Carotid Atherosclerosis in Men With Low Levels of HDL Cholesterol
Background and Purpose A low HDL cholesterol (HDL-C) frequently occurs in conjunction with a desirable LDL cholesterol (LDL-C) and is a risk factor for coronary heart disease (CHD). Additionally, the presence of carotid atherosclerosis is a strong and independent predictor of morbidity and mortality in patients with CHD. This article describes the prevalence and correlates of sonographically detected carotid atherosclerosis in men with low levels of HDL-C and CHD but without elevated levels of LDL-C or total cholesterol.
Methods High-resolution B-mode ultrasonography was used to quantify intima-media wall thickness (IMT) in the common and internal carotid arteries and at the carotid artery bifurcation in 202 randomly selected male veterans with CHD and low levels of HDL-C who are participating in the VA HDL Intervention Trial. Ultrasonographic measurement of carotid artery wall stiffness was determined in a subset of 94 of these individuals.
Results The mean maximum and single greatest carotid artery IMT measurements were 1.41 and 2.58 mm, respectively. The prevalence of ultrasound-detected carotid atherosclerosis as defined by a mean maximum IMT ≥1.3 mm was 58.9% and by single maximum IMT ≥1.5 mm was 87.1%. IMT was associated with increased age, lower extremity arterial disease, systolic blood pressure, and ultrasonographically measured carotid artery stiffness.
Conclusions Men with low levels of HDL-C and CHD but without elevated LDL-C or total cholesterol have a very high prevalence of ultrasound-detected carotid artery atherosclerosis.
Carotid atherosclerosis is a strong and independent predictor of morbidity and mortality in patients with CHD.1 2 3 4 5 6 7 8 High concentrations of plasma LDL-C and total cholesterol are associated with an increased prevalence of CA. Furthermore, drug therapy to reduce LDL-C has been shown to decrease the extent of CA.9 10 11 12 Approximately 50% of CHD patients, however, do not have high levels of LDL-C. In these patients the prevalence of low levels of HDL-C is over 40%.13 14
High-resolution B-mode ultrasonographic measurement of the combined thickness of the carotid arterial intima-media complex has been previously used for noninvasively detecting early carotid atherosclerosis. This measurement is also a reliable end point for interventional trials to assess disease progression. Unlike angiographic procedures that focus on changes in the lumen, ultrasonography provides noninvasive imaging of the arterial wall. Ultrasonography can also directly quantify the response of early atherosclerotic changes to risk factor modification. In addition, the measurement of carotid arterial IMT by high-resolution ultrasound techniques varies less than angiographic measurement of coronary or carotid arteries.15 Therefore, smaller sample sizes may be required to detect therapeutic benefits or to accurately assess the presence of early atherosclerosis.
The present study was conducted in a subgroup of 202 men currently enrolled in the Department of Veterans Affairs Cooperative Study No. 363 High-Density Lipoprotein Intervention Trial (HIT) to determine the prevalence of CA in individuals with low HDL-C whose LDL-C (and total cholesterol) are in a desirable or “normal” range.
Subjects and Methods
The HIT is a multicenter, randomized, double-blind, placebo-controlled study of 2531 men with CHD designed to determine whether raising HDL-C and lowering triglycerides with gemfibrozil will prevent myocardial infarction and CHD death. A complete description of the study rationale and design has been previously published.16 Men with CHD who had no other conditions likely to result in death in the ensuing 5 years were eligible if they were aged <73 years with HDL-C <40 mg/dL, LDL-C <140 mg/dL, and triglycerides <300 mg/dL.
Three of 20 centers (Lexington, Ky; Memphis, Tenn; and Minneapolis, Minn) participated in the ultrasound investigation of carotid atherosclerosis. All participants at these centers were eligible regardless of carotid artery symptoms or ultrasound findings unless they had previously undergone a bilateral carotid endarterectomy. Individuals with a history of unilateral carotid endartecectomy had ultrasound scanning limited to the unoperated carotid artery. There were no statistically significant differences between subjects who participated in this ultrasound study and the entire HIT cohort with regard to mean age, lipid levels, or the prevalence of cigarette use, hypertension, diabetes, or clinically evident cerebrovascular disease (data not shown).
Ultrasound scanning and reading of carotid arteries were performed by trained sonographers and B-mode image readers according to a previously described protocol.15 After a circumferential scan, sonographers used a high-resolution 10-MHz ultrasound system (Biosound Phase 2) to obtain longitudinal B-mode images of the arterial wall boundaries in each of the 12 defined carotid segments. The primary objective was to image and record on videotape the maximum IMT in each segment. All images were centrally analyzed by trained readers. The maximum IMT of each segment was computed by use of locations of crosshairs placed on the wall boundaries to a precision of 0.05 mm.
Several traditional measures of CCA stiffness (arterial strain, pressure strain elastic modulus, arterial distensibility, and arterial compliance) were ultrasonically determined in subjects from two of the participating centers (Memphis and Lexington; n=94) with the use of previously described methods.17 18 Arterial strain is defined as the fractional increase in diameter during the cardiac cycle produced by the arterial pressure pulse. To account for the magnitude of the pulse pressure in assessing stiffness, the pressure strain elastic modulus is defined as the ratio of pulse pressure to arterial strain. Arterial distensibility is defined as the fractional increase in volume of an arterial segment during the cardiac cycle divided by the pulse pressure, and arterial compliance is defined as the absolute increase in volume of an arterial segment during the cardiac cycle divided by the pulse pressure.
A standardized questionnaire was used to assess baseline demographic characteristics including age, race, marital status, and years of education. A history of selected medical conditions was obtained by medical record review and by asking participants whether a physician had ever told them that they had or were prescribed medication for any of the following conditions: diabetes, hypertension, chronic obstructive pulmonary disease, angina, myocardial infarction, congestive heart failure, abdominal aortic aneurysm, stroke, transient ischemic attack, or LEAD. The Rose claudication questionnaire was also used to assess for symptomatic LEAD.19 To assess for hemodynamically significant LEAD, the ABI was measured in all subjects while they were in a supine position. An ABI <0.85 was defined as hemodynamically significant LEAD.2 6 7 10
Specific health habit information included cigarette use, alcohol intake, physical activity, and current prescribed medication usage. Smoking status was classified as “current,” “past,” or “never.” Alcohol intake was classified as “none” (denied alcoholic consumption in the past 3 months), “light” (consuming <1 drink per day during the past 3 months), “moderate” (1 to 3 drinks per day), or “heavy” (>3 drinks per day). Physical activity was classified as “low,” “moderate,” or “high” according to the frequency with which participants engaged in strenuous exercise or hard physical labor per week (none=low; <3 times per week=moderate; ≥3 times per week=high).
Plasma samples for lipid analysis were obtained in the morning after a 12- to 14-hour fast and mailed frozen to a central lipid laboratory. The HIT central laboratory participates in the Centers for Disease Control and Prevention lipid standardization program and serves as a regional network reference laboratory for that program. The measurement of lipids was performed by standard enzymatic techniques described elsewhere.16 LDL-C was calculated according to the Friedewald formula.20
Determination of CA
The prevalence of CA was determined with the use of the 12 near (closest to the skin and ultrasound probe) and far wall IMT measurements from the left and right ICA, CCA, and bifurcation. The mean maximum thickness for all analyzed segments for each individual segment and the single greatest IMT were determined. The distribution of mean maximum arterial wall thickness measurement was determined by segment. CA was considered present if the mean maximum carotid IMT was ≥1.3 mm. Individuals with a single wall thickness measurement ≥1.5 mm were also defined as having evidence of ultrasound-detected CA. IMT measurements greater than these values have been shown to exceed the population mean by 2 SDs and are associated with an increased risk of vascular morbidity and mortality.21 22 23 Because similar results were obtained for the left and right carotid arteries, the mean of the two sides is presented as the IMT for each carotid artery segment.
For continuous variables, t tests were used to compare differences between mean risk factor levels in participants with CA and those without. For categorical variables, the univariate association between the variable and CA was examined with the use of 2×2 contingency tables, ORs, and a χ2 test of significance.
With the use of logistic regression, age-adjusted univariate ORs and 95% confidence intervals were then calculated to compare the prevalence of selected risk factors in those with and without CA. A stepwise regression model was constructed with CA as the dependent variable and age-adjusted risk variables significant at P<.15 in univariate analyses as independent variables. The relationships between carotid and lower extremity atherosclerosis as well as carotid IMT and carotid artery stiffness were examined and correlation coefficients determined.
Table 1⇓ shows selected baseline characteristics and the age-adjusted univariate ORs for the presence of ultrasound-defined carotid disease (mean maximum IMT ≥1.3 mm). The mean age was 64 years, and 96% were white. Eighty-three percent had a history of cigarette use, but only 17% were currently smoking. Clinically evident cerebrovascular disease as assessed by a history of stroke, transient ischemic attack, or contralateral carotid endarterectomy was present in 12%. LEAD was noted in 37 of 202 individuals (18%); 13 (6%) were considered symptomatic by the Rose claudication questionnaire or by a history of surgery for LEAD. Clinically evident cerebrovascular disease or LEAD was present in 53 men (26%) . Ultrasound-detected CA as defined by a mean maximum IMT ≥1.3 mm or a single maximum IMT >1.5 mm was present in 59% and 87% of individuals, respectively. Individuals with LEAD, with previous myocardial infarction, or who were currently smoking cigarettes were at increased risk for carotid disease. There was no association of carotid IMT with alcohol use, hypertension, diabetes, cerebrovascular disease, or lipid levels.
Table 2⇓ shows the population distribution of mean and single maximum IMT measurements by arterial segment. An average of 10 carotid artery segments per subject (of a possible 12) were analyzable. The mean IMT was as follows: ICA, 1.40 mm; CCA, 1.16 mm; and bifurcation, 1.72 mm. The mean single maximum IMT was 2.58 mm. In comparison, with the use of similar methods, the median IMT for the ICA, CCA, and bifurcation in 65-year-old white men in the general population has been reported as 0.77, 0.76, and 1.00 mm, respectively.21 The mean IMT measurements observed in our participants would place them in the upper 10% of a community cohort matched for age, race, and sex.21
Stepwise logistic regression analysis was conducted with carotid artery disease, defined by a mean maximum carotid IMT ≥1.3 mm, as the dependent variable (Table 3⇓). When we controlled for other variables, carotid artery disease was associated with increased age (OR=2.13 per 10 years; P=.002), systolic blood pressure (OR=1.4 per 10 mm Hg; P=.002), and the presence of LEAD (OR=3.97; P=.01). There was a trend toward an association with current smoking status (OR=2.25; P=.06).
Table 4⇓ provides data on the mean and several percentile values of the four measures of CCA stiffness. The mean value of arterial strain was approximately 5%, with values ranging from approximately 3% to 8%. The mean value of distensibility was approximately 1.5%/kPa (1 kPa=7.6 mm Hg), with values ranging from approximately 0.8%/kPa to 2.6%/kPa. The mean value of compliance was approximately 8.5 mm3/kPa for a 1-mm-long segment of the CCA, with values ranging from approximately 4.5 to 14.0 mm3/kPa. The mean value of the pressure strain elastic modulus was approximately 150 kPa, with values ranging from approximately 77 to 250 kPa.
There was a weak inverse relationship between mean maximum carotid arterial thickness and the ABI (P=.001, R2=.08), indicating that individuals with hemodynamically significant LEAD had greater CA. As measured by pressure strain elasticity (a measure of early CA, carotid arterial stiffness) and ABI, there was a correlation between carotid and lower extremity atherosclerosis (P=.02, R2=.06). Similar findings were observed with ABI and carotid artery distensibility (P=.02, R2=.05). No association was seen between carotid strain and ABI. There was an association between arterial IMT and stiffness as assessed by distensibility and pressure strain elasticity (P=.02, R2=.05 and P<.001, R2=.12, respectively).
Our results indicate that ultrasound-detected CA as well as hemodynamically and clinically evident LEAD are extremely common in men with CHD and low levels of HDL-C. These results have important clinical implications because CA of this magnitude is associated with stroke, future CHD events, and death.23 24 25 26 27 28 29 30 More than half of the individuals in our study had a mean carotid artery IMT measurement >1.3 mm. Eighty-four percent of men had evidence of ultrasound-detected CA when we used a definition of carotid disease that included a single maximum carotid IMT measurement ≥1.6 mm. The extent of CA observed in our subjects has been previously reported to be associated with a twofold or greater odds for stroke23 and would place them in the upper 10% of previously reported community cohorts. Additionally, for each standard deviation increase in IMT, a 20% increase in stroke has been reported to occur.23 LEAD detected by symptoms or hemodynamic testing has also been associated with a reduction in length and quality of life.1 2 3 4 5 6 7 8
Subject and ultrasound characteristics of 10 different studies are compared with our results (Table 5⇓). When compared with the HIT cohort, only one third of healthy community-living individuals21 and 75% of elderly in the Cardiovascular Health Study23 had CA of equal or greater magnitude. The average age in this latter report was 75 years, 10 years older than our cohort. Similar to our study, the Monitored Atherosclerosis Regression Study enrolled subjects with CHD regardless of carotid disease status.9 Nevertheless, the mean CCA IMT in our cohort is approximately 70% greater than that in the Monitored Atherosclerosis Regression Study (1.2 versus 0.7 mm), a trial that selected for patients with high LDL-C. In fact, the extent of disease in HIT enrollees is comparable to that in studies that preselect individuals for the presence of CA10 11 12 13 31 32 (Table 5⇓). The high prevalence in our cohort may be related to male sex, age, and low HDL-C in addition to the presence of CHD.
Our definitions of CA have been used previously. The wall thickness measurements considerably exceed the established normal range for community-living individuals of similar age, race, and sex21 23 Additionally, ultrasound measurement of carotid arterial IMT varies less than angiographic measurement of either coronary or carotid arteries.15 Therefore, it is unlikely that our findings are due to misclassification of our participants.
To our knowledge this is the first report describing carotid and lower extremity atherosclerosis in individuals with low levels of HDL-C and desirable levels of LDL-C. The importance and generalizability of these findings are emphasized by the high prevalence of diffuse atherosclerosis in this cohort8 as well as the frequency with which this lipid profile occurs in community-living individuals with CHD.13 14
There was an age-adjusted association between the presence of LEAD, smoking, systolic blood pressure, and ultrasound-detected carotid arterial disease. These associations remained even when we controlled for other variables, although smoking did not quite meet statistical significance (P=. 06). Additionally, there was a correlation between carotid arterial IMT and carotid arterial stiffness, a measure of early CA. We also demonstrated that both carotid artery IMT and stiffness are correlated with symptomatic or hemodynamic LEAD. This latter finding has not to our knowledge been previously reported and supports the concept that atherosclerosis is frequently a systemic process.
Increased arterial stiffness is a possible mechanism in the initiation and/or progression of atherosclerosis and hypertension; elevated arterial stiffness is associated with a number of cardiovascular risk factors, including age, male sex, lipoprotein abnormalities, and diabetes.25 26 27 28 29 30 Measurement of arterial IMT and stiffness detects early atherosclerosis before it becomes hemodynamically significant. These measures can be used to identify individuals at increased risk of having or developing disease in other vascular beds and have implications for atherosclerosis detection, prevention, and treatment.25 26 27 28 29 30 33
Unlike hemodynamic or symptomatic atherosclerosis, increased arterial IMT and stiffness may be reversed quickly by pharmacological, dietary, and perhaps physical activity interventions.9 10 11 12 While more evidence about the prognostic significance of increased arterial stiffness and the effects of interventions on this parameter would be useful, the potential benefit is considerable.
Our study did not demonstrate an association between a history of hypertension or diabetes with carotid arterial IMT. When we controlled for other variables, systolic blood pressure and current smoking status were only weakly associated with CA. These factors have been previously demonstrated to be strong independent predictors of carotid artery disease.34 35 36 37 The reason(s) for the lack of association in our study are not known but could be due to sample size, sex, and the extremely high prevalence of carotid disease in our population.
Previous studies of individuals with markedly elevated LDL-C and total cholesterol have shown a beneficial effect of lipid intervention on the rate of carotid artery plaque progression.9 10 11 12 Whether such benefits will also be seen in patients with lipid profiles similar to our cohort is not yet known and is the focus of further investigations. Lipid levels have also been previously shown to be associated with CA. The lipid enrollment criteria in our study resulted in a homogeneous distribution of lipids, thereby minimizing any ability to detect associations between commonly measured lipids and CA.
Surgical intervention and/or risk factor modification has been shown to be beneficial in individuals with hemodynamically significant cerebrovascular atherosclerosis.38 39 40 The demonstration that nonocclusive CA as measured by IMT and arterial stiffness is also associated with increased morbidity and mortality will likely result in the identification of a large number of individuals at risk for future vascular events. The optimal management of these individuals is not known, but aggressive risk factor modification appears warranted.
In summary, our findings indicate that ultrasound-detected CA is very common in men with low levels of HDL-C and CHD but without elevated levels of LDL-C or total cholesterol. The presence of LEAD and previous myocardial infarction were strongly associated with increased carotid IMT. Carotid IMT and ABI-measured LEAD were also associated with carotid arterial stiffness. A better understanding of the prevalence and predictors of diffuse atherosclerosis combined with attempts at secondary disease prevention appear warranted in this high-risk group.
Selected Abbreviations and Acronyms
|ABI||=||ankle-brachial blood pressure index|
|CCA||=||common carotid artery|
|CHD||=||coronary heart disease|
|HIT||=||High Density Lipoprotein Intervention Trial|
|ICA||=||internal carotid artery|
|LEAD||=||lower extremity arterial disease|
Participating VA Medical Centers. Ann Arbor, Mich: William Kou,* G.B. John Mancini,* Scott Sample, Nicole Champagne. Boston, Mass: William E. Boden,* Carol Chapin, Dorothy Gilroy, Nancy Aicardi, Lisa Kerry, David LeFebvre. Chicago, Ill: Mary Ann Papp,* Sue Stanford, Kristin Oberg, Towanda Redmond, Sandy Monreal, Hope Thomas. Cincinnati, Ohio: Laura F. Wexler,* Judy Shaffer,* Elizabeth Snow, Karen Johnson. Fresno, Calif: Prakash C. Deedwania,* Eva Murphy, Elnora Bugay, Joyce King, Kathy Butler, Karen Marshall. Houston, Tex: Douglas L. Mann,* Peter Kuo, Carl Tyler, Donna Espadas, Adrian Chee. Huntington, WVa: Robert C. Touchon,* Ken Peart, Carol Harless, Mark Babb. Lexington, Ky: James W. Anderson,* Belinda Smith, Lorraine Buchanan, Kitty Cox, Jo Ellen Logan. Little Rock, Ark: Fred H. Faas,* Sharon Thomas, Julia Washam, Keena Ridings. Long Beach, Calif: Moti L. Kashyap,* Nancy Downey, Rebecca Knight, Jahandar R. Saleh, Pooneh Rahimi. Louisville, Ky: S. Abraham Joseph,* Ellis Samols,* Diane Kinny, Loretta Pignatora, Tom Sugg. Manchester, NH: Michael Mayo-Smith,* Margaret Carson, Linda Lavoie, Dana Gillie, David Havron. Memphis, Tenn: Marshall B. Elam,* Gale Rutan,* Linda Harris, Judy Pinson, Rhonda Childress, Rebecca Manning, Mary Jones. Milwaukee, Wis: Gordon Schectman,* Sue Ristow, Carol Parker. Minneapolis, Minn: Timothy J. Wilt,* Linda Schlasner, Marlys Nelson, Debbie Rootes. Portland, Ore: Henry DeMots,* Lori Gray, Susan Bagnoli, Teresa Tucker, Karina Martin. Salem, Va: Ali Iranmanesh,* Douglas C. Russell,* Sara Clary, Cindy Stephens, Liza Wertz. San Juan, Puerto Rico: Esteban Linares,* Maria S. Velazquez, Maria De Lourdes Cruz. Washington, DC: Vasilios Papademetriou,* Madeline Metcalfe, Patty Dandenau. West Los Angeles, Calif: Jerome M. Hershman*, Bramah N. Singh,* Patricia McCloy, Deb Kistner, Katherine Goddart.
Cochairs. VA Medical Center, Minneapolis, Minn: Hanna Bloomfield Rubins (cochair), Joanne Karvonen. VA Medical Center, Boston, Mass: Sander J. Robins (cochair).
VA Cooperative Studies Program Coordinating Center. West Haven, Conn: Dorothea Collins (study biostatistician), Marika K. Iwane (former study biostatistician), Peggy Antonelli, Rae Bartozzi, Cindy Cushing, Raymond Kilstrom, Rich Vinisko, Joan Derrico, John Brennan.
VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center. Albuquerque, NM: Mike R. Sather (chief), Carol L. Fye (clinical research pharmacist), Mariann Drago, Roy Fetter, William Gagne, Carol Green, Linda Richards, Marylyn Widlund.
Central Lipid Laboratory. Lipid Research Laboratory, Endocrinology Division, Department of Medicine, New England Medical Center Hospitals, Boston, Mass: Ernst J. Schaefer (director), Judith R. McNamara, Carol Huang, Tanya Massov, Carl DeLuca.
ECG Coding Center. University of Minnesota, School of Public Health, Division of Epidemiology, Minneapolis, Minn: Richard S. Crow (director), Marsha McDonald, Cheryl Swanson, Carmen O’Donnell.
Nutrition Consultant. VA Medical Center, Richmond, Va: Kathleen Smith.
Committees: Data Monitoring Board: Thomas A. Pearson (chair), Antonio M. Gotto (vice chair), Kent R. Bailey, Barry R. Davis, Alfred F. Parisi, Basil M. Rifkind, Robert Zelis. Executive Committee: Hanna B. Rubins and Sander Robins (cochairs), William E. Boden, Marshall B. Elam, Carol L. Fye, David J. Gordon, Marika K. Iwane, Ernst J. Schaefer, Gordon Schectman, Timothy J. Wilt, Janet Wittes. Endpoints Committee: Marshall B. Elam (chair), Richard Crow, Henry DeMots, Esteban Linares, Gale Rutan, Hanna B. Rubins (ex-officio). Planning Committee: Hanna B. Rubins and Sander J. Robins (cochairs), William E. Boden, Marshall B. Elam, Carol L. Fye, David J. Gordon, Marika K. Iwane, Raj Lakshman, Ernst J. Schaefer, Gordon Schectman, Janet Wittes.
The VA HIT is funded by the Department of Veterans Affairs, VA Cooperative Studies Program, and by a grant from Parke Davis, Division of the Warner Lambert Co.
Reprint requests to Timothy J. Wilt, MD, MPH, Section of General Internal Medicine (111-0), Minneapolis VAMC, 1 Veterans Dr, Minneapolis, MN 55417.
1 Principal investigator.
- Received April 15, 1997.
- Revision received June 24, 1997.
- Accepted June 24, 1997.
- Copyright © 1997 by American Heart Association
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