Atherosclerosis in coronary arteries and aorta among Greenlanders:an autopsy study

Henning Sloth Pedersen a,*, Gert Mulvad a, William P. Newman, III b,Donald A. Boudreau b

a The Primary Health Care Clinic, P.O. Box 1001, DK-3900 Nuuk, Greenlandb Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA, USA

Received 21 December 2002; received in revised form 9 June 2003; accepted 13 June 2003

Atherosclerosis 170 (2003) 93�/103

www.elsevier.com/locate/atherosclerosis

Abstract

In a cross-sectional autopsy study of 107 Inuit in Greenland, the extent of arterial surface involvement with atherosclerosis was

evaluated in the presence of known or estimated environmental risk factors for coronary heart disease (CHD): age, gender, obesity,

serum lipids, smoking, and hypertension. Mean, median, and range values for all of the risk factor variables and for the extent of

atherosclerosis in the thoracic aorta, abdominal aorta, right coronary artery, and left anterior descending coronary artery are

reported by age strata, along with the results of covariant analysis of the dependence of the extent of atherosclerosis upon the risk

factors. No significant differences between females and males were found in either the risk factors or prevalence and extent of

atherosclerosis in the aorta and in the coronary arteries. It appears that the extent of advanced atherosclerotic lesions in

Greenlanders appears to be the same as that previously reported in a similar study in Alaska Natives.

# 2003 Elsevier Ireland Ltd. All rights reserved.

Keywords: Inuit; Greenland; Atherosclerosis; Risk factors; Coronary heart disease

1. Introduction

Low mortality from ischaemic heart disease (IHD)

has been reported among Inuit [1�/3]. The ratios

between age standardized mortality rates of IHD in

Greenland Inuit (1968�/1985) and Denmark (1980) was

0.5 (95% CI: 0.4�/0.6) for males and 0.9 (95% CI: 0.7�/

1.1) for females [2]. In Alaska, the corresponding ratios

for natives versus non-natives were 0.59 and 0.61 (1979�/

1988) [4]; however, more recent reports indicated that

the death rate of IHD among Alaska Eskimo may now

exceed that of non-native Alaskans [5]. Canadian Inuit

were also reported to have a substantially lower rate of

death from IHD than the rest of the population [6].

Caution has been recommended in the evaluation of

these findings since they are based upon reviews of death

certificates [7]; however, the underlying suggestion of

reduced risk of IHD mortality in these populations has

been intriguing.

Among the various possible explanations suggested

by investigators for low IHD mortality reported among

Inuit is that this population group had lower prevalence

and/or less extent of atherosclerotic lesions in the

coronary arteries. However, studies have suggested

that there is no difference in the degree of atherosclerosis

among Greenland natives and Danes, as interpreted by

ultrasonographic investigation of the carotid and fe-

moral arteries [8] and by X-ray examinations of the

lumbar spine to diagnose arteriosclerotic complications

of the abdominal aorta [9]. This is in accordance with a

recent study of cardiovascular risk factors in Inuit of

Greenland which showed the prevalence of heavy

smoking, obesity, blood pressure and total serum

cholesterol are similar in Greenland and Denmark,

although it was reported that the low density lipoprotein

cholesterol (LDL-C) and triglyceride concentrations

were lower in Greenlanders [10].

It is generally felt that for studies of diseases such as

IHD, autopsy results provide the only conclusive* Corresponding author. Tel.: �/299-344-424; fax: �/299-344-425.

E-mail address: hsp@greennet.gl (H.S. Pedersen).

0021-9150/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/S0021-9150(03)00240-5

evidence of outcome. However, only three autopsy

studies among Inuit have been reported: two of these

[11,12] were inconclusive, but suggested that athero-

sclerosis among Inuit in Alaska was not uncommon; thethird was a systematic evaluation of the prevalence and

extent of atherosclerotic lesions in the coronary arteries

and aorta in Alaska natives compared with Alaska non-

natives. Indeed, findings in the latter were that of a

substantially lower extent of raised lesions in the native

population [13,14]. The purpose of this report is to

describe the findings of an autopsy study in the Green-

landic population in regard to environmental IHD riskfactors and the extent of atherosclerosis in the aorta and

coronary arteries.

2. Materials and methods

During the period of the study (1990�/1994) the

population of Greenland natives, (‘‘Greenlanders’’),

was approximately 55 000, of which most (82%) livedin Greenland and the rest mainly in Denmark. As in

other epidemiological studies, a Greenlander was de-

fined as a person born in Greenland. Over the years,

some genetic admixture with Caucasians has taken

place; however, until 1960, the non-Greenlander popu-

lation was less than 5%, increasing to a level of 18% in

the 1980s, and then declining to 12% in 1996 [15]. The

Greenlanders today constitute the largest geographicalconcentration of a total of 167 000 Circumpolar Inuit.

The study cases included Greenlanders ]/18 years of

age and were obtained primarily from the capital city,

Nuuk, and from Ilulissat, a small community northwest

of Nuuk. Since the central Greenlandic hospital is in

Nuuk, some cases from other areas of the country were

also included. During the data collection period (Nuuk:

1990�/1994; Ilulissat: 1991�/1994), a total of 342 deathsoccurred in the study areas, for which 107 autopsies

(31%) were performed and included in the study. This

sample constitutes 26.4% of the total deaths in Green-

land among adult Inuit during the study period. As

there were no trained pathologists in Greenland, two

clinicians in Nuuk and one in Ilulissat received special

training in standardized autopsy and specimen collec-

tion procedures at Gentofte Hospital in Denmark andLouisiana State University Health Science Center

(LSUHSC), New Orleans, LA, USA. To minimize

selection bias, cases were excluded only because: (a)

relatives refused or were unable to be contacted; (b) a

prosector was not available; or (c) contagion risk was

high.

Height, from the vertex of the cranium to the base of

the heel, and weight were both determined prior toautopsy. Body mass index (BMI) was calculated as the

weight in kg divided by the square of the height in

meters. Blood was collected by syringe and needle from

the vena cava, heart, or aorta; separated by centrifuga-

tion into serum and cells; and frozen. The aorta and the

coronary arteries were systematically collected accord-

ing to protocol. The aorta, removed 2 cm proximal tothe ligamentum arteriosum and 2 cm distal to the iliac

bifurcation, was opened longitudinally on the dorsal

surface midway between the openings of the intercostal

and lumbar arteries. The opened aorta was flattened

with the adventitial surface down and bisected along a

line on the ventral surface midway between the celiac,

superior mesenteric, and inferior mesenteric ostia. The

right half was frozen for chemical analyses and the lefthalf fixed in buffered neutral formalin for shipping and

subsequent staining. The coronary arteries were opened

longitudinally and fixed in the same manner as the aorta

(all segments remained in formalin for periods of days

until shipping). The right coronary artery was removed

from its point of origin in the right anterior sinus of

Valsalva to the point where it passed down the posterior

interventricular sulcus. The left anterior coronary arterywas removed from the origin at the left main coronary at

its bifurcation downward along the anterior interven-

tricular sulcus to the apex. The arteries were shipped to

the Department of Pathology, LSUHSC, where they

were stained with Sudan IV and sealed in flat, poly-

propylene pouch bags with 10% buffered formalin.

Specimens, identified only by code numbers, were

processed in batches containing specimens from otherpopulations so that graders had no knowledge of age,

sex, cause of death, or ethnic group. For lesion grading,

the aorta was divided in two sections: the thoracic

section, from a horizontal line through the first paired

intercostals to a horizontal line through the upper edge

of the orifice of the celiac artery; and the abdominal

section, extending from the same line through the upper

edge of the celiac orifice, to a horizontal line drawnthrough the vertex of the iliac bifurcation.

Visual grading of the lesions was done independently

by three pathologists at LSUHSC, specially trained in

using methods developed for the International Athero-

sclerosis Project [16]. Lesions were evaluated by visual

inspection and palpation of the specimens in the sealed

pouch bags [17]. The thoracic aorta and the abdominal

aorta segments were graded separately. Recorded foreach segment was the estimated total percentage of the

intimal surface involved with all types of atherosclerotic

lesions and the proportion contributed by each of the

four types of grossly distinguishable lesions: flat or

slightly elevated intimal lesions that stained distinctly

with Sudan IV were designated as fatty streaks; fibrous

plaques were firm, elevated, pale gray, glistening intimal

lesions that sometimes had sudanophilic deposits super-imposed on their intimal surfaces; complicated lesions

were those in which there was grossly visible hemor-

rhage, ulceration, or thrombus, with or without calcium

deposits; and calcified lesions were areas in which

H.S. Pedersen et al. / Atherosclerosis 170 (2003) 93�/10394

calcium was detectable either visually or by palpation,

without the above attributes of a complicated lesion.

The term raised lesion was defined to be the sum of the

extent of fibrous plaques, complicated lesions andcalcified lesions in a given arterial segment.

Total serum cholesterol levels were determined using

the cholesterol-oxidase method (Gilford Systems Ciba-

Corning, Oberlin, OH) and the Gilford SBA 300

spectrophotometer. The high density lipoprotein cho-

lesterol (HDL-C) concentration was determined after

precipitation of serum by heparin MnCl2 (Bio-Rad ECS

Division, Anaheim, CA). The cholesterol assay wasstandardized with reference material obtained from the

College of American Pathologists, Northfield, IL. Con-

centration of the very low density lipoprotein�/low

density lipoprotein cholesterol (VLDL�/LDL-C) was

calculated as the difference between total serum choles-

terol and HDL-C. Thiocyanate, a marker for smoking,

was analyzed using a method [18] adapted for the

Gilford SBA 300 that allowed detection of athiocyanate�/ferric nitrate complex by measuring the

amount of color produced when that complex is formed.

A threshold thiocyanate level of 90 mmol/l for classifying

a subject as a smoker was established using unpublished

observations collected during one of the studies by the

PDAY research group [19]. It should be noted that the

threshold was established in a US population study and,

therefore, may not be precisely applicable in othergroups.

Kidney samples were saved in 10% buffered formalin

and processed for examination by light microscopy.

Under the 10�/ objective, the outer diameters of the

media of the cortical renal arteries were measured.

Those with outer diameters of 80�/300 mm were eval-

uated. The thicknesses of the arteries’ intima were

measured under the 40�/ objective. These measure-ments were combined to calculate the renal measure-

ment of hypertension (RMI). The RMI is defined as

being equivalent to intima thickness/outer media dia-

meter. Using age and the RMI in a published equation,

an algorithm has been established that estimates mean

blood pressure (MBP: systolic blood pressure�/2�/

diastolic blood pressure, all divided by 3). MBP less

than 110 mmHg is considered normotensive and MBPequal to or greater than 110 mmHg is considered

hypertensive [20].

Statistical analyses, using SAS version 8.2 (SAS

Institute, Inc., Cary, NC), included general descriptive

statistics, the chi-square or Fisher’s exact test for

distribution comparisons, Student’s t-test for gender

differences, and the general linear models (GLM)

procedure for covariance. To minimize the error ofpossible false positives in grading minimal lesion pre-

sence, lesion prevalence estimates were based on cases

with 5% or more of extent of arterial surface involve-

ment [19]. Where appropriate to better approximate

normal distributions, the lesion data were log-trans-

formed after addition of 0.01 to each data point to avoid

zeros. It is recognized that pre- and post-mortem events,

especially in hospitalized patients, may affect serumanalytes; therefore, to minimize bias due to possible

hemodilution effects upon analyte concentrations, the

blood analytes (lipids and thiocyanate) in seven cases

(two female; five male) for which the value of total

serum cholesterol was less than 100 mg/dl were excluded

from analyses [21].

3. Results

Of the original 107 autopsy cases, 102 were available

for analyses after five were excluded: two because of

severity of burns that affected the organs of interest; two

because the bodies were found more that 3 months after

death; and one in which cardiac surgery prevented the

use of the arteries. The autopsies were all performed nolater than 48 h after death, and all the bodies except one

were without putrefication; in one case we observed

putrefication caused by the bacteria Clostridium perfrin-

gens . Also, in two cases the right coronary artery, and in

one case the left anterior descending artery, were lost in

storage, handling, or transport. Cases were classified

into one of three broad categories of cause-of-death:

coronary heart disease (CHD); CHD-related (knownhypertension, diabetes, and/or chronic renal disease); or

basal (non-CHD, non-CHD-related) and Table 1 shows

the distribution of cases among these categories. Among

the 61 males 20 had a violent death (nine accidents, eight

suicides, three homicides) and among the 46 females ten

had a violent death (two accidents, one suicide and

seven homicides). As reported in many of the past

studies and cited in the references, atherosclerotic lesionsmay begin in early youth as fatty streaks that potentially

progress to raised lesions in early adulthood, and may

then become complicated lesions in later years. Usually,

by age 60, the factors of influence in the earlier years of

life have set the stage for subsequent arterial pathology

during the remaining years. While it would be desirable

to stratify the data in this study by decade, the lack of a

sufficiently large number of cases prohibits doing this.Therefore, to best illustrate the progression of athero-

sclerosis in the Greenlanders, the cases were partitioned

into intervals of early youth (age B/24 years), early

adulthood (25�/34 years), mid-life (35�/59 years), and

late life (60�/89). Basal cases represent the category for

which there is the least potential for autopsy selection

bias due to prevalence of CHD, a concern whenever

selection includes hospitalized patients [22,23]. As canbe seen, most (72%) of the cases are basal and there was

no significant difference in the distribution of cause-of-

death by gender. An issue of concern, discussed later, is

H.S. Pedersen et al. / Atherosclerosis 170 (2003) 93�/103 95

that 56% (57/102) of the study cases were of age]/60

years.

Summary descriptive statistics for all cases and also

stratified by sex, are shown in Table 2a for age, blood

analytes (total cholesterol, LDL�/VLDL-C, HDL-C,

thiocyanate), BMI, and estimated MBP. None of the

variables were found to differ significantly between

females and males. Of note are the mean and median

values for the serum lipids which are relatively high in

comparison to the currently recommended guidelines

[24]. In Table 2b, the distribution of risk factor variables

in the sample are described in terms of their respective

Table 1

Greenland autopsy study: number of cases by broad cause-of-death classification and age

Cause of death category Age (years)

B/24 25�/34 35�/59 60�/89 Totals

M F M F M F M F

CHD 0 0 0 0 0 0 1 5 6 (6%)

CHD related 0 0 0 0 2 3 10 8 23 (23%)

Basal (non-CHD; non-CHD-related) 4 0 4 3 18 11 18 15 73 (72%)

Totals 4 0 4 3 20 14 29 28 102

M, males; F, females.

Table 2

Greenland autopsy study

Variable N Mean S.E.M. Median Minimum Maximum P

(a ) Descriptive statistics for risk factors associated with atherosclerosis and CHD

Age (years) 102 59.38 1.77 63.00 19.00 89.00

F 45 61.27 2.49 64.00 25.00 85.00

M 57 57.89 2.48 60.00 19.00 89.00 0.3466

BMI (kg/m2) 102 23.74 0.48 23.10 13.30 37.50

F 45 23.41 0.82 22.40 13.30 37.00

M 57 24.01 0.58 23.70 16.00 37.50 0.5446

Est. MBP (mmHg) 87 106.67 1.15 107.23 80.92 126.14

F 37 107.68 1.74 106.09 86.05 122.47

M 50 105.92 1.54 107.56 80.92 126.14 0.4546

Thiocyanate (mmol/l) 78 67.94 3.62 62.75 22.50 164.00

F 38 69.74 4.89 66.25 27.00 153.50

M 40 67.19 5.37 61.25 22.50 164.00 0.8322

Total serum cholesterol

(mg/dl)

83 223.37 8.30 217.00 100.50 398.50

F 39 224.28 11.41 217.00 115.50 391.00

M 44 222.57 12.07 217.75 100.50 398.50 0.9186

HDL-C (mg/dl) 54 51.29 4.41 41.25 9.50 146.00

F 26 55.10 6.28 52.25 9.50 146.00

M 28 47.75 6.21 39.75 13.50 140.00 0.4099

LDL�/VLDL-C (mg/dl) 54 167.95 9.76 162.50 37.50 329.50

F 26 161.12 13.03 162.75 43.50 315.00

M 28 174.30 14.55 162.50 37.50 329.50 0.5048

Risk factors All cases Females Males P

(b ) Comparison of CHD risk factors by gender

Obesity (BMI]/30) 13.7% (14/102) 20.0% (9/45) 8.8% (5/57) 0.1472

Smoking (thiocyanate]/90

g/l)

16.9% (14/83) 15.4% (6/39) 18.2% (8/44) 1.0000

High LDL�/VLDL-C (]/

130 mg/dl)

68.5% (37/54) 69.2% (18/26) 67.9% (19/28) 1.0000

Low HDL-C (B/40 mg/dl) 48.2% (26/54) 46.2% (12/26) 50.0% (14/28) 0.7926

Hypertension (estimated

MBP]/110)

39.1% (34/87) 40.5% (15/37) 38.0% (19/50) 0.8277

MBP is estimated from renal artery morphology and thiocyanate is used as a marker for smoking. Probabilities are for no difference between

females (F) and males (M). Values are percentages (ratios) of gender groups for each variable; for some, data were not available for all cases.

H.S. Pedersen et al. / Atherosclerosis 170 (2003) 93�/10396

high risk categories. The high serum lipid levels seen in

Table 2a are manifest here in the form of large

proportions of the group (68.5% with high LDL�/

VLDL-C and with 48.2% low HDL-C) having high

risk as marked by these; however, the risk measure of

obesity appears to be low (20% in females; 8.8% in

males). The estimated proportion of smokers

(thiocyanate]/90 mg/l) is 15.4% for females and 18.2%

for males, while the prevalence of estimated hyperten-

sion is 40.5% in females and 38.0% in males.

Prevalence of atherosclerotic fatty streaks and raised

lesions, assessed as the percent of cases with 5% or more

arterial surface involvement, is shown in Table 3 for all

cases and for basal cases. Ideally, these data should be

stratified not only by gender but also by appropriate age

ranges; however, as can be seen in Table 1 there are very

few (n�/11) cases below age 35 years, therefore, strata

cell counts would be too low for meaningful compar-

isons. Indeed, the fact that slightly more than half of the

cases are 60 years or older suggests that age may well be

a contributing factor in the observation that, with the

single exception of the difference for fatty streaks in the

abdominal aorta for all cases (which vanishes for the

basal cases), there are no significant differences in

prevalence between females and males. In an attempt

to determine whether age is influencing the lack of an

expected gender difference, comparisons were per-

formed within the younger and older age groupings of

ageB/40 years (n�/17) and age]/40 years (n�/85), the

generally accepted age-threshold of increased risk for

CHD in males. In each case the same conclusion of no

prevalence difference was found. For these reasons, the

prevalence data are presented as shown in Table 3

without age stratification.

The extent of arterial surface involved with athero-

sclerotic lesions in the four arterial segments evaluated

in the study is described by the summary statistics in

Table 4a, where results are presented for all cases, for

males, and for females. As a group, the distributions of

lesion extent among the segments appear to follow a

pattern similar to that reported by autopsy studies in

Blacks and Whites in New Orleans [25] and in Alaska

natives and non-natives [14], with the greatest extent

found in the abdominal aorta, followed in descending

order by the thoracic aorta, left anterior descending

coronary artery, and right coronary artery. Although

females in Greenland do seem to have greater extent of

raised lesion involvement than males in both the

abdominal (60.6 vs. 46.6%) and thoracic (39.6 vs.

28.5%) aorta, this difference is not statistically signifi-

cant and does not appear to follow a consistent pattern

among the other segments for either fatty streaks or

raised lesions. Since there was not a clear gender

difference in the extent of atherosclerosis, the cases

Table 3

Greenland autopsy study: estimated prevalence of atherosclerosis in the aorta and coronary arteries*/all cases and basal cases

Variable Basal cases All cases

n % Positive P n % Positive P

Abdominal aorta, FS 73 78.1 102 72.5

F 29 62.1 45 64.4

M 44 88.6 0.0100 57 79.0 0.1214

Thoracic aorta, FS 73 91.8 102 92.2

F 29 96.6 45 93.3

M 44 88.6 0.3920 57 91.2 1.0000

Left anterior descending coronary artery, FS 72 36.1 101 32.7

F 28 32.1 44 27.3

M 44 38.6 0.6229 57 36.8 0.3932

Right coronary artery, FS 72 48.6 100 44.0

F 29 48.3 44 45.5

M 43 48.8 1.0000 56 42.9 0.8410

Abdominal aorta, RL 73 80.2 102 86.3

F 29 86.2 45 91.1

M 44 77.3 0.3828 57 82.5 0.2554

Thoracic aorta, RL 73 69.9 102 77.5

F 29 69.0 45 77.8

M 44 70.5 1.0000 57 77.2 1.0000

Left anterior descending coronary artery, RL 72 65.3 101 73.3

F 28 67.9 44 75.0

M 44 63.6 0.8023 57 71.9 0.8222

Right coronary artery, RL 72 66.7 100 71.0

F 29 65.5 44 72.7

M 43 67.4 1.0000 56 69.6 0.8528

Values are case totals and percent of cases that are positive for lesions (]/5% extent involvement). Probabilities are for no difference between

females (F) and males (M). FS, fatty streaks; RL, raised lesions.

H.S. Pedersen et al. / Atherosclerosis 170 (2003) 93�/103 97

Table 4

Greenland autopsy study

Variable n Mean S.E.M. Median Minimum Maximum P

(a ) Descriptive statistics for extent of aortic and coronary artery atherosclerosis in all cases

Abdominal

aorta, FS

102 14.70 1.45 10.20 0.00 68.40

F 45 15.22 2.47 8.80 0.00 68.40

M 57 14.29 1.74 11.00 1.50 63.30 0.3232

Thoracic

aorta, FS

102 14.67 1.00 10.70 1.60 50.20

F 45 14.70 1.25 12.70 1.60 39.30

M 57 14.64 1.51 10.40 1.60 50.20 0.4516

Left anterior

descending

coronary ar-

tery, FS

101 4.96 0.65 2.70 0.00 37.80

F 44 3.70 0.64 2.20 0.00 19.80

M 57 5.94 1.03 2.90 0.00 37.80 0.2271

Right cor-

onary ar-

tery, FS

100 6.78 0.86 3.90 0.00 41.80

F 44 6.48 1.16 3.65 0.00 30.80

M 56 7.01 1.24 4.05 0.00 41.80 0.7307

Abdominal

aorta, RL

102 52.76 3.37 63.95 0.00 97.70

F 45 60.55 5.26 76.80 0.00 97.70

M 57 46.62 4.24 50.30 0.00 96.10 0.1698

Thoracic

aorta, RL

102 33.39 2.75 31.55 0.00 96.10

F 45 39.63 4.40 37.50 0.00 96.10

M 57 28.46 3.37 22.60 0.00 96.10 0.3883

Left anterior

descending

coronary ar-

tery, RL

101 34.83 3.36 19.50 0.00 97.70

F 44 33.87 5.24 17.65 0.00 97.70

M 57 35.58 4.41 32.30 0.00 94.80 0.8860

Right cor-

onary ar-

tery, RL

100 34.54 3.36 31.55 0.00 97.70

F 44 35.29 5.23 25.55 0.00 97.70

M 56 33.96 4.41 31.55 0.00 97.70 0.8580

BMI Estimated MBP HDL-C (mg/dl) LDL�/VLDL-C (mg/dl) Estimated smoker

Age n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

n % yes

(b ) CHD quantitative risk factors and extent of atherosclerosis

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/10

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8

Table 4 (Continued )

Variable n Mean S.E.M. Median Minimum Maximum P

CHD quantitative risk factors

B/24 4 24.6 (0.7) 24.1

(23.6,26.7)

4 83.0 (1.0) 83.2

(80.9,84.8)

3 51.7 (6.4) 51.0

(41.0,63.0)

3 227.3 (3.6) 229.0

(220.5,232.-

5)

4 50.0

25�/34 7 23.3 (1.2) 22.6

(18.6,27.4)

6 90.4 (1.8) 89.2

(86.1,98.1)

3 38.7 (6.3) 44.5

(26.0,45.5) 3

3 163.3 (55.8) 126.5

(90.5,273.0)

5 40.0

35�/59 34 24.1 (0.7) 23.1

(16.5,35.8)

27 104.0 (1.3) 103.9 (92.1,

126.1)

19 62.5 (8.7) 59.0

(12.5,146.0)

19 166.1 (16.9) 163.0

(57.5,313.0)

28 25.0

60�/99 57 23.6 (0.7) 22.9

(13.3,37.5)

50 112.0 (1.1) 113.6

(94.5,123.3)

36 40.6 (4.9) 33.0

(2.0,140.0)

36 143.6 (12.8) 137.0

(31.5,329.5)

46 6.5

Abdominal aorta Thoracic aorta Left descending coronary artery Right coronary artery

Age n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

Atherosclerosis-fatty streaks

B/24 4 31.9 (13.4) 27.5

(9.3,63.3)

4 29.7 (5.1) 27.2

(20.3,44.3)

4 2.6 (1.5) 1.7 (0.0,7.0) 3 2.3 (2.3) 0.0 (0.0,6.8)

25�/34 7 30.4 (7.0) 31.7

(6.1,58.3)

7 14.0 (2.2) 12.0

(8.7,25.0)

7 1.2 (0.7) 0.3 (0.0,4.7) 7 0.5 (0.3) 0.0 (0.0,1.7)

35�/59 34 20.8 (2.8) 16.2

(2.0,68.4)

34 14.7 (1.9) 10.2

(2.7,44.3)

33 6.4 (1.3) 3.3

(0.0,29.8)

34 6.1 (1.4) 3.4

(0.0,41.8)

60�/99 57 8.0 (0.8) 6.8

(0.0,22.8)

57 13.7 (1.3) 10.7

(1.6,50.2)

57 4.8 (0.9) 2.2

(0.0,37.8)

56 8.3 (1.2) 5.7

(0.0,34.5)

Abdominal aorta Thoracic aorta Left descending coronary artery Right coronary artery

Age n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

n Mean

(S.E.M.)

Median

(Mn, Mx)

Atherosclerosis-raised lesions

B/24 4 0.0 (0.0) 0.0 (0.0,0.0) 4 0.4 (0.4) 0.0 (0.0,1.7) 4 0.9 (0.8) 0.2 (0.0,3.3) 3 0.8 (0.8) 0.0 (0.0,2.5)

25�/34 7 0.5 (0.5) 0.0 (0.0,3.5) 7 0.0 (0.0) 0.0 (0.0,0.0) 7 0.8 (0.5) 0.0 (0.0,3.3) 7 0.7 (0.5) 0.0 (0.0,3.3)

35�/59 34 32.2 (4.61) 22.4

(0.0,87.1)

34 13.7 (2.3) 8.7

(0.0,46.4)

33 22.6 (4.5) 8.5

(0.0,81.0)

34 20.0 (4.0) 12.1

(0.0,94.7)

60�/99 57 75.2 (2.5) 78.5

(22.2,97.7)

57 51.6 (2.9) 55.0

(8.2,96.1)

57 48.5 (4.5) 43.1

(0.0,97.7)

56 49.4 (4.5) 48.6

(0.0,97.7)

F, females; M, males. Lesions values are % total vessel surface involved; probabilities are for no differences between females and males. FS, fatty streaks; RL, raised lesions. Values, shown by age

level, are mean (S.E.M.) and median (minimum, maximum). Values for atherosclerotic lesion extent are percent of total surface area involved.

H.S

.P

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9

were pooled and analyzed by age levels ageB/24, 25�/34,

35�/59 and �/60 years. The age-stratified results are

shown in Table 4b for both environmental risk factor

variables and lesion extent. For the risk factors, no

apparent change with age is seen for the BMI or the

HDL-C, while the mean and median estimated MBP

appears to increase (83.0�/112.0 and 83.2�/113.6 mmHg,

respectively) and that of the LDL�/VLDL-C (227.3�/

143.6 and 229.0�/137.0 mg/dl, respectively) appears to

decrease. Both mean and median of the extent of

atherosclerotic lesions are seen to increase as age

increases, with the exception of fatty streaks in the

aorta. The estimated smoking risk (serum thiocyanate]/

90 mg/l) is seen to decrease by age level, possibly

suggesting that smoking may be increasing in younger

Greenlanders as compared with their elders; however,

this may instead be due to sampling bias as a result of

higher mortality among smokers.Table 5 presents a summary, by sex, of the analysis of

dependence of the extent of the atherosclerotic lesions in

the aorta and coronary arteries upon the risk factor

covariants of age (years), smoking (thiocyanate�/90 mg/

l), estimated hypertension (MBP�/110), high LDL�/

VLDL-C (]/130 mg/dl), low HDL-C (B/40 mg/dl),

and obesity (BMI]/30). Lesion values were log-trans-

formed and, to minimize potential sampling bias, only

the basal cases were included in this analysis. The model

results are the probabilities of random influence for each

variable after adjusting for the co-variables. No sig-

nificant interactions were found among the independent

variables. There is no obvious indication of a strong

dependent association of lesions upon risk factors, with

the exception of raised lesions upon age. In males, age is

clearly an influential variable for raised lesions in all

segments (P B/0.001), but less so for females, where the

only instance of raised lesion dependence upon age is inthe thoracic aorta (P�/0.0453). The only other risk

factor variables upon which significant lesion depen-

dence was found were in females where smoking (P�/

0.0310), low HDL-C (P�/0.0381), and obesity (P�/

0.0436) showed significant influence upon fatty streaks

in the abdominal aorta.

4. Discussion

The sample cases in this study were comprised

primarily of subjects from the capital city, Nuuk, and

from a rural community, Ilulissat. The hospital in Nuukis the central hospital for all of Greenland, so some cases

from other areas of the country were also included. For

the period of data collection, 1990�/1994, the study

sample represents 26.4% of all adult deaths in Greenland

and is, therefore, a reasonable sampling of the rural

versus urban population distribution, as well as a

substantial sampling of all deaths in the country. As

this was an autopsy study of atherosclerosis, the majorunderlying cause of CHD, it was necessary to determine

whether there was any substantial selection bias due to

CHD deaths alone. Since 72% of the cases were basal

(i.e. cause-of-death was non-CHD or non-CHD re-

lated), this would seem to provide a margin of safety

in this regard. Because of the small sample size due to

the difficulties and resource demands associated with

Table 5

Greenland autopsy study*/basal cases (n�/73): covariant analysis of the dependence of the extent of atherosclerosis in the aorta and coronary

arteries upon risk factors

Risk factors Aorta Coronary arteries

Abdominal Thoracic Left anteriror descending Right

FS RL FS RL FS RL FS RL

Females (n�/ 29)

Age (years) 0.7139 0.8612 0.3833 0.0453 0.8696 0.4377 0.7013 0.1438

Smoking (thiocyanate]/90 mg/l) 0.0310 0.6384 0.7713 0.3720 0.6443 0.4227 0.7157 0.8929

Hypertension (MBP]/110) 0.0965 0.4961 0.6738 0.9978 0.5038 0.1781 0.5598 0.8881

High LDL�/VLDL-C (]/130 mg/dl) 0.3731 0.5773 0.8220 0.0852 0.4313 0.6833 0.5527 0.3162

Low HDL-C (B/40 mg/dl) 0.0381 0.0708 0.5954 0.5849 0.9205 0.5523 0.4937 0.7342

Obesity (BMI]/30) 0.0436 0.8531 0.3009 0.1441 0.5675 0.6196 0.6190 0.2490

Males (n�/44)

Age (years) 0.2117 B/0.0001 0.0920 B/0.0001 0.2626 B/0.0001 0.0962 0.0007

Smoking (Thiocyanate]/90 mg/l) 0.4207 0.4938 0.7270 0.9516 0.6963 0.6289 0.7756 0.3901

Hypertension (MBP]/110) 0.7388 0.5483 0.7808 0.3436 0.2537 0.1852 0.2056 0.1881

High LDL�/VLDL-C (]/130 mg/dl) 0.6974 0.6178 0.6437 0.7267 0.2146 0.4371 0.2626 0.6762

Low HDL-C (B/40 mg/dl) 0.7031 0.7064 0.8644 0.2790 0.1492 0.2910 0.3813 0.5799

Obesity (BMI]/30) 0.9702 0.5533 0.2135 0.5604 0.4089 0.7294 0.4336 0.6047

Table values are probabilities of random influence after adjusting for covariates; significant associations are in bold font. FS, fatty streaks; RL,

raised lesions.

H.S. Pedersen et al. / Atherosclerosis 170 (2003) 93�/103100

collecting autopsy specimens, data from all available

cases were included in as many of the analyses as

possible, as indicated in table headers. Also, there is

always a concern when analyzing blood that wascollected post mortem, especially in the case of subjects

who expired while hospitalized, and as described earlier,

blood analyte data from seven cases in which hemodilu-

tion was suspected were excluded.

Greenlanders appear to have a high prevalence of

some of the CHD risk factors. The mean and median

values for the serum lipids (Table 2a) are relatively high

in comparison to the currently recommended guidelines[24]. Indeed, more than half (69.2% females; 67.9%

males) have high LDL�/VLDL-C and almost half

(46.2% females; 50.0% males) have low HDL-C as

seen in Table 2b. It may be argued that the attempt to

limit hemodilution bias by excluding low values of blood

analytes from calculations may have resulted in a

reverse-bias. However, a review of the calculations

without exclusions indicated otherwise: all of theexcluded HDL-C values except one (46 mg/dl for one

male) were less than the cut-point for CHD risk (B/40

mg/dl) and when all data were included, the re-calcu-

lated values for High LDL�/VLDL-C were found to be

Females: 64.3%, males: 57.6%; and females: 46.4%,

males: 57.63% for low HDL-C, neither being of

significant difference by gender. For hypertension, the

figures (40.5% females; 38.0% males) are likewise high incomparison to the reported 15.7�/29.8% in other popu-

lations world-wide [26,27]. On the other hand, the

prevalence of obesity (20.0% females; 8.8% males)

appears to be comparable to, or perhaps a bit lower

than that reported in Europe and North America [28].

Lastly, the estimated prevalence of smoking (15.4%

females; 18.2% males), compares favorably with that

reported for ‘‘heavy smokers’’ (14.5% females; 31.0%males) in an epidemiological study conducted in Green-

land during the same time period [10], but appears to be

low compared with the reported 30% or more for

northern Europe [29]. Since the thiocyanate levels in

the excluded cases (34.5�/83.0 mg/l) were all below the

smoking estimator cut-point of ]/90 mg/l, they could

not be implicated here. However, as also noted pre-

viously, the estimator cut-point for thiocyanate as amarker for smoking was established in a different

population with different dietary habits and may,

therefore, be an imprecise measure in this population

group. Furthermore, there is also the possibility that

some of the cases were patients that expired in the

course of lengthy hospitalization during which cessation

of smoking was required, leading to possible false

negative results of classification; however, the longhalf-life of serum thiocyanate [30] should reduce this

risk.

Prevalence of raised lesions, indicating advanced

atherosclerosis, ranges from 69.9 to 80.2% in the aorta

and 65.3�/66.7% in the coronary arteries of the Green-

landers in this study (Table 3). The one observed

significant difference in prevalence between females

and males, seen in the fatty streaks of the abdominalaorta, does not seem to argue strongly for a difference in

prevalence of atherosclerosis by gender, and all differ-

ences vanish for the basal cases. The absence of a gender

difference in prevalence is consistent with the observed

absence of any significant gender differences for the risk

factors in this study sample. Of course, the dispropor-

tionate number of older cases cannot be completely

dismissed as a possible biasing influence upon theseobservations, despite the fact that gender comparisons

within younger and older age-groupings (age B/40 and

]/40 years), as previously noted, also showed no

statistically significant differences.

In all four arterial segments in this study, the

minimum and maximum extent of atherosclerosis ran-

ged from 0 to 3.3% for cases in the 15�/24 years age

range and 0�/97% in the �/60 years age range for themore advanced raised lesions. Although the upper level

of the range for raised lesions increased with age, only in

the aorta did the minima rise above zero, beginning with

the cases above age 34 years, following the expected

pattern of lesion progression reported in other autopsy

studies. Also, only in the aorta was there found any

gender difference in atherosclerosis, with females having

a greater mean extent of raised lesions than males;however, this was not statistically significant. In the

abdominal aorta, females had 60.6% mean surface

involvement with raised lesions versus 46.6% in males,

and in the thoracic aorta, the difference was 39.6 versus

28.5%. This may be associated with the greater pre-

valence of obesity found in females.

Analysis of the association of aortic and coronary

atherosclerotic lesions with generally known risk factorsis summarized in Table 4b, Table 5. In Table 4b, as has

been reported in autopsy studies of other population

groups, the extent of the clinically significant raised

lesions in both the aorta and the coronary arteries

increases with age. On the other hand, fatty streaks seem

to increase with age in the right coronary artery and left

anterior descending coronary artery, but not in the

aorta. This may be a consequence of raised lesionprogression in lesion-prone areas initially occupied by

fatty streaks. In Table 5, there is the first suggestion of

significant gender differences. Males show a statistically

significant (P B/0.001) dependence of raised lesions

upon age in all segments, whereas only for raised lesions

in the thoracic aorta does age rise to significance as a

contributing factor for females. In females, smoking

(P�/0.0310), obesity (P�/0.0436), and low HDL-C(P�/0.0381) show strong influence on fatty streaks in

the abdominal aorta, but this is not seen in males. The

latter two may reflect the gender differences in pre-

valence seen in Table 2b for obesity (20.0% in females

H.S. Pedersen et al. / Atherosclerosis 170 (2003) 93�/103 101

vs. 8.8% in males) and Low HDL-C (46.2% in females

vs. 50.0% in males), despite the fact that these were not

statistically significant. The risk factor variables of

estimated hypertension and high LDL�/VLDL-C donot seem to contribute significantly to the model for

either gender.

A final observation is that the prevalence of advanced

atherosclerosis (raised lesions) among Greenlanders in

this study is very high as compared with that reported

for Alaska native Eskimo and Indians in a similar

autopsy study in those groups. Prevalence of raised

lesions in Alaska natives was found to be 30.0�/44.6% inthe aorta and 39.7�/45.2% in the coronary arteries [14]

compared with 77.5�/86.3 and 71.0�/73.3%, respectively,

reported here for Greenlanders. Although mean age is

not explicitly mentioned in the Alaska study, one can

estimate it based on the reported age-range counts. It is

evident that it is somewhat lower by approximately 30

years for the Alaska cases, so age difference may well

account for the large difference in prevalence. However,comparing extent of coronary lesions in the comparable

age ranges in this study to that reported for Alaska

shows that the mean extent of raised lesion involvement

in the Greenlanders appears to be the same as that of the

Alaska natives. In that study, the mean values (%)

reported for raised lesions in males/females for the 15�/

24 years age range were 0.9/0.0 in the left anterior

descending coronary (LAD) and 0.5/2.0 in the rightcoronary (RC), and in the 25�/34 years age range the

values were 4.7/0.9 and 3.1/1.0, respectively. In the

Greenlanders, the values for the combined genders in

the 15�/24 years range were 0.9 in the LAD, 0.8 in the

RC; and for the 25�/34 years range, 0.8 and 0.7,

respectively. Despite the mixed gender values for the

latter, it seems clear that no appreciable differences are

apparent between the extent of raised lesions in thecoronary arteries of the Greenland and Alaska natives

in those two age-matched groups. Furthermore, since

the Alaska study included non-native cases and reported

that extent of atherosclerosis was less in natives than in

non-natives, one can infer that the Greenlanders have

less atherosclerosis than Alaska non-natives.

There are two conclusions that can be made from

these data. First, no evident differences were observed,either in regard to the prevalence and extent of athero-

sclerosis or to the commonly associated risk factors,

between females and males in the Greenlanders of this

study. This possible lack of gender difference in athero-

sclerosis is of interest, especially if there is indeed less

IHD mortality in both females and males this popula-

tion, since pre-menopausal women below age 60 years

are reported to develop CHD at half the rate of men[31�/33]. The second conclusion is that the extent of

advanced atherosclerosis in Greenland natives in the age

range B/35 years, although based upon a small sample

size (n�/11), is the same as has been reported in Alaska

natives and less than that reported for Alaska non-

natives, supporting the suggestion that reduced extent of

atherosclerosis may be a factor in the low IHD mortality

in this population.

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