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Coronary artery calcification: “empty your cup”
Editorial
Coronary artery calcification: “...empty your cup...” John A. Rumberger, PhD, MD Columbus, Ohio
See related article on page 806. The professor was serving tea during his initial interview with a new student; he poured the liquid into his visitor’s cup and then kept on pouring.“The cup is overflowing, no more will go in,” said the student.“Like this cup,” the professor said, “you are full of your own opinions and speculations. How can I teach you unless you first empty your cup?”
The article by Doherty et al1 in this issue of the Journal presents an abridgment of literature regarding coronary calcification and atherosclerotic disease.The paper contains many facts intertwined with a collection of opinions and speculations. I believe that their “cup was overflowing” when they wrote the manuscript and have presented coronary mineralization in an unnecessarily controversial and confusing fashion. Speculation regarding coronary calcium as “good, bad, or [its pathophysiology] uncertain” does not serve a clinically useful purpose.The real issues are as follows: (1) Can coronary artery calcium be used as a surrogate marker for coronary atherosclerotic plaque disease? (2) Can it be quantified noninvasively? (3) Does its measure provide for diagnostic and prognostic information? (4) And does it have the potential to facilitate monitoring of atherosclerotic plaque progression or stabilization? I believe the preponderance of current evidence, and quantification of coronary calcium by electron beam CT (EBCT) in particular, support an affirmative response to these questions. Although the role of calcium in vascular disease indeed remains “unclear,” it is intimately associated with mural atheromatous plaque.2 Calcification as part of plaque development is an active process regulated in a fashion similar to bone mineralization.2,3 As we learn more about the pathophysiology of coronary atherosclerotic disease, inflammation and the consequences of inflammatory reaction (scarring and fibrosis) emerge as hallmarks of developing or developed atheromata.4 The presence of soft tissue calcification is acknowledged to be representative of current or remote inflammation or inflammatory reaction.The concept of coronary artery mineralization as a consequence of or a marker for ongoing or prior inflammation and repair in the vascular system is consistent with these principles. Calcification may indeed assist with plaque stabilization (“good” as Reprint requests: John A. Rumberger, PhD, MD, Diagnostic Cardiovascular Consultants, 300 E. Town St, Suite 1400, Columbus, Ohio 43215. E-mail: [email protected] Am Heart J 1999;137:774-6. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/1/93199
suggested by Doherty et al1), but the morphology of “vulnerable” plaque also commonly includes histologic calcification. Farb et al5 have demonstrated that plaque rupture or plaque erosion are the dominant local mechanisms responsible for coronary thrombosis. In their study, 69% of ruptured plaques and 25% of eroded plaques had histologic calcification.Although clearly not all atheromatous plaques contain calcium,6 plaque disease is commonly present at multiple sites.The absence of calcification at 1 site does not exclude its presence elsewhere in the coronary tree.The presence of coronary calcification should be viewed therefore as neither good nor bad, but implicating a prior or ongoing process of inflammation or repair concurrent with or as a consequence to atherosclerotic plaque development. A direct relation has been established between coronary artery calcium area or “score” as measured by EBCT and histologic6 and in vivo intravascular ultrasound7,8 measures of atherosclerotic plaque burden on a heartby-heart, vessel-by-vessel, and segment-by-segment basis. In my view, these data validate the measured quantity of coronary calcification by EBCT as a noninvasive surrogate marker for atherosclerotic plaque burden.The extent of coronary atheromatous disease remains the most powerful predictor of subsequent or recurrent cardiac events.9 The implications for prognostication using EBCT and the quantity of coronary calcium is predicated on the fact that the greater the quantity of calcification the greater the extent of disease.Although coronary calcium per se may not be able to discriminate “vulnerable” from “stable” plaque, the potential for a single plaque to erupt like Mount Vesuvius is underscored by 2 important principles: (1) volcanoes do not occur in the desert (ie, there must be plaque present before it can become unstable), and (2) volcanoes occur only in mountainous regions (ie, rupture or erosion occurs predominantly against a background of diffuse as well as focal atheromatous disease).As EBCT calcium score or area increases, the likelihood of a potentially unstable lesion increases because there are more candidate plaques of variable morphologic characteristics present in direct proportion to the amount of detectable calcified plaques. Risk factors can be identified that are moderately accurate predictors (in the aggregate) of the development of coronary atherosclerotic disease. However, these factors are less accurate predictors of the extent of coronary disease.A recently published study by Schmermund et al10 examined risk factors as they related to the prediction of angiographic disease severity and, in the same patients, prediction of the severity
American Heart Journal Volume 137, Number 5
of coronary artery calcification as measured by EBCT.As has been reported previously,11 only about one third of the variability in the extent of angiographic disease severity was explained by risk factors; however, these risk factors predicted to the same level of confidence the severity or extent of coronary artery calcification. Thus regardless of the uncertain nature of the link between coronary atherosclerosis and coronary calcium, both appear to be influenced by the same environmental, habitual, and genetic factors. There have been 3 large studies regarding prognostication and EBCT.The first, by Detrano et al,12 was conducted in largely symptomatic patients.The second was from Arad’s laboratory in a cohort of initially asymptomatic middle-aged individuals observed for a mean of 19 months,13 and the third was also from Detrano’s laboratory done in asymptomatic, mostly elderly men.14 The study by Arad et al15 has now been extended to a 3.6-year follow-up. In the later investigation they found that the presence of a moderate calcium score (≥160) engendered a relative risk for a cardiovascular event that was up to 10-fold greater than that demonstrated by Framingham for conventional risk factor assessment alone.16 All 3 studies consistently demonstrated that the combined risk for “hard” and “soft” coronary events increased in direct proportion to the EBCT calcium score.These data further support the notion that quantification of coronary calcium by EBCT has the potential to provide a noninvasive tool for cardiac prognostication in symptomatic and asymptomatic individuals over a short to medium time period (19 to 47 months). However, these investigations prompt the necessity of conducting larger studies examining younger and older subjects. Data continue to suggest that the use of lipid-lowering medications can stabilize plaques.Williams et al17 studied atherosclerotic monkeys after a lipid-lowering diet or diet plus pravastatin therapy.The monkeys in the pravastatin-treated group had better coronary dilatory function and developed plaque characteristics consistent with plaque stability (significantly fewer intimal and medial macrophages, less calcification, and less intimal neovascularization) when compared with diet therapy alone, despite no differences in overall plaque size. Callister et al18 have also suggested that the EBCT calcium score can be used to monitor progression of plaque burden during lipid-lowering therapy.Although these are limited experimental investigations which, again, will require larger and more inclusive trials, they do support the concept that coronary calcification has the potential to be used as a means to address therapeutic interventions directed at plaque progression or stabilization. As pointed out by Doherty et al,1 there are well known limitations of contrast arteriography to define the actual anatomic severity of regional luminal narrow-
Rumberger 775
ing. Histologic measures of stenosis severity have shown that relations between plaque area and lumen area are not necessarily constant, and one must be aware of the extent to which remodeling influences these measures.19 Data presented in Figs 1 to 3 of the article by Doherty et al1 reiterate the known but imperfect relation between stenosis and calcified and noncalcified plaque area. The final point relates to the issues of ethnicity, coronary calcium, and coronary disease. Most studies have shown a higher preponderance of coronary risk factors in blacks. However, comparisons of coronary heart disease incidence rates in blacks and whites have not shown consistent differences on the basis of ethnicity alone. In the ARIC study, which used standardized procedures for identifying and classifying cardiovascular morbidity and mortality, age-adjusted rates of coronary heart disease tended to be similar or higher in white than in black men and higher in black than white women.20 The NHANES I Epidemiologic Follow-up Study also found a higher incidence of coronary heart disease in black than white women aged 25 to 54 years, and lower rates in black than in white men at all ages.21 Thus the lower incidence of subclinical coronary disease detected by EBCT in blacks compared with whites as noted by Doherty et al1 is consistent with a lowered incidence of disease in the (mostly) men studied. In summary, the presence of quantifiable coronary artery calcium is for all practical purposes pathognomonic of the presence of coronary atherosclerotic plaque disease.The total calcium score or area determined by EBCT is indicative of the total atherosclerotic plaque burden, although it is not necessarily predictive of the severity of luminal stenoses on a site-by-site basis. As a noninvasive surrogate measure of the overall extent of disease, the EBCT calcium score has been shown to be of prognostic importance in symptomatic and asymptomatic patients, but the potential for its use as a marker for vulnerable versus stable plaque has not been defined. Finally, recent data support the proposal of expanded investigations using the EBCT calcium score to determine progression, stabilization, and possibly regression of coronary plaque disease through serial imaging.
References 1. Doherty TM, Detrano RC, Mautner SL, Mautner GC, Shavelle RM. Coronary calcium: the good, the bad, and the uncertain. Am Heart J 1999;137:806-14. 2. Wexler L, Brundage B, Crouse J, Detrano R, Fuster V, Maddahi J, et al. Coronary artery calcification: pathophysiology, epidemiology, image methods and clinical implications - a scientific statement from the American Heart Association. Circulation 1996;94:1175-92. 3. Fitzpatrick LA, Severson A, Edwards WD, Ingram RT. Diffuse calcification in human coronary arteries: association of osteopontin with atherosclerosis. J Clin Invest 1994;94:1597-604.
American Heart Journal May 1999
776 Rumberger
4. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-9. 5. Farb A, Burke AP, Tang AL, Liang Y, Mannan P, Smialek J, et al. Coronary plaque erosion without rupture into a lipid core: a frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:1354-63. 6. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium areas by electron beam computed tomography and coronary atherosclerotic plaque area: a histopathologic correlative study. Circulation 1995;92:2157-62. 7. Baumgart D, Schmermund A, Goerge G, Haude M, Ge J, Adamzik M, et al. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol 1997;30:57-647. 8. Schmermund A, Baumgart D, Adamzik M, Ge J, Grönemeyer D, Seibel R, et al. Comparison of electron-beam computed tomography and intracoronary ultrasound in detecting calcified and noncalcified plaque in patients with acute coronary syndromes and no or minimal to moderate angiographic coronary artery disease. Am J Cardiol 1998;81:141-6. 9. Hasdai D, Bell MR, Grill DE, Berger PB, Garratt KN, Rihal CS, et al. Outcome greater or equal to 10 years after successful percutaneous transluminal coronary angioplasty. Am J Cardiol 1997;79:1005-11. 10. Schmermund A, Baumgart D, Görge G, Grönemeyer D, Seibel R, Bailey KR, et al. Measuring the effect of risk factors on coronary atherosclerosis: coronary calcium score vs. angiographic disease severity. J Am Coll Cardiol 1998;31:1267-73. 11. Wang XL, Tam C, McCredie RM, Wilchen DE. Determinants of severity of coronary artery disease in Australian men and women. Circulation 1994;89:1974-81. 12. Detrano R, Tzung H, Wang S, Puentes G, Fallavollita J, Shields P, et al. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 1996;27:285-90. 13. Arad Y, Spadaro LA, Goodman K, Liedo-Perez A, Sherman S,
14.
15.
16.
17.
18.
19.
20.
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Lerner G, et al. Predictive value of electron beam computed tomography of the coronary arteries: 19-month follow-up of 1173 asymptomatic subjects. Circulation 1996;93:1951-3. Secci A, Wong N, Tang W, Wang S, Doherty T, Detrano R. Electron beam computed tomographic coronary calcium as a predictor of coronary events: comparison of two protocols. Circulation 1997;96:1122-9. Arad Y, Spadaro LA, Goodman K, Liedo A, Sherman S, Guerci AD. 3.6 years follow-up of 1136 asymptomatic adults undergoing electron beam CT (EBCT) of the coronary arteries [abstract]. J Am Coll Cardiol 1998;31:210A. Bostom AG, Cupples LA, Jenner JL, Ordovas JM, Seman LJ, Wilson PW, et al. Elevated plasma lipoprotein (a) and coronary heart disease in men aged 55 years and younger. JAMA 1996; 276:544-8. Willams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 1998;31:684-91. Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med 1998;339:1972-8. Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick LA, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using non-decalcifying methodology. J Am Coll Cardiol 1998;31:126-33. White AD, Folsom AR, Chambless LE, Sharret AR, Yang K, Conwil D, et al. Community surveillance of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) Study: methods and initial two years’ experience. J Clin Epidemiol 1996;49:223-33. Gillum RF, Mussoline ME, Madans JH. Coronary heart disease incidence and survival in African-American women and men. The NHANES I Epidemiologic follow-up study. Ann Intern Med 1997;17:111-8.
Coronary artery calcification: “...empty your cup...” John A. Rumberger, PhD, MD Columbus, Ohio
See related article on page 806. The professor was serving tea during his initial interview with a new student; he poured the liquid into his visitor’s cup and then kept on pouring.“The cup is overflowing, no more will go in,” said the student.“Like this cup,” the professor said, “you are full of your own opinions and speculations. How can I teach you unless you first empty your cup?”
The article by Doherty et al1 in this issue of the Journal presents an abridgment of literature regarding coronary calcification and atherosclerotic disease.The paper contains many facts intertwined with a collection of opinions and speculations. I believe that their “cup was overflowing” when they wrote the manuscript and have presented coronary mineralization in an unnecessarily controversial and confusing fashion. Speculation regarding coronary calcium as “good, bad, or [its pathophysiology] uncertain” does not serve a clinically useful purpose.The real issues are as follows: (1) Can coronary artery calcium be used as a surrogate marker for coronary atherosclerotic plaque disease? (2) Can it be quantified noninvasively? (3) Does its measure provide for diagnostic and prognostic information? (4) And does it have the potential to facilitate monitoring of atherosclerotic plaque progression or stabilization? I believe the preponderance of current evidence, and quantification of coronary calcium by electron beam CT (EBCT) in particular, support an affirmative response to these questions. Although the role of calcium in vascular disease indeed remains “unclear,” it is intimately associated with mural atheromatous plaque.2 Calcification as part of plaque development is an active process regulated in a fashion similar to bone mineralization.2,3 As we learn more about the pathophysiology of coronary atherosclerotic disease, inflammation and the consequences of inflammatory reaction (scarring and fibrosis) emerge as hallmarks of developing or developed atheromata.4 The presence of soft tissue calcification is acknowledged to be representative of current or remote inflammation or inflammatory reaction.The concept of coronary artery mineralization as a consequence of or a marker for ongoing or prior inflammation and repair in the vascular system is consistent with these principles. Calcification may indeed assist with plaque stabilization (“good” as Reprint requests: John A. Rumberger, PhD, MD, Diagnostic Cardiovascular Consultants, 300 E. Town St, Suite 1400, Columbus, Ohio 43215. E-mail: [email protected] Am Heart J 1999;137:774-6. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/1/93199
suggested by Doherty et al1), but the morphology of “vulnerable” plaque also commonly includes histologic calcification. Farb et al5 have demonstrated that plaque rupture or plaque erosion are the dominant local mechanisms responsible for coronary thrombosis. In their study, 69% of ruptured plaques and 25% of eroded plaques had histologic calcification.Although clearly not all atheromatous plaques contain calcium,6 plaque disease is commonly present at multiple sites.The absence of calcification at 1 site does not exclude its presence elsewhere in the coronary tree.The presence of coronary calcification should be viewed therefore as neither good nor bad, but implicating a prior or ongoing process of inflammation or repair concurrent with or as a consequence to atherosclerotic plaque development. A direct relation has been established between coronary artery calcium area or “score” as measured by EBCT and histologic6 and in vivo intravascular ultrasound7,8 measures of atherosclerotic plaque burden on a heartby-heart, vessel-by-vessel, and segment-by-segment basis. In my view, these data validate the measured quantity of coronary calcification by EBCT as a noninvasive surrogate marker for atherosclerotic plaque burden.The extent of coronary atheromatous disease remains the most powerful predictor of subsequent or recurrent cardiac events.9 The implications for prognostication using EBCT and the quantity of coronary calcium is predicated on the fact that the greater the quantity of calcification the greater the extent of disease.Although coronary calcium per se may not be able to discriminate “vulnerable” from “stable” plaque, the potential for a single plaque to erupt like Mount Vesuvius is underscored by 2 important principles: (1) volcanoes do not occur in the desert (ie, there must be plaque present before it can become unstable), and (2) volcanoes occur only in mountainous regions (ie, rupture or erosion occurs predominantly against a background of diffuse as well as focal atheromatous disease).As EBCT calcium score or area increases, the likelihood of a potentially unstable lesion increases because there are more candidate plaques of variable morphologic characteristics present in direct proportion to the amount of detectable calcified plaques. Risk factors can be identified that are moderately accurate predictors (in the aggregate) of the development of coronary atherosclerotic disease. However, these factors are less accurate predictors of the extent of coronary disease.A recently published study by Schmermund et al10 examined risk factors as they related to the prediction of angiographic disease severity and, in the same patients, prediction of the severity
American Heart Journal Volume 137, Number 5
of coronary artery calcification as measured by EBCT.As has been reported previously,11 only about one third of the variability in the extent of angiographic disease severity was explained by risk factors; however, these risk factors predicted to the same level of confidence the severity or extent of coronary artery calcification. Thus regardless of the uncertain nature of the link between coronary atherosclerosis and coronary calcium, both appear to be influenced by the same environmental, habitual, and genetic factors. There have been 3 large studies regarding prognostication and EBCT.The first, by Detrano et al,12 was conducted in largely symptomatic patients.The second was from Arad’s laboratory in a cohort of initially asymptomatic middle-aged individuals observed for a mean of 19 months,13 and the third was also from Detrano’s laboratory done in asymptomatic, mostly elderly men.14 The study by Arad et al15 has now been extended to a 3.6-year follow-up. In the later investigation they found that the presence of a moderate calcium score (≥160) engendered a relative risk for a cardiovascular event that was up to 10-fold greater than that demonstrated by Framingham for conventional risk factor assessment alone.16 All 3 studies consistently demonstrated that the combined risk for “hard” and “soft” coronary events increased in direct proportion to the EBCT calcium score.These data further support the notion that quantification of coronary calcium by EBCT has the potential to provide a noninvasive tool for cardiac prognostication in symptomatic and asymptomatic individuals over a short to medium time period (19 to 47 months). However, these investigations prompt the necessity of conducting larger studies examining younger and older subjects. Data continue to suggest that the use of lipid-lowering medications can stabilize plaques.Williams et al17 studied atherosclerotic monkeys after a lipid-lowering diet or diet plus pravastatin therapy.The monkeys in the pravastatin-treated group had better coronary dilatory function and developed plaque characteristics consistent with plaque stability (significantly fewer intimal and medial macrophages, less calcification, and less intimal neovascularization) when compared with diet therapy alone, despite no differences in overall plaque size. Callister et al18 have also suggested that the EBCT calcium score can be used to monitor progression of plaque burden during lipid-lowering therapy.Although these are limited experimental investigations which, again, will require larger and more inclusive trials, they do support the concept that coronary calcification has the potential to be used as a means to address therapeutic interventions directed at plaque progression or stabilization. As pointed out by Doherty et al,1 there are well known limitations of contrast arteriography to define the actual anatomic severity of regional luminal narrow-
Rumberger 775
ing. Histologic measures of stenosis severity have shown that relations between plaque area and lumen area are not necessarily constant, and one must be aware of the extent to which remodeling influences these measures.19 Data presented in Figs 1 to 3 of the article by Doherty et al1 reiterate the known but imperfect relation between stenosis and calcified and noncalcified plaque area. The final point relates to the issues of ethnicity, coronary calcium, and coronary disease. Most studies have shown a higher preponderance of coronary risk factors in blacks. However, comparisons of coronary heart disease incidence rates in blacks and whites have not shown consistent differences on the basis of ethnicity alone. In the ARIC study, which used standardized procedures for identifying and classifying cardiovascular morbidity and mortality, age-adjusted rates of coronary heart disease tended to be similar or higher in white than in black men and higher in black than white women.20 The NHANES I Epidemiologic Follow-up Study also found a higher incidence of coronary heart disease in black than white women aged 25 to 54 years, and lower rates in black than in white men at all ages.21 Thus the lower incidence of subclinical coronary disease detected by EBCT in blacks compared with whites as noted by Doherty et al1 is consistent with a lowered incidence of disease in the (mostly) men studied. In summary, the presence of quantifiable coronary artery calcium is for all practical purposes pathognomonic of the presence of coronary atherosclerotic plaque disease.The total calcium score or area determined by EBCT is indicative of the total atherosclerotic plaque burden, although it is not necessarily predictive of the severity of luminal stenoses on a site-by-site basis. As a noninvasive surrogate measure of the overall extent of disease, the EBCT calcium score has been shown to be of prognostic importance in symptomatic and asymptomatic patients, but the potential for its use as a marker for vulnerable versus stable plaque has not been defined. Finally, recent data support the proposal of expanded investigations using the EBCT calcium score to determine progression, stabilization, and possibly regression of coronary plaque disease through serial imaging.
References 1. Doherty TM, Detrano RC, Mautner SL, Mautner GC, Shavelle RM. Coronary calcium: the good, the bad, and the uncertain. Am Heart J 1999;137:806-14. 2. Wexler L, Brundage B, Crouse J, Detrano R, Fuster V, Maddahi J, et al. Coronary artery calcification: pathophysiology, epidemiology, image methods and clinical implications - a scientific statement from the American Heart Association. Circulation 1996;94:1175-92. 3. Fitzpatrick LA, Severson A, Edwards WD, Ingram RT. Diffuse calcification in human coronary arteries: association of osteopontin with atherosclerosis. J Clin Invest 1994;94:1597-604.
American Heart Journal May 1999
776 Rumberger
4. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-9. 5. Farb A, Burke AP, Tang AL, Liang Y, Mannan P, Smialek J, et al. Coronary plaque erosion without rupture into a lipid core: a frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:1354-63. 6. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium areas by electron beam computed tomography and coronary atherosclerotic plaque area: a histopathologic correlative study. Circulation 1995;92:2157-62. 7. Baumgart D, Schmermund A, Goerge G, Haude M, Ge J, Adamzik M, et al. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol 1997;30:57-647. 8. Schmermund A, Baumgart D, Adamzik M, Ge J, Grönemeyer D, Seibel R, et al. Comparison of electron-beam computed tomography and intracoronary ultrasound in detecting calcified and noncalcified plaque in patients with acute coronary syndromes and no or minimal to moderate angiographic coronary artery disease. Am J Cardiol 1998;81:141-6. 9. Hasdai D, Bell MR, Grill DE, Berger PB, Garratt KN, Rihal CS, et al. Outcome greater or equal to 10 years after successful percutaneous transluminal coronary angioplasty. Am J Cardiol 1997;79:1005-11. 10. Schmermund A, Baumgart D, Görge G, Grönemeyer D, Seibel R, Bailey KR, et al. Measuring the effect of risk factors on coronary atherosclerosis: coronary calcium score vs. angiographic disease severity. J Am Coll Cardiol 1998;31:1267-73. 11. Wang XL, Tam C, McCredie RM, Wilchen DE. Determinants of severity of coronary artery disease in Australian men and women. Circulation 1994;89:1974-81. 12. Detrano R, Tzung H, Wang S, Puentes G, Fallavollita J, Shields P, et al. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 1996;27:285-90. 13. Arad Y, Spadaro LA, Goodman K, Liedo-Perez A, Sherman S,
14.
15.
16.
17.
18.
19.
20.
21.
Lerner G, et al. Predictive value of electron beam computed tomography of the coronary arteries: 19-month follow-up of 1173 asymptomatic subjects. Circulation 1996;93:1951-3. Secci A, Wong N, Tang W, Wang S, Doherty T, Detrano R. Electron beam computed tomographic coronary calcium as a predictor of coronary events: comparison of two protocols. Circulation 1997;96:1122-9. Arad Y, Spadaro LA, Goodman K, Liedo A, Sherman S, Guerci AD. 3.6 years follow-up of 1136 asymptomatic adults undergoing electron beam CT (EBCT) of the coronary arteries [abstract]. J Am Coll Cardiol 1998;31:210A. Bostom AG, Cupples LA, Jenner JL, Ordovas JM, Seman LJ, Wilson PW, et al. Elevated plasma lipoprotein (a) and coronary heart disease in men aged 55 years and younger. JAMA 1996; 276:544-8. Willams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 1998;31:684-91. Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med 1998;339:1972-8. Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick LA, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using non-decalcifying methodology. J Am Coll Cardiol 1998;31:126-33. White AD, Folsom AR, Chambless LE, Sharret AR, Yang K, Conwil D, et al. Community surveillance of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) Study: methods and initial two years’ experience. J Clin Epidemiol 1996;49:223-33. Gillum RF, Mussoline ME, Madans JH. Coronary heart disease incidence and survival in African-American women and men. The NHANES I Epidemiologic follow-up study. Ann Intern Med 1997;17:111-8.