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Cigarette Smoking, Lipids, Lipoproteins, and Extracranial Carotid Artery Atherosclerosis
E it
I
Cigarette Smoking, Lipids, Lipoproteins, and Extracranial Carotid Artery Atherosclerosis In this issue of the Proceedings (pages 259 to 267), Homer and associates present results of a study that shows that cigarette smoking is a highly potent risk factor in extracranial carotid artery stenosis and that this effect remains even after the influence of other strong risk factors, such as age, hypertension, and serum concentration of low-density lipoprotein (LDL) cholesterol, has been considered. In addition, after adjustment for age and sex, total and LDL cholesterol were positively associated with carotid artery stenosis, the high-density lipoprotein (HDL):total cholesterol ratio showed a negative relationship, and HDL cholesterol and triglycerides showed no significant association. In multivariate analysis, the only lipid or lipoprotein fraction to remain significantly related to carotid artery stenosis was LDL cholesterol. The study sample was obtained from patients referred to the Mayo Clinic for carotid angiography, and inference to the general population necessitates caution. Studies in which angiography is used in patient populations may have limited generalizabilitybecause subjects in these studies are selected on the basis of symptoms or other indications ofatherosclerotic disease. Thus, patients referred for this procedure are inherently different from the general population, including clinical manifestations and access to the health-care system. Nevertheless, the wide variation of carotid disease present, ranging from no discernible stenosis to severe stenosis, Address reprint requests to Dr. G. S. Tell, Department of Public Health Sciences, Bowman Gray School of Medicine, 300 South Hawthorne Road, Winston-Salem, NC 27103. Mayo Clin Proc 66:327-331, 1991
supports the representativeness ofthe findings. Even if the patients were highly selected, the observed associations would probably be at least as strong as those found if a wider range of the population was studied, including normal healthy volunteers and patients with overt cardiovascular or cerebrovascular disease. Studies of Specific Patient Populations.-Other studies of patient populations have also found cigarette smoking to be strongly associated with carotid artery atherosclerotic disease. My colleagues and I previously reported a strong relationship between smoking and extracranial carotid artery atherosclerosis, measured as the degree of wall thickening in patients referred for diagnostic B-mode ultrasonography.!" We found the effect of current cigarette smoking to be almost equivalent to that of an additional 2 decades of aging. In agreement with Homer and colleagues, we also found a strong association between duration of cigarette smoking and carotid disease. Two studies of patients with hypercholesterolemia have also identified cigarette smoking as a strong risk factor for extracranial carotid artery atherosclerosis assessed by ultrasonography.v" In addition to the correlation with smoking, Poli and co-workers' found that the thickness of the intimal-medial complex of the common carotid arteries was significantly greater in patients with hypercholesterolemia than in a comparable group of control subjects with normal cholesterol levels. Schuster and associates" reported that carotid artery atherosclerosis is associated with the extent of the increase in the total cholesterol level in patients with familial hyperlipidemias. Study ofTwins.-Haapanen and colleagues" investigated the relationship between smoking and carotid artery atherosclerosis in a sample of 49 twins, discordant for smoking. In comparison with nonsmokers, the age-adjusted odds ratio among smokers for having carotid stenosis was
327
328
EDITORIAL
5.99 (stenosis defined as at least 15% luminal stenosis measured by pulsed Doppler ultrasonography). As measured by B-mode ultrasonography, the mean area of all carotid plaques was 3.2 times greater in the smoking twins than in the nonsmoking twin partners, and the thickness ofthe inner layer of the carotid arteries was significantly greater in the smoking twins. For smokers, the odds ratio of having a total area of carotid plaques of 10 mm'' or more was 3.97 and for carotid inner layer thickening of 1.2 mm or more was 5.91, relative to nonsmokers. These odds ratios remained significantly increased among smokers after adjustment for plasma cholesterol level, diastolic blood pressure, and body mass index. Population-Based Studies.-As previously mentioned, the generalizability of results obtained from patient populations or, as in the foregoing case, twins may be questioned. The identification of smoking and lipids or lipoproteins as risk factors for extracranial carotid artery atherosclerosis and stenosis in population-based studies would therefore strengthen the evidence about the significance of results from clinically based studies, ifthe studies meet a minimum of commonality of measurement methods and statistical analyses. Results from several recent population-based studies confirm the positive association between smoking and atherosclerosis in the general population. In the population-based Framingham study, 7 the presence of extracranial carotid artery disease measured by duplex imaging was significantly correlated with total serum cholesterol (measured 8 years before examination) and with a history of smoking. In a cross-sectional population-based study of Finnish men," cigarette smoking was the strongest determinant of carotid artery atherosclerosis as measured by Bmode ultrasonography, independent of the effects of other risk factors. A strong and graded relationship between serum LDL cholesterol and the frequency of carotid artery atherosclerosis was also found. HDL cholesterol was negatively related to carotid artery atherosclerosis only in men free of ischemic heart disease. In a 2-year follow-up study, the group reported that the
Mayo elin Proc, March 1991, Vol 66
atherosclerosis progressed faster in men who were current smokers or who had high serum LDL cholesterol levels than in others and that LDL cholesterol and pack-years of smoking were the two strongest predictors (after age) of the progression of common carotid intimal-medial thickening during this period." HDL and HDL2 cholesterol levels measured at baseline were unrelated to the progression of atherosclerosis. In the MONICA study (monitoring of trends in mortality and morbidity and their determinants in cardiovascular disease) in Augsburg, Germany, which included almost 1,400 randomly selected men and women, a positive (although weak) association was found between cigarette smoking and presence of plaques as assessed by ultrasonography among men. 10 Furthermore, in men only, the investigators found a significant negative relationship with the HDL:total cholesterol ratio and a borderline significant positive relationship with total cholesterol. Most recently, in the ARIC (Atherosclerosis Risk in Communities) study;'! the proportion of smokers among cases, defined as those participants who were in approximately the upper 10th percentile of intimal-medial thickness, was more than twice (41% versus 18%) that among control subjects, defined as those who had no wall thickening as measured by B-mode ultrasonography. Both cases and control subjects were free of clinical cardiovascular and cerebrovascular disease. A mean of 29 pack-years of smoking was reported among cases in comparison with 14 pack-years in control subjects. In addition, cases with carotid artery atherosclerosis had statistically significantly higher mean levels of plasma total cholesterol, LDL cholesterol, and total triglyceride and lower mean levels ofHDL cholesterol than did control subjects. The odds ratio for current smokers versus never or former smokers was 3.9 (95% confidence interval, 2.6 to 5.9) after adjustment for age, hypertension, and LDL cholesterol. The differences in total and LDL cholesterol between cases and control subjects remained significant after adjustment for other risk factors in multivariate analyses, but the difference in HDL cholesterol was no longer significant.
Mayo
cue Proc, March 1991, Vol 66
In the Honolulu Heart Program, smoking was found to be less strongly associated with atherosclerosis in the intracranial cerebral arteries than in the coronary arteries and abdominal aorta. 12 As in most autopsy studies, however, only the most distal portions of the intracranial internal carotid arteries were included; the more proximal portions ofthe carotid circulation were not assessed in this study. Reportedly, risk factors do not uniformly affect all arteries, and even within regional arterial beds, various segments are affected to different degrees. 1,13 Within the brain, for example, atherosclerosis in the large arteries has been related to age, diastolic blood pressure, and serum cholesterol level, whereas atherosclerosis in the small arteries has been related to diastolic blood pressure and serum triglycerides." Conclusion.-That cigarette smoking may precipitate clinical events through association with high fibrinogen levels, hemoglobin concentration, and myocardial oxygen supply has been reported previously.v" The consistent associations of cigarette smoking with atherosclerotic disease in the coronary arteries, aorta, and now the extracranial carotid arteries also indicate an atherogenic role. The evidence for a strong, graded, and biologically plausible association between cigarette smoking (measured in various ways) and extracranial carotid artery atherosclerosis is fairly consistent across diverse study designs and populations, and the strength of this association further indicates that this relationship is real. The emerging pattern of findings that relate lipids and lipoproteins to extracranial carotid artery atherosclerosis in these studies is less clear than in the case of smoking. The considerable diversity of findings reported among the various studies possibly reflects the strengths and weaknesses implicit in the various study designs, the methods of measurement, and the procedures used for selection of patients and participants. Nonetheless, even though the magnitude of the association between lipids or lipoproteins and extracranial carotid artery atherosclerosis is consistently less than that found for smoking, this result does not negate
EDITORIAL
329
an actual relationship. Furthermore, a possible underestimation of the true effect or bias (or both) due to intraindividual variability, measurement variability, and potential selection bias cannot be ruled out. Although the relationship between lipids or lipoproteins and extracranial carotid artery atherosclerosis seems to be weaker and less consistent than that for smoking, the atherogenic role of severallipids and lipoproteins-most notably, LDL cholesterol-seems to be supported by many studies. Although the mechanism of action of cigarette smoking and lipoproteins on atherosclerosis as measured by the various imaging techniques is incompletely understood at present, as are the possible interactive effects between smoking and lipids or lipoproteins, cigarette smoking undoubtedly exerts a strong and independent effect on the risk of extracranial carotid artery atherosclerosis in human populations. The unequivocal findings of this association provide additional evidence vindicating cigarette smoking as the single most important preventable cause of morbidity, disability, and mortality. Comment.-A comment on the methods and reporting ofthe measurement of arterial atherosclerotic disease is warranted. For in vivo investigation of carotid artery atherosclerosis, contrast angiography and Doppler sonography are used to assess the arterial lumen, and B-mode ultrasonography is capable of measuring the thickness of the vessel wall as a reflection of the extent of atherosclerosis rather than merely disturbed flow patterns or luminal stenosis. Because it is invasive and potentially harmful, angiography cannot be used in studies of the general population. Therefore, the availability of noninvasive imaging ultrasonographic techniques during the past few years has been encouraging in that even mild vascular lesions and wall irregularities of extracranial carotid arteries can now be studied. This development has facilitated the study of asymptomatic healthy subjects as well as symptomatic patients and thus has enabled investigators to study a wider range of atherosclerotic lesions than was possible previously.
330
EDITORIAL
Stenosis is usually expressed as percent narrowing ofthe luminal diameter and is often used as a measure of arterial disease caused by atherosclerotic plaques. With arteriography, however, the investigation of the early phases of atherosclerosis, which is initially evident only as structural changes in the arterial wall, is not possible. As reported by Glagov and Zarins.!" atherosclerotic lesions that are not ulcerated or surmounted by thrombi typically maintain circular or regular, almost ovoid configurations on cross section. As the plaque enlarges, it bulges outwardly away from the lumen, and the lumen tends to continue to be round; thus, the plaque is effectively sequestered from the lumen, and patency and luminal symmetry are maintained. This development may result in compensatory dilatation of the arterial wall and has been observed in all atherosclerotic-prone locations studied.F'!" Therefore, one cannot simply equate the degree of luminal stenosis with the extent of the plaque: an artery with early arterial wall thickening may maintain an adequate lumen, and functionally important stenosis may be delayed until the lesion occupies 40% of the internal elastic lamina area. 17 In contrast to arteriography, B-mode ultrasonography allows direct measurement of the arterial wall (intima and media) thickness. Although this method more accurately measures the extent of atherosclerosis, several factors can compromise the integrity of the images obtained, including the range of ultrasound velocity, deposits of calcium and cholesterol in the arterial wall, and physical characteristics of subjects such as obesity. Although most stenotic disease identified in the current study by Homer and associates was probably attributable to atherosclerosis, some patients classified as normal may, in fact, have had early carotid artery atherosclerosis. This issue is unlikely to affect the major conclusions of their study; in fact, if patients with moderate disease were misclassified as having no disease, the effects of the risk factors are probably underestimated. Nevertheless, it behooves us to be as precise as possible in scientific reporting.
Mayo Clin Proc, March 1991, Vol 66
Acknowledgment.-I thank Drs. Gerardo Heiss, Curt Furberg, and Maurice Mittelmark for helpful comments on a preliminary version of this editorial. Grethe S. Tell, dr.philos., M.P.H. Section on Epidemiology Department of Public Health Sciences Bowman Gray School of Medicine Winston-Salem, North Carolina
REFERENCES 1.
2. 3.
4.
5.
6.
7.
8.
9.
10.
Tell GS, Howard G, McKinney WM: Risk factors for site specific extracranial carotid artery plaque distribution as measured by B-mode ultrasound. J Clin Epidemiol 42:551-559, 1989 Tell GS, Howard G, McKinney WM, Toole JF: Cigarette smoking cessation and extracranial carotid atherosclerosis. JAMA 261:1178-1180, 1989 Tell GS, Howard G, Evans GW, Smith ML, McKinney WM, Toole JF: Cigarette smoking and extracranial carotid atherosclerosis, Adv Exp Med BioI 273:39-49, 1990 Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R: Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. Atherosclerosis 70:253261, 1988 Schuster HM, Kroner KK, Keller C, Spengel FA, Wolfram G, Zollner N: Atherosclerosis of the carotid arteries documented by duplex scan as a predictor of coronary artery disease in familial hyperlipidemias. Klin Wochenschr 65:34-39, 1987 Haapanen A, Koskenvuo M, Kaprio J, Kesaniemi YA, Heikkila K: Carotid arteriosclerosis in identical twins discordant for cigarette smoking. Circulation 80:1016, 1989 O'Leary DH, Anderson KM, Kase CS, WolfPA, Kannel WE: Extracranial carotid atherosclerosis in a general population: the Framingham study (abstract). Stroke 19:143,1988 Salonen JT, Seppanen K, Rauramaa R, Salonen R: Risk factors for carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Ann Med 21:227-229, 1989 Salonen R, Salonen JT: Progression of carotid atherosclerosis and its determinants: a population-based ultrasonography study. Atherosclerosis 81:33-40, 1990 Gostomzyk J-G, Heller W-D, Gerhardt P, Lee PN, Keil U: B-scan ultrasound examination of the carotid arteries within a representative population (MONICA ProjectAugsburg). Klin Wochenschr 66 (Suppl 11):5865, 1988
EDITORIAL
Mayo Clin Proc, March 1991, Vol 66
11.
12. 13. 14. 15.
Heiss G, SharrettAR, Barnes R, Chambless LE, Szklo M, Alzola C: Carotid atherosclerosis measured by Bmode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol (in press) Reed D, Marcus E, Hayashi T: Smoking as a predictor of atherosclerosis in the Honolulu Heart Program. Adv Exp Med BioI 273:17-25, 1990 Reed DM, Resch JA, Hayashi T, MacLean C, Yano K: A prospective study of cerebral artery atherosclerosis. Stroke 19:820-825, 1988 McGill HC Jr: The cardiovascular pathology of smoking. Am Heart J 115:250-256, 1988 Weintraub WS: Cigarette smoking as a risk factor for coronary artery disease. Adv Exp Med Biol 273:2737, 1990
16.
331
Glagov S, Zarins CK: Quantitating atherosclerosis: problems of definition. In Clinical Diagnosis of Atherosclerosis: Quantitative Methods of Evaluation. Edited by MG Bond, W Insull Jr, S Glagov, AB Chandler, JF Cornhill. New York, Springer-Verlag, 1983, pp 11-35 17. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ: Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 316:1371-1375, 1987 18. Zarins CK, Weisenberg E, Kolettis G, Stankunavicius R, Glagov S: Differential enlargement of artery segments in response to enlarging atherosclerotic plaques. J Vasc Surg 7:386-392,1988
I
Cigarette Smoking, Lipids, Lipoproteins, and Extracranial Carotid Artery Atherosclerosis In this issue of the Proceedings (pages 259 to 267), Homer and associates present results of a study that shows that cigarette smoking is a highly potent risk factor in extracranial carotid artery stenosis and that this effect remains even after the influence of other strong risk factors, such as age, hypertension, and serum concentration of low-density lipoprotein (LDL) cholesterol, has been considered. In addition, after adjustment for age and sex, total and LDL cholesterol were positively associated with carotid artery stenosis, the high-density lipoprotein (HDL):total cholesterol ratio showed a negative relationship, and HDL cholesterol and triglycerides showed no significant association. In multivariate analysis, the only lipid or lipoprotein fraction to remain significantly related to carotid artery stenosis was LDL cholesterol. The study sample was obtained from patients referred to the Mayo Clinic for carotid angiography, and inference to the general population necessitates caution. Studies in which angiography is used in patient populations may have limited generalizabilitybecause subjects in these studies are selected on the basis of symptoms or other indications ofatherosclerotic disease. Thus, patients referred for this procedure are inherently different from the general population, including clinical manifestations and access to the health-care system. Nevertheless, the wide variation of carotid disease present, ranging from no discernible stenosis to severe stenosis, Address reprint requests to Dr. G. S. Tell, Department of Public Health Sciences, Bowman Gray School of Medicine, 300 South Hawthorne Road, Winston-Salem, NC 27103. Mayo Clin Proc 66:327-331, 1991
supports the representativeness ofthe findings. Even if the patients were highly selected, the observed associations would probably be at least as strong as those found if a wider range of the population was studied, including normal healthy volunteers and patients with overt cardiovascular or cerebrovascular disease. Studies of Specific Patient Populations.-Other studies of patient populations have also found cigarette smoking to be strongly associated with carotid artery atherosclerotic disease. My colleagues and I previously reported a strong relationship between smoking and extracranial carotid artery atherosclerosis, measured as the degree of wall thickening in patients referred for diagnostic B-mode ultrasonography.!" We found the effect of current cigarette smoking to be almost equivalent to that of an additional 2 decades of aging. In agreement with Homer and colleagues, we also found a strong association between duration of cigarette smoking and carotid disease. Two studies of patients with hypercholesterolemia have also identified cigarette smoking as a strong risk factor for extracranial carotid artery atherosclerosis assessed by ultrasonography.v" In addition to the correlation with smoking, Poli and co-workers' found that the thickness of the intimal-medial complex of the common carotid arteries was significantly greater in patients with hypercholesterolemia than in a comparable group of control subjects with normal cholesterol levels. Schuster and associates" reported that carotid artery atherosclerosis is associated with the extent of the increase in the total cholesterol level in patients with familial hyperlipidemias. Study ofTwins.-Haapanen and colleagues" investigated the relationship between smoking and carotid artery atherosclerosis in a sample of 49 twins, discordant for smoking. In comparison with nonsmokers, the age-adjusted odds ratio among smokers for having carotid stenosis was
327
328
EDITORIAL
5.99 (stenosis defined as at least 15% luminal stenosis measured by pulsed Doppler ultrasonography). As measured by B-mode ultrasonography, the mean area of all carotid plaques was 3.2 times greater in the smoking twins than in the nonsmoking twin partners, and the thickness ofthe inner layer of the carotid arteries was significantly greater in the smoking twins. For smokers, the odds ratio of having a total area of carotid plaques of 10 mm'' or more was 3.97 and for carotid inner layer thickening of 1.2 mm or more was 5.91, relative to nonsmokers. These odds ratios remained significantly increased among smokers after adjustment for plasma cholesterol level, diastolic blood pressure, and body mass index. Population-Based Studies.-As previously mentioned, the generalizability of results obtained from patient populations or, as in the foregoing case, twins may be questioned. The identification of smoking and lipids or lipoproteins as risk factors for extracranial carotid artery atherosclerosis and stenosis in population-based studies would therefore strengthen the evidence about the significance of results from clinically based studies, ifthe studies meet a minimum of commonality of measurement methods and statistical analyses. Results from several recent population-based studies confirm the positive association between smoking and atherosclerosis in the general population. In the population-based Framingham study, 7 the presence of extracranial carotid artery disease measured by duplex imaging was significantly correlated with total serum cholesterol (measured 8 years before examination) and with a history of smoking. In a cross-sectional population-based study of Finnish men," cigarette smoking was the strongest determinant of carotid artery atherosclerosis as measured by Bmode ultrasonography, independent of the effects of other risk factors. A strong and graded relationship between serum LDL cholesterol and the frequency of carotid artery atherosclerosis was also found. HDL cholesterol was negatively related to carotid artery atherosclerosis only in men free of ischemic heart disease. In a 2-year follow-up study, the group reported that the
Mayo elin Proc, March 1991, Vol 66
atherosclerosis progressed faster in men who were current smokers or who had high serum LDL cholesterol levels than in others and that LDL cholesterol and pack-years of smoking were the two strongest predictors (after age) of the progression of common carotid intimal-medial thickening during this period." HDL and HDL2 cholesterol levels measured at baseline were unrelated to the progression of atherosclerosis. In the MONICA study (monitoring of trends in mortality and morbidity and their determinants in cardiovascular disease) in Augsburg, Germany, which included almost 1,400 randomly selected men and women, a positive (although weak) association was found between cigarette smoking and presence of plaques as assessed by ultrasonography among men. 10 Furthermore, in men only, the investigators found a significant negative relationship with the HDL:total cholesterol ratio and a borderline significant positive relationship with total cholesterol. Most recently, in the ARIC (Atherosclerosis Risk in Communities) study;'! the proportion of smokers among cases, defined as those participants who were in approximately the upper 10th percentile of intimal-medial thickness, was more than twice (41% versus 18%) that among control subjects, defined as those who had no wall thickening as measured by B-mode ultrasonography. Both cases and control subjects were free of clinical cardiovascular and cerebrovascular disease. A mean of 29 pack-years of smoking was reported among cases in comparison with 14 pack-years in control subjects. In addition, cases with carotid artery atherosclerosis had statistically significantly higher mean levels of plasma total cholesterol, LDL cholesterol, and total triglyceride and lower mean levels ofHDL cholesterol than did control subjects. The odds ratio for current smokers versus never or former smokers was 3.9 (95% confidence interval, 2.6 to 5.9) after adjustment for age, hypertension, and LDL cholesterol. The differences in total and LDL cholesterol between cases and control subjects remained significant after adjustment for other risk factors in multivariate analyses, but the difference in HDL cholesterol was no longer significant.
Mayo
cue Proc, March 1991, Vol 66
In the Honolulu Heart Program, smoking was found to be less strongly associated with atherosclerosis in the intracranial cerebral arteries than in the coronary arteries and abdominal aorta. 12 As in most autopsy studies, however, only the most distal portions of the intracranial internal carotid arteries were included; the more proximal portions ofthe carotid circulation were not assessed in this study. Reportedly, risk factors do not uniformly affect all arteries, and even within regional arterial beds, various segments are affected to different degrees. 1,13 Within the brain, for example, atherosclerosis in the large arteries has been related to age, diastolic blood pressure, and serum cholesterol level, whereas atherosclerosis in the small arteries has been related to diastolic blood pressure and serum triglycerides." Conclusion.-That cigarette smoking may precipitate clinical events through association with high fibrinogen levels, hemoglobin concentration, and myocardial oxygen supply has been reported previously.v" The consistent associations of cigarette smoking with atherosclerotic disease in the coronary arteries, aorta, and now the extracranial carotid arteries also indicate an atherogenic role. The evidence for a strong, graded, and biologically plausible association between cigarette smoking (measured in various ways) and extracranial carotid artery atherosclerosis is fairly consistent across diverse study designs and populations, and the strength of this association further indicates that this relationship is real. The emerging pattern of findings that relate lipids and lipoproteins to extracranial carotid artery atherosclerosis in these studies is less clear than in the case of smoking. The considerable diversity of findings reported among the various studies possibly reflects the strengths and weaknesses implicit in the various study designs, the methods of measurement, and the procedures used for selection of patients and participants. Nonetheless, even though the magnitude of the association between lipids or lipoproteins and extracranial carotid artery atherosclerosis is consistently less than that found for smoking, this result does not negate
EDITORIAL
329
an actual relationship. Furthermore, a possible underestimation of the true effect or bias (or both) due to intraindividual variability, measurement variability, and potential selection bias cannot be ruled out. Although the relationship between lipids or lipoproteins and extracranial carotid artery atherosclerosis seems to be weaker and less consistent than that for smoking, the atherogenic role of severallipids and lipoproteins-most notably, LDL cholesterol-seems to be supported by many studies. Although the mechanism of action of cigarette smoking and lipoproteins on atherosclerosis as measured by the various imaging techniques is incompletely understood at present, as are the possible interactive effects between smoking and lipids or lipoproteins, cigarette smoking undoubtedly exerts a strong and independent effect on the risk of extracranial carotid artery atherosclerosis in human populations. The unequivocal findings of this association provide additional evidence vindicating cigarette smoking as the single most important preventable cause of morbidity, disability, and mortality. Comment.-A comment on the methods and reporting ofthe measurement of arterial atherosclerotic disease is warranted. For in vivo investigation of carotid artery atherosclerosis, contrast angiography and Doppler sonography are used to assess the arterial lumen, and B-mode ultrasonography is capable of measuring the thickness of the vessel wall as a reflection of the extent of atherosclerosis rather than merely disturbed flow patterns or luminal stenosis. Because it is invasive and potentially harmful, angiography cannot be used in studies of the general population. Therefore, the availability of noninvasive imaging ultrasonographic techniques during the past few years has been encouraging in that even mild vascular lesions and wall irregularities of extracranial carotid arteries can now be studied. This development has facilitated the study of asymptomatic healthy subjects as well as symptomatic patients and thus has enabled investigators to study a wider range of atherosclerotic lesions than was possible previously.
330
EDITORIAL
Stenosis is usually expressed as percent narrowing ofthe luminal diameter and is often used as a measure of arterial disease caused by atherosclerotic plaques. With arteriography, however, the investigation of the early phases of atherosclerosis, which is initially evident only as structural changes in the arterial wall, is not possible. As reported by Glagov and Zarins.!" atherosclerotic lesions that are not ulcerated or surmounted by thrombi typically maintain circular or regular, almost ovoid configurations on cross section. As the plaque enlarges, it bulges outwardly away from the lumen, and the lumen tends to continue to be round; thus, the plaque is effectively sequestered from the lumen, and patency and luminal symmetry are maintained. This development may result in compensatory dilatation of the arterial wall and has been observed in all atherosclerotic-prone locations studied.F'!" Therefore, one cannot simply equate the degree of luminal stenosis with the extent of the plaque: an artery with early arterial wall thickening may maintain an adequate lumen, and functionally important stenosis may be delayed until the lesion occupies 40% of the internal elastic lamina area. 17 In contrast to arteriography, B-mode ultrasonography allows direct measurement of the arterial wall (intima and media) thickness. Although this method more accurately measures the extent of atherosclerosis, several factors can compromise the integrity of the images obtained, including the range of ultrasound velocity, deposits of calcium and cholesterol in the arterial wall, and physical characteristics of subjects such as obesity. Although most stenotic disease identified in the current study by Homer and associates was probably attributable to atherosclerosis, some patients classified as normal may, in fact, have had early carotid artery atherosclerosis. This issue is unlikely to affect the major conclusions of their study; in fact, if patients with moderate disease were misclassified as having no disease, the effects of the risk factors are probably underestimated. Nevertheless, it behooves us to be as precise as possible in scientific reporting.
Mayo Clin Proc, March 1991, Vol 66
Acknowledgment.-I thank Drs. Gerardo Heiss, Curt Furberg, and Maurice Mittelmark for helpful comments on a preliminary version of this editorial. Grethe S. Tell, dr.philos., M.P.H. Section on Epidemiology Department of Public Health Sciences Bowman Gray School of Medicine Winston-Salem, North Carolina
REFERENCES 1.
2. 3.
4.
5.
6.
7.
8.
9.
10.
Tell GS, Howard G, McKinney WM: Risk factors for site specific extracranial carotid artery plaque distribution as measured by B-mode ultrasound. J Clin Epidemiol 42:551-559, 1989 Tell GS, Howard G, McKinney WM, Toole JF: Cigarette smoking cessation and extracranial carotid atherosclerosis. JAMA 261:1178-1180, 1989 Tell GS, Howard G, Evans GW, Smith ML, McKinney WM, Toole JF: Cigarette smoking and extracranial carotid atherosclerosis, Adv Exp Med BioI 273:39-49, 1990 Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R: Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. Atherosclerosis 70:253261, 1988 Schuster HM, Kroner KK, Keller C, Spengel FA, Wolfram G, Zollner N: Atherosclerosis of the carotid arteries documented by duplex scan as a predictor of coronary artery disease in familial hyperlipidemias. Klin Wochenschr 65:34-39, 1987 Haapanen A, Koskenvuo M, Kaprio J, Kesaniemi YA, Heikkila K: Carotid arteriosclerosis in identical twins discordant for cigarette smoking. Circulation 80:1016, 1989 O'Leary DH, Anderson KM, Kase CS, WolfPA, Kannel WE: Extracranial carotid atherosclerosis in a general population: the Framingham study (abstract). Stroke 19:143,1988 Salonen JT, Seppanen K, Rauramaa R, Salonen R: Risk factors for carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Ann Med 21:227-229, 1989 Salonen R, Salonen JT: Progression of carotid atherosclerosis and its determinants: a population-based ultrasonography study. Atherosclerosis 81:33-40, 1990 Gostomzyk J-G, Heller W-D, Gerhardt P, Lee PN, Keil U: B-scan ultrasound examination of the carotid arteries within a representative population (MONICA ProjectAugsburg). Klin Wochenschr 66 (Suppl 11):5865, 1988
EDITORIAL
Mayo Clin Proc, March 1991, Vol 66
11.
12. 13. 14. 15.
Heiss G, SharrettAR, Barnes R, Chambless LE, Szklo M, Alzola C: Carotid atherosclerosis measured by Bmode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol (in press) Reed D, Marcus E, Hayashi T: Smoking as a predictor of atherosclerosis in the Honolulu Heart Program. Adv Exp Med BioI 273:17-25, 1990 Reed DM, Resch JA, Hayashi T, MacLean C, Yano K: A prospective study of cerebral artery atherosclerosis. Stroke 19:820-825, 1988 McGill HC Jr: The cardiovascular pathology of smoking. Am Heart J 115:250-256, 1988 Weintraub WS: Cigarette smoking as a risk factor for coronary artery disease. Adv Exp Med Biol 273:2737, 1990
16.
331
Glagov S, Zarins CK: Quantitating atherosclerosis: problems of definition. In Clinical Diagnosis of Atherosclerosis: Quantitative Methods of Evaluation. Edited by MG Bond, W Insull Jr, S Glagov, AB Chandler, JF Cornhill. New York, Springer-Verlag, 1983, pp 11-35 17. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ: Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 316:1371-1375, 1987 18. Zarins CK, Weisenberg E, Kolettis G, Stankunavicius R, Glagov S: Differential enlargement of artery segments in response to enlarging atherosclerotic plaques. J Vasc Surg 7:386-392,1988