epidemiology of abdominal aortic aneurysms · epidemiology of abdominal aortic aneurysms 209 sion...

Epidemiologic ReviewsCopyright © 1999 by The Johns Hopkins University School of Hygiene and Public HealthAll rights reserved

Vol. 21, No. 2Printed in USA.

Epidemiology of Abdominal Aortic Aneurysms

James F. Blanchard1"3

INTRODUCTION

Abdominal aortic aneurysms are responsible for asubstantial public health burden in developed coun-tries. In 1991, abdominal aneurysm was cited as theprimary or secondary cause of 12,711 deaths in theUnited States (1). Aortic aneurysms of unspecifiedsite, many of which were probably abdominal, werecited for a further 4,108 deaths. It has been estimatedthat abdominal aneurysms cause 1-2 percent of alldeaths among men over the age of 65 in the UnitedStates (2). In Canada, vital statistics data show thatthere are approximately 1,000 deaths attributable toabdominal aneurysm annually (3). Since abdominalaneurysms often escape clinical detection, these vitalstatistics data probably underestimate the true magni-tude of mortality related to abdominal aneurysm.

Abdominal aneurysms are also responsible for con-siderable morbidity and health care costs. In theUnited States in 1992, abdominal aneurysm was citedas the primary diagnosis for approximately 53,000hospital discharges, and there were approximately40,000 surgical operations for this aneurysm (1). InCanada in 1990, abdominal aneurysm was cited as theprimary diagnosis for 5,638 hospitalizations (3).

Mortality and morbidity related to abdominalaneurysm has increased substantially in recentdecades. In the United States, the number of deathsdue to abdominal aneurysm increased by almost 20percent between 1979 and 1991, and the number ofrelated hospitalizations more than doubled (1). InEngland and Wales, the number of deaths due toabdominal aneurysm increased by 53 percent between1974 and 1984 (4). In Canada, the number of hospital-

Received for publication May 26, 1998, and accepted for publica-tion July 6, 1999.

Abbreviations: HDL, high density lipoprotein; LDL, low densitylipoprotein; VLDL, very low density lipoprotein.

1 Epidemiology Unit, Public Health Branch, Manitoba Health,Winnipeg, Manitoba, Canada.

2 Department of Community Health Sciences, Faculty ofMedicine, University of Manitoba, Winnipeg, Manitoba, Canada.

3 Department of Medical Microbiology, Faculty of Medicine,University of Manitoba, Winnipeg, Manitoba, Canada.

Reprint requests to Dr. James F. Blanchard, Manitoba Health,4058-300 Carlton Street, Winnipeg, Manitoba R3B 3M9, Canada.

izations related to abdominal aneurysm increasedalmost fourfold between 1970 and 1990 (3). Similarly,in Western Australia, the number of surgical operationsfor abdominal aneurysm more than doubled betweenthe early 1970s and the early 1980s (5).

Despite the public health importance of abdominalaneurysms, much is still unknown with respect to theiretiology. Historically, they have been considered sim-ply a manifestation of atherosclerosis (6-8). However,this conventional theory has come under increasingchallenge in the past two decades. Whereas aortic ath-erosclerosis is common, a relatively small proportionof persons develop aneurysmal disease. Furthermore,epidemiologic, genetic, and biochemical research indi-cates that the etiology of abdominal aneurysm is dis-tinct from atherosclerosis per se.

The first part of this review provides an overview ofthe definition, pathophysiology, and natural history ofabdominal aneurysm. In the second part, descriptiveand analytic epidemiologic studies are reviewed withan emphasis on their implications for etiology.

LITERATURE SEARCH

In preparation for this paper, a review of theEnglish-language scientific literature was conducted.This was performed primarily by searching theMEDLINE® databases for the time period 1966through December 1998. Keywords used in the searchincluded "aneurysm," "aorta," and "aortic aneurysm."In addition, a search was performed using "aneurysm"as a Medical Subject Heading. The bibliographies ofarticles found through the MEDLINE® search werealso searched for relevant articles.

BACKGROUND

Definition and classification of aortic aneurysms

An aneurysm is a localized dilation of an artery. Itwas described in 1581 by Fernel as ".. .the dilatation ofan artery full of spiritous blood" (9). True aneurysmsinvolve the dilation of all three layers of the arterialwall: the intima (the innermost layer facing the

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208 Blanchard

lumen), the media (the middle layer), and the adventi-tia (the outermost layer) (8, 9). False aneurysms do notinvolve the dilation of all three layers of the arterialwall but rather are due to a disruption of the arterialwall (9). A dissecting aneurysm is a particular form offalse aneurysm that most often results from the degen-eration of the arterial media, tearing of the intima, andsubsequent development of a hematoma in the arterialwall (10).

Most aneurysms occur in the aorta, and most aorticaneurysms occur in the infrarenal abdominal aorta.Studies from various populations have shown that90-95 percent of abdominal aneurysms involve theinfrarenal aorta (11-14). Etiologically, most aorticaneurysms are classified as "acquired," distinguishingthem from aneurysms that result from genetic diseasessuch as Marfan's syndrome and Ehlers-Danlos syn-drome. Historically, the large majority (>90 percent) ofacquired aortic aneurysms were etiologically desig-nated "atherosclerotic," based on the common patho-logic finding of coexistent atheromatous lesions and theabsence of other obvious specific etiologic conditions(15). However, current reporting standards recommendthat these aneurysms be classified as "nonspecific"until their etiology is more clearly defined (16).

Pathophysiology of abdominal aneurysm

Dobrin has described the development of an arterialaneurysm as a ".. .classic case of material failure" (17).The primary structural elements of the aortic wall areelastin and collagen (6, 18). Fibers of distensibleelastin are arranged in concentric lamenae in the aorticmedia, forming the primary load-bearing structure ofthe aortic wall. In comparison with that of other mam-mals, the human abdominal aorta has fewer elasticlamenae than would be expected based on the hemo-dynamic load (6). This may partly explain the propen-sity for aneurysms to develop in the abdominal aorta.The largely acellular adventitial layer of the aorta iscomposed primarily of large amounts of elastin andcollagen, and it provides much of the tensile strengthof the aortic wall (18, 19).

It has been suggested that failure of elastin is the ini-tiating factor in the development of an aneurysm,resulting in an increased mechanical load on the colla-gen which forms a very strong but indistensible "safetynet" (6, 17-19). Experimental models of aneurysm for-mation have shown that isolated destruction of elastinresults in an arterial dilation of only 25-65 percent,and that for further aneurysmal dilation and subse-quent rapture to occur there must also be failure of thecollagen (6, 20).

Several factors have been proposed as contributorsto the weakening of the aortic wall and aneurysmal

dilation. One factor is the natural degradation ofelastin. The half-life of elastin has been estimated asapproximately 70 years (6), and the adult aorta doesnot appear to manufacture functional elastin (6, 21,22). This may partly explain the fact that abdominalaneurysms occur primarily late in life. Some investi-gators have suggested that genetically determinedanomalies in the constitutional proteins in the aorticwall render some individuals prone to aneurysm for-mation (2, 18, 23). However, as yet, no important spe-cific genetic defects in the primary structure of theaorta have been identified.

There is a growing body of scientific evidence sug-gesting that an imbalance between proteolytic activityand antiproteolytic activity in the aorta is associatedwith the formation of abdominal aneurysms (24-32).Several studies have shown that persons with abdomi-nal aneurysm have higher levels of elastolytic activitythan persons with occlusive aortic disease or patientswith neither abdominal aneurysm nor occlusive dis-ease (25-32). The precise nature and source of theelastolytic activity is uncertain (6, 25, 29, 30). In addi-tion to enhanced elastolytic activity, some small stud-ies have demonstrated a reduction in the antiproteo-lytic activity within the aneurysm wall (27, 33, 34).

Inflammation has also been proposed as a factorweakening the aortic wall and leading to aneurysm for-mation. Pathologic studies have shown that abdominalaneurysms are often infiltrated by inflammatory cellsinvolving the aortic media and adventitia (35—38). Therole of and stimulus for inflammation in the formationof abdominal aneurysms has yet to be delineated.However, Gregory et al. (39) and Tilson et al. (40)have proposed a role for autoimmunity in this process.

Natural history of disease

While some abdominal aneurysms remain stable insize, the natural history of most of them involves slowexpansion. Overall, most clinical case studies whichhave observed the natural history of these aneurysmshave found that the expansion rate is variable, andsome abdominal aneurysms do not appear to changeappreciably in size. In most studies, the overall meanexpansion rate is 0.25-0.50 cm per year (41^14).However, mean expansion rates increase as a functionof size. In a surgical case series described by Guirguisand Barber (43), the expansion rate (maximal trans-verse diameter) was 0.2 cm per year for abdominalaneurysms in the 3- to 4-cm range and 0.4 cm per yearfor those in the 5- to 6-cm range. Similar findings havebeen reported for patients with abdominal aneurysmdetected by population screening. Bengtsson et al. (45)followed 88 such patients and found that the expansionrates were quite variable. They reported mean expan-

Epidemiol Rev Vol.21, No. 2, 1999

Epidemiology of Abdominal Aortic Aneurysms 209

sion rates of 0.08 cm per year among persons withabdominal aneurysms less than 4.0 cm in diameter and0.33 cm per year among those with abdominalaneurysms with an initial diameter of 4.0 cm or more.

With increasing early detection and improved surgi-cal prognosis, most deaths that are directly attributedto abdominal aneurysm result from aortic rupture. Therisk of rupture depends on size. Although prospectivedata on the full natural history of abdominal aneurysmare scarce because of surgical intervention, it is esti-mated that the 5-year risk of rupture is approximately75 percent for abdominal aneurysms greater than 7.0cm in diameter (46-49). The risks of rupture for abdom-inal aneurysms with diameters of >6.0 cm and 5.0-5.9cm have been estimated at 35 percent and 25 percent,respectively (46-49). The risk of rupture for abdomi-nal aneurysms less than 5 cm in diameter appears to below. In their surgical case series, Guirguis and Barber(43) reported cumulative 6-year rupture rates of 2 per-cent for aneurysms 4-5 cm in diameter and 1 percentfor aneurysms less than 4 cm in diameter. Similar find-ings have been reported from other study centers(50-52).

The case fatality rate for ruptured abdominalaneurysms is extremely high. Approximately 50 per-cent of persons with a ruptured abdominal aneurysmwho reach a hospital do not survive. Since up to 70percent of persons with rupture do not survive longenough to reach a hospital, the overall case fatality isover 80 percent (53).

In contrast, the operative mortality for abdominalaneurysm has declined over the past two decades (53).Surgical mortality rates in the 1950s and early 1960sranged from 13 percent to 15 percent, and theydeclined to 5-7 percent in the late 1960s and early1970s (53). More recently, reported surgical mortalityrates have been in the 2-5 percent range, despite anincrease in surgery for persons with other comorbidconditions (53).

METHODOLOGICAL ISSUES

Important methodological issues must be consideredin reviewing descriptive and analytic epidemiologicstudies of abdominal aneurysm. Among these issues,case definition and case detection are of particularimportance.

Case definition

There have been several proposed clinical definitionsfor abdominal aneurysm (16, 54-59). Most definitionsuse criteria that are intended to identify persons withabnormal aneurysmal dilation of the infrarenal aorta,without explicit regard to the clinical significance or

prognosis. The Society for Vascular Surgery and theInternational Society for Cardiovascular Surgery rec-ommend that an abdominal aneurysm be defined by anaortic diameter that is at least 50 percent greater thannormal (16). However, this definition is difficult toapply, since criteria for defining "normal" aortic diam-eter are not clearly established and aortic diameters dif-fer by age, sex, and body size. Zwiebel discouragesspecific size criteria and suggests that from a radiologicperspective, "the primary criterion for sonographicdiagnosis of an aneurysm is a focal increase in the cal-iber of the affected vessel" (54, p. 56). However, thistopographic definition may be difficult to reproduce inpractice. Other researchers have proposed definitionsbased on the absolute or relative diameter of theinfrarenal aorta. McGregor et al. (55) proposed that anabdominal aneurysm was present if the infrarenal aor-tic diameter was at least 3.0 cm. Although this defini-tion may be more reproducible, such a definition doesnot account for the fact that the normal aortic diametervaries; therefore, definitions based on the ratio of thediameter of the infrarenal aorta relative to that of thesuprarenal aorta have been developed. Sterpetti et al.(56) proposed that the infrarenal diameter exceed thesuprarenal diameter by at least 1.5 times. Alcorn et al.(57) have suggested a much more sensitive case defin-ition wherein an abdominal aneurysm is present if theinfrarenal diameter exceeds the suprarenal diameter byat least 1.2 times.

The selection of a case definition that is based onclinical significance is problematic, since expansionrates are variable. Collin (58) proposed a definitionbased on clinical relevance wherein an abdominalaneurysm was present if the maximal diameter was 4.0cm or the infrarenal aortic diameter exceeded thesuprarenal diameter by at least 0.5 cm. The clinicalrationale for using a 4.0-cm cutoff is supported by theobservation that the occurrence of rupture or acuteexpansion is rare in smaller abdominal aneurysms(60). Another approach was proposed by Ouriel et al.(59), wherein a ratio of the aortic diameter to that ofthe third lumbar vertebral body that is greater than 1 isused to define a clinically significant aortic dilation.They found that this definition was better at distin-guishing ruptured abdominal aneurysms (n = 36) thanwere definitions that used the absolute infrarenal aor-tic diameter, the diameter relative to the diameter of anage- and sex-matched population, or a ratio based onthe diameter of the supraceliac aorta.

The choice of a case definition in epidemiologicstudies of abdominal aneurysm can have a substantialimpact on the results. The use of a very sensitive casedefinition such as that proposed by Alcorn et al. (57)results in much higher prevalence estimates than more

Epidemiol Rev Vol. 21, No. 2, 1999

210 Blanchard

restrictive case definitions. Case definition may alsohave important implications for etiologic studies ofabdominal aneurysm. The inclusion of cases definedby minimal aortic dilation may identify factors that areassociated with the initiation of aneurysm formationbut not factors associated with further dilation. This isan important consideration, since current concepts ofabdominal aneurysm pathogenesis suggest that theseprocesses may involve different pathophysiologicmechanisms. Factors associated primarily with degen-eration of elastin in the aortic media may lead only tominor dilation (6, 20). Additional factors associatedwith destruction of elastin and collagen in the aorticadventitia may be required for the development of fur-ther aneurysmal dilation and aortic rupture (19).

A further difficulty in choosing a case definition foretiologic investigations of abdominal aneurysmsrelates to the fact that they are not pathologicallyhomogeneous. Although the large majority are non-specific in origin, the inclusion of cases due to famil-ial defects in collagen or those due to causes such astrauma or infection will attenuate observed risk factorassociations.

Case detection

The detection of abdominal aneurysms is hamperedby the fact that they are rarely accompanied by pathog-nomonic symptoms. Surgical case series have demon-strated that only 19-43 percent of patients have sug-gestive symptoms (50, 61, 62). Clinical examination isnot a highly accurate method for detection. In generalclinical settings, the sensitivity of clinical examinationis usually less than 50 percent (63, 64). The low sensi-tivity of clinical examination and the frequent lack ofsymptoms result in a high prevalence of undetectedabdominal aneurysms (65-67). The positive predictivevalue of clinical examination is also low, ranging from15 percent to 50 percent depending on the prevalenceof abdominal aneurysm and the clinical criteria used(64, 68, 69).

Since many abdominal aneurysms go undetected,descriptive epidemiologic studies using data sourcesthat rely on clinical detection are prone to underesti-mation of the true prevalence. In this regard, popula-tion screening studies and necropsy studies in popula-tions with high necropsy rates are less biased. Analyticstudies focusing on risk factors for abdominalaneurysm are also prone to biases due to differentialcase detection. Spurious associations will result whencase detection is influenced by variables associatedwith the risk factor under study (diagnostic suspicionbias). In this regard, factors that enhance clinicalscrutiny, such as the presence of coexistent conditions(particularly those involving the vascular system) or

the existence of presumed risk factors, may result inspurious positive associations. This type of bias maybe found in prospective studies in which case detectionis not active but instead relies on routine clinical detec-tion or death certification. Similarly, selection biasmay be introduced into case-control studies unlesscontrols are selected such that they are subject to thesame level of clinical scrutiny as are the cases. Riskfactor studies based on population screening are lessprone to this type of bias. However, since they requirea large sample size for identification of an adequatenumber of cases, they often rely on less precise riskfactor measurement.

Temporality

The early development of an abdominal aneurysm isgenerally an insidious process. Therefore, most epi-demiologic studies are based on prevalent cases ratherthan incident cases. As a result, it is difficult to deter-mine the temporal sequence between risk factor expo-sure and aneurysm formation in cross-sectional andretrospective studies. Prospective studies are lessprone to temporal biases. However, unless active casedetection is performed at enrollment, cases prevalentat study initiation are likely to be misclassified as inci-dent cases during the follow-up period.

Cross-sectional and retrospective studies may also bebiased by the effect that some risk factors have on thenatural history of abdominal aneurysm. In this regard,factors that are associated with aneurysm rupture orpremature mortality may be underrepresented in caseseries derived cross-sectionally or retrospectively.

DESCRIPTIVE EPIDEMIOLOGY

Descriptive epidemiologic studies are generallybased on prevalent cases rather than incident cases.Most early studies of the occurrence of abdominalaneurysm were based on necropsy series (11, 12, 65,70). More recently, data from population-based clini-cal case series (5, 13, 71), administrative healthrecords (1, 3, 4, 72, 73), vital statistics (3, 74, 75), andpopulation screening programs (14, 57, 64, 76-80)have been used to describe the epidemiology ofabdominal aneurysm.

Age and sex

One of the most striking and consistent findingsfrom descriptive epidemiologic studies is the increasedprevalence of abdominal aneurysm with advancingage (1, 57, 65, 70, 74, 76). Since most abdominalaneurysms are asymptomatic, it is difficult to assignand analyze the average ages of onset and incidence



for abdominal aneurysm. Although variations inmethodology and case definition make comparisonsbetween different studies problematic, a sharp rise inprevalence has been seen in most studies after the ageof 60 years (figures 1 and 2). In epidemiologicnecropsy studies (65, 70) and screening studies (57,76), prevalence is less than 1 percent among personsunder 60 years of age. Thereafter, prevalence risesquickly, and it appears to plateau above 80 years ofage. Accounting for this rapid increase in prevalence,the incidence of abdominal aneurysm evidently risessharply in the sixth and seventh decades. These find-ings are supported by mortality data from vital statis-tics registers. In an analysis of US mortality data,Lilienfeld et al. (74) showed a substantial increase inthe mortality rate for aortic aneurysm with age in allbirth cohorts in both men and women. The sharpestincreases in mortality rates were seen between the agesof 40 and 70 years, with some leveling in older agegroups. A more recent review of US mortality statisticsalso reported higher mortality rates with advancingage, with the sharpest increase in mortality beginningbetween the ages of 55 and 64 years (1).

Abdominal aneurysms are substantially more com-mon among men than among women. Studies frommortality statistics registers have consistently demon-strated a higher mortality rate among men than amongwomen (1, 3, 4, 70, 74). Among White men andwomen in the United States, the male:female mortalityratio is 4.5 (74). In Canada, among persons aged >55

years, the male:female mortality ratio is 3.6 (3). In datafrom England and Wales, the age-adjusted mortalityrate for aortic aneurysm was more than twice as highamong men as among women (4).

Studies based on clinical cases of abdominalaneurysm have also shown a higher frequency amongmen. A study by Melton et al. (71) based on clinicaldiagnoses of abdominal aneurysm in Rochester,Minnesota, found a 2.3-fold higher crude incidencerate among men than among women between 1971 and1980. Lilienfeld et al. (73) reviewed hospital dischargerecords from the Minneapolis-St. Paul, Minnesota,metropolitan area for 1979-1984. They found that age-adjusted rates of hospitalization were 5-10 timeshigher among men than among women. Similarly,Millar et al. (3) reported a 4.7-fold increase in the age-adjusted hospitalization rate for abdominal aneurysmamong Canadian men in 1990.

Since abdominal aneurysms often escape clinicaldetection, studies based on death registration or clini-cal diagnoses may be influenced by detection bias.However, necropsy studies and screening surveys havealso found a higher prevalence of abdominal aneurysmamong men. In a study from Malmo, Sweden,Bengtsson et al. (70) showed that the overall preva-lence of abdominal aneurysm upon necropsy wastwice as high among men as among women (4.3 per-cent vs. 2.1 percent). The greatest difference in preva-lence was for persons aged less than 80 years, afterwhich the prevalences converged (figure 1). A

- • - Malmo, Male

- * - Malmo, Female

-a- Kansas City, Male

- a - Kansas City, Female

20 30 40 50 60 70

Age (years)

80 90

FIGURE 1. Postmortem prevalence of abdominal aortic aneurysm (AAA) by age and sex in necropsy studies from Malmo, Sweden (70) andKansas City, Missouri (65).


212 Blanchard

12% -i

10%-

5 8% -

o 6% -

15| 4% -

2%-

0%

- • - Rotterdam, Males

- * - Rotterdam, Females

- ° - Pittsburgh, Males andFemales

20 30 40 50 60

Age (years)

70 80 90

FIGURE 2. Prevalence of abdominal aortic aneurysm (AAA) by age and sex in ultrasound screening studies from Rotterdam, The Netherlands(76) and Pittsburgh, Pennsylvania (57). For the Rotterdam study, an abdominal aneurysm was defined as 1) an infrarenal aortic diameter >3.5cm or 2) an infrarenal diameter >1.5 times greater than the suprarenal diameter. For the Pittsburgh study, an abdominal aneurysm was definedas 1) a history of abdominal aneurysm repair, 2) an infrarenal aortic diameter >3.0 cm, or 3) an infrarenal diameter >1.2 times greater than thesuprarenal diameter.

necropsy study conducted in Kansas City, Missouri, byMcFarlane (65) revealed a 2.6-fold increase in preva-lence for persons aged less than 70 years and a 1.6-foldincrease in persons over the age of 70. Most screeningsurveys have included only men. However, a recentscreening survey in Rotterdam, The Netherlands,found a much higher prevalence among men thanamong women (76). Overall, the prevalence wasalmost 6 times higher among men. The male:femaleprevalence ratio was quite consistent in all age groupsover 55 years (figure 2). Similarly, a recent screeningstudy of US veterans by Lederle et al. (80) found thatmales had a 1.6- to 4.5-fold higher prevalence thanfemales, depending on the case definition used. Thescreening study by Alcorn et al. (57) found a preva-lence ratio of 2.3 for men versus women (14.2 percentvs. 6.2 percent) in persons aged 65 years or older.

Time trends

Several studies have indicated an increase in theprevalence of abdominal aneurysm in various popula-tions during the past few decades (3,5, 65, 70, 71, 81).This may be partly due to an increasing size of higherrisk populations. Although most studies of temporaltrends have adjusted for the age distribution of thestudy population, there may be residual confounding

due to the increasing survival of higher risk subpopu-lations. Another explanation for this observed increaseis enhanced detection. However, several studies havealso demonstrated stable or increased rates of rupturedabdominal aneurysm and emergency cases of abdomi-nal aneurysm (5, 71, 81). Since surgical care hasimproved and surgery is now more common, the fre-quency of these cases would probably decline ifincreased detection of asymptomatic or uncomplicatedabdominal aneurysms were not accompanied by anactual increase in incidence. Furthermore, at least onestudy has shown that the increase in incidence hasoccurred for all sizes of abdominal aneurysms. In thepopulation-based study of clinically diagnosed abdom-inal aneurysms in Rochester, Minnesota, Melton et al.(71) demonstrated that while the largest age-adjustedincrease in the prevalence was for small and asympto-matic abdominal aneurysms, there was also a 16 per-cent increase in the incidence of large abdominalaneurysms between 1960-1961 and 1971-1980.

In Western Australia between 1980-1982 and1986-1988, age-standardized mortality due to abdom-inal aneurysm increased by 36 percent among menover age 55 and by 24 percent among women over age55 (5). The largest increases in mortality wereobserved for deaths occurring during emergency andelective hospital admissions, with smaller increases for



nonhospital deaths. In Goteborg, Sweden, the age-standardized mortality rate for ruptured abdominalaneurysm increased by an average of 2.4 percent peryear between 1960 and 1980, despite a decline in sur-gical mortality for ruptured aneurysm (81). In inter-preting these findings, the possible influence ofincreased detection of small abdominal aneurysms onthe attribution of mortality to abdominal aneurysmshould be considered.

In Canada, mortality statistics demonstrate a stableage-adjusted mortality rate for ruptured and unrup-tured abdominal aneurysms between 1979 and 1991(3). In contrast, the age-adjusted hospitalization rateincreased by 52 percent among men and 29 percentamong women over the same time period (3).

Necropsy studies from Sweden and the UnitedStates have shown substantial increases in thenecropsy detection rate over the past few decadesamong both men and women (65, 70). Bengtsson et al.(70) reported that the age-standardized prevalence ofabdominal aneurysm at necropsy increased by an aver-age of 4.7 percent per year among men and by 3.0 per-cent per year among women between 1958 and 1986 inMalmo, Sweden. McFarlane (65) also reported anincrease in the prevalence of abdominal aneurysmbetween 1950-1959 and 1970-1984 in Kansas Cityamong both men (1.5-fold increase) and women (2.5-fold increase). Although the authors of these reportsdid not note any temporal changes in the necroscopytechniques or case definitions over time, the extent towhich such changes occurred would have influencedthe observed temporal increases in prevalence.

Racial differences

There are indications of racial differences in theprevalence of abdominal aneurysm and abdominalaneurysm-specific mortality, especially among men (1,82, 83). US mortality statistics show that theWhiterBlack age-adjusted mortality ratios for abdomi-nal aneurysm are 2-3 among men (1). In contrast,among US women, the White:Black mortality ratiosare close to 1. A case-control study by LaMorte et al.(82) based on hospital discharge records inMassachusetts found that the odds ratio for abdominalaneurysm repair was 2.4 for White race. Racial differ-ences observed in these studies may be influenced byhigher detection rates among Whites. A study in NorthCarolina reported on the prevalence of abdominalaneurysm discovered incidentally upon necropsy orabdominal computed tomographic scan (83). Amongpersons over 50 years of age, the highest prevalencewas seen among White men (5.4 percent), followed byWhite women (1.9 percent) and Black men andwomen (1.0 percent and 1.1 percent), respectively.

While this study is less likely to have been biased bydifferential clinical detection, the age distribution ofpatients was not reported, so confounding due to agecannot be excluded as an explanation. The screeningstudy by Lederle et al. (80) reported odds ratios of1.4-2.4 for White race compared with Black race afteradjustment for multiple variables.

Etiologic implications of descriptive epidemiology

Descriptive studies using differing methodologieshave revealed some important themes that must beconsidered in assessing the etiology of abdominalaneurysm.

Age effects. The incidence of abdominal aneurysmincreases with age. With regard to extrinsic risk factorsfor abdominal aneurysm, the sharp increase with agemight indicate some combination of the following cir-cumstances: 1) the exposure to the risk factor must beprolonged, 2) there is a long latency period betweenrisk factor exposure and aneurysm development, and3) the aorta becomes more susceptible to risk factorswith advancing age.

Sex differences. Men are at higher risk for abdom-inal aneurysm than women. The reasons for this arenot clear. Hormonal factors, genetic susceptibility,increased exposure to important risk factors, or a com-bination of these variables may play a role amongmen.

Temporal trends. In many populations, the preva-lence of abdominal aneurysm appears to be rising. Thistrend contrasts with declining rates of clinical mani-festations of atherosclerosis, such as coronary heartdisease and stroke, and appears to indicate differencesin etiologic factors (71, 84-86). However, these con-trasting temporal trends may also indicate a longerlatency between risk factor exposure and diseasedevelopment for abdominal aneurysm.

Racial differences. Although racial differences inthe occurrence of abdominal aneurysm have not beenextensively studied, it appears that in the United Statesabdominal aneurysms are substantially more commonamong White men than among Black men. Differencesbetween White women and Black women are small.Much of this difference among men could be due todifferential detection resulting from enhanced accessto clinical care in the White population. Possible etio-logic explanations include differential genetic suscep-tibility between men and women and increased expo-sure to important risk factors among White men. Theincidence of common clinical manifestations of ather-osclerosis (such as coronary heart disease) does notshow such striking differences between Black men andWhite men in the United States (84, 87); thus, from anetiologic perspective, the difference is inconsistent


214 Blanchard

with the theory that abdominal aneurysms are a mani-festation of atherosclerosis.

RISK FACTOR STUDIES

Until recently, there were very few analytic studiesdirected toward identifying risk factors for abdominalaneurysm. So far, most studies have focused only onatherosclerotic risk factors (see table 1).

Cigarette smoking

Tobacco smoking is one of the most commonly citedrisk factors for abdominal aneurysm. It has beenassessed in several analytic epidemiologic studies ofvarying designs (table 1). Five prospective studieshave demonstrated a strong association betweentobacco smoking and aortic aneurysm, with relative

risks ranging from 2.6 to 9.0 for various levels of reg-ular smoking (88-92). In three studies, a significantdose response was demonstrated (88-90), while theother two studies only reported on one measure oftobacco exposure (91, 92).

There were potentially important methodologicalproblems in all of these prospective studies. Three ofthe studies included thoracic aortic aneurysms, whichmay have different risk factors than abdominalaneurysms (88-90). All of the studies relied primarilyon passive methods of case detection, rendering themsusceptible to detection bias. Four of the studies reliedon death certification (88-91), and only one of theseverified the death certificate diagnosis (88). Theprospective study by Reed et al. (92) relied primarilyon review of hospital and clinical records; thus, forthe most part, only clinically apparent abdominalaneurysms were included. Adjustment for risk factors

TABLE 1. Results of analytic epidemiologic studies measuring the associations between abdominal aortic aneurysm (AAA) andcigarette smoking, hypertension, lipid/lipoprotein levels, and diabetes mellitus

Author(s) andlocation of study

(ref. no.)

Reed et al., United States (92)

Hammond and Garfinkel, UnitedStates (89)

Strachan, United Kingdom (91)

Doll and Peto, United Kingdom(90)

Kahn, United States (88)

Collin et al., United Kingdom (77)

Pleumeekers et al., TheNetherlands (76)

Alcorn et al., United States (57)

Lederie et al., United States (80)

LaMorte et al., United States(82)

Cole et al., Canada (93)

Norrgard et al., Sweden (100)

Casedefinition and

detection Cigarettesmoking

Prospective studiet

Clinical (82%) and autopsy (18%)AAAs

Death certificate (all aorticaneurysms)

Death certificate (AAA)

Death certificate (nonsyphiliticaortic aneurysms)

Death certificate (nonsyphiliticaortic aneurysms)

Positive

Positive

Positive

Positive

Positive

Statistical association with abdominal aortic aneurysm

Hypertension

Positive (systolic BP*,not diastolic BP)

NA*

Positive (diastolic BP,not systolic BP)

NA

NA

Cross-sectional (screening) studies

Ultrasound; diameter 24.0 cmor suprarenal:infrarenaldifference 20.5 cm

Ultrasound; diameter 23.5 cm orsuprarenakinfrarenal ratio 21.5

Ultrasound; diameter 23.0 cm orsuprarenahinfrarenal ratio 21.2

Ultrasound; diameter 23.0 cm orsuprarenal:infrarenal ratio 21.5

Retrospective

Surgical AAA cases

Hospital-based AAA cases

Surgical AAA cases

NA

Positive

Positive

Positive

None(clinical diagnosis)

None

Positive(clinical hypertension)


(case-control) studies

Positive

Positive

NA



NA

Lipid/lipoproteinlevels

Positive(total cholesterol)

NA

None

NA

NA

NA

Positive (total cho-lesterol, not HDL*

cholesterol)

Positive (HDLcholesterol, nottotal cholesterol)

Positive(self-report)

NA

Positive (HDLcholesterol)

Positive(VLDL* + LDL°

cholesterol,HDL cholesterol)

Diabetesmellitus

None(blood glucose)

NA

None(blood glucose)

NA

NA

NA

None(clinical diagnosis)

None(blood glucose)

Inverse(self-report)

Inverse(clinical diagnosis)

NA

NA

' BP, blood pressure; NA, data not available; HDL, high density lipoprotein; VLDL, very low density lipoprotein; LDL, low density lipoprotein.



other than age was performed in only two of the stud-ies (91, 92).

Cross-sectional ultrasound screening surveys andcase-control studies have also demonstrated an associ-ation between cigarette smoking and abdominalaneurysm (57, 76, 78-80, 82, 93). The reported expo-sure measurement in each of these studies was eithercurrent smoking or past smoking history, without fur-ther exploration of a dose response. Odds ratio esti-mates from the cross-sectional studies have generallybeen lower than those reported from prospective orcase-control studies. This may be partly explained bythe fact that studies based on screening surveys are lessprone to detection bias. Another reason for these dif-ferences may be the use of a more sensitive and lessspecific case definition for abdominal aneurysm inscreening studies. In support of this notion, two of thescreening studies found stronger associations whenmore stringent case definitions were used (78, 80).

Family history

Familial aggregation of abdominal aneurysm hasbeen demonstrated in several studies using variousdesigns (94-99). In a large case-control study byDarling et al. (94), 15 percent of abdominal aneurysmpatients reported an abdominal aneurysm in at leastone first degree relative as compared with 1.8 percentof controls (odds ratio = 9.7). A similar study byJohansen and Koepsell (95) reported that 19 percent ofthe cases had at least one first degree relative with anabdominal aneurysm in comparison with only 2.4 per-cent of controls (odds ratio = 11.6).

Other studies have estimated the prevalence ofabdominal aneurysm among family members ofabdominal aneurysm patients without comparison withan explicit control group. In these studies, 11-20 per-cent of cases were found to have at least one firstdegree relative with an abdominal aneurysm. Some ofthese studies relied solely on the report of the indexcase (96, 97). A potential bias inherent in this approachis the influence a positive family history of abdominalaneurysm may have on the clinical detection of anabdominal aneurysm in other family members.Another potential source of bias in these studies is dif-ferential recall, with the diagnosis of an abdominalaneurysm leading to enhanced knowledge or recall ofone's family history.

Other studies have been based on ultrasound screen-ing of family members (98, 99). Although this willreduce detection bias, interpretation of these results iscomplicated by a lack of information on whether therewas familial clustering of other risk factors, notablysmoking. For example, in a screening study byWebster et al. (99), all of the family members who

were discovered to have an abdominal aneurysm weresmokers. Similarly, in a study by Fitzgerald et al. (98),73 percent of the newly discovered familial cases werein smokers.

Increased blood pressure

Increased blood pressure is a commonly cited riskfactor for abdominal aneurysm. However, the resultsof analytic studies which have assessed the associationbetween increased blood pressure and abdominalaneurysm have been mixed (57, 76-80, 82, 91-93).The results of prospective and case-control studieshave generally indicated that increased blood pressureis associated with abdominal aneurysm (82, 91-93).However, screening studies, which are less prone todetection bias, have generally not found this associa-tion (76,77) or have found a weak association (57, 80).

Two prospective studies found an increase in the riskof abdominal aneurysm with increasing blood pressure(91, 92). Reed et al. (92) reported that increasing sys-tolic blood pressure at baseline was associated with anincreased risk of subsequent clinically diagnosedabdominal aneurysm. The relative risk for persons inthe fourth quartile of systolic blood pressure (>145mmHg) was 2.0 in comparison with persons with sys-tolic blood pressures less than 119 mmHg at baseline.Results of the Whitehall Study, reported by Strachan(91), showed that each 10-mmHg increase in diastolicblood pressure at baseline was associated with a rela-tive risk of 1.5 for subsequent mortality due to abdom-inal aneurysm. As was discussed above, the wide-spread medical opinion that hypertension is a riskfactor for abdominal aneurysm may have influencedthese results through detection bias. Furthermore,since increased blood pressure has been reported toincrease the expansion rate and risk of rupture, someof the observed increase in risk may be a measure ofinfluence on the development of complications relatedto abdominal aneurysm (i.e., rupture or acute expan-sion) rather than on the actual incidence of abdominalaneurysm (51).

Two case-control studies have also assessed theassociation between elevated blood pressure andabdominal aneurysm (82, 93). A hospital-based studyby LaMorte et al. (82) compared histories of hyperten-sion, as documented in the hospital charts, between102 patients who underwent surgical repair of anabdominal aneurysm and controls who had an appen-dectomy at the same two hospitals. They found anodds ratio of 3.6 for clinically diagnosed hypertension,after adjustment for age, sex, smoking, and race.Cole et al. (93) compared hospital-based abdominalaneurysm cases with a hospital control group com-prised of persons with conditions other than cardiovas-


216 Blanchard

cular disease, diabetes, or cancer. They found that theprevalence of hypertension (defined as blood pressure>140/90 or current treatment for elevated blood pres-sure) was 47 percent among abdominal aneurysmcases and 27 percent among controls.

Results from screening studies in which detectionbias has been reduced have not consistently demon-strated an increased prevalence of elevated blood pres-sure among persons with abdominal aneurysm (76, 77,79). A screening study by Pleumeekers et al. (76) foundthat the age-adjusted prevalence of hypertension,defined as systolic blood pressure >160 mrnHg or dia-stolic blood pressure >95 mmHg or current antihyper-tensive treatment, was higher among abdominalaneurysm patients than among those without abdominalaneurysm (29 percent vs. 27 percent among men; 42percent vs. 33 percent among women). However, thesedifferences were not statistically significant. Resultsfrom the Oxford Screening Programme of men aged65-74 years, reported by Collin et al. (77), also failed toshow an increased incidence of hypertension (diastolicblood pressure >105 mmHg or current use of antihy-pertensive medication) among those with an abdominalaneurysm. Two screening studies have indicated anassociation between hypertension and abdominalaneurysm. Alcorn et al. (57) found that current treat-ment of hypertension was associated with a slightlyincreased prevalence of abdominal aneurysm (10.4 per-cent vs. 8.7 percent; p = 0.042). However, they foundno association between average levels of systolic ordiastolic blood pressure and abdominal aneurysm.Lederle et al. (80) also found that hypertension wasassociated with a small but statistically significant asso-ciation between a self-reported history of hypertensionand abdominal aneurysm (adjusted odds ratios were1.14—1.25 for various aneurysm case definitions).

Serum lipids and lipoproteins

Several studies have examined the relation betweenserum levels of lipids and lipoproteins and abdominalaneurysm (57, 76, 80, 91-93, 100). Two prospectivestudies have produced conflicting results (91, 92).Reed et al. (92) found that the incidence of clinicallydiagnosed abdominal aneurysm increased withincreasing baseline serum levels of cholesterol but notwith levels of triglycerides. Overall, the relative riskwas 2.3 when persons in the fourth quartile of serumcholesterol level (>240 mg/dl) were compared withthose in the first quartile (<193 mg/dl). In contrast, thestudy by Strachan (91) found no association betweenbaseline cholesterol level and risk of death due toabdominal aneurysm. In both of these studies, relativerisk estimates were adjusted for age, sex, blood pres-sure, and smoking.

In two case-control studies, investigators haveexamined the relation between abdominal aneurysmand serum levels of cholesterol and lipoproteins (93,100). Norrgard et al. (100) compared serum levels oftotal cholesterol, high density lipoprotein (HDL) cho-lesterol, very low density lipoprotein (VLDL) plus lowdensity lipoprotein (LDL) cholesterol, and triglyc-erides among 51 surgical abdominal aneurysm cases tolevels in a population-based control group. Personswith a history of cardiovascular, liver, or endocrinedisease were excluded from the control group.Significantly increased levels of triglycerides andVLDL + LDL cholesterol and significantly decreasedlevels of HDL cholesterol were found among men andwomen with abdominal aneurysm in comparison withcontrols (100). There was no significant difference inserum levels of total cholesterol. A study by Cole et al.(93) compared serum levels of HDL cholesterolamong 78 hospital-based abdominal aneurysm casesand controls appearing at the same hospital for condi-tions other than cardiovascular disease, diabetes, orcancer. They found that cases had significantlydecreased HDL cholesterol levels compared with con-trols. In both of these case-control studies, the exclu-sion of controls with diseases associated with alteredlevels of serum lipids and lipoproteins, but not caseswith such diseases, may have exacerbated selectionbiases and spuriously increased the associationbetween cholesterol and lipoprotein abnormalities andabdominal aneurysm.

Cross-sectional screening studies have also providedconflicting results. The study by Pleumeekers et al.(76) found a small but statistically significant increasein mean serum total cholesterol levels among men withabdominal aneurysm. An increase was also seenamong women with abdominal aneurysm, but it wasnot statistically significant. No differences in serumlevels of HDL cholesterol were reported between per-sons with and without abdominal aneurysm in eithermen or women. In contrast, the study by Alcorn et al.(57) found a significantly increased prevalence ofabdominal aneurysm among those with lower HDLcholesterol levels (<40 mg/dl). They also found thatpersons with LDL cholesterol levels greater than 160mg/dl had a slightly higher prevalence of abdominalaneurysm than those with lower levels. Lederle et al.(80) found statistically significant adjusted odds ratiosof 1.33-1.54 (depending on the case definition) forself-reported high cholesterol levels. However, theyreported that there were missing data on hypercholes-terolemia for many of the subjects. Furthermore, whenthey compared self-reports with clinical findings for asubset of the participants, they found that the accuracyof the self-reports was suboptimal.



Diabetes mellitus

The few previous analytic studies regarding diabetesmellitus and abdominal aneurysm suggest that there iseither no association or an inverse association. Twoprospective studies found no association between serumglucose levels and subsequent abdominal aneurysm (91,92). A case-control study in Massachusetts by LaMorteet al. (82) found that the prevalence of diabetes amongpersons who underwent surgery for abdominal aneu-rysm was slightly lower than that among patients whohad appendectomy and substantially lower than thatamong patients who had femoral bypass. Assessment ofthe presence of diabetes was based on chart reviews orcomputerized hospital records.

Screening studies have also shown a low prevalenceof diabetes among persons with abdominal aneurysm(57, 79). Smith et al. (79) found that persons with anabdominal aneurysm detected by a community screen-ing program had a lower prevalence of diabetes (5 per-cent) than persons without abdominal aneurysm (6percent). The Rotterdam Study also found a lowerprevalence of diabetes among persons with abdominalaneurysm (76). Alcorn et al. (57) found little differencein the prevalence of abdominal aneurysm by bloodglucose level. Lederle et al. (80) found a significantinverse association between diabetes and abdominalaneurysm after adjusting for multiple factors.

Other risk factors

Several other risk factors have been proposed forabdominal aneurysm (101-103). One study of 47abdominal aneurysm patients reported a higher fre-quency of a deficient phenotype of a-1-antitrypsinthan would be expected in the general population(103). Two studies have found a much higher preva-lence of inguinal hernia among men with abdominalaneurysm than among patients with aortic occlusivedisease, prompting the authors to suggest that theremay be an enhanced, generalized proteolytic processamong abdominal aneurysm patients (101, 102). Afew studies have examined the relation betweenabdominal aneurysm and trace metals such as copperand zinc; results have been inconsistent (24).Recently, case series described by Juvonen et al. (104)and Blasi et al. (105) have provided evidence thatChlamydia pneumoniae infection is common inabdominal aneurysm tissue. The study by Blasi et al.(105) also showed that a high proportion of abdominalaneurysm patients had serologic evidence of past C.pneumoniae infection. However, since neither of thesestudies included a non-abdominal aneurysm controlgroup, it is difficult to interpret the etiologic signifi-cance of their findings.

Etiologic implications of risk factor studies

Previous research into risk factors for abdominalaneurysm has provided some important clues regard-ing etiology, but many questions remain unanswered.

Cigarette smoking. The relation between smokingand abdominal aneurysm seems indisputable, since sev-eral analytic studies using a variety of methods havefound a strong epidemiologic association (57, 76,78-80, 82, 88-93). While the strength of the associationand the presence of a dose response suggest a causalrelation, etiologic mechanisms are unclear. It may bethat some of smoking's effect is mediated through ath-erosclerosis. However, since most persons with aorticatherosclerosis do not develop aneurysms, other mecha-nisms are probably also present. Enhanced elastolysis isone possibility. Cigarette smoking has been shown toperturb the protease/antiprotease imbalance, leading todegradation of elastic tissue in the lungs (106-108).Such a process may also affect the aorta.

Hypertension. On the basis of previous epidemio-logic studies, the relation between elevated blood pres-sure and abdominal aneurysm is not entirely clear.Because there is some evidence that beta blockers mayreduce the expansion rate of abdominal aneurysms(109, 110), these studies may have been partly con-founded by the use of antihypertensive agents inhypertensive subjects. If hypertension does play a rolein abdominal aneurysm formation, it may do sothrough an increase in the hemodynamic load on theaortic wall. In support of this, there is some evidencethat elevated blood pressure increases the expansionrate of existing abdominal aneurysms (51).

Lipids and lipoproteins. The relation betweenabdominal aneurysm and serum levels of lipids andlipoproteins is also unclear. In general, studies thathave found positive associations have relied on clini-cally detected cases. Three screening studies using dif-ferent methods with respect to case definition andexposure measurement have provided conflictingresults. To the extent that serum lipids and lipoproteinsare implicated in the causation of abdominalaneurysm, their effect may be mediated through theiratherogenic properties.

Diabetes mellitus. The few studies that have exam-ined the association between diabetes mellitus andabdominal aneurysm have demonstrated either no rela-tion or an inverse relation. This finding appears to con-flict with the atherosclerotic theory of abdominalaneurysm pathogenesis. It has been suggested that dia-betes causes a macroangiopathy that is separate fromits atherogenic effects and is characterized by a loss ofcompliance and calcification of the aorta (111-114).These changes may stabilize the aorta and render itsomewhat resistant to aneurysmal dilation.

Epidemiol Rev Vol.21, No. 2, 1999

218 Blanchard

Family history. The observation of a familial ten-dency for abdominal aneurysm suggests a role forgenetic factors in the etiology of abdominal aneurysm.However, the genetic basis of abdominal aneurysmremains unclear. Research directed toward identifica-tion of genetic defects in genes coding for matrix pro-teins, connective tissue proteases, and antiproteaseshas not yielded definitive results. Recently, someinvestigators have also proposed a role for geneticallydetermined autoimmune mechanisms in abdominalaneurysm pathogenesis (38, 40).

CONCLUSIONS

Despite its increasing public health importance,abdominal aneurysm remains an enigmatic disease.However, recent research has brought new insight intoits pathophysiology. Discoveries with respect toabdominal aneurysm risk factors and etiologic mecha-nisms could have important public health benefits.First, identification of modifiable risk factors providesan opportunity for primary prevention in high risk pop-ulations. Second, since abdominal aneurysm is a slowlyprogressive disease, understanding its pathophysiologyoffers the hope of therapeutic intervention that can alterthe natural history of disease and improve outcomes. Inthis regard, it will be important to distinguish risk fac-tors for dilation and rupture from those associated withthe initiation of abdominal aneurysm formation. Third,elucidation of factors that are associated with the risk ofdeveloping an abdominal aneurysm would facilitate theidentification of high risk individuals. This may offerthe hope of secondary prevention of abdominalaneurysm complications should the benefits of screen-ing be demonstrated in clinical trials.

The atherosclerotic theory of abdominal aneurysmcausation appears to be overly simplistic in light ofemerging evidence from epidemiologic and basicresearch studies. Still, more conclusive research isrequired to clarify the relation between atheroscleroticrisk factors and abdominal aneurysm. In particular, theassociations between hypertension and serum lipidsand lipoproteins and abdominal aneurysm requiremore investigation. The relation between diabetes mel-litus and abdominal aneurysm also merits furtherresearch. If the initial findings of an inverse relationare verified, new insight may be gained with respect toaortic biology and pathophysiology. Because of themethodological difficulties involved in studying abdom-inal aneurysm, the generation of more definitive find-ings in these areas might require the use of a largeprospective study which features active case detectionwith periodic radiologic imaging.

Analytic epidemiologic studies will also berequired in order to explore emerging etiologic

hypotheses. Genetic epidemiologic approaches shouldbe rigorously applied to better understand the geneticbasis of abdominal aneurysm. There have been manysmall clinical studies and case series exploring factorssuch as proteolytic and antiproteolytic activity,autoimmunity, and infection in relation to abdominalaneurysm. However, to begin to test these hypotheses,larger, well designed epidemiologic studies with bet-ter measurement and analysis of other risk factors willbe required.

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