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HDL, HDL2, and HDL3 Subfractions, and the

Risk of Acute Myocardial Infarction
A Prospective Population Study in Eastern Finnish Men
Jukka T. Salonen, MD, PhD, MPH; Riitta Salonen, MD; Kari Seppanen, MPh;
Rainer Rauramaa, MD, PhD; and Jaakko Tuomilehto, MD, PhD

Background. We investigated the association of cholesterol concentrations in serum high

density lipoprotein (HDL) and its subfractions HDL2 and HDL3 with the risk of acute
myocardial infarction in 1,799 randomly selected men 42, 48, 54, or 60 years old.
Methods and Results. Baseline examinations in the Kuopio Ischaemic Heart Disease Risk
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Factor Study were done during 1984-1987. In Cox multivariate survival models adjusted for age
and examination year, serum HDL cholesterol of less than 1.09 mmol/l (42 mg/dl) was
associated with a 3.3-fold risk of acute myocardial infarction (95% confidence intervals [CI],
1.7-6.4), serum HDL2, cholesterol of less than 0.65 mmol/1 (25 mg/dl) was associated with a
4.0-fold risk of acute myocardial infarction (95% CI, 1.9-8.3), and serum HDL3 cholesterol of
less than 0.40 mmol/l (15 mg/dl) was associated with a 2.0-fold (95% CI, 1.1-4.0) risk of acute
myocardial infarction. Adjustments for obesity, ischemic heart disease, other cardiovascular
disease, maximal oxygen uptake, systolic blood pressure, antihypertensive medication, serum
low density lipoprotein cholesterol, and triglyceride concentrations reduced the excess risks
associated with serum HDL, IIDL2, and HDL3 cholesterol in the lowest quartiles by 52%, 48%,
and 41%, respectively. Additional adjustments for alcohol consumption, cigarettes smoked
daily, smoking years, and leisure time energy expenditure reduced these excess risks associated
with low HDL, HDL2, and HDL3 cholesterol levels by another 26%, 24% and 21%, respectively.
Conclusions. Our data confirm that both total HDL and HDL2 levels have inverse associations
with the risk of acute myocardial infarction and may thus be protective factors in ischemic
heart disease, whereas the role of HDL3 remains equivocal. (Circulation 1991;84:129-139)

S everal prospective population studies have re- have been reported' observed a stronger inverse
ported an inverse association between circu- association for HDL2 than for HDL3 cholesterol with
lating high density lipoprotein (HDL) choles- the risk of IHD. In none of the previous studies was
terol concentration and risk of ischemic heart disease the effect of the random variability in individual HDL
(IHD)'-11; in two studies, the inverse relation did not cholesterol values taken into account. Nor have
achieve statistical significance,'2'13 and in two other thepotential confounders of the association between
studies, no association was found.14"5 Most studies HDL cholesterol and AMI risk been comprehen-
have reported decreased levels of both HDL2 and sively controlled. Because previous findings were
HDL3 cholesterol in patients with acute myocardial controversial and inconclusive, we investigated the
infarction (AMI) and in those with severe coronary associations of serum HDL, HDL2, and HDL3 cho-
artery disease.'6 The only prospective study of IHD lesterol levels with the risk of AMI.
from which data on HDL2 and HDL3 subfractions
From the Department of Community Health and General Subjects
Practice (J.T.S.), University of Kuopio, Kuopio, the Research The Kuopio Ischaemic Heart Disease Risk Factor
Institute of Public Health (R.S.), University of Kuopio, Kuopio,
the Kuopio Research Institute of Exercise Medicine (K.S., R.R.), Study (KIHD) is a population study with the purpose
Kuopio, and the Department of Epidemiology, National Public of investigating previously unestablished risk factors
Health Institute of Finland (J.T.), Helsinki, Finland. for AMI and carotid atherosclerosis'7 in Eastern
Supported by grants from the Finnish Academy and the Ministry Finnish men, the population with the highest re-
of Education of Finland. corded incidence of IHD and mortality from IHD.18
Address for correspondence: Professor Jukka T. Salonen, Uni-
versity of Kuopio, P.O. Box 6, 70211 Kuopio, Finland. The present analysis is based on those who partici-
Received June 27, 1990; revision accepted February 19, 1991. pated in KIHD between March 1984 and December
130 Circulation Vol 84, No 1 July 1991

1987. The study sample included 2,155 Eastern Finn- lesterol were taken of a total of 322 men 1-5 years
ish men 42, 48, 54, or 60 years old at the time of after baseline examinations.
baseline examination. Of these, 1,821 men (84.5%)
participated. Serum cholesterol levels in the main Other Risk Factor Measurements
lipoprotein fractions were assessed for 1,799 men. No The current number of cigarettes, cigars, and
exclusions were made for the present analysis. pipefuls of tobacco smoked daily as well as the
Lipid Analysis duration of regular smoking (years); history of myo-
cardial infarction, angina pectoris, and other IHD;
The examination protocol and measurements have and presence of hypertension and use of antihyper-
been previously described in detail. 19,20 Subjects gave tensive medication were recorded using a self-admin-
blood specimens for lipoprotein separation between istered questionnaire, which was checked by an in-
8:00 and 10:00 AM on Tuesday, Wednesday, or Thurs- terviewer. The participants were reinterviewed
day after having abstained from ingesting alcohol for regarding medical history by a physician. A subject
3 days, from smoking for 12 hours, and from eating was considered a current smoker if he had ever
for 12 hours. After the subject had rested in the
supine position for 30 minutes, blood was drawn with smoked on a regular basis or had smoked cigarettes,
Terumo Venoject VT-100PZ vacuum tubes (Terumo cigars, or a pipe within the past 30 days. Subjects who
Corp., Tokyo). No tourniquet was used. had not smoked within the past 30 days were defined
For lipoprotein analysis, serum was separated by as nonsmokers and given a score of 0 for number of
centrifugation at 20°C for 10 minutes at 2,000g after cigarettes, cigars, and pipefuls of tobacco smoked
coagulation at room temperature for 1 hour. Samples daily. Smoking years were considered the sum of
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were stored at 4°C for no more than 2 days before years of smoking regardless of when smoking started
separation of lipoproteins. All ultracentrifugations and stopped and whether it had occurred continu-
were done at 10°C with a Kontron TGA-65 ultracen- ously or during several periods. Alcohol consumption
trifuge (Kontron, Zurich). The main fractions (very was assessed by instructed and interview-checked
low density lipoprotein [VLDL], low density lipopro- 4-day food recording.20 Total leisure time energy
tein [LDL], and HDL) were separated as described by expenditure was measured with a modified Taylor
Carlson.21 Serum was centrifuged for 16 hours at questionnaire concerning the activities within the
115,000g. VLDL was recovered as the top fraction and previous 12 months.19
HDL was recovered as the supernatant after precipi- Resting blood pressure was measured between
tation of the bottom fraction with dextran sulfate and 8:00 and 10:00 AM on the first examination day by one
magnesium chloride. The cholesterol concentration in nurse with a random-zero mercury sphygmomanom-
LDL was calculated as the difference between the eter. The measuring protocol included, after a supine
bottom and HDL fractions. rest of 5 minutes, three measurements in the supine
The HDL2 and HDL3 subfractions were separated position, one after 1 minute of standing, and two in
during a second ultracentrifugal spin at 108,000g for the sitting position with 5-minute intervals. The
62 hours against a density of 1.125 g/cm3 as described mean of all six systolic blood pressure values was
by Kirstein and Carlson.22 The top and bottom used in the present analysis. In the present study,
fractions were separated by the tube slicing tech-
nique. In this procedure, the HDL1 subfraction, a hypertension was defined as supine systolic blood
negligible component of total HDL, is included in the pressure (mean of two last measurements) of 160
HDL2 subfraction. Thus, the HDL subfraction, cal- mm Hg or more, sitting systolic blood pressure (mean
culated as the difference between total HDL and of two measurements) of 165 mm Hg or more, pre-
HDL3, consists mainly of HDL2. exercise sitting systolic blood pressure of 170 mm Hg
The cholesterol contents of all lipoprotein frac- or more, supine diastolic blood pressure (mean of
tions were measured enzymatically (CHOD-PAP two last measurements) of 95 mm Hg or more, sitting
method, Boehringer Mannheim, Mannheim, FRG) diastolic blood pressure (mean of two measure-
on the day after the last spin. All tests were run in ments) of 100 mm Hg or more, preexercise sitting
duplicate. A Seronorm Lipid (Nycomed, Oslo, Nor- diastolic blood pressure of 105 mm Hg or more, or
way) control serum sample was included in each daily self-reported history of hypertension or use of cur-
batch of cholesterol determinations. The between- rent antihypertensive medication.
batch coefficient of variation during 1984-1987 was The respiratory gas exchange was measured on a
2.2% for total HDL, 5.2% for LDL, 9.2% for HDL, breath-by-breath basis with the MGC 2001 system
10.8% for HDL2, and 14.2% for HDL3 cholesterol (Medical Graphics Corp., Minneapolis, Minn.) dur-
(210 batches). There was no linear trend in the ing a symptom-limited exercise test. The testing
quarterly control mean values over time. Tracking of protocol consisted of a linear increase of work load
serum HDL cholesterol values over time was studied by 20 W/min.19 Highest oxygen uptake (average of
annually by taking repeat serum HDL cholesterol 8 seconds) during the test was defined as Vo2max.
measurements using the same method in random Men were determined to have IHD if they reported a
subsamples from the study cohort of approximately history of myocardial infarction, angina pectoris, or
65 men. Repeat measurements of serum HDL cho- other IHD; reported use of medication for angina
Salonen et al HDL and Eastern Finnish Men 131

pectoris; or had ischemia during the maximal exer- among fatal cases required an exclusion of any other
cise tolerance test.19 Exercise electrocardiograms good evidence for another cause of death and either
were coded manually by one cardiologist. The criteria typical, atypical, or inadequately described symp-
for ischemia were 1) ischemic electrocardiogram, toms; evidence of chronic coronary occlusion, steno-
defined as horizontal or down-sloping ST depression sis, or old myocardial scarring at necropsy without
of 0.5 mm or more or upsloping ST depression of 1.0 typical, atypical, or inadequately described symp-
mm or more; 2) typical angina pectoris pain leading toms; or a good history of chronic IHD.
to discontinuation of exercise; or 3) maximal heart The coverage of the registry is checked against the
rate during exercise of 130 beats/min or less. Diabe- computerized national hospital discharge and death
tes was defined as previous diagnosis of diabetes or certificate registers. We obtained the diagnostic in-
fasting blood glucose of 8.0 mmol/l or more. formation and dates of all heart attacks in our study
Determination of Follow-up Events cohort by record linkage based on the uniform Finn-
A prospective registry for AMI was established in ish personal identification code (social security num-
the province of Kuopio as a part of the World Health ber). No personal identification codes were missing
Organization MONICA Project in 1982.23 This reg- in either our study cohort or the heart attack registry
istry collects detailed diagnostic information on all data. There were no losses to follow-up.
suspected fatal and nonfatal AMI events among the Between March 1984 and December 1988, a "def-
population, which includes the present cohort. The inite" or "possible" fatal or nonfatal AMI was regis-
events are then classified according to explicitly de- tered in 97 subjects of the present study. In the case
fined, uniform diagnostic criteria into the categories of multiple events, the first one for each subject was
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of definite AMI, possible AMI, no AMI, and insuf- considered to be the endpoint in our present analysis.
ficient data.23 This classification was based on au- The follow-up periods for individual subjects varied
topsy, serial electrocardiographic findings, cardiac between 1 and 43/4 years.
enzymes, symptoms, and history of IHD. About half
of the fatal cases were autopsied. Serial electrocar- Statistical Methods
diographic changes were classified according to the Three dummy (0, 1) variables were constructed
Minnesota Code into five categories. Cardiac en- that compared the three lowest (lst, 2nd, and 3rd)
zymes were routinely determined each day since quartiles of serum HDL, HDL2, and HDL3 choles-
hospitalization of the patient. Aspartate aminotrans- terol with the highest (4th) quartile: 1st versus 4th,
ferase, lactate dehydrogenase (LD), LD2, creatinine 2nd versus 4th, and 3rd versus 4th. These were
kinase, and creatinine kinase-MB levels were used, entered simultaneously into BMDP Cox proportional
and the determination of enzymes was standardized hazards models,24,25 separate models for serum HDL,
among several hospitals participating in the AMI HDL2, and HDL3 cholesterol dummies, and a joint
Registry Study in Finland. Enzymes were coded as model for both HDL2 and HDL3 dummies. Three
definite if the highest value of any of the enzymes was different sets of covariates were entered: first, age
twice the upper limit of the normal range and no and examination year (as three dummy variables,
other cause for the elevation was apparent. Hospi- 1985 versus other, 1986 versus other, and 1987 versus
talized patients were interviewed shortly after hospi- other); second, age, examination year (as above),
tal admission. In fatal cases, data on symptoms were body mass index (kg/M2), history of or prevalent IHD
obtained from medicolegal reports and, when neces- (yes versus no), other cardiovascular disease (yes
sary, by interviewing relatives. Symptoms were coded versus no), maximal oxygen uptake (ml/kg/min), sys-
as typical if the chest pain lasted for at least 20 tolic blood pressure (mean of six measurements),
minutes in the absence of noncardiac, nonatheroscle- antihypertensive medication (yes versus no), serum
rotic causes. LDL cholesterol concentration (mmol/l), and serum
In the present study, fatal and nonfatal events with triglyceride concentration (mmol/1); and third, all
the diagnostic category of definite or possible AMI variables listed above plus alcohol consumption (g/
were regarded as end points. An event was regarded day), cigarette pack-years, and total leisure time
as a definite AMI if at least one of the following energy expenditure (kcal/12 mo).
conditions was met: definite electrocardiographic The goodness of fit of the proportional hazards
changes; typical, atypical, inadequately described models was examined by analyzing changes in the
symptoms combined with probable electrocardio- proportionality of hazards with time and with risk
gram and abnormal enzymes; typical symptoms and factor levels. The results indicated that the applica-
abnormal enzymes; or naked-eye appearance of fresh tion of the models was appropriate. In addition, the
AMI and/or recent coronary occlusion found at simplest models (including three dummy variables
necropsy regardless of other findings. Possible non- for HDL, age, and examination year) were fitted
fatal AMI was confirmed if there were typical symp- using events in only the first 21/2 or the last 21/4 years
toms combined with probable electrocardiogram or of follow-up time. According to the deviance test for
equivocal enzymes or atypical or inadequately de- homogeneity of coefficients, there were no significant
scribed symptoms combined with probable electro- differences in the coefficients for HDL dummies
cardiogram and equivocal enzymes. Possible AMI between these two models.
132 Circulation Vol 84, No 1 July 1991

TABLE 1. Mean Age-Adjusted Serum HDL, HDL2, and HDL3 Cholesterol Values in Subgroups According to Their Strongest
Binary Determinants
Serum HDL cholesterol Serum HDL2 cholesterol Serum HDL3 cholesterol
No Yes* pt No Yes p No Yes p
medication 1.33 1.16 <0.001 0.88 0.74 <0.001 0.45 0.43 <0.001
(0.0080) (0.0123) (0.0077) (0.0111) (0.0019) (0.0037)
Diabetes or fasting blood
glucose of at least 8.0
mmol/l 1.30 1.15 <0.001 0.86 0.72 <0.001 0.44 0.42 0.009
(0.0070) (0.0300) (0.0070) (0.0260) (0.0020) (0.0070)
History of or prevalent
ischemic heart disease 1.32 1.26 <0.001 0.87 0.82 <0.001 0.45 0.44 0.007
(0.0089) (0.0110) (0.0084) (0.0105) (0.0022) (0.0027)
History of other
cardiovascular disease 1.30 1.23 <0.001 0.86 0.80 0.002 0.45 0.43 0.006
(0.0077) (0.0163) (0.0073) (0.0152) (0.0019) (0.0044)
Current smokert 1.30 1.26 0.011 0.86 0.83 0.023 0.45 0.45 NS
(0.0084) (0.0123) (0.0080) (0.0118) (0.0021) (0.0030)
HDL, high density lipoprotein.
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*Number of men in the "yes" categories: 395 receiving antihypertensive medication, 90 with diabetes or elevated fasting blood glucose,
777 with history of or prevalent ischemic heart disease, 312 with other cardiovascular disease, and 571 current smokers.
tStatistical significance of the differences between mean values; NS denotes p>0.050.
tEver smoked on a regular basis or smoked cigarettes, cigars, or a pipe within 30 days before the examination.
Values in parentheses indicate SEM.

Risk factor-adjusted relative hazards were esti- antihypertensive medication had 12.0% lower serum
mated as antilogarithms of coefficients for binary (0, HDL cholesterol and 15.9% lower serum HDL2
1) independent variables. Their confidence intervals cholesterol levels than those not receiving antihyper-
were estimated based on the assumption of the tensive medication (Table 1). Fasting plasma insulin
asymptomatic normality of estimates. Risk factor- level, antihypertensive medication, alcohol consump-
adjusted population attributable fractions for multi- tion, maximal oxygen uptake, body mass index, and
categorical risk factors were computed according to age were the strongest determinants of serum HDL
Walter26 using the estimates of relative hazards de- and HDL2 cholesterol levels in multivariate regres-
rived from the Cox models. sion models (Table 2). Men with diabetes, IHD, or
The attenuation of the relative hazard estimates other cardiovascular disease also had decreased se-
due to random variability over time was corrected by rum HDL, HDL2, and HDL3 cholesterol levels (Ta-
replacing the baseline quartile-specific baseline se- ble 1), but these conditions had no independent
rum HDL cholesterol mean values with mean values association with serum HDL or its subfractions in the
in the same groups in repeat measurements of serum multivariate regression analysis. Alcohol consump-
HDL cholesterol during the follow-up period. Prod- tion, plasma insulin concentration, antihypertensive
uct-moment correlations between baseline and repeat medication, maximal oxygen uptake, and years of
values were computed. This procedure corresponds to smoking were most strongly partially associated with
the nonparametric method to correct for the regres- serum HDL3 cholesterol (Table 2).
sion dilution bias in relative hazard estimates sug- The strongest predictors of AMI other than HDL
gested by MacMahon and coworkers.27 Second, the cholesterol in the present study cohort were current
"usual" serum HDL cholesterol concentrations were cigarettes smoked daily, history of IHD, maximal
approximated using the simple imputation method. oxygen uptake (inverse), age, antihypertensive med-
The linear regression equation, based on all 322 ication, systolic blood pressure, and, if the current
repeat measurements, was 0.63xbaseline HDL cho- systolic blood pressure was not entered into the
lesterol+0.39. All tests of significance were two sided. model, years of hypertension. Neither serum LDL
cholesterol, serum total triglycerides, body mass in-
Results dex, fasting blood glucose, fasting plasma insulin
The mean values and ranges of serum HDL, concentration (mIU/l), nor diabetes (yes versus no)
HDL2, and HDL3 cholesterol concentrations were had a statistically significant association with the risk
1.29, 0.85, and 0.44 mmol/l and 0.52-3.05, 0.07-2.77, of AMI in the present analysis.
and 0.13-0.83 mmol/l, respectively. The unadjusted Cox models adjusted for age and examination
correlation between serum HDL2 and HDL3 choles- years compared the three lowest quartiles of HDL
terol concentrations was 0.138. The strongest corre- cholesterol and its subfractions (as three dummy
lates of serum HDL, HDL2, and HDL3 cholesterol variables) with the highest quartiles. In these models,
are presented in Tables 1 and 2. Men receiving HDL cholesterol of less than 1.09 mmol/l (42 mg/dl)
Salonen et al HDL and Eastern Finnish Men 133

TABLE 2. Main Behavioral and Biological Correlates of Serum HDL, HDL2, and HDL3 Cholesterol Concentrations
Serum HDL cholesterol Serum HDL2 cholesterol Serum HDL3 cholesterol
Unadjusted r Partial P* Unadjusted r Partial 1B Unadjusted r Partial /3
Fasting plasma insulin (mIU/l) -0.22 -0.10 -0.20 -0.08 -0.12 -0.09
Antihypertensive medication
(yes versus no) -0.22 -0.14 -0.20 -0.13 -0.13 -0.08
Alcohol consumption (g/day) 0.13 0.14 0.11 0.13 0.10 0.09
Maximal oxygen uptake (mI/kg/min) 0.22 0.11 0.20 0.10 0.12 0.05
Body mass index (kg/M2) -0.22 -0.12 -0.22 -0.13 ..
Age (yr) -0.02 0.10 -0.01 0.08 ... ...

Smoking years -0.06 -0.07 -0.05 .. .t -0.05 -0.05

Cigarettes, cigars, and pipefuls
smoked daily -0.06 .. .t -0.05 -0.06 -0.03 ...

Plasma fibrinogen (g/l) -0.12 -0.04 -0.12 -0.05 -0.03

Multiple r2 ... 0.130 ... 0.113 ... 0.040
HDL, high density lipoprotein.
*Standardized partial coefficient from step-up least-squares regressions models including all independent variables shown in the order of
entry to the model for serum HDL cholesterol. Correlation and regression coefficients with absolute value of at least 0.06 depart statistically
significantly from 0.
tNot entered in the step-up procedure (,B is too low to enter).
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was associated with a 3.32-fold risk of AMI, serum (yes versus no), and serum triglyceride and LDL
HDL2 cholesterol of less than 0.65 mmol/1 (25 mg/dl) cholesterol concentrations did not influence these
was associated with a 4.00-fold risk of AMI, and relative hazards. When additional adjustments were
serum HDL3 cholesterol of less than 0.40 mmol/l (15 made for body mass index, history of or prevalent
mg/dl) was associated with a 2.04-fold risk of AMI IHD or other cardiovascular disease, maximal oxygen
(Table 3). Adjustments for body mass index, diabetes uptake, systolic blood pressure, antihypertensive

TABLE 3. Excess Risk of Acute Myocardial Infarction in Three Lowest Quartiles of Serum HDL, HDL2, and HDL3 Cholesterol
Concentrations Compared With Highest Quartile
Adjusted for potential
Adjusted for potential confounders, behavioral
Serum cholesterol Adjusted for age and confounders and behavioral determinants of HDL* and the
concentration examination year determinants of HDL* other HDL subfraction
95% 95% 95%
Relative confidence Relative confidence confidence
mmol/l mg/dl hazard intervals hazard intervals Relative hazard intervals
< 1.07 <41 3.32 1.73-6.37 1.82 0.88-3.75 NA NA
1.07-1.24 41-47 2.00 1.00-3.98 1.17 0.56-2.45 NA NA
1.25-1.47 48-57 1.46 0.71-3.00 1.11 0.53-2.31 NA NA
> 1.47 >57 1.00 ... 1.00 ... NA NA
<0.65 <25 4.00 1.93-8.26 2.20 0.98-4.90 2.09 0.95-5.12
0.65-0.80 25-30 2.56 1.19-5.49 1.45 0.64-3.26 1.44 0.63-3.24
0.81-1.01 31-39 1.97 0.89-4.32 1.45 0.64-3.26 1.43 0.61-3.21
>1.01 >39 1.00 ... 1.00 ... 1.00 ...

<0.40 < 15 2.04 1.05-3.98 1.48 0.73-2.98 1.44 0.70-2.94
0.40-0.44 15-16 1.61 0.82-3.19 1.47 0.72-2.98 1.32 0.64-2.71
0.45-0.50 17-19 1.44 0.71-2.94 1.35 0.66-2.76 1.31 0.64-2.70
>0.50 >19 1.00 ... 1.00 ... 1.00
HDL, high density lipoprotein; NA, not applicable.
*Age (yr) (NS), examination years (three dummy variables) (NS, NS, p<0.01), body mass index (kg/m2) (NS), history of or prevalent
ischemic heart disease (yes versus no) (p<0.01), other cardiovascular disease (yes versus no) (NS), maximal oxygen uptake (ml/kg/min)
(p<O.OS), systolic blood pressure (mean of six measurements, mm Hg) (NS), antihypertensive medication (yes versus no), serum low density
lipoprotein cholesterol (mmol/l) (NS), serum triglyceride concentration (mmol/l) (NS), alcohol consumption (g/day) (NS), cigarettes
smoked daily (p<0.001), smoking years (NS), and total leisure time energy expenditure in the previous 12 months (kcal).
134 Circulation Vol 84, No 1 July 1991

TABLE 4. Partial Excess Risks of Acute Myocardial Infarction Associated With Blood Lipids, Smoking,
and Hypertension
Adjusted for potential confounders and
Adjusted for age and examination year* behavioral determinants of HDLt
Relative hazard 95% confidence intervals Relative hazard 95% confidence intervals
Serum HDL cholesterol
(mM and mg/dl)
<1.07 (<41) 2.80 1.44-5.45 1.83 0.91-3.69
1.07-1.24 (41-47) 1.74 0.87-3.50 1.42 0.70-2.87
1.25-1.47 (48-57) 1.39 0.67-2.87 1.08 0.52-2.25
>1.47 (>57) 1.00 ... 1.00
Serum LDL cholesterol
(mM and mg/dl)
>4.77 (>184) 1.09 0.60-1.98 1.17 0.64-2.12
4.00-4.76 (154-183) 1.16 0.63-2.11 1.21 0.67-2.20
3.38-3.99 (130-153) 0.94 0.49-1.81 1.05 0.55-1.99
<3.38 (<130) 1.00 ... 1.00
Current smoking
Yest 1.96 1.30-2.94 1.79 1.18-2.71
No 1.00 ... 1.00
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Yes 1.85 1.20-2.85 1.40 0.89-2.20
No 1.00 ... 1.00 ...

HDL, high density lipoprotein; LDL, low density lipoprotein.

*From Cox models including age, examination year (three dummy variables), and eight terms for risk factors shown
in the table.
tAge, examination year (three dummy variables), body mass index (kg/m2), history of prevalent ischemic heart
disease (yes versus no), other cardiovascular disease (yes versus no), maximal oxygen uptake (ml/kg/min), serum
triglyceride concentration (mmol/l), alcohol consumption (g/day), total leisure time energy expenditure in the previous
12 months (kcal), and eight terms for risk factors shown in the table.
tEver smoked on a regular basis or smoked cigarettes, cigars, or a pipe within 30 days before baseline examination.

medication (yes versus no), and serum LDL choles- of HDL2 and HDL3 cholesterol, when entered simul-
terol or serum triglyceride concentration, the excess taneously, were 2.44 (95% CI, 1.12-5.28), 1.60 (95%
risks (relative hazard minus 1) associated with serum CI, 0.72-3.54), and 1.62 (95% CI, 0.73-3.59) for
HDL, HDL2, and HDL3 cholesterol in the lowest HDL2 and 1.46 (95% CI, 0.72-2.95), 1.34 (95% CI,
quartile decreased by 52%, 48%, and 41%, respec- 0.66-2.71), and 1.31 (95% CI, 0.64-2.70) for HDL3,
tively. The decrease in excess risk was mainly a result respectively. The respective relative hazards adjusted
of history of IHD and Vo2max. Inclusion of diabetes for all potential confounders and behavioral deter-
(yes versus no) in the model did not change the minants of HDL are shown in Table 3.
relative hazards. Additional adjustments for alcohol In a Cox model that includes age, examination
consumption (g/day), current cigarettes, cigars, and year, serum HDL and LDL cholesterol levels (three
pipefuls smoked daily, smoking years, and leisure dummy variables each), smoking (within 30 days),
time energy expenditure (kcal/yr) reduced these ex- and hypertension, the excess risk in men in the lowest
cess risks an additional 26%, 24%, and 21%, respec-
tively (Table 3). quartile of serum HDL cholesterol was greater (rel-
In a Cox model including in addition to age and ative hazard, 2.80) than that for smoking (relative
examination years both serum HDL2 and HDL3 hazard, 1.96) and hypertension (relative hazard,
cholesterol dummies, the three lowest quartiles of 1.85) (Table 4). When history of or prevalent cardio-
HDL2 cholesterol were associated with 3.74-fold vascular disease and maximal oxygen uptake were
(95% CI, 1.80-7.78), 2.48-fold (95% CI, 1.16-5.33), added into the model, these excess risks were appre-
and 1.97-fold (95% CI, 0.89-4.33) risks of AMI. ciably reduced (by 18% for smoking and 53% for
When HDL2 was simultaneously included in the hypertension). The inclusion of terms for interactions
model, the impact of HDL3 cholesterol was reduced. between HDL dummies and smoking or between
The respective relative hazards for the three lowest HDL dummies and hypertension did not affect the
quartiles of HDL3 cholesterol were 1.66 (95% CI, relative hazard estimates for HDL quartiles to a
0.84-3.27), 1.40 (95% CI, 0.70-2.78), and 1.38 (95% significant degree. Also, the addition of interaction
CI, 0.68-2.80). In a Cox model adjusted for potential terms did not improve the fit of the model, as judged
confounders (second model in Table 3), the relative based on the change in the deviance for the entire
hazards (with 95% CIs) for the three lowest quartiles model.
Salonen et al HDL and Eastern Finnish Men 135

TABLE 5. Mean Serum HDL Cholesterol Levels at Baseline and in Surveys of Subsamples 1-5 Years After Baseline Measurement
Mean concentration in each category (number of subjects with repeat measurements)
Years after baseline
At Difference Difference
Baseline quartile (mmol/l) baseline between quartiles 1-3 3-5 1-5 between quartiles
Serum HDL cholesterol
<1.07 0.95 (421) 0.98 (42) 0.97 (50) 0.98 (92)
1.07-1.24 1.16 (466) 0.21 1.15 (36) 1.11 (56) 1.13 (92) 0.15
1.25-1.47 1.36 (473) 0.20 1.29 (32) 1.23 (49) 1.26 (81) 0.13
>1.48 1.69 (437) 0.33 1.49 (20) 1.38 (37) 1.42 (57) 0.16
Range of mean serum HDL
cholesterol 0.74 ... 0.51 0.41 ...
HDL, high density lipoprotein.

The percentages of AMIs attributable to low HDL follow-up period of the present study). The average
cholesterol were 67% when adjusted for age and difference between quartile specific mean values was
examination years, 35 % when adjusted for the poten- 0.25 mmol/l for baseline measurements and 0.15
tial confounding factors listed in the first footnote of mmol/l (41% less) for measurements 1-5 years after
Table 3, and 24% when also adjusted for behavioral baseline.
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determinants of HDL listed in the footnote of Table The relative hazards in the quartiles of baseline
3. The- respective population attributable percent- serum HDL cholesterol concentration with adjust-
ages for smoking and hypertension were 23% and ment for the potential confounding factors listed in
30% with adjustments for age and examination year the footnote of Table 3 are presented in Figure 1.
and 19% and 17% with additional adjustments for The relative hazards are plotted against quartile-
the potential confounders defined in Table 4. specific mean values of both baseline HDL choles-
In the multivariate Cox models adjusted for age terol and HDL cholesterol during the follow-up. The
and examination year, both serum HDL (z= -3.61, latter curve represents the association between se-
p<0.001) and serum HDL2 (z=-3.43,p<0.001) cho- rum HDL cholesterol and AMI risk when corrected
lesterol concentrations had significant independent for the regression dilution bias.
associations with the risk of AMI. The association of When adjusted for age, examination year, IHD,
serum HDL3 cholesterol with AMI did not reach other cardiovascular disease, systolic blood pressure,
statistical significance in a two-sided test (z=-1.92, antihypertensive medication, and serum LDL choles-
p=0.07). An increase of 1.0 mmol/l in HDL, HDL2, terol, an increment of 1 mg/dl in serum HDL cho-
and HDL3 cholesterol reduced the risk of AMI by lesterol was associated with a 2.4% (4.1% with
79%, 79%, and 94%, respectively. When adjusted for correction for regression dilution bias) reduction in
age, examination year, maximal oxygen uptake, prev- AMI risk, and an increment of 10% in HDL choles-
alent IHD, other cardiovascular disease, body mass terol was associated with a 10% (corrected, 17%)
index, baseline serum LDL cholesterol and triglycer- reduction in AMI risk. An additional adjustment for
ide concentrations, systolic blood pressure, and anti- cigarette pack-years decreased the respective (uncor-
hypertensive medication, an increase of 1.0 mmol/l in rected) decrements of AMI risk to 2.2% and 9%.
baseline HDL cholesterol was associated with a 61%
decline of AMI risk. The respective decline associ- Discussion
ated with an increase (mmol/l) in the usual HDL Earlier, we reported preliminary findings concern-
cholesterol was 76%. ing the roles of HDL2 and HDL3 subfractions with
The unadjusted correlations between baseline regard to the risk of AMI.28 The present data confirm
measurement and repeat measurements 1-3 years that HDL2 subfraction has an inverse association with
after baseline measurement were 0.72 (n=130) for the risk of AMI, whereas the role of HDL3 remains
serum HDL cholesterol and 0.57 (n=365) for serum equivocal. The association was stronger for HDL2
LDL cholesterol concentrations. The respective cor- than HDL3, and the association of HDL3 with AMI
relation coefficients for baseline versus 3-5-year lost its statistical significance when adjustment was
postbaseline measurements were 0.67 (n=192) and made for HDL2. The impact of neither total HDL nor
0.52 (n=481). The baseline quartile-specific mean its subfractions was weakened by adjustments for age,
serum HDL cholesterol concentrations for measure- serum LDL cholesterol or triglyceride concentrations,
ments at baseline and 1-3 and 3-5 years after obesity, or diabetes. Decreased serum HDL2 choles-
baseline are presented in Table 5. The differences in terol was found in men who received antihypertensive
serum HDL cholesterol mean values between the medication, had high body mass index or high fasting
lowest and the highest baseline quartiles were 0.74 plasma insulin, or currently smoked. Elevated serum
mmol/l at baseline and 0.44 mmol/l (41% less) an HDL3 cholesterol was associated with high alcohol
average of 1-5 years after baseline (during the consumption and high maximal oxygen uptake. Serum
136 Circulation Vol 84, No 1 July 1991

Relative Hazard of AMI

2.1 0
-*--- Uncorrected * Regression-corrected

1.9 -

1.7 H

1.5 H

1.3 h

1.1 K

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0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7

S-HDL-Cholesterol (mmol/1)
FIGURE 1. Plot of risk factor-adjusted relative hazard of acute myocardial infarction (AMI) in baseline quartile-specific serum
(S) high density lipoprotein (HDL) cholesterol mean values at baseline (uncorrected) and 1-5 years after baseline (corrected for
regression dilution bias).

HDL3 cholesterol correlated appreciably with alcohol Study,5 Israeli Ischaemic Heart Disease Study,6 Mul-
consumption and weakly with plasma insulin, antihy- tiple Risk Factor Intervention Trial,7 Coronary Pri-
pertensive medication, maximal oxygen uptake, and mary Prevention Trial,8 Lipid Research Clinics Prev-
duration of smoking. alence Mortality Follow-up Study,9'3' Helsinki Heart
In the present analysis, a very concervative ap- Study,10 and British Regional Heart Study.1' Statis-
proach was taken, and the major behavioral determi- tically nonsignificant inverse trends were observed in
nants of HDL (smoking, alcohol consumption, and the Minnesota Businessmen Study12 and the Finnish
physical activity) were controlled for. Because HDL cohort of the Seven Countries Study.'3 In the first
may be a major mediating biological mechanism in analysis of the British Regional Heart Study, a sig-
the effect of smoking, alcohol, and exercise on IHD nificant inverse association was observed between
risk, the analytical approach may also be considered nonfasting serum HDL cholesterol and incidence of
to represent an overadjustment. IHD, but this association was substantially weakened
The strong age-adjusted inverse association of and lost its statistical significance by adjusting for the
total serum HDL cholesterol with the risk of AMI is standard coronary risk factors, including non-HDL
in accord with the observations of earlier prospective cholesterol.32 In a later analysis based on a longer
population studies. The relative hazard, an estimator follow-up, the inverse association continued to be
of relative risk, was 3.3 when the lowest quartile (less significant after risk factor adjustment.'1 Men in the
than 42 mg/dl) and the highest quartile (57 mg/dl or lowest quintile (less than 0.93 mmol/1, or 36 mg/dl)
more) were compared. In the Framingham study, had a 2.0-fold risk compared with those in the highest
serum HDL cholesterol in the bottom quintile (less quintile (at least 1.33 mmol/l, or 51 mg/dl). In two
than 35 mg/dl) was associated with a 4.1-fold in- studies, there was no association between HDL and
creased risk factor-adjusted 12-year mortality from IHD risk.14"15 Of these two studies, the study from
IHD compared with HDL cholesterol of 55 mg/dl or Gothenburg was based on only 18 case-control pairs,
more in 1,007 men free of IHD who were 50-79 years including several men on lipid-altering medication.
old.29 In the same men, both the age-adjusted and the Previous studies of HDL cholesterol and IHD risk
risk factor-adjusted relative hazards of myocardial have not taken into account the attenuation of the
infarction in the lowest quartile (36 mg/dl or less) relation resulting from random measurement vari-
was 1.7 (95% CI, 1.0-2.9) compared with the highest ability and the regression of HDL cholesterol values
quartile (53 mg/dl or more).30 toward the mean over time. If no correction for this
Low serum HDL cholesterol was also significantly regression dilution bias is applied, the present data
associated with increased mortality from IHD in the agree with the estimates from four prospective US
Livermore Study,' Honolulu Heart Study,2 Framing- studies that a 1-mg/dl (0.026-mmol/1) increment in
ham Study,3,29'30 Tromso Heart Study,4 Oslo Heart HDL cholesterol level was associated with a 2-3%
Salonen et al HDL and Eastern Finnish Men 137

decrement in IHD risk.9 With the correction, the question, however, of whether only HDL2 or HDL3
respective decrement of AMI risk in our data was subfraction is protective of IHD may be irrelevant
approximately 4%. According to our data, the poten- because both fractions participate in the reverse
tial impact of HDL cholesterol in the prevention of cholesterol transport.35
IHD is impressive. If the association between HDL Theoretically, serum HDL cholesterol could be an
and IHD was causal, the elevation of all HDL values indicator of another factor rather than a true protec-
of less than 1.5 mmol/l (58 mg/dl) to above this value tive factor per se. First, it reflects the levels of cigarette
would theoretically prevent between 35% and 67% of smoking, physical activity, and alcohol consumption
AMIs, depending on which other factors are assumed and is associated with obesity, diabetes, and hyperten-
to change with HDL cholesterol. In the present study sion. The inverse association of serum HDL and
cohort with a short average follow-up, a low serum HDL2 cholesterol with the risk of AMI persisted in
HDL cholesterol concentration appears to be a our data, however, even after adjustments for all of
stronger risk factor for AMI than smoking, hyperten- these factors in a multivariate analysis. Also, in the
sion, or serum LDL cholesterol concentration. In Lipid Research Clinics Follow-up Study, the associa-
addition to the shortness of follow-up, the weakness tion of cigarette smoking with cardiovascular disease
of the association between serum LDL cholesterol mortality was independent of HDL cholesterol, and
and AMI risk could have been a result of the weaker the inverse relation between alcohol consumption and
tracking (greater random variability) of LDL than cardiovascular disease mortality was only partially
HDL cholesterol over time. mediated through HDL cholesterol.31
Quantitative estimates of the association between It is also possible that decreased serum HDL is an
HDL and IHD must be interpreted cautiously be- indicator of another metabolic disorder that could be
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cause differences can be caused by a number of the true etiologic factor. Reduced HDL could reflect
factors. In prospective studies, the characteristics of inefficient catabolism of triglyceride-rich lipoproteins
the subjects, length of follow-up, choice and deter- and be associated with chylomicron remnants. Low
mination of follow-up events, blood sampling, treat- HDL cholesterol is associated with decreased lipopro-
ment of serum or plasma samples, and method of tein lipase activity and increased hepatic lipase activity.
HDL measurement may be relevant. In the present Low serum HDL cholesterol concentration can be a
study, blood samples were drawn from resting sub- consequence of either a decreased number of HDL
jects in the supine position after a 12-hour fast and particles in the circulation or a reduced size of HDL
abstinence from smoking in the morning, and lipo- particles resulting from cholesterol depletion. These
protein fractions were separated from unfrozen se- two conditions may not have the same etiologic rele-
rum samples, and analyzed within 2 days. Serum vance. The absence of accelerated atherogenesis in
HDL was separated with a combination of ultracen- patients with low or no HDL35-37 speaks against a
trifugation and precipitation, and HDL3 was sepa- direct causal role of HDL in atherogenesis. In addition,
rated with a second ultracentrifugal spin at the site of coronary artery disease has been reported in persons
blood sampling. Despite the time-consuming analyt- with familial hyper-HDL2-cholesterolemia.38
ical procedure, the measurement variabilities of In our study cohort with a very high incidence of
HDL, HDL2, and HDL3 cholesterol measurements AMI and a short average follow-up, serum HDL
were considerably large. Because random variability cholesterol concentration was one of the strongest
in the risk factor measurements attenuates associa- predictors of AMI. The lack of the predictive power
tions with disease outcomes, the greater measure- of serum LDL cholesterol may be a result of the short
ment variability for HDL3 than for HDL2 cholesterol follow-up because LDL conceivably increases the
may account for a part of or the entire difference in risk of AMI through promotion of the progression of
the strength of their association with AMI risk. coronary atherosclerosis as well as a result of large
The early Livermore Study is the only prospective random variability over time. Serum LDL cholesterol
population study that has investigated the association was the strongest determinant of the progression of
of HDL subfractions with the risk of IHD.1 In that carotid atherosclerosis in a 2-year follow-up study of
study, both HDL2 and HDL3 fractions were signifi- a subsample of the present subjects with B-mode
cantly inversely associated with the risk of an IHD ultrasonography, whereas serum HDL cholesterol
event, even though the association was stronger for had no association with atherosclerosis progression
HDL2 than for HDL3 fraction. In most case-control in this small cohort.39 An identical finding was ob-
studies comparing subjects with and without angio- served in a 2-year coronary atherosclerosis progres-
graphically assessed coronary artery disease, lower sion study with repeat angiograms.40 On the other
levels of HDL2 and HDL3 cholesterol have been hand, in two other angiography studies,34,41 HDL
observed in cases than in controls.'6 In most studies, cholesterol had an inverse relation with atheroscle-
there has been a greater proportionate difference in rosis progression. These observations provide some
HDL2, although there have been some exceptions.33 support for the hypothesis of differential pathoge-
In addition, in the National Heart, Lung, and Blood netic mechanisms for the effects of serum LDL and
Institute Type II Intervention Study,34 the extent of HDL cholesterol in IHD.
coronary atherosclerosis associated with both HDL Because the protective impact of serum HDL
subfractions but significantly with only HDL3. The cholesterol concentration becomes detectable in such
138 Circulation Vol 84, No 1 July 1991

a short follow-up, the effect of HDL may be mediated 6. Goldbourt U, Holtzman E, Neufeld HN: Total and high
through pathways other than atherogenesis; the re- density lipoprotein cholesterol in the serum and risk of
verse cholesterol transport from arteries to the liver mortality: Evidence of a threshold effect. Br Med J 1985;290:
may not be the only antiatherogenic mechanism of 7. Multiple Risk Factor Intervention Trial Research Group:
HDL. There are other possible alternative or parallel Relationship between baseline risk factors and coronary heart
mechanisms for the protective effect of HDL. First, disease and total mortality in the Multiple Risk Factor Inter-
HDL may act as an antioxidant; that may explain why vention Trial. Prev Med 1986;15:254-273
it is associated in cell culture with increased prosta- 8. Gordon DJ, Knoke J, Probstfield JL, Superko R, Tyroler HA,
cyclin production42 and reduced platelet aggregabil- for the Lipid Research Clinics Program: High density lipopro-
tein cholesterol and coronary heart disease in hypercholes-
ity.43 As an antioxidant, HDL inhibits the oxidation terolemic men: The Lipid Research Clinics Coronary Primary
of cholesterol and the formation of lipid peroxides, Prevention Trial. Circulation 1986;74:1217-1225
which are cytotoxic for the endothelium44 and inhibit 9. Gordon DJ, Probstfield JL, Carrison RJ, Neaton JD, Castelli
prostaglandin synthesis at certain levels.45 Also, apo- WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA:
lipoprotein A-I has been observed to stabilize se- High-density lipoprotein cholesterol and cardiovascular dis-
ease: Four prospective American studies. Circulation 1989;79:
creted prostacyclin.46 Second, HDL has been found 8-15
to promote fibrinolysis.47 Third, high levels of HDL 10. Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick
may reduce the uptake of LDL by endothelial cells by H: Relation between baseline lipid and lipoprotein values and
competing for the LDL receptor.48 Fourth, HDL may the incidence of coronary heart disease in the Helsinki Heart
Study. Am J Cardiol 1989;63:H42-H47
prevent the formation of LDL aggregates, which 11. Pocock SJ, Shaper AG, Phillips AN: Concentrations of high
appear to facilitate the influx of LDL to the endo- density lipoprotein cholesterol, triglycerides, and total cho-
thelial cells.49 Finally, HDL counteracts in vitro the lesterol in ischaemic heart disease. Br Med J [Clin Res]
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activation of platelets by LDL.50 Apolipoprotein A-I 1989;298:998-1002

12. Keys A: Alpha lipoprotein (HDL) cholesterol in the serum
has been found to increase the solubility of choles- and the risk of coronary heart disease and death. Lancet
terol in bile.51 1980;2:603-606
The role of HDL as an antioxidant and its impact 13. Keys A, Karvonen MJ, Punsar S, Menotti A, Fidanza F, Farchi
on platelet function and thrombogenesis deserve G: HDL serum cholesterol and 24-year mortality of men in
thorough studies. The effect of HDL and its subfrac- Finland. Int J Epidemiol 1984;134:428-435
14. Wiklund 0, Wilhelmsen L, Elmfeldt D, Wedel H, Valek J,
tions on atherosclerosis progression must be investi- Gustafson A: Alpha-lipoprotein cholesterol concentration in
gated in large population cohorts with repetitive relation to subsequent myocardial infarction in hypercholes-
assessments of atherosclerosis. In conclusion, the terolemic men. Atherosclerosis 1980;37:47-53
present data provide confirmation of the inverse 15. Levy RI, Klimov AN: High density lipoprotein cholesterol and
association between serum HDL and HDL2 choles- mortality in USSR and US middle-aged men: The Collabora-
tive US/USSR Mortality Follow-up Study (abstract). Circula-
terol and the risk of IHD, whereas the role of HDL3 tion 1987;76(suppl IV):IV-67
remains only suggestive. Our findings are consistent 16. Miller NE: Associations of high density lipoprotein subclasses
with the concept that high HDL blood levels or and apolipoproteins with ischemic heart disease and coronary
associated metabolic factors are protective for IHD. atherosclerosis. Am Heart J 1987;113:589- 597
17. Salonen JT: Is there a continuing need for longitudinal
Acknowledgments epidemiologic research? The Kuopio Ischaemic Heart Disease
Risk Factor Study. Ann Clin Res 1988;20:46-50
We are grateful to Professor Kalevi Pyorala and 18. Keys A: Seven countries: A Multivariate Analysis of Death and
Dr. Pertti Palomaki, Kuopio University Hospital, for Coronary Heart Disease. Cambridge, Mass/London, Harvard
providing access to data of the AMI Registry in the University Press, 1980
19. Salonen JT, Lakka T: Assessment of physical activity in
province of Kuopio, to Dr. Esko Taskinen and Dr. population studies-Validity and consistency of the methods
Juha Venalainen for supervising the maximal exer- in the Kuopio Ischaemic Heart Disease Risk Factor Study.
cise tests, and to Dr. Jaakko Eranen for coding the Scand J Sports Sci 1987;9:89-95
exercise electrocardiograms. 20. Ihanainen M, Salonen R, Seppanen R, Salonen JT: Nutrition
data collection in the Kuopio Ischaemic Heart Disease Risk
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HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A
prospective population study in eastern Finnish men.
J T Salonen, R Salonen, K Seppänen, R Rauramaa and J Tuomilehto

Circulation. 1991;84:129-139
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doi: 10.1161/01.CIR.84.1.129
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1991 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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