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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1280-1286.)
© 1995 American Heart Association, Inc.

Articles

Apolipoprotein E4 Phenotype Is Not an Important Risk Factor for Coronary Heart Disease or Stroke in Elderly Subjects

Johanna Kuusisto; Leena Mykkänen; Kari Kervinen; Y. Antero Kesäniemi; Markku Laakso

From the Department of Medicine, Kuopio University Hospital (J.K., L.M., M.L.), and the Department of Internal Medicine, Oulu University Hospital and Biocenter Oulu, University of Oulu (K.K., Y.A.K.), Finland.

Correspondence to Markku Laakso, MD, Department of Medicine, University of Kuopio, POB 1777, 70211 Kuopio, Finland. E-mail laakso@uku.fi.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract The allele e4 (apo e4) of apolipoprotein E (apo E) has been associated with an increased risk for coronary heart disease (CHD) in cross-sectional studies in middle-aged subjects. We investigated the risk of CHD and stroke with respect to the number of apo e4 alleles in a prospective study of a Finnish nondiabetic cohort including 1067 subjects 65 to 74 years old at baseline. During the 3.5-year follow-up, CHD mortality was 2.8%, total CHD incidence 6.9%, and the cumulative occurrence of CHD (prevalence at baseline and the 3.5-year incidence combined) 17.0%. The incidence of stroke was 3.4%, and the cumulative occurrence of stroke was 6.0%. The CHD mortality was 3.4% in subjects with no apo e4 allele (n=734), 1.7% in those with one apo e4 allele (n=296), and 0% in subjects with two apo e4 alleles (n=37) (P=NS between the three groups). The incidence of CHD according to the number of apo e4 alleles was 6.9% (no apo e4 alleles), 7.4% (one apo e4 allele), and 2.7% (two apo e4 alleles), and the cumulative occurrence of CHD was 16.5%, 18.6%, and 13.5%, respectively (P=NS). The incidence of stroke was 3.8% in subjects with no apo e4 allele, 2.7% in those with one apo e4 allele, and 0% in those with two apo e4 alleles (P=NS). The cumulative occurrence of stroke was 6.0%, 6.4%, and 2.7%, respectively (P=NS). In conclusion, in contrast to middle-aged subjects, the risk of cardiovascular disease in elderly subjects with apo e4 is not increased. Consequently, the allele e4 of apo E cannot be regarded as an important risk factor for CHD or stroke in the elderly.

Key Words: apolipoprotein E • coronary disease • stroke • cardiovascular disease

	Introduction

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Cardiovascular diseases, including CHD and stroke, are the most important causes of mortality and morbidity in Western countries. Several studies have indicated that the classic cardiovascular risk factors—smoking, high blood pressure, low HDL cholesterol, and in most studies, also high total cholesterol—are important predictors of CHD events in elderly as well as middle-aged subjects.^{1 2 3 4} Lately, new cardiovascular risk factors such as apolipoproteins, including apo E, have been a focus of keen investigation.

Apo E is an essential part of lipoprotein metabolism. It is present in lipoprotein particles and mediates lipoprotein binding to the LDL and lipoprotein remnant receptors. The gene coding for apo E is located on chromosome 19 near the genes for apos C-I and C-II. Three different alleles, e2, e3, and e4, account for the apo E polymorphism and determine the six phenotypes E2/2, E2/3, E2/4, E3/3, E4/3, and E4/4.^{5 6}

Apo E polymorphism explains 7% of the variation in total and LDL cholesterol and apo B levels.⁶ Compared with the e3 allele, the e4 allele is associated with higher and the allele e2 with lower serum total and LDL cholesterol and apo B levels. Furthermore, allele e2 is associated with an increased risk for type III hyperlipoproteinemia.^{7 8}

The role of apo E in atherosclerosis has been a focus of intensive research. A recent study showed that knockout mice lacking apo E develop spontaneous atherosclerosis at an early age.⁹ Apo E is also produced by macrophages, especially foam cells participating in the atherosclerotic process.¹⁰ In young males, the E4/3 phenotype has been shown to be associated with more severe atherosclerosis compared with other phenotypes.¹¹ There are also several studies on the effect of apo E phenotypes on CHD risk, but the results of these studies are somewhat contradictory. In some studies, apo E4 has been associated with an increased risk for CHD,^{12 13 14 15 16} but other studies have failed to verify this association.^{17 18 19} Since most of these studies have been cross-sectional, conflicting results could be due to patient selection.^{12 13 14 15 16 17 18 19} Information on the effect of apo E polymorphism on the risk of stroke is limited to two cross-sectional studies.^{20 21}

Since there are no prospective population-based studies on the impact of apo E polymorphism on cardiovascular risk and since information on the significance of apo E polymorphism in elderly subjects is limited, we investigated 3.5-year mortality, 3.5-year incidence, and the cumulative occurrence of CHD and stroke in a nondiabetic cohort of 1067 Finnish subjects 65 to 74 years old. Because apo e4 allele frequency in Finnish young and middle-aged subjects has been reported to be among the highest in the world,^{22 23} the Finnish population is particularly interesting in this respect.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Research Design and Methods at Baseline Study
Study Population at Baseline
The baseline examination was conducted in Kuopio, eastern Finland, between February 1986 and April 1988. The formation²⁴ and representativeness²⁵ of the study population have been described in detail previously. Briefly, 1910 subjects born between 1912 and 1921 were randomly selected from the population register of all inhabitants of Kuopio. A postal questionnaire containing questions about diagnosis of diabetes, ability to move, and willingness to participate in the study was sent to each subject. Eighty-three subjects from this sample were excluded because they were too ill to participate. Eventually, 1299 of 1827 eligible subjects participated in the examination at baseline, giving an overall participation rate of 71%. In the present study, all subjects with a previous history of diabetes or newly diagnosed diabetes at the baseline study were excluded from all statistical analyses. Consequently, the study population at baseline consisted of 1069 nondiabetic subjects. Apo E phenotypes were available in 1067 of 1069 subjects, and these 1067 subjects formed the final study population.

Alcohol consumption was determined according to the subject's estimate of the average number of glasses of alcoholic drinks ingested per week. In statistical analyses, subjects were classified as alcohol users or nonusers. Smoking habits were defined as current smoking.

Weight and height were measured with subjects in light clothing without shoes. Body mass index was calculated by weight per height squared (kilograms per meter squared). Waist circumference (centimeters) was measured at the level of the umbilicus and hip circumference at the level of the greatest hip girth with the subject standing and breathing normally. Body fat distribution was measured by waist-to-hip ratio.

Blood pressure was measured with a mercury sphygmomanometer on the right arm with subjects in the supine position after a 5-minute rest. Two readings were taken (1.5-minute interval); the second reading was used in statistical analyses. In each measurement, blood pressure was read to the nearest 2 mm Hg. Subjects were defined as having hypertension if systolic blood pressure was >160 mm Hg or diastolic blood pressure >95 mm Hg or if the subject was receiving drug treatment for hypertension.

Diagnosis of Previous CHD Events
A conventional 12-lead resting ECG was recorded, and all ECGs were classified according to the Minnesota code.²⁶ Symptoms suggestive of angina pectoris or MI were recorded with the Rose Cardiovascular Questionnaire²⁷ by a specially trained nurse. All medical records of subjects who reported that they had been admitted to the hospital for chest pain or symptoms suggestive of MI before the baseline examination were reviewed by one of the authors (L.M.). WHO MONICA project criteria for verified definite and possible MI,²⁸ as modified by the FINMONICA AMI Register Study Group,²⁹ based on chest pain symptoms, ECG changes, and enzyme determinations, were used in the ascertainment of previous MI. Previous MI was defined to be present if a subject had had a possible or definite MI according to hospital records before the baseline examination or if there was a major Q wave (Minnesota code 1.1 or 1.2) on ECG at baseline.

Diagnosis of Previous Stroke
All medical records of subjects who reported that they had been admitted to the hospital for symptoms suggestive of stroke before the baseline examination were reviewed by one of the authors (L.M.). WHO criteria for definite and possible stroke were used in the ascertainment of the previous stroke, which was defined as a clinical syndrome consisting of neurological deficits persisting over 24 hours and observed by a neurologist, in the absence of other diseases explaining the symptoms.³⁰ Thromboembolic and hemorrhagic strokes, but not subarachnoid hemorrhage, were included in the diagnosis of stroke.

Glucose Tolerance
WHO diagnostic criteria for diabetes mellitus were used to classify subjects without previously known diabetes.³¹ The criteria are as follows: (1) diabetes mellitus, fasting venous plasma glucose >7.8 mmol/L or 2-hour venous plasma glucose >11.1 mmol/L in a 75-g oral glucose tolerance test; (2) impaired glucose tolerance, fasting venous plasma glucose <7.8 mmol/L and 2-hour venous plasma glucose of 7.8 to 11.0 mmol/L; and (3) normal glucose tolerance, fasting and 2-hour venous plasma glucose <7.8 mmol/L. Previously known diabetes was considered to be present if a physician had made the diagnosis.

Determination of Apo E Phenotypes
The apo E phenotype was determined from the plasma with isoelectric focusing and immunoblotting techniques using commercial antibodies.^{22 32} In the literature, genotype/phenotype concordance has generally been reported to be high in nondiabetic subjects^{33 34} but less consistent in diabetic subjects.³⁵ In one publication, the concordance between genotype and phenotype was low in both nondiabetic and diabetic subjects.³⁶ In our own laboratory, the genotype/phenotype concordance has been studied in another patient population. Genotype was determined by solid-phase minisequencing kit, and the results were compared with phenotype determined by isoelectric focusing. Of 62 subjects tested, the genotype differed from phenotype in only one subject (K.K., unpublished observations).

Other Laboratory Methods
Blood samples were taken between 7:30 and 9:30 AM after a 12-hour fast. All subjects underwent a 75-g oral glucose tolerance test. Venous blood samples for glucose and insulin determinations were taken before and 2 hours after the glucose load. Plasma glucose was determined by the glucose oxidase method (Glucose Auto & Stat HGA-1120 analyzer, Daiichi). Plasma insulin concentration measured as milliunits per liter (1 mU/L=6.0 pmol/L) was determined from samples stored at -70°C by a commercial double-antibody solid-phase radioimmunoassay (Phadeseph Insulin RIA 100; Pharmacia Diagnostics, AB).³⁷ Serum HDL cholesterol was determined after precipitation of LDL and VLDL with dextran sulfate and MgCl₂.³⁸ Commercial enzymatic methods were used in the determination of cholesterol (Monotest, Boehringer Mannheim)³⁹ and triglycerides (Peridocrome, Boehringer Mannheim).⁴⁰ Commercial control sera were used to standardize the measurements of cholesterol and triglycerides (Seronorm, Seronorm Lipid, Nycomed). LDL cholesterol was calculated according to the Friedewald formula: LDL cholesterol equals total cholesterol minus [HDL cholesterol plus (total triglyceride/2.20)] in millimoles per liter in subjects with total triglyceride level <4.5 mmol/L. Serum apo B and apo AI were determined from samples stored at -70^°C by a commercial immunochemical method (Kone Diagnostics) based on the measurement of immunoprecipitation at 340 nm.⁴¹

Research Design and Methods at Follow-up Study
Study Population and Follow-up Period
The follow-up study was conducted between March 1990 and June 1991. Of 1069 nondiabetic subjects who participated in the baseline study, 75 had died during the follow-up and 99 were not willing or were too ill to participate in the follow-up study. Thus, 895 subjects participated, giving an overall participation rate of 90%.

The follow-up period was defined as the period between the baseline and follow-up studies for those who participated. The mean follow-up period for the participants was 3.5 years (range, 2.7 to 5.2 years). Subjects were invited to the follow-up study in the same order in which they participated in the baseline study. For nonparticipants, the follow-up period was defined as the period between baseline study and June 30, 1991 (the day when the last subject participated in the follow-up study), and deaths and cardiovascular events during this period were recorded.

Diagnosis of New CHD Events
A conventional 12-lead ECG was taken, and ECG findings were classified according to the Minnesota code.²⁶ Symptoms suggestive of angina pectoris or MI were recorded with the Rose Cardiovascular Questionnaire²⁷ by the same specially trained nurse as in the baseline study. Medical records of those participants who reported hospitalization for chest pain or other symptoms suggestive of MI during the follow-up and of all nonparticipants and of those who died during the follow-up were reviewed by one of the authors (J.K.).

FINMONICA criteria for definite and possible MI based on chest pain symptoms, ECG changes, and enzyme determinations were used to ascertain a new MI during the follow-up period.^{28 29} Death certificates of all those who died during the follow-up were reviewed (J.K.). Hospital and autopsy records were used in the final classification of the causes of death. All deaths were coded according to ICD9.⁴²

CHD death during the follow-up was defined as a death caused by CHD (ICD9 codes 410 through 414). For participants, a new nonfatal MI during the follow-up was defined as follows: (1) a definite or possible MI verified at the hospital by the FINMONICA criteria^{28 29} or (2) a new major Q-QS change on the ECG (progression from no Minnesota Q-QS code to code 1.1 or 1.2 or from Minnesota Q-QS code 1.3 to 1.1). For nonparticipants, a new nonfatal MI was defined as a definite or possible MI verified at the hospital by the WHO criteria (because these subjects did not participate in the follow-up study, no new ECG was available for coding). All CHD events included CHD deaths or nonfatal MIs. If a subject had more than one CHD event during the follow-up, only one was included in the statistical analyses.

Diagnosis of New Stroke Events
Medical records of all nonparticipants and those who died during the follow-up, as well as medical records of those participants who reported hospitalization for symptoms suggestive of stroke during the follow-up, were reviewed by one of the authors (J.K.). Also, the death certificates of all those who died during the follow-up were reviewed (J.K.). Hospital and autopsy records were used in the final classification of the causes of death. All deaths were coded according to ICD9.⁴²

WHO criteria for verified and possible stroke were used in the ascertainment of a new stroke, which was defined as at baseline, ie, a clinical syndrome consisting of a neurological deficit observed by a neurologist and persisting over 24 hours (nonfatal stroke) in the absence of other diseases explaining the symptoms.³⁰ Death from stroke included the ICD9 codes 431 through 434. Thromboembolic and hemorrhagic strokes but not subarachnoid hemorrhage were included in the diagnosis of stroke. A computed tomograph was performed in most cases but was not required for the diagnosis of stroke. In the following analyses, nonfatal and fatal strokes are combined because of a limited number of stroke end points. If a subject had more than one stroke during the follow-up, only one stroke event was included in the statistical analyses.

Statistical Methods
Data analyses were conducted with the SPSS/PC+ programs. Data are given as mean±SEM or percentages. Student's two-tailed t test for independent samples, ² test, or ANOVA was used to assess the differences between the groups when appropriate. The comparison between the two groups in Table 2 was performed only if the probability value for ANOVA over the three groups was P<.05. Because triglyceride and insulin concentrations were not normally distributed, they were logarithmically transformed in all statistical analyses.

View this table: [in this window] [in a new window]   Table 2. Baseline Characteristics and Cardiovascular Risk Factors by Apo E4 Allele Number

Approval by the Ethics Committee
This study was approved by the Ethics Committee of the Kuopio University Hospital. All study subjects gave informed consent.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Altogether, 396 men and 671 women were included in the study. Table 1 shows the apo E phenotype distribution and the allele frequencies in our study population. As in most populations, the phenotype E3/3 was the most common, followed by the phenotype E4/3. Together, these two constituted 87.1% of all phenotypes. The phenotypes E2/3, E4/4, E4/2, and E2/2 formed the remaining 12.9% of the phenotypes. The allele frequencies were 77.8% for e3, 17.4% for e4, and 4.8% for e2.

View this table: [in this window] [in a new window]   Table 1. Distribution of Apo E Phenotypes in the Study Population, Lipoproteins by Apolipoprotein Phenotype, and Apo E Allele Frequencies by Sex

Total cholesterol, LDL cholesterol, and apo B levels according to the apo E phenotype are also shown in Table 1. Compared with phenotype E3/3, phenotype E2/3 was associated with lower levels of total and LDL cholesterol as well as a lower level of apo B. Phenotypes E4/3 and E4/4 were not associated with significantly higher levels of total or LDL cholesterol or apo B compared with phenotype E3/3.

To investigate the effect of the apo E e4 gene-dose on the risk of CHD and stroke, we determined both cardiovascular risk factors and the risk of CHD and stroke by the number of apo E e4 alleles (none=734, one=296 [E4/2 or E4/3], two=37 [E4/4]). As shown in Table 2, there were no significant differences in baseline characteristics and cardiovascular risk factors between the three groups, with the exception of angina pectoris, which was more common in the group with one apo e4 allele, and the concentration of apo B, which also was significantly higher in the group with one apo e4 allele compared with the group with no apo e4 alleles.

The incidence rates of CHD and stroke were defined as new fatal or nonfatal events during the 3.5-year follow-up. The cumulative occurrence rates of CHD and stroke were defined as all nonfatal events before the baseline examination and all fatal or nonfatal events during the 3.5-year follow-up combined. The 3.5-year CHD mortality in the whole study population was 2.8% (30/1067), the 3.5-year incidence of all CHD events 6.9% (74/1067), and the cumulative occurrence of all CHD events 17.0% (181/1067). The association of CHD mortality, CHD incidence, and cumulative CHD occurrence with apo e4 allele dose is shown in Fig 1. None of CHD event rates were related to increasing apo e4 dose. In contrast, the number of CHD events was somewhat decreased, albeit not significantly, in subjects with apo e4 homozygosity. The results were essentially similar in both sexes (data not shown).

View larger version (51K): [in this window] [in a new window]   Figure 1. Bar graph showing 3.5-year CHD mortality (front), CHD incidence (middle), and the cumulative occurrence of all CHD events (back) by the number of apo e4 alleles.

The 3.5-year incidence of stroke was 3.4% (36/1067), and the cumulative occurrence of stroke in the study population was 6.0% (64/1067). There was no significant association between apo e4 gene dose and the incidence of stroke or the cumulative occurrence of stroke (Fig 2). Subjects with apo e4 homozygosity had somewhat decreased risk for stroke. Because of the small number of stroke events, the analyses were not performed for stroke mortality or separately for men and women.

View larger version (77K): [in this window] [in a new window]   Figure 2. Bar graph showing 3.5-year stroke incidence (front) and cumulative occurrence of all stroke events (back) by the number of apo e4 alleles.

In addition, we examined the cardiovascular risk in subjects with phenotypes E2/2 and E2/3 (n=81). Compared with phenotype E3/3, there was a slight but insignificant decrease in CHD events. In contrast, there was no difference in stroke events between the two groups (data not shown).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, allele e4 of apo E was not a significant risk factor for CHD or stroke in elderly nondiabetic subjects. Neither incidence nor cumulative occurrence of CHD or stroke increased with increasing number of apo e4 alleles. In contrast to previous studies including young subjects and their age-matched control subjects, compared with the risk of subjects with no apo e4 allele, cardiovascular risk in subjects with apo e4 homozygosity was even slightly decreased.

Previous population-based studies have indicated that the traditional cardiovascular risk factors, such as male sex, smoking, high blood pressure, diabetes, and low HDL cholesterol, all predict cardiovascular disease not only in the middle-aged but also in the elderly.^{1 3 4} However, the relative risk of high cholesterol has been found to be much smaller in the elderly, and only large studies have been able to find any association between high cholesterol and cardiovascular risk in elderly subjects.^{1 2} Several studies show no association between the two in elderly populations,^{43 44 45} including our own previous study on the present study population.⁴⁶ In nondiabetic subjects, previous MI and male sex predicted CHD death, and in addition to these risk factors, systolic blood pressure, current smoking, and low HDL cholesterol predicted all CHD events.⁴⁶ Risk factors for stroke in nondiabetic subjects were previous stroke, hypertension, and high insulin concentration.⁴⁷ In contrast, total cholesterol was not associated with the risk of CHD or stroke.^{46 47}

Since the classic risk factors do not explain all cardiovascular morbidity and mortality, new risk factors have been sought. In recent years, apolipoproteins have been one of the main targets of interest. Apo E modulates lipoprotein transport and metabolism, and its polymorphism explains about 7% of cholesterol variation at the population level.⁶ In the studies on the middle-aged, apo E2 has been found to be associated with lower total and LDL cholesterol and apo B levels compared with apo E3⁸ ; conversely, apo E4 is associated with higher total and LDL cholesterol and apo B levels compared with apo E3.⁷ The risk of CHD in relation to apo E polymorphism has been investigated in about 20 studies.^{12 13 14 15 16 17 18 19 48 49 50 51 52 53 54} In 2 studies, the apo E genotype^{12 19} and in others the phenotype was determined. All but 2 studies have been case-control studies, and there are no previous prospective population-based studies. Moreover, most studies have included only subjects <65 years old, and the studies including subjects >65 years old have had a wide age range, including also younger subjects.^{13 50 52} In most studies, the apo e4 allele has been more frequent in patients with CHD than in control subjects.^{12 13 14 15 16 48 49 50 51 52 53 54} Van Bockxmeer and Mamotte¹² showed that in young men <40 years old referred to coronary angioplasty, apo e4 homozygosity was 16-fold compared with control subjects. Three case-control studies have not demonstrated an association between apo e4 allele frequency and CHD.^{17 18 19} There are 2 case-control studies on the impact of apo E polymorphism determined by phenotyping on the risk of stroke.^{20 21} Both studies also included elderly patients. One of the studies showed an association between apo e4 allele and stroke,²⁰ whereas the other showed an inverse association between apo e2 allele and stroke but no association between apo e4 allele and stroke.²¹

In the present study, cardiovascular risk factors were not affected by the number of apo e4 alleles, with the exception of apo B concentration, which was significantly higher in subjects with one apo e4 allele. In contrast to most previous studies,^{5 6} total and LDL cholesterol were not significantly higher in patients with the apo e4 allele, even though there was a slight trend toward higher total and LDL cholesterol levels in subjects with one or two apo e4 alleles. Moreover, the risk for CHD or stroke did not increase with the increment in the dose of apo e4 alleles. In contrast, the risk for cardiovascular events was smaller, even if insignificantly so, in subjects with apo e4 homozygosity. Our findings suggest that the importance of apo E polymorphism as a cardiovascular risk decreases with aging.

It is very likely that the apo e4 allele exerts its increased risk for CHD mainly in the middle-aged. Studies on both nondiabetic^{12 13 14 15 16} and diabetic subjects^{53 54} show a strong association between the apo e4 allele and CHD risk in subjects <40 years old. The present study supports this concept by demonstrating a relative loss of the apo e4 allele frequency (17.3%) compared with those of middle-aged and young Finnish populations (22.7% and 19.4%, respectively), which, in turn, are among the highest in the world.^{22 23} On the basis of our findings and previous studies, we can hypothesize that subjects with apo e4 are heterogeneous with respect to cardiovascular risk. A subset of subjects with the apo e4 allele die of CHD at a relatively young age. Another subset of apo e4–positive patients survive into old age and have a low risk for CHD. Interestingly, these same subjects are still at high risk for Alzheimer's disease, which is associated with the apo e4 allele.^{55 56 57 58 59 60} In fact, in a subpopulation of the present study, we have shown a striking impact of the number of apo e4 alleles on the risk of Alzheimer's disease. The prevalence of Alzheimer's disease was 2.9% in subjects with no apo e4 allele but 21.4% in subjects with two e4 alleles of apo E.⁶¹

Finally, why does the significance of the apo e4 allele as a cardiovascular risk factor decrease with aging? This lower risk may reflect the diminished impact of the apo e4 allele on LDL cholesterol level in old age⁶² or lower relative cardiovascular risk of cholesterol in elderly subjects.^{43 44 45 46} Alternatively, subjects with the apo e4 allele who survive into old age may have protective factors against cardiovascular disease. It remains to be shown whether genetic or environmental factors or their interaction explains this heterogeneity in cardiovascular risk in subjects with apo e4 alleles.

	Selected Abbreviations and Acronyms

 

apo = apolipoprotein CHD = coronary heart disease ECG = electrocardiogram ICD9 = ninth revision of the International Classification of Diseases MI = myocardial infarction WHO = World Health Organization

	Acknowledgments

 
This study was supported by grants from the Medical Research Council of the Academy of Finland, the Helena Vuorenmies Foundation, the Aarne and Aili Turunen Foundation, the Yrjö Jahnsson Foundation, the Finnish Heart Research Foundation, the Finnish Society of Cardiology, the Orion Corporation Research Foundation, and the Finnish Medicine Foundation. The authors thank Saija Kortetjärvi and Tuulikki Haataja for their skillful technical assistance.

Received February 19, 1995; accepted May 26, 1995.

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