease*
JACC: CARDIOVASCULAR IMAGING
VOL. 3, NO. 9, 2010
© 2010 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2010.08.002
EDITORIAL COMMENT
Not All Body Fat Weighs Equally in the Acceleration of Coronary Artery Disease* Daniel S. Berman, MD, Victor Y. Cheng, MD, Damini Dey, PHD Los Angeles, California
As a component of the metabolic syndrome, abdominal obesity has been more closely associated with both cardiovascular events (1–3) and acute coronary syndrome (4) than standard measures of adiposity such as body mass index (5). Abdominal visceral adipose tissue (VAT) is a specific measurement of abdominal obesity. Abdominal VAT has been linked to insulin resistance and hepatic production of inflammatory factors, potentially through direct hepatic drainage of its metabolites (6). See page 908
Computed tomography (CT) is recognized as a highly effective, accurate, and reproducible technique for measuring VAT by detecting the characteristic low Hounsfield units of fat (7,8). On noncontrast CT, abdominal VAT has been linked to development of myocardial infarction (9). In this issue of iJACC, Ohashi et al. (10) report further evidence of the relationship between abdominal VAT and the pathogenesis of coronary atherosclerosis and acute coronary syndrome. In 427 patients with known or suspected coronary artery disease who underwent coronary computed tomography angiography (CTA), the authors report the relationships between axially imaged abdominal VAT area and noncalcified coronary plaques on coronary CTA. Increased abdominal VAT area was signifi*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Division of Nuclear Medicine, Department of Imaging, and Division of Cardiology, Department of Medicine, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. This work was supported in part by grants from the Eisner Foundation, the Glazer Foundation, the Lincy Foundation, and the National Institute of Biomedical Imaging and Bioengineering (R21EB006829 to Dr. Dey). Dr. Berman receives research grant support from Siemens Medical Systems. Dr. Cheng reports that he has no relationships to disclose.
cantly associated with both the presence and extent of noncalcified plaques, whereas other body composition measures (subcutaneous adipose tissue, body mass index, waist circumference) were not. The most striking new observation was that increased VAT area was also independently associated with the presence of 3 plaque characteristics previously shown to be related to an increased risk of acute plaque rupture: positive remodeling, lowattenuation plaque, and adjacent spotty calcification (11,12). These findings represent another step toward gaining insight into the mechanism by which VAT is associated with acute coronary syndrome and support the hypothesis that VAT contributes to the instability of coronary arterial plaques. Noticeably absent from this work, however, are data regarding pericardial fat (visceral fat around the heart) and pericoronary fat (fat immediately adjacent to the coronary artery). While pericardial fat correlates strongly with abdominal VAT (13,14), paracrine effects of the pericardial and pericoronary fat beds may be more potent determinants of coronary plaque development and progression than VAT. Mazurek et al. (15) studied adipose tissue adjacent to the right coronary artery removed during surgical bypass surgery and found it to contain significantly higher levels of inflammatory markers than subcutaneous fat. This finding has been substantiated in subsequent publications (16,17) and suggests that proximity of pericardial fat to the coronary arteries amplifies its paracrine role in promoting inflammation, resulting in a local toxic effect on the coronary arteries. Evidence that the pericardial fat may directly affect plaque development has also been provided by a 3-dimensional ultrasound study that demonstrated eccentric atherosclerotic plaques develop with a spatial orientation suggestive of a relationship with pericardial fat
Berman et al. Editorial Comment
JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 9, 2010 SEPTEMBER 2010:918 –20
(18). Further, autopsy evidence has shown that coronary arteries with large necrotic cores have more macrophages in the periadventitial fat than in vessels without a lipid core (19). Pericardial fat can be quantified by cardiac CT, and multiple publications have implicated its role in the pathophysiology of coronary atherosclerosis. In a report from the Multi-Ethnic Study of Atherosclerosis (MESA) study, Ding et al. (20) showed that pericardial fat on noncontrast CT was associated with increased coronary calcium burden. Mahabadi et al. (21) recently described a strong association between pericoronary fat volume on noncontrast CT and the presence of calcified plaque in the underlying coronary segment. Alexopoulos et al. (22) observed on coronary CTA a significant increase in adipose tissue volume within the pericardial sac (epicardial adipose tissue) with increasing severity of coronary luminal stenosis. In this last study, epicardial adipose tissue volume was larger in patients with mixed or noncalcified plaques, prompting the authors to suggest that epicardial adipose tissue may be associated with the “most dangerous” plaques. Pericardial fat has also been linked to the development of major adverse cardiac events (MACE). Mahabadi et al. (23) studied the associations between pericardial fat and visceral VAT on noncontrast CT with subsequent cardiovascular events in asymptomatic participants of the Framingham Heart Study. In this study, after adjustment for standard clinical measures including body mass index and waist circumference, pericardial fat was more strongly associated with subsequent events than abdominal VAT. Interestingly, pericardial fat was predominantly associated with MACE, whereas only abdominal VAT was associated with stroke. These findings suggest the two fat beds may
REFERENCES
1. Rosenbaum M, Leibel RL, Hirsch J. Obesity. N Engl J Med 1997;337: 396 – 407. 2. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968 –77. 3. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjöström L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Goth-
impact atherogenesis differently, with abdominal VAT having a more systemic effect and pericardial fat a more local effect on the coronary arteries (24). In a case-control study in which pericardial fat was measured from noncontrast coronary calcium CT by a semiautomated method, we found that asymptomatic patients who experienced MACE exhibited a greater pericardial fat volume when compared with event-free control subjects (24). The addition of pericardial fat volume to conventional clinical risk stratification and coronary artery calcium score improved the prediction of MACE in this population. In a subsequent case-control study of patients who underwent myocardial perfusion imaging within 6 months of noncontrast CT, we have shown that, after adjusting for the coronary calcium score, pericardial fat volume was strongly associated with ischemia (25). The findings of Ohashi et al. (10) provide important information regarding the relationship between abdominal VAT and the genesis of acute coronary syndromes. However, existing literature continues to speak strongly for an even more important role for the fat around the heart. As evidence supporting the relationship between increased pericardial fat, coronary atherosclerosis, and adverse coronary events continues to mount, measurement of pericardial fat from cardiac CT appears primed to ultimately become a routine complement to the information gained from plaque evaluation. This assessment could generate CT information regarding the activity of the atherosclerotic process, potentially adding meaningfully to clinical risk assessment. Reprint requests and correspondence: Dr. Daniel S. Berman, Department of Imaging, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 1258, Los Angeles, California 90048. E-mail: [email protected].
enburg, Sweden. Br Med J (Clin Res Ed) 1984;289:1257– 61. 4. Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005;366:1640 –9. 5. Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21:697–738. 6. Klein S. The case of visceral fat: argument for the defense. J Clin Invest 2004;113:1530 –2. 7. Kvist H, Chowdhury B, Grangard U, Tylen U, Sjöström L. Total and vis-
ceral adipose-tissue volumes derived from measurements with computed tomography in adult men and women: predictive equations. Am J Clin Nutr 1988;48:1351– 61. 8. Yoshizumi T, Nakamura T, Yamane M, et al. Abdominal fat: standardized technique for measurement at CT. Radiology 1999;211:283– 6. 9. Nicklas BJ, Penninx BW, Cesari M, et al. Association of visceral adipose tissue with incident myocardial infarction in older men and women: the Health, Aging and Body Composition Study. Am J Epidemiol 2004;160: 741–9.
919
920
Berman et al. Editorial Comment
10. Ohashi N, Yamamoto H, Horiguchi J, et al. Association between visceral adipose tissue area and coronary plaque morphology assessed by CT angiography. J Am Coll Cardiol Img 2010;3:908 –17. 11. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol 2007;50:319 –26. 12. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009;54:49 –57. 13. Wheeler GL, Shi R, Beck SR, et al. Pericardial and visceral adipose tissues measured volumetrically with computed tomography are highly associated in type 2 diabetic families. Invest Radiol 2005;40:97–101. 14. Dey D, Suzuki Y, Suzuki S, et al. Automated quantitation of pericardiac fat from noncontrast CT. Invest Radiol 2008;43:145–53. 15. Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460 – 6.
JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 9, 2010 SEPTEMBER 2010:918 –20
16. Baker AR, Silva NF, Quinn DW, et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol 2006;5:1. 17. Yudkin JS, Eringa E, Stehouwer CD. “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 2005;365:1817–20. 18. Sacks HS, Fain JN. Human epicardial adipose tissue: a review. Am Heart J 2007;153:907–17. 19. Vela D, Buja LM, Madjid M, et al. The role of periadventitial fat in atherosclerosis. Arch Pathol Lab Med 2007;131:481–7. 20. Ding J, Hsu FC, Harris TB, et al. The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr 2009; 90:499 –504. 21. Mahabadi AA, Reinsch N, Lehmann N, et al. Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: a segment analysis. Atherosclerosis 2010;211:195–9. 22. Alexopoulos N, McLean DS, Janik M, Arepalli CD, Stillman AE, Raggi P. Epicardial adipose tissue and coro-
nary artery plaque characteristics. Atherosclerosis 2010;210:150 – 4. 23. Mahabadi AA, Massaro JM, Rosito GA, et al. Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study. Eur Heart J 2009;30:850 – 6. 24. Cheng VY, Dey D, Tamarappoo B, et al. Pericardial fat burden on ECGgated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events. J Am Coll Cardiol Img 2010;3: 352– 60. 25. Tamarappoo BK, Dey D, Shmilovich H, et al. Increased pericardial fat volume measured from non-contrast CT predicts myocardial ischemia by single photon emission computed tomography (abstr). J Cardiovasc Comput Tomogr 2010;4:S65.
Key Words: abdominal fat y computed tomography y coronary CT angiography y metabolic syndrome y pericardial fat y rupture-prone plaque y visceral fat.
VOL. 3, NO. 9, 2010
© 2010 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2010.08.002
EDITORIAL COMMENT
Not All Body Fat Weighs Equally in the Acceleration of Coronary Artery Disease* Daniel S. Berman, MD, Victor Y. Cheng, MD, Damini Dey, PHD Los Angeles, California
As a component of the metabolic syndrome, abdominal obesity has been more closely associated with both cardiovascular events (1–3) and acute coronary syndrome (4) than standard measures of adiposity such as body mass index (5). Abdominal visceral adipose tissue (VAT) is a specific measurement of abdominal obesity. Abdominal VAT has been linked to insulin resistance and hepatic production of inflammatory factors, potentially through direct hepatic drainage of its metabolites (6). See page 908
Computed tomography (CT) is recognized as a highly effective, accurate, and reproducible technique for measuring VAT by detecting the characteristic low Hounsfield units of fat (7,8). On noncontrast CT, abdominal VAT has been linked to development of myocardial infarction (9). In this issue of iJACC, Ohashi et al. (10) report further evidence of the relationship between abdominal VAT and the pathogenesis of coronary atherosclerosis and acute coronary syndrome. In 427 patients with known or suspected coronary artery disease who underwent coronary computed tomography angiography (CTA), the authors report the relationships between axially imaged abdominal VAT area and noncalcified coronary plaques on coronary CTA. Increased abdominal VAT area was signifi*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Division of Nuclear Medicine, Department of Imaging, and Division of Cardiology, Department of Medicine, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. This work was supported in part by grants from the Eisner Foundation, the Glazer Foundation, the Lincy Foundation, and the National Institute of Biomedical Imaging and Bioengineering (R21EB006829 to Dr. Dey). Dr. Berman receives research grant support from Siemens Medical Systems. Dr. Cheng reports that he has no relationships to disclose.
cantly associated with both the presence and extent of noncalcified plaques, whereas other body composition measures (subcutaneous adipose tissue, body mass index, waist circumference) were not. The most striking new observation was that increased VAT area was also independently associated with the presence of 3 plaque characteristics previously shown to be related to an increased risk of acute plaque rupture: positive remodeling, lowattenuation plaque, and adjacent spotty calcification (11,12). These findings represent another step toward gaining insight into the mechanism by which VAT is associated with acute coronary syndrome and support the hypothesis that VAT contributes to the instability of coronary arterial plaques. Noticeably absent from this work, however, are data regarding pericardial fat (visceral fat around the heart) and pericoronary fat (fat immediately adjacent to the coronary artery). While pericardial fat correlates strongly with abdominal VAT (13,14), paracrine effects of the pericardial and pericoronary fat beds may be more potent determinants of coronary plaque development and progression than VAT. Mazurek et al. (15) studied adipose tissue adjacent to the right coronary artery removed during surgical bypass surgery and found it to contain significantly higher levels of inflammatory markers than subcutaneous fat. This finding has been substantiated in subsequent publications (16,17) and suggests that proximity of pericardial fat to the coronary arteries amplifies its paracrine role in promoting inflammation, resulting in a local toxic effect on the coronary arteries. Evidence that the pericardial fat may directly affect plaque development has also been provided by a 3-dimensional ultrasound study that demonstrated eccentric atherosclerotic plaques develop with a spatial orientation suggestive of a relationship with pericardial fat
Berman et al. Editorial Comment
JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 9, 2010 SEPTEMBER 2010:918 –20
(18). Further, autopsy evidence has shown that coronary arteries with large necrotic cores have more macrophages in the periadventitial fat than in vessels without a lipid core (19). Pericardial fat can be quantified by cardiac CT, and multiple publications have implicated its role in the pathophysiology of coronary atherosclerosis. In a report from the Multi-Ethnic Study of Atherosclerosis (MESA) study, Ding et al. (20) showed that pericardial fat on noncontrast CT was associated with increased coronary calcium burden. Mahabadi et al. (21) recently described a strong association between pericoronary fat volume on noncontrast CT and the presence of calcified plaque in the underlying coronary segment. Alexopoulos et al. (22) observed on coronary CTA a significant increase in adipose tissue volume within the pericardial sac (epicardial adipose tissue) with increasing severity of coronary luminal stenosis. In this last study, epicardial adipose tissue volume was larger in patients with mixed or noncalcified plaques, prompting the authors to suggest that epicardial adipose tissue may be associated with the “most dangerous” plaques. Pericardial fat has also been linked to the development of major adverse cardiac events (MACE). Mahabadi et al. (23) studied the associations between pericardial fat and visceral VAT on noncontrast CT with subsequent cardiovascular events in asymptomatic participants of the Framingham Heart Study. In this study, after adjustment for standard clinical measures including body mass index and waist circumference, pericardial fat was more strongly associated with subsequent events than abdominal VAT. Interestingly, pericardial fat was predominantly associated with MACE, whereas only abdominal VAT was associated with stroke. These findings suggest the two fat beds may
REFERENCES
1. Rosenbaum M, Leibel RL, Hirsch J. Obesity. N Engl J Med 1997;337: 396 – 407. 2. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968 –77. 3. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjöström L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Goth-
impact atherogenesis differently, with abdominal VAT having a more systemic effect and pericardial fat a more local effect on the coronary arteries (24). In a case-control study in which pericardial fat was measured from noncontrast coronary calcium CT by a semiautomated method, we found that asymptomatic patients who experienced MACE exhibited a greater pericardial fat volume when compared with event-free control subjects (24). The addition of pericardial fat volume to conventional clinical risk stratification and coronary artery calcium score improved the prediction of MACE in this population. In a subsequent case-control study of patients who underwent myocardial perfusion imaging within 6 months of noncontrast CT, we have shown that, after adjusting for the coronary calcium score, pericardial fat volume was strongly associated with ischemia (25). The findings of Ohashi et al. (10) provide important information regarding the relationship between abdominal VAT and the genesis of acute coronary syndromes. However, existing literature continues to speak strongly for an even more important role for the fat around the heart. As evidence supporting the relationship between increased pericardial fat, coronary atherosclerosis, and adverse coronary events continues to mount, measurement of pericardial fat from cardiac CT appears primed to ultimately become a routine complement to the information gained from plaque evaluation. This assessment could generate CT information regarding the activity of the atherosclerotic process, potentially adding meaningfully to clinical risk assessment. Reprint requests and correspondence: Dr. Daniel S. Berman, Department of Imaging, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 1258, Los Angeles, California 90048. E-mail: [email protected].
enburg, Sweden. Br Med J (Clin Res Ed) 1984;289:1257– 61. 4. Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005;366:1640 –9. 5. Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21:697–738. 6. Klein S. The case of visceral fat: argument for the defense. J Clin Invest 2004;113:1530 –2. 7. Kvist H, Chowdhury B, Grangard U, Tylen U, Sjöström L. Total and vis-
ceral adipose-tissue volumes derived from measurements with computed tomography in adult men and women: predictive equations. Am J Clin Nutr 1988;48:1351– 61. 8. Yoshizumi T, Nakamura T, Yamane M, et al. Abdominal fat: standardized technique for measurement at CT. Radiology 1999;211:283– 6. 9. Nicklas BJ, Penninx BW, Cesari M, et al. Association of visceral adipose tissue with incident myocardial infarction in older men and women: the Health, Aging and Body Composition Study. Am J Epidemiol 2004;160: 741–9.
919
920
Berman et al. Editorial Comment
10. Ohashi N, Yamamoto H, Horiguchi J, et al. Association between visceral adipose tissue area and coronary plaque morphology assessed by CT angiography. J Am Coll Cardiol Img 2010;3:908 –17. 11. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol 2007;50:319 –26. 12. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009;54:49 –57. 13. Wheeler GL, Shi R, Beck SR, et al. Pericardial and visceral adipose tissues measured volumetrically with computed tomography are highly associated in type 2 diabetic families. Invest Radiol 2005;40:97–101. 14. Dey D, Suzuki Y, Suzuki S, et al. Automated quantitation of pericardiac fat from noncontrast CT. Invest Radiol 2008;43:145–53. 15. Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460 – 6.
JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 9, 2010 SEPTEMBER 2010:918 –20
16. Baker AR, Silva NF, Quinn DW, et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol 2006;5:1. 17. Yudkin JS, Eringa E, Stehouwer CD. “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 2005;365:1817–20. 18. Sacks HS, Fain JN. Human epicardial adipose tissue: a review. Am Heart J 2007;153:907–17. 19. Vela D, Buja LM, Madjid M, et al. The role of periadventitial fat in atherosclerosis. Arch Pathol Lab Med 2007;131:481–7. 20. Ding J, Hsu FC, Harris TB, et al. The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr 2009; 90:499 –504. 21. Mahabadi AA, Reinsch N, Lehmann N, et al. Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: a segment analysis. Atherosclerosis 2010;211:195–9. 22. Alexopoulos N, McLean DS, Janik M, Arepalli CD, Stillman AE, Raggi P. Epicardial adipose tissue and coro-
nary artery plaque characteristics. Atherosclerosis 2010;210:150 – 4. 23. Mahabadi AA, Massaro JM, Rosito GA, et al. Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study. Eur Heart J 2009;30:850 – 6. 24. Cheng VY, Dey D, Tamarappoo B, et al. Pericardial fat burden on ECGgated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events. J Am Coll Cardiol Img 2010;3: 352– 60. 25. Tamarappoo BK, Dey D, Shmilovich H, et al. Increased pericardial fat volume measured from non-contrast CT predicts myocardial ischemia by single photon emission computed tomography (abstr). J Cardiovasc Comput Tomogr 2010;4:S65.
Key Words: abdominal fat y computed tomography y coronary CT angiography y metabolic syndrome y pericardial fat y rupture-prone plaque y visceral fat.