Etiologic factors in progression of carotid stenosis: A 10-year study in 905 patients

Etiologic factors in progression of carotid stenosis: A 10-year study in 905 patients

Etiologic factors in progression of carotid stenosis: A 10-year study in 905 patients Laura Garvey, MD, Michel S. Makaroun, MD, Visala S. Muluk, MD, M...

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Etiologic factors in progression of carotid stenosis: A 10-year study in 905 patients Laura Garvey, MD, Michel S. Makaroun, MD, Visala S. Muluk, MD, Marshall W. Webster, MD, and Satish C. Muluk, MD, Pittsburgh, Pa Purpose: The purpose of this study was to determine the etiologic factors in the progression of carotid stenosis. Methods: We performed prospective serial duplex scan surveillance of 1470 carotid arteries in 905 asymptomatic patients during a 10-year period, with an average follow-up interval of 29 months and an average of 3.0 scans per carotid artery. Vascular laboratory and hospital records were used to collect risk factor information. The data were analyzed with proportional hazards modeling. Results: We examined several demographic, clinical, and laboratory risk factors that were chosen because of their potential relevance to atherosclerotic disease. These factors were analyzed with univariate proportional hazards modeling, in which time to progression of stenosis was the outcome variable. The six significant predictors (P < .05) were age, sex, systolic pressure, pulse pressure (systolic pressure – diastolic pressure), total cholesterol, and high-density lipoprotein (HDL). All, except HDL, were positive predictors of time to disease progression. With multivariate modeling, only pulse pressure and HDL remained as significant independent predictors of stenosis progression. The risk ratio for a 10–mm Hg rise in pulse pressure was 1.12, and the risk ratio for a 10-mg/dL decrease in HDL was 1.20. Conclusion: In this large cohort of patients who were followed prospectively for carotid stenosis, pulse pressure and HDL were found to be the key risk factors for carotid stenosis progression. The fact that pulse pressure superseded systolic pressure in multivariate modeling may shed light on the biology of carotid plaque progression. Further, our identification of these modifiable risk factors may help in the design of therapeutic trials for the prevention of progression of carotid atherosclerosis. (J Vasc Surg 2000;31:31-8.)

Recent trial results have shown that carotid endarterectomy can reduce the risk of stroke among patients with severe carotid stenosis.1-4 With serial carotid duplex scan surveillance for patients who were asymptomatic at a large Veteran’s Administration Hospital, we found that the risk of disease progression is substantial.5 We observed an annualized progression risk of 9.3% in the at-risk population.5 Although our previous study helped to delineate the natural history of progression of carotid stenosis, it failed to From the Divisions of Vascular Surgery and General Internal Medicine (Dr V.S. Muluk), University of Pittsburgh Medical Center and Veterans Administration Medical Center. Competition of interest: nil. Presented at the Forty-seventh Scientific Meeting of the International Society for Cardiovascular Surgery, North American Chapter, Washington, DC, Jun 8–9, 1999. Reprint requests: Dr Satish C. Muluk, A-1011 PUH, 200 Lothrop St, Pittsburgh, PA 15213. Copyright © 2000 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter. 0741-5214/2000/$12.00 + 0 24/6/103232

closely examine which biologic risk factors are associated with this progression. Instead, the previous work helped to delineate the subgroups at high risk for progression primarily on the basis of duplex scan criteria. Although large cross-sectional studies have consistently associated age, sex, blood pressure, serum cholesterol, and smoking with the presence of carotid atherosclerosis, these associations are made on the basis of one duplex scan examination per patient.6-10 Because serial duplex scanning was not performed, the effect of these risk factors on disease progression remains unknown. In this prospective study of a large cohort of patients with carotid stenosis, we attempted to define potentially modifiable cardiovascular risk factors that are predictive of progression of carotid stenosis. Although our previous paper primarily recognized the anatomic risk factors that are associated with progression, this paper seeks to identify the biologic risk factors that are associated with progression in an effort to focus preventive intervention and to alter the natural history of carotid disease. 31

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PATIENTS AND METHODS The study period encompasses the 10-year interval from September 1988 to September 1997, during which time the noninvasive laboratory at the Pittsburgh Veteran’s Administration Medical Center performed 6775 carotid duplex scan studies in 4171 patients. Of these patients, 1004 were asymptomatic at the time of the initial study and had at least one follow-up study more than 6 months after the baseline study and at least one carotid artery that had not undergone carotid endarterectomy (CEA). The patients were considered to be asymptomatic if they had absence of transient ischemic attack, amaurosis fugax, or stroke in the 6-month interval before the baseline study. The initial patient referral to the laboratory was done by internists and surgeons for varied indications. Although the patients’ physicians ordered some of the follow-up studies, most studies were performed because the laboratory schedules routine follow-up appointments for all patients at intervals of 6 to 12 months. This is the result of a prospective strategy to track the clinical and ultrasound scan course of these patients. Carotid arteries that had undergone CEA before the baseline study were excluded from analysis. In addition, if a patient underwent CEA after the baseline study, the stenosis data after the CEA were excluded from analysis. As we noted in a previous publication,5 we have had a policy for the last 8 to 10 years of offering CEA to patients at good risk with severe (≥80%) stenosis. However, several asymptomatic severe lesions were followed among patients who declined surgery or among those with significant medical risk factors. At each patient’s visit to the laboratory, a registered nurse would obtain a detailed neurologic history and yes/no responses to questions about smoking, hypertension, hyperlipidemia, and diabetes. Blood pressure in both arms was obtained, and a carotid duplex scan study (Accuson 128XP, Mountain View, Calif) was performed. The degree of internal carotid artery (ICA) stenosis was determined on the basis of velocity criteria that were validated at our institution by means of comparison with contrast angiography,5 yielding stenosis categories of none (0 to 14% stenosis), mild (15% to 49%), moderate (50% to 79%), severe (80% to 99%), preocclusive, and occluded. With angiography as a gold standard, sensitivity and specificity with our criteria ranged from 70% to 99%.5 In addition, we found excellent overall agreement between duplex scan and angiography (κ = 0.85).5 Sensitivity, specificity, and kappa statistic were determined after the review of 487 ICAs that were visualized in 248 consecutive carotid angiograms per-


formed during a 4-year period (October 1993 to June 1997). The angiographic data were compared with the respective duplex scan study results.5 To capture only the progression events of potential clinical significance, we defined progression as an increase in ICA stenosis to ≥ 50% for carotid arteries with baseline stenosis < 50% or an increase to a higher category of stenosis if the baseline stenosis was ≥ 50%. Thus, a transition from the category of no stenosis to the category of mild stenosis was not considered as progression but all other increases in stenosis category were considered as progression. As previously reported,5 the vascular laboratory data were extracted into Access (Microsoft, Redmond, Wash), a relational database. The total cholesterol, low-density lipoprotein cholesterol (LDL), and highdensity lipoprotein cholesterol (HDL), hemoglobin A1C (HbA1C), and medication data were retrieved from the hospital’s central computing system and then imported into Access. Our intent was that all the patients would have at least one cholesterol profile within the first 6 months after their first carotid duplex scan study. However, some patients refused and others missed appointments to have cholesterol testing. Of the 1004 patients, 905 patients (90%) had at least one cholesterol profile during the period of serial carotid study. The mean interval between the baseline study and the first cholesterol profile was 5.8 months. The analysis of etiologic factors is limited to this subset of 905 patients (1470 carotid arteries). Among these 905 patients, 277 (30.6% of the patients, and 63% of patients with known diabetes) had HbA1C determinations. All of the other analyzed variables (age, sex, race, systolic pressure, diastolic pressure, pulse pressure, history of diabetes, history of hyperlipidemia, history of hypertension, obesity, and smoking status) were available in all 905 patients. For the patients in whom more than one cholesterol profile or HbA1C test were performed during the period of serial carotid study, the mean value for each laboratory value was used in the analysis. We used Access for descriptive statistics, SAS (SAS Institute, Cary, NC) for Cox proportional hazards regression modeling and Kaplan-Meier method plots, and Excel (Microsoft) for exponential curve fitting of the Kaplan-Meier method plots. Progression was considered to be an outcome event for the involved carotid artery, in the same way that death is treated in a mortality study. A carotid artery was considered to be withdrawn if CEA was performed after the baseline study and at the point of the last serial duplex scan study. Kaplan-Meier method plots were carried out to the time point when the standard error reached 10%

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of the value of the survival distribution function. Statistical significance was inferred at the .05 level. RESULTS We followed 1701 carotid arteries among 1004 total patients, identified as described previously. The baseline demographic and clinical characteristics were typical for patients followed in major vascular laboratories, with the exception of the predominant male gender of the Veterans Administration hospital setting (Table I). Table I also shows a relative predominance of low-grade (none or mild) baseline stenosis among these patients. The mean follow-up period of the patients was 28 months, and the mean number of scans per patient was 2.9. The risk of progression among all ICAs was found to increase steadily from the time of entry for as long as 7 years of follow-up examination. These data closely follow an exponential curve (correlation coefficient, 0.99), with an annualized progression rate of 9.3% of the at-risk population. Of the 3471 follow-up duplex scan studies, 91 (2.6%) showed regression of the degree of stenosis. Thirty-two of these instances of regression occurred among the 328 patients who demonstrated progression in this study and had at least one post-progression duplex scan study. Thus, the incidence rate of “fall-back” of stenosis after progression was 9.8% (32 of 328). These patients were included in our analysis because it is reasonable to assume that the some degree of “fall-back” will be found in any real-world setting. Even if these patients had been excluded, our results would not have been substantively altered. Test reproducibility at our vascular laboratory is comparable with other excellent centers, with a 92% incidence rate of the same degree of stenosis on repeat examinations performed less than 30 days apart.5 Therefore, it is likely that most cases of observed regression represent true plaque regression. As discussed in the previous section, the analysis of etiologic factors was limited to 905 patients (1470 carotid arteries) who had at least one complete cholesterol profile (total cholesterol, LDL, HDL) performed during the period in which they were followed for carotid stenosis. This group represents 90% of the entire cohort of 1004 patients. Among this subset, the mean follow-up period was 30 months and the mean number of scans per patient was 3.0 (not significantly different from the values for the entire cohort of 1004 patients). The demographic features of this group were also not significantly different from those of the entire cohort. Our initial analytic strategy was to use univariate proportional hazards modeling to determine the pre-

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Table I. Demographic and clinical features Baseline patient characteristics (n = 1004 patients) Mean age (years) Sex, male History of: Angina Myocardial infarction Current smoking Any smoking Hyperlipidemia Diabetes Hypertension

65.5 98% 33% 35% 42% 90% 41% 31% 56%

Baseline distribution of ICA stenosis (n = 1701 ICAs) None Mild (15% to 49%) Moderate (50% to 79%) Severe (80% to 99%) Preocclusive Occluded

57% 18% 14% 8% 2% 0%*

ICA, Internal carotid artery. *Occluded ICAs were excluded from analysis (see Methods section).

dictive value of 15 variables that may have an etiologic role in the progression of atherosclerosis (Table II). Of these variables, six had statistically significant effects on the time to progression. HDL was found to be a negative predictor of the time to progression (risk ratio, <1), but the other five variables (age, male sex, systolic blood pressure, pulse pressure, and total cholesterol) were positive predictors (risk ratio, >1). All six variables were entered into a stepwise multivariate model, and two (pulse pressure and HDL) were found to retain independent predictive value for the time to progression. These variables are indicated with boldfacing in Table II. The remaining variables failed to retain significant predictive value in the multivariate model. The risk ratio for a 10–mm Hg rise in pulse pressure was 1.12, whereas the risk ratio for a 10-mg/dL fall in HDL was 1.20. To further define the importance of HDL and pulse pressure, we stratified patients into the following four groups: (1) HDL of 35 mg/dL or more and pulse pressure of less than 80 mm Hg, (2) HDL of less than 35 mg/dL and pulse pressure of less than 80 mm Hg, (3) HDL of 35 mg/dL or more and pulse pressure of 80 mm Hg or more, and (4) HDL of less than 35 mg/dL and pulse pressure of 80 mm Hg or more. The Kaplan-Meier method curves for these four groups of carotid arteries (Fig 1) show the separate and cumulative effects of these two risk factors. Our analysis included 565 patients in whom both carotid arteries were followed serially and 340

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underwent cholesterol-lowering therapy (P = .04), and we therefore concluded that the use of the medication was simply serving as a marker for elevated cholesterol in the univariate analysis. The design of this study did not allow us to specifically examine the effect of cholesterol-lowering therapy on carotid stenosis progression.

Fig 1. Kaplan-Meier method curves show probability of freedom from progression as function of time. Four curves are result of stratification of carotid arteries with two dichotomous variables (high-density lipoprotein, ≥35 or <35 mg/dL; pulse pressure, ≥80 or <80 mm Hg). Numbers below figure refer to number of at-risk carotid arteries for each subgroup at 0, 18, 36, and 54 months. HDL, Highdensity lipoprotein; PP, pulse pressure.

patients in whom a single carotid artery was followed. To address the possibility that the results were affected by the combination of these two groups into a single analysis, we separately analyzed all the left (n = 743) and all the right (n = 727) carotid arteries. The results with these two separate analyses were similar to the results of the analysis of all 1470 carotid arteries together. In each analysis, HDL and pulse pressure were still the only two variables that independently predicted the time to progression in multivariate analysis (HDL, P = .03 for left and P = .04 for right; pulse pressure, P < .01 for both left and right). We attempted to analyze the role of cholesterollowering medications in our patient cohort. The medication data were available for 595 of the 905 patients (65.7%). Of these 595 patients, 125 (21.0%) underwent cholesterol-lowering therapy during at least part of the time they were being followed for carotid stenosis. With proportional hazards analysis among these 595 patients, the use of cholesterol-lowering medication was a significant positive predictor of the time to progression in univariate analysis (P = .03), but it did not retain significance in multivariate modeling. Total cholesterol levels were significantly higher among patients who

DISCUSSION Large, population-based studies have attempted to identify those people in the general population with the highest risk for the development of significant carotid stenosis. With the quantification of risk factors for atherosclerosis and the performance of carotid duplex scan examinations on the patients, these studies have associated age, sex, hypertension, cholesterol, and smoking with the presence of carotid atherosclerosis.6-13 A single carotid duplex scan was performed per person, and most results showed early, hemodynamically insignificant disease. Because follow-up carotid studies were not done, the role of these risk factors in the progression from early atherosclerosis to more significant stenosis was not defined. Although our cohort was predominantly male and in a veterans hospital, it is currently the largest study to associate cardiovascular risk factors with the progression of carotid stenosis. Similar to the previously mentioned cross-sectional studies, our univariate analysis identified age, sex, systolic blood pressure, pulse pressure, total cholesterol, and HDL as risk factors predictive of carotid stenosis progression. In contrast, elevated LDL levels, a history of hypertension, and a history of smoking, all of which are considered to be important risk factors for the presence of carotid stenosis,14 were not associated with disease progression. As previously mentioned by Muluk et al,5 male sex was significantly associated with carotid stenosis progression in a univariate analysis but failed to retain importance in the multivariate model. Because 98% of our population was male, the significance of these results is questionable. A population with a greater proportion of women should be assessed to determine the relevance of gender as a predictor of carotid disease progression. Although various cross-sectional studies have correlated systolic blood pressure or a history of hypertension with the presence of carotid atherosclerosis, our results identified systolic blood pressure and pulse pressure as the blood pressure components predictive of progressive carotid disease. A history of hypertension had no association with worsening carotid stenosis. In a prior study, Muluk et al5 postulated that ele-

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Table II. Cox proportional hazards regression model analysis Univariate model

Demographic variables Age (years)† Sex, male Race, nonwhite Clinical variables SBP (mm Hg)† DBP (mm Hg)† Pulse pressure (mm Hg)† Total cholesterol (mg/dL)† LDL (mg/dL)† HDL (mg/dL)† HbA1C (%)† History of diabetes History of hyperlipidemia History of hypertension Obesity Smoking status, current smoker Smoking status, never smoked

95% CI

Entered into multivariate model

Multivariate model


Risk ratio*


Risk ratio*

95% CI

.03 .03 .19

1.014† 9.4

1.00-1.03 1.32-67.1

yes yes no

>.1 >.1

.007 .68 .001 .03 .45 .006 .41 .07 .052 .12 .50 .09 .25




1.009† 1.003†

1.00-1.01 1.00-1.01



yes no yes yes no yes no no no no no no no

.0001 >.1






*Risk ratio is shown only for variables with statistically significant effect on probability of progression. †Variables were analyzed as continuous variables. Therefore, the risk ratios for these variables represent the increased risk associated with a 1 unit increase in the value of variable. This fact is reflected in the apparently “low” values of the risk ratios for these variables. Unmarked variables were analyzed as dichotomous (no/yes) variables. Boldfacing indicates variables that retained independent predictive value in the final multivariate model. CI, Confidence interval; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HbA1C, hemoglobin A1C.

vated blood pressure measurements were necessary to identify uncontrolled disease, which may better correlate with stenosis progression. Although both systolic blood pressure and pulse pressure were significant predictors of progression in our univariate analysis, only pulse pressure retained its predictive value in multivariate analysis. Recent studies of elderly (>60 years) patients have shown a relationship between pulse pressure and cardiovascular disease.15-18 In an elderly population, increased elastic artery stiffness is the primary effect that will cause the systolic pressure to rise and the diastolic pressure to fall. Isolated systolic measurements underestimate arterial wall stiffness, and pulse pressure represents a pulsatile component of the arterial pressure that more accurately represents the degree of atherosclerosis.15 After the examination of 300 duplex scan results in elderly individuals who were hypertensive and normotensive, Franklin et al15 concluded that pulse pressure was the single best blood pressure component to predict the presence of carotid stenosis. Because pulse pressure correlates with the degree of arterial stiffness and the presence of carotid atherosclerosis, it is perhaps not surprising to discover that it is also the blood pressure component most predictive of progression from early disease to more significant stenosis. The identification of pulse pressure as a risk fac-

tor predictive of carotid disease progression is potentially useful for preventive medical therapy. SuttonTyrrell et al19 found that 71 participants who underwent treatment with a diuretic or β blocker for blood pressure control had slower progression of carotid stenosis when compared with a placebo group. Although this study suggests that antihypertensive drug therapy reduces the risk of carotid stenosis progression, future investigation is needed to expand on these findings. More recent studies have determined that acetyl-cholinesterase inhibitors and β blockers have variable effects on cerebral blood flow depending on the degree of carotid stenosis present.20,21 However, these same studies have neglected to investigate whether the drugs have a protective effect against the progression of stenosis. Whereas the lack of an association between a history of hypertension and carotid disease progression was unexpected, the finding that a history of smoking was unassociated is less surprising. The number of pack-years of cigarette smoking previously has been shown to increase the risk for stroke in a dosedependent manner.14 In fact, Whisnant et al22 examined the results of 752 carotid angiograms and determined that the duration of smoking was the smoking variable most strongly related to the presence of carotid artery stenosis. Therefore, it seems reasonable


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to assume that the duration of smoking or the number of pack-years would be predictive of carotid disease progression and that the history of smoking would not. Although our study did not examine duration or pack-years, a similar, smaller study of carotid disease progression by Salonen and Salonen23 found that the number of pack-years was associated with an increase in mean intima-media carotid thickness over time. Because stroke risk decreases 2 to 5 years after smoking cessation,14 it is possible that the same beneficial effect could exist for carotid stenosis progression. Further data accumulation in a population with a higher proportion of nonsmokers is needed to test this hypothesis. Ninety percent of our population had admitted to smoking at some point in time, a fact that makes our cohort less than ideal for an analysis of smoking as a risk factor. Total cholesterol, LDL, and HDL have all been associated with an increased risk of carotid stenosis. In our multivariate analysis, a decreased HDL level was the only blood lipid level significant for progression of carotid stenosis. One reason for this result could be our elderly study cohort. HDL levels appear to be relatively stable throughout life, and LDL and total cholesterol levels peak from age 45 to 60 years in American men and decline thereafter.24,25 The stability of HDL levels over time allows for a more consistent association with the risk of carotid stenosis progression in men over the age of 60 years.19,26,27 In an attempt to prevent the progression of carotid stenosis, several studies have shown that the prolonged use of cholesterol-lowering medications is associated with carotid wall thinning.28-31 However, these studies correlate a decrease in carotid wall thickness with different blood lipid levels. Mack et al30 associated an increased HDL level with improved carotid disease, and Crouse et al31 found a decreased LDL level to be predictive of carotid wall thinning. This discrepancy could be caused by the different degree of stenosis present in each cohort. Unfortunately, the role that lipoproteins play in the reversal of early lesions versus advanced, severe lesions is poorly understood. Elevated glycosylated hemoglobin (HbA1c) levels have been associated with carotid atherosclerosis in both individuals who are diabetic and individuals who are not diabetic.32,33 However, our results did not show any association between increased HbA1c levels and the progression of carotid disease. An assessment of diabetic control over time with multiple HbA1c levels may better correlate with the degree of worsening carotid stenosis. It is unknown whether the strict control of diabetes will alter the progression of carotid disease and reduce the primary stroke risk.14

CONCLUSION In conclusion, elevated pulse pressure and decreased HDL levels correlate with a higher risk for worsening carotid stenosis over time. Modification of these risk factors with medical therapy may prevent the natural progression of carotid stenosis and reduce the chance of stroke. We suggest that special attention be paid to these factors in the design of therapeutic trials for patients with carotid stenosis. We thank P. Elaine Householder, Margaret Brunsell, and Marlene Waszkiewicz, the nurses who perform carotid testing in the Veterans Administration vascular laboratory, and our nurse clinical coordinator, Stacy Love. REFERENCES 1. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-53. 2. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421-8. 3. European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (029%) carotid stenosis. Lancet 1991;337:1235-43. 4. Hobson R, Weiss D, Fields W, Goldstone J, Moore W, Towne J. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. N Engl J Med 1993;328:221-7. 5. Muluk SC, Muluk VS, Sugimoto H, Ree RY, Trachtenberg J, Steed DL, et al. Progression of asymptomatic carotid stenosis: a natural history study in 1004 patients. J Vasc Surg 1999;29:208-16. 6. Wilson W, Hoeg J, D’Agostino R, et al. Cumulative effects of high cholesterol levels, high blood pressure, and cigarette smoking on carotid stenosis. N Engl J Med 1997;337:516-22. 7. Heiss G, Sharrett A, Barnes R, Chambless L, Szklo M, Alzola C. Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol 1991;134:250-6. 8. Fine-Edelstein J, Wolf P, O’Leary D, et al. Precursors of extracranial carotid atherosclerosis in the Framingham study. Neurology 1994;44:1046-50. 9. O’Leary D, Polak J, Kronmal R, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health study. Stroke 1992;23:1752-60. 10. Salonen R, Salonen J. Determinants of carotid intima-media thickness: a population-based ultrasonography study in Eastern Finnish men. J Intern Med 1991;229:225-31. 11. Salonen R, Seppanen K, Rauramaa R, Salonen J. Prevalence of carotid atherosclerosis and serum cholesterol levels in Eastern Finland. Arteriosclerosis 1988;8:788-92. 12. O’Leary D, Anderson K, Wolf P, Evans J, Poehlman H. Cholesterol and carotid atherosclerosis in older persons: the Framingham study. Ann Epidemiol 1992;2:147-53. 13. Homer D, Ingall T, Baker H, O’Fallon W, Kottke B, Whisnant J. Serum lipids and lipoproteins are less powerful predictors of extracranial carotid artery atherosclerosis than are cigarette smoking and hypertension. Mayo Clin Proc 1991;66:259-67.

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14. Gorelick P. Stroke prevention. Arch Neurol 1995;52:347-55. 15. Franklin S, Sutton-Tyrell K, Belle S, Weber M, Kuller L. The importance of pulsatile components of hypertension in predicting carotid stenosis in older adults. J Hypertens 1997; 15:1143-50. 16. Sutton-Tyrell K, Alcorn H, Wolfson S, Kelsey S, Kuller L. Predictors of carotid stenosis in older adults with and without isolated systolic hypertension. Stroke 1993;24:355-61. 17. Witteman J, Grobbe D, Valkenburg H, van Hemert A, Stijnen T, Burger H. J-shaped relation between change in diastolic blood pressure and progression of aortic atherosclerosis. Lancet 1993;343:504-7. 18. Madhavan S, Ooi W, Cohen H, Alderman M. Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 1994;23:395-401. 19. Sutton-Tyrrell K, Wolfson S, Kuller L. Blood pressure treatment slows the progression of carotid stenosis in patients with isolated systolic hypertension. Stroke 1994;25:44-50. 20. Akopov S, Simonian N. Comparison of isradipine and enalapril effects on regional carotid circulation in patients with hypertension with unilateral carotid artery stenosis. J Cardiovasc Pharmacol 1997;30:562-70. 21. Kawakami N, Yamashita T, Nakano S, et al. Effect of angiotensin converting enzyme inhibitor on chronic ischemic patients. Acta Neurol Scand 1996;166:93-5. 22. Whisnant J, Homer D, Ingall T, Baker H Jr, O’Fallon W, Wiebers D. Duration of cigarette smoking is the strongest predictor of severe extracranial carotid artery atherosclerosis. Stroke 1990;21:707-14. 23. Salonen R, Salonen J. Progression of carotid atherosclerosis and its determinants: a population-based ultrasonography study. Atherosclerosis 1990;81:33-40. 24. Wilson P, Anderson K, Harris T, Kannel W, Castelli W.

DISCUSSION Dr Joseph H. Rapp (San Francisco, Calif). Dr Muluk and his associates have analyzed the atherosclerotic risk profiles of patients who undergo ultrasound scan studies for asymptomatic carotid stenosis. Although their list of risk factors analyzed seems short by today’s standards, the authors did include the three classic factors: blood pressure, plasma lipid levels, and smoking history or tobacco use. The authors found that although several factors were associated with plaque progression with univariant analysis, only a low level of high-density lipoprotein (HDL) and a wide pulse pressure were associated when multivariant analysis was used. These findings are not all that surprising. HDL and the major apoprotein component of HDL, apo A-1, have repeatedly been found, as the author pointed out, to be powerful predictors of atherosclerosis progression. HDL is involved in reverse cholesterol transport, which returns cholesterol to the liver for excretion. Low HDLs also can reflect elevated triglyceride-rich lipoproteins, an independent risk factor for peripheral vascular disease. Possibly even more important, HDL can act as a potent antioxidant, is a potent anti-inflammatory agent, and has been shown to protect animals from septic shock when present in high amounts. The basic data that suggest that pulse pressure is an

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27. 28.







Determinants of change in total cholesterol and HDL-C with age: the Framingham study. J Gerontol 1994;49:M252-7. Kannel W, Vokonas P. Demographics of the prevalence, incidence, and management of coronary heart disease in the elderly and in women. Ann Epidemiol 1992;2:5-14. Corti M, Guralnik J, Salive ME, et al. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA 1995;274:539-45. Wallace R, Colsher P. Blood lipid distributions in older persons. Ann Epidemiol 1992;2:15-21. Hodis H, Mack W, Dunn M, et al. Intermediate-density lipoproteins and progression of carotid arterial wall intimamedia thickness. Circulation 1997;95:2022-6. Blankenhorn D, Selzer R, Crawford D, et al. Beneficial effects of colestipol-niacin therapy on the common carotid artery. Circulation 1993;88:20-8. Mack W, Selzer R, Hodis H, et al. One-year reduction and longitudinal analysis of carotid intima-media thickness associated with colestipol/niacin therapy. Stroke 1993;24:1779-83. Crouse J III, Byington R, Bond M, et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol 1995;75:455-9. Beks P, Mackaay A, deVries H, deNeeling J, Bouter L, Heine R. Carotid artery stenosis is related to blood glucose level in an elderly Caucasian population: the Hoorn study. Diabetologia 1997;40:290-8. Vitelli LL, Shahar E, Heiss G, et al. Glycosylated hemoglobin level and carotid intimal-medial thickening in nondiabetic individuals. The Atherosclerosis Risk in Communities Study [see comments]. Diabetes Care 1997;20:1454-8.

Submitted Jun 8, 1999; accepted Aug 13, 1999.

important player in the atherogenic milieu are equally interesting. Wide pulse pressure drives macromolecules across cell membranes in tissue culture, and it also may amplify the mechanical stresses on the arterial wall. The findings of this paper are intuitively clear and may help us define a group of patients who are at higher risk for plaque progression, but there are several issues that I have asked the authors to clarify. First, it is clear that the study group contains patients who had only one carotid artery entered into the study and patients who had two carotid arteries entered. Given that you are comparing the effect of systemic factors on plaque progression, this could be a statistical nightmare. How did you handle this problem? Second, during the decade of your study, lipid-lowering agents became one of the most commonly prescribed classes of drugs in the Veterans Administration system. Although this is unlikely to change your findings regarding HDL, it would lower LDL levels and possibly make that value seem less prominent in the analysis. How many of your patients were undergoing treatment with lipid-lowering drugs and for how long? Third, as in most Veterans Administration populations,

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90% of your patients were smokers. Your study claims that only 42% were actively smoking. I hope patients in Pittsburgh are more honest than they are in San Francisco, because my patients are notorious liars when it comes to reporting active smoking. I wonder how valid it is to claim that HDL levels and pulse pressure are more important than smoking tobacco in causing carotid plaque progression? Finally, you suggest that we might modify low HDL and wide pulse pressure and thereby slow the progression of carotid stenosis. I am certain that this is true because HDL levels and pulse pressure are among the most difficult risk factors to alter. In fact, if your findings are correct, it suggests that once these patients have significant atherosclerotic plaque develop at the carotid bifurcation, progression of these lesions is virtually inevitable. I thank the Society for the privilege of discussing this interesting paper. Dr Satish C. Muluk. Dr Rapp, I thank you for your comments. I will try to answer them in sequence. The first is an important statistical issue in terms of combining the patients who contributed two carotid arteries with those who contributed one carotid artery. There is the potential for bias under certain circumstances. We combined them because we were looking at progression events in an artery and not patient outcomes. And so our statisticians advised us that combining was the best way to capture all of the available progression data. We did analyze the left and right carotid arteries completely separately from one another, so we had separate analyses of left and right. And the conclusions were the same. The same independent risk factors were shown to be important. Because of that, we believed that it continued to be valid to combine the two groups in this manner. The issue of cholesterol-lowering therapy is an important one. Unfortunately, it is one that is not possible for us to definitively answer. I can tell you that we have medication data on 565 of the 905 patients. And of that group on whom we have medication data, 21% were undergoing cholesterollowering therapy. The nature of our dataset does not let us say how long they were undergoing therapy, unfortunately, until we are able to accumulate more data on this issue. We can say that cholesterol-lowering therapy was actually a positive predictor of progression. That may simply be because cholesterol therapy was a marker for a high cholesterol level, and we are not suggesting that therapy increases the risk of progression. It is probably the reverse. But our study is not designed to answer that question in a definitive way. The issue of smoking is, of course, very important. And even though only 42% said they were smoking, I suspect that quitting may mean that they simply quit in the last 2 days or something of that sort. I do not doubt that we understate the percentage of smokers. Because there is such a high proportion of smoking, it may be a background variable that is not subject to much alterability in any case. In terms of the alterability of HDL and pulse pressure, you are absolutely right that HDL is one of the variables that is very difficult to alter. I would point out though that the study that used gemfibrozil was successful in raising HDL and did show a change in stroke outcome in that study. And


there are more tolerable drugs, one of them being Apo A1 Milano, that may be suitable in this regard. Dr John J. Ricotta (Stony Brook, NY). Dr Muluk, that was a nice presentation. I missed whether this was a prospective or a retrospective study? Dr Muluk. This was a prospective study. The patients were followed on a prospective strategy to follow them at every 6-month to 12-month intervals. Dr Ricotta. And were all the endpoints looked at each time the patient was seen? Dr Muluk. The cholesterol data were examined at one or more intervals. And there was no specific strategy in terms of the number of cholesterol studies that a patient underwent. On the other hand, all of the other variables were examined every study visit, namely, the blood pressure and all of the other variables. Dr Ricotta. The final question to follow Dr Rapp’s comments. Did you look at the status of the contralateral artery? If the contralateral artery had undergone a carotid endarterectomy or if there was a high-grade stenosis, did that affect progression? Dr Muluk. Absolutely. In fact, we reported previously that having a contralateral stenosis was an important predictor of rapid time to progression. We did not include it in this analysis because we were looking at what we believed were etiologic or biologic factors that would cause progression to occur. And we did not perceive the anatomic character of the opposite side or the ipsilateral side to be in that category, so we were focused more on etiologic factors in this study. But the contralateral carotid stenosis is a major correlate of time to progression. Dr Jack L. Cronenwett (Lebanon, NH). Dr Muluk, this is a very powerful dataset. Was it large enough to allow you to look at the correlation between factors that predicted stenosis and the severity of initial stenosis? In other words, were there any differences in predictors for patients who had minimal versus more severe stenosis at outset? Dr Muluk. In fact, there were. And we reported previously that having a stenosis of > 50% in the ipsilateral internal carotid artery or in the ipsilateral external carotid artery or in the contralateral internal carotid artery were all independently correlated with progression. And, in fact, we believe that those criteria can be used to define subsets of patients who should be followed more frequently than other patients. We do not see this data in the same light because the anatomic features that you see at the end of baseline study are more powerful predictors of progression than are these atherosclerotic risk factors. We see these factors instead as potentially modifiable factors that may have a role in the biology of why plaques progress. Dr James M. Estes (Boston, Mass). Did you identify any correlation between the progression of plaque and the development of symptoms? Dr Muluk. In this study, we have not yet done that. We are looking at symptoms. But the way they are coded in our dataset, they are incomplete at the moment. So, it is not possible for us to make any definitive statement about that. But that is an obvious and very important issue for us to examine.