1 Department of Radiology, University Hospital of Tromsø, Tromsø, Norway.
2 Institute of Community Medicine, School of Medicine, University of Tromsø, Tromsø, Norway.
3 Department of Thoracic and Cardiovascular Surgery, University Hospital of Tromsø, Tromsø, Norway.
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ABSTRACT |
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aneurysm; aorta; abdominal; lipoproteins; HDL cholesterol; prevalence; risk factors; ultrasonography
Abbreviations: CI, confidence interval; HbA1c, glycated hemoglobin; HDL, high density lipoprotein
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INTRODUCTION |
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Several large studies have addressed the epidemiology of abdominal aortic aneurysms (816
). Atherosclerosis is probably an important factor in the etiology of abdominal aortic aneurysm, although disturbances in the connective tissue metabolism may also be involved (9
, 17
22
). A number of studies have shown that abdominal aortic aneurysm and atherosclerosis share many risk factors such as age, smoking, hypercholesterolemia, and hypertension (11
, 16
, 23
26
).
Some previous studies of abdominal aortic aneurysm have been population based (810
, 12
, 13
, 27
), but the definition of abdominal aortic aneurysm has differed, making comparisons of prevalence rates difficult. It has been known for more than 150 years that abdominal aortic aneurysm is four times more frequent in men than in women (28
). Thus, several studies have been performed among men only (8
, 11
, 12
, 14
). Studies including both genders are important as there may be differences between the genders with regard to risk factors.
Smoking has been emphasized as an independent risk factor for abdominal aortic aneurysm (9, 16
, 23
, 29
, 30
), but only two of the larger population-based studies (9
, 30
) have addressed smoking in detail. The role of high density lipoprotein (HDL) cholesterol in the development of abdominal aortic aneurysm has been the subject of several studies. In most studies, high HDL cholesterol has been found to correlate with a low prevalence of abdominal aortic aneurysm (9
, 18
, 19
, 25
, 31
33
), but there have also been negative findings (13
). It is presently unknown whether hypertension is a risk factor for abdominal aortic aneurysm. Some studies indicate such a relation (16
, 27
, 29
, 30
, 34
36
), while other studies found no association (5
, 13
, 14
, 24
).
The aim of the present report was to study the prevalence of and risk factors for abdominal aortic aneurysm, as well as the distribution of infrarenal aortic diameter, in both men and women in a general population.
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MATERIALS AND METHODS |
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The fourth cross-sectional survey of the Tromsø population started in September 1994 and was completed in October 1995. The study comprised two screening visits 412 weeks apart. All inhabitants 25 years or older were invited to the first visit, and 27,159 subjects, 77 percent of the eligible population, participated. A protocol similar to that used in the previous surveys in this population (37) was followed. The examination included standardized measurements of height, weight, blood pressure, nonfasting serum lipids, and blood cell counts. A self-administered questionnaire handed in at the screening examination covered information about current and previous cigarette smoking, physical activity in leisure time, currently or previously treated hypertension, and a medical history of angina pectoris, diabetes mellitus, asthma, myocardial infarction, and stroke. Persons were classified as having low physical activity in leisure time if they denied any high intensity physical activity and had low intensity activity less than 3 hours per week during the last year before the survey.
All subjects aged 5574 years and a random 510 percent sample in the other age groups were eligible for the second visit. Eligible subjects also included a small group of men aged 4054 years (see below) previously identified as having a high risk of coronary heart disease (38). All eligible subjects who attended the first screening were, at the first screening, invited to the second visit, which comprised inter alia ultrasonographic measurements of aortic diameters, waist and hip circumference, and blood sampling. A total of 6,892 subjects, 79 percent of those who were eligible, were subject to ultrasound measurements of the abdominal aortic diameter. The age-specific attendance rates (based on age by December 31, 1994) were 62, 81, 83, 79, and 58 percent in the age groups 2544, 4554, 5564, 6574, and 7584 years, respectively. Thirty-seven attendees who had previous surgeries to insert a graft in the abdominal aorta, 320 men (aged 4054 years) who belonged to the nonrandom sample of men with a high risk of cardiovascular disease, and 149 subjects (2.2 percent) whose abdominal aorta was not visualized sufficiently to make exact diameter measurements were excluded from further analysis. Thus, 6,386 (2,962 men and 3,424 women) subjects were included in the analysis.
Cardiovascular risk factors
Height and weight were measured in light clothing without shoes. Body mass index was calculated as the weight divided by the square of height (kg/m2). The waist/hip ratio was calculated as the waist circumference divided by the maximal hip circumference. Blood pressure was recorded before blood sampling in a separate, quiet room with only a nurse present. An automatic device (Dinamap Vital Signs Monitor 1846; Criticon, Inc., Tampa, Florida) was used. After the participant had been seated for 2 minutes, three recordings were made at 2-minute intervals. The lower of the two last values of blood pressure was used. A venipuncture was performed with the subjects in a sitting position. A short-lasting venous stasis applied to the upper arm was released before blood sampling. Serum total cholesterol and triglycerides were analyzed by enzymatic colorimetric methods with commercial kits (CHOD-PAP for cholesterol and GPO-PAP for triglycerides; Boehringer-Mannheim, Mannheim, Germany). Serum HDL cholesterol was measured after the precipitation of lower density lipoprotein with manganese chloride. Plasma fibrinogen was measured using PT-Fibrinogen reagent (Instrumentation Laboratory, Milan, Italy). Serum creatinine was measured by the HiCo Creatinine Jaffé method with a kinetic colorimetric assay on automated clinical chemistry analyzers (Boehringer-Mannheim). Glycated hemoglobin (HbA1c) was measured from the hemolysate by a latex-enhanced turbidimetric immunoassay (Unimate 3 HBA1C; Roche Diagnostics Corporation, Indianapolis, Indiana). The analyses were done at the Department of Clinical Chemistry, University Hospital of Tromsø, Norway. Hypertension was defined as a systolic blood pressure of >160 mmHg, a diastolic blood pressure of >95 mmHg, or drug treatment for hypertension (current or previous). Pack-years were calculated as the number of cigarettes smoked per day (previously or currently) multiplied by the duration of smoking (years) divided by 20.
Ultrasonography of the abdominal aorta
The ultrasonographic measurements of the abdominal aorta were performed by four examiners as described previously (39). The subjects were examined in the supine position and/or in the left decubitus position when necessary. No instructions on food or fluid intake were given prior to the examination. The examination was carried out with a 3.5-MHz sector probe (Acuson 128-XP; Acuson Corporation, Mountain View, California). The abdominal aorta was first visualized in the longitudinal plane and was examined from the diaphragm to the bifurcation. The aorta was then examined in the axial plane with scans perpendicular to the longitudinal plane. Aortic diameters were measured at the level of the renal arteries, 1 cm distal to this level, and at the bifurcation level. In addition, the maximal infrarenal aortic diameter was measured. Both transverse and anterior-posterior diameters were measured. The external aortic diameter was measured with electronic calipers in both the anterior-posterior and transverse planes. All the measurements were made online on images that were frozen in systole. The inter- and intraobserver variability was determined at the beginning and at the end of the study. Measurement variability, estimated both as the mean absolute difference between two measurements and as 2 standard deviations of the mean arithmetic difference, was less than 4 mm for measurements of the maximal infrarenal aortic diameter (39
).
An abdominal aortic aneurysm was present if one or more of the following criteria were met: 1) the aortic diameter at the renal level was equal to or greater than 35 mm in either the anterior-posterior or the transverse plane; 2) the infrarenal aortic diameter was 5 mm larger than the renal aortic diameter in either plane; and/or 3) a localized dilatation of the aorta was present. If an abdominal aortic aneurysm was suspected to be present, the patients were examined by computed tomography and referred to the Department of Cardiovascular Surgery for clinical evaluation and follow-up.
Statistical analysis
Age-adjusted characteristics of men and women with and without an abdominal aortic aneurysm were calculated using analysis of variance. Associations between abdominal aortic aneurysm and cardiovascular risk factors as well as prevalent cardiovascular diseases were determined by using multiple logistic regression. Age was included in the analysis as age at the ultrasound examination. Ninety-five percent confidence intervals were calculated. Two-sided p values were used throughout, and p < 0.05 was considered to indicate statistical significance. The SAS software package was used (40).
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RESULTS |
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The risk of abdominal aortic aneurysm increased strongly with age in the multivariate model (table 3). The waist/hip ratio was positively related to the risk of abdominal aortic aneurysm. The point estimate was higher in women but not statistically significantly different from that in men (p > 0.2). High serum total cholesterol was a relatively weak risk factor for abdominal aortic aneurysm, whereas high HDL cholesterol was strongly associated with a low risk of abdominal aortic aneurysm in both genders. We found that systolic blood pressure was a risk factor in women only (p < 0.001). As the risks of abdominal aortic aneurysm for previous and current use of antihypertensive medication were similar (results not shown), the two dichotomous variables were combined. Ever use of antihypertensive medication was associated with increased risk of abdominal aortic aneurysm in both genders (table 3) even when adjusted for current systolic blood pressure. The effect of ever use of antihypertensive medication was found in both low (systolic blood pressure of <140 mmHg) and high (systolic blood pressure of 140 mmHg) blood pressure groups in both genders. We found no relation between pulse pressure and the risk of abdominal aortic aneurysm (results not shown).
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There was a strong inverse association between serum HDL cholesterol levels and the prevalence of abdominal aortic aneurysm. A dose-response relation was found between the levels of serum HDL cholesterol (categorzed as <1.20 (reference), 1.201.39, 1.401.59, 1.601.79, and >1.79 mmol/liter) and the prevalence of abdominal aortic aneurysm in both men and women (p < 0.001). The multivariate-adjusted odds ratios for abdominal aortic aneurysm with serum HDL cholesterol concentrations were 0.72 (95 percent confidence interval (CI): 0.53, 0.99), 0.45 (95 percent CI: 0.31, 0.67), 0.51 (95 percent CI: 0.34, 0.77), and 0.33 (95 percent CI: 0.22, 0.51) when comparing with the reference group (HDL cholesterol of <1.20 mmol/liter). Analysis both with and without serum triglycerides was performed. Notably, this did not change the results with regard to HDL cholesterol.
Smoking was strongly associated with the risk of abdominal aortic aneurysm. The duration of smoking (not the number of cigarettes smoked per day) was the most important smoking variable associated with increased risk of abdominal aortic aneurysm. There was a strong linear dose-response relation with an increasing duration of smoking (p < 0.001). When comparing never smokers with those having a smoking duration of 120, 2130, 3140, and >40 years, we found that the multivariate-adjusted odds ratio for abdominal aortic aneurysm increased from 1.4 (95 percent CI: 0.8, 2.4) (120 years) to 8.0 (95 percent CI: 5.0, 12.6) (>40 years) when never smokers were the reference group. When adjusted for duration of smoking, there were no significant associations between the number of cigarettes smoked per day and the risk of abdominal aortic aneurysm (results not shown). Smoking measured as pack-years was significantly associated with the risk of abdominal aortic aneurysm in both genders, but the association was entirely explained by the duration of smoking (results not shown). The risk of abdominal aortic aneurysm decreased slowly after the cessation of smoking, and the reduction in risk was mainly due to the reduced duration of smoking. When adjusting for smoking duration, the risk of abdominal aortic aneurysm even 20 years after the cessation of smoking was not statistically significantly different from the risk for current smokers.
Subjects with abdominal aortic aneurysm were more likely to have a self-reported history of myocardial infarction, angina pectoris, or hypertension, but no relations were found with self-reported diabetes mellitus, asthma, or stroke (results not shown).
In a subgroup analysis, we included 2,336 men and 2,998 women who reported no history of myocardial infarction, angina pectoris, stroke, or diabetes. There were 158 men and 49 women with abdominal aortic aneurysm. The results from this stratified analysis confirmed the strong associations of serum HDL cholesterol and smoking with the risk of abdominal aortic aneurysm in both genders, with plasma fibrinogen and blood platelet count in men, and with systolic blood pressure in women. The impact of physical activity in leisure time in men was somewhat stronger in this stratified analysis (odds ratio = 0.64; 95 percent CI: 0.45, 0.92).
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DISCUSSION |
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The complex pathogenesis of abdominal aortic aneurysm is still under debate. Conventionally, the development of abdominal aortic aneurysm has been attributed to atherosclerotic degeneration of the vessel wall (21). Atherosclerosis may increase the pressure load on the vessel and decrease the capacity of the wall to bear that load, leading to the formation of an abdominal aortic aneurysm (17
). Louwrens et al. (19
) concluded, however, that dilating and stenosing diseases are two distinct pathologic entities. Our results indicate that the risk factors for the development of abdominal aortic aneurysm and atherosclerosis are overlapping, but they should be confirmed in a prospective study design.
All aneurysms included in our analysis were previously unknown. Thus, knowledge of abdominal aortic aneurysm has probably not influenced the risk factor levels, although some persons may have been aware of the high risk of cardiovascular diseases and changed their living habits accordingly. The results were, however, unchanged when we restricted the analysis to subjects without known cardiovascular diseases. If an abdominal aortic aneurysm persists over years, it will cause turbulence of the blood flow, which may stimulate the blood platelets and the coagulation system. Thus, the existence of an abdominal aortic aneurysm may have increased fibrinogen and reduced blood platelet count. The increased plasma fibrinogen in subjects with abdominal aortic aneurysm may reflect this. A direct relation cannot, however, be excluded.
A striking finding in the present study is the highly significant relation between low HDL cholesterol and the risk of abdominal aortic aneurysm. Similar and less pronounced relations have been found in some (9, 18
, 25
, 31
, 33
), but not all (13
), previous studies. The risk of having an abdominal aortic aneurysm was 70 percent lower in subjects with a serum HDL cholesterol level of >1.79 mmol/liter compared with subjects with a serum HDL cholesterol level of <1.20 mmol/liter. It seems therefore likely that a low serum HDL cholesterol level, as a part of the atherogenic process, is a risk factor for developing an abdominal aortic aneurysm.
The blood sample was nonfasting, which has influenced the serum triglyceride level. As the misclassification is nondifferential, this has attenuated any relation between serum triglycerides and the risk of abdominal aortic aneurysm. In the multivariate analysis (table 3), we found no relation between the serum triglyceride level and abdominal aortic aneurysm risk.
Smoking is strongly associated with the risk of abdominal aortic aneurysm (table 3). The duration of smoking was the most important smoking variable associated with the risk of abdominal aortic aneurysm. The number of cigarettes per day or pack-years were not statistically significantly associated with abdominal aortic aneurysm risk when adjusted for duration. Cessation of smoking reduces the risk of abdominal aortic aneurysm slowly and mainly due to the reduced duration of smoking. The present findings are in accordance with those reported by Wilmink et al. (23) in a nested case-control study and several previous studies (9
, 11
, 16
, 17
, 25
27
, 41
, 42
), but, in a recent population-based study by Vardulaki et al. (30
), the level of cigarette use was reported as a stronger risk indicator than was duration of smoking.
It is at present not clarified whether hypertension increases the risk of abdominal aortic aneurysm (13, 14
, 16
, 24
, 25
, 27
, 30
, 34
, 35
). We found a significant relation between systolic blood pressure and abdominal aortic aneurysm in women but not in men. Ever use of antihypertensive medication was significantly associated with the risk of abdominal aortic aneurysm in both genders in our study, which supports a role of hypertension, as the use of antihypertensive medication probably is a proxy measure for long-term hypertension.
Some previous reports have indicated that the diameter of the abdominal aorta increases throughout life (43, 44
). Recently, it has been suggested that the diameter of the infrarenal aorta increases only in a part of the population (45
). As we do not have longitudinal data, we are not able to address this question properly. However, as the median maximal infrarenal aortic diameter increases only marginally with age from the age of 55 years, our data may give some support to the notion that a substantial increase in diameter with increasing age is found in a minority of the population. The 75th percentile does, however, increase considerably with age in men. Therefore, this minority cannot be negligible.
Because of the different criteria used for the definition of abdominal aortic aneurysm, it is difficult to compare the prevalence of abdominal aortic aneurysm in different epidemiologic studies. In the present study, the criteria for the diagnosis were set to give a high sensitivity for finding an abdominal aortic aneurysm. In spite of this, we found no persons with abdominal aortic aneurysm who were aged less than 48 years. As shown in table 1, the prevalence of abdominal aortic aneurysm in men was reduced from 8.9 percent to 8.2 percent and 2.3 percent if the criteria are set to >29 mm or >39 mm of maximal infrarenal aortic diameter, respectively. In women, the abdominal aortic aneurysm prevalence was reduced from 2.2 percent to 1.7 percent and 0.4 percent, respectively, if the criteria are similarly altered. In order to compare the prevalence of abdominal aortic aneurysm from different studies, it is important that the criteria for diagnosis are given and that the measurements of the abdominal aorta are done with a high degree of precision.
In our study, the attendance rate was relatively high as the aortic diameter was measured in 79 percent of the eligible persons. However, the attendance rate in the 2544 and 7584 year age groups was 62 percent and 58 percent, respectively. Although the overall attendance rate is higher than in most of the published studies, still a significant number did not attend the survey. Under the age of 55 years (with a total attendance rate of 71 percent), abdominal aortic aneurysms are very rare in our population, and the low number of invited subjects precludes a more detailed analysis of possible nonresponse bias. However, such bias should not influence our finding of a low prevalence.
The majority of our subjects were aged 5574 years. The subjects who came to the first screening of the study, but did not attend ultrasound examination, had slightly higher levels of some, but not all, cardiovascular risk factors (low HDL cholesterol and current smoking, but similar blood pressure and lower total cholesterol) than those who attended the ultrasound examination (results not shown). However, because only 11 percent of those who attended the first screening did not attend the ultrasound examination, the mean values of risk factors were very similar in those who were examined with ultrasound and those who attended the first screening only. The major possible nonresponse bias is thus connected to the 9 percent of the eligible persons who never were examined. We find it unlikely that this relatively small group of subjects can seriously bias our findings.
The lower attendance rate by subjects aged over 74 years is of some greater concern as this age group has the highest prevalence of abdominal aortic aneurysm. However, the number of subjects invited was low, and the confidence intervals were wide. Thus, bias can hardly change the finding of a high prevalence of abdominal aortic aneurysm in old people, and the relatively few subjects included in these age groups cannot materially influence the analysis of risk factors for abdominal aortic aneurysm.
In conclusion, our study shows that abdominal aortic aneurysm is a disease of the elderly that is 46 times more prevalent among men than women. Tobacco smoking and low concentrations of serum HDL cholesterol are strong independent risk factors for abdominal aortic aneurysm in both genders. Our results also indicate a significant effect of blood pressure on the risk of developing abdominal aortic aneurysm.
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ACKNOWLEDGMENTS |
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The authors acknowledge the assistance of the ultrasound technicians (Heidi Bliktun, Fred Machielse, and Laila Olsen).
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NOTES |
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REFERENCES |
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