Geographic Origin as a Determinant of Carotid Artery Intima-Media Thickness and Brachial Artery Flow-Mediated Dilation
The Cardiovascular Risk in Young Finns Study
Objective— People living in eastern Finland have ≈40% higher coronary heart disease mortality rates than western Finns. Whether this is because of genetic or environmental factors is unknown. We examined the effect of geographic family origin on subclinical atherosclerosis among young Finns.
Methods and Results— As part of a longitudinal follow-up study, we measured carotid intima-media thickness (IMT) in 2264 and brachial flow-mediated dilation (FMD) in 2109 white adults, aged 24 to 39 years. Subjects from eastern Finland had greater IMT and lower FMD compared with western subjects. These differences accentuated when the subjects’ family origin (grandparents’ birthplace) was taken into account and remained significant after adjusting for several environmental factors. Among subjects with all grandparents born in eastern or western Finland, IMTs were (mean±SEM) 0.592±0.003 versus 0.565±0.005 mm (P<0.0001), respectively. The corresponding FMD values were 7.61±0.15% versus 8.75±0.26%; P<0.01. The number of grandparents born in eastern Finland was directly related to IMT (P<0.0001) and inversely to FMD (P<0.05).
Conclusions— Young adults originating from eastern Finland have greater carotid IMT and lower brachial FMD than western Finns. Consistent with a hereditable component predisposing to or protecting from atherosclerosis, these differences accentuated when subjects’ family origin was taken into account.
Finland has high coronary heart disease (CHD) mortality, but the risk is unequally distributed within the country. People living in eastern Finland have ≈40% higher CHD mortality rates than those living in western Finland. In the Seven Countries Study in the 1960s1 and in the World Health Organization Monitoring Trends Determinants in Cardiovascular Disease (WHO MONICA) project in the 1980s,2 eastern Finnish men were leading the world statistics in CHD mortality. Higher rates for hypertension, smoking, and hypercholesterolemia in the eastern parts of the country were considered to explain the excess risk. Therefore, a national program, the North Karelia Project, was launched in the 1970s to influence diet and other lifestyles to lower risk factor levels.3 The results of this population strategy have been successful. From the 1970s, CHD mortality rates among working-age population have declined by 65% in the whole country.4 The differences in conventional risk factor levels between eastern and western Finland have become smaller because of adoption of similar lifestyle and diet.5 Despite these diminishing regional contrasts in risk factor levels and the overall decline in mortality, the gradient between the eastern and western parts of the country has remained virtually unchanged from the 1960s,6 with persistently higher mortality rates in the east. This may suggest that genetic differences exist in CHD susceptibility between the people of the eastern and western parts of the country.6 Although the Finnish population has previously been considered ethnically very homogenous,7 recent genetic analyses have provided evidence in support of 2 independent groups settling in Finland.8
In population studies, noninvasive ultrasound methods can be used to assess early vascular changes related to atherosclerosis. Increased carotid intima-media thickness (IMT) is a structural marker of subclinical atherosclerosis. It correlates with risk factors,9–11 relates to the severity of coronary artery disease,12 and predicts cardiovascular events in populations.13 The brachial artery flow-mediated dilation (FMD) is a functional marker of endothelial health. It has been shown to occur mainly in response to endothelial release of NO.14 Brachial FMD responses correlate with coronary endothelial function15 and predict future cardiovascular events in patient groups.16
The Cardiovascular Risk in Young Finns is a follow-up study of atherosclerosis precursors in children and young adults. The study was planned in the 1970s,17 and a main objective was to provide insight for the east-west difference in cardiovascular risk within Finland.18 The latest follow-up study was conducted in 200111,19 and included an ultrasound examination to assess carotid IMT and brachial FMD. We hypothesized that the geographic family origin of young adults in Finland would have influence on these preclinical vascular changes.
For a more detailed description, please see online data supplement, available at http://atvb.ahajournals.org.
The Young Finns Study was launched in 1980 and has been performed in 5 centers in Finland. The east-west division was made according to the epidemiologic borderline for CHD (Figure 1). A total of 3596 subjects, 1753 from east and 1843 from west, participated in 198018 (80% of those invited). In 2001, we re-examined 2264 of these individuals (now aged 24 to 39 years).19 Subjects gave written informed consent, and the study was approved by local ethics committees.
Height and weight were measured, and body mass index (BMI) was calculated. Blood pressure measurement values were obtained from 3-year-olds with an ultrasound device and from the older children and adolescents with a standard mercury sphygmomanometer.20 In 2001, a random zero sphygmomanometer was used.
Standard methods were used for serum lipids. Plasma high sensitive C-reactive protein (CRP) concentrations were analyzed by latex turbidometric immunoassay (Wako Chemicals GmbH). Birth weight, socioeconomic status (number of parental school years in 1980, number of own school years in 2001), alcohol use, smoking, physical activity, and diet (butter use, including butter-based mixtures, and daily use of vegetables) were acquired using questionnaires. Physical activity index was calculated by assessing the duration, intensity, and frequency of physical activity. Daily intake of energy and macronutrients were computed based on the 48-hour recall interviews (from half of the cohort). Details of methods have been presented previously.11,19,21
Ultrasound studies were performed using Sequoia512 ultrasound mainframes (Acuson). Carotid IMT was measured in 2264 subjects as described previously.11 The between-visit coefficient of variation (CV) of IMT measurements was 6.4%.11
Brachial artery studies were performed successfully for 2109 subjects as reported.22 The 3-month between-visit CV was 3.2% for brachial artery diameter and 26.0% for FMD.
Eastern and western subjects were first compared according to their baseline origin (1980) and current residency (2001). Then, the effect of family origin was assessed by comparing subjects with all 4 grandparents born in eastern or western Finland (n=1131). Finally, we correlated IMT and FMD values with the number of grandparents born in eastern Finland (n=1720; Figure I, available online at http://atvb.ahajournals.org).
Grandparents’ birthplaces were inquired in a questionnaire in 1980. Internal migration in Finland was sparse in the beginning of the 20th century and has increased since the 1920s.23 Therefore, we used grandparents’ birthplace to assess subjects’ geographic family origin.
Comparisons in clinical characteristics were performed using t test for continuous variables and χ2 test for categorical variables. The comparisons in ultrasound variables were performed with linear regression analysis adjusted for age (and for brachial diameter when comparing FMD). To study whether the east-west difference is independent of current risk factors and childhood risk factors identified 21 years earlier, we performed stepwise multivariate regression analysis with age and sex forced into the models. The relationships between the number of grandparents born in east and ultrasound variables were examined with linear regression analysis adjusted for age and sex (in FMD also for baseline brachial diameter).
Values for carotid IMT, triglycerides, and CRP were log10-transformed before analyses because of skewed distributions. To ease the interpretation of the results, mean and β-values are shown for nontransformed values. Statistical tests were performed with SAS, and statistical significance was inferred at a 2-tailed P value <0.05.
Biological Risk Markers
Adult (year 2001) and childhood (year 1980, baseline) characteristics of study subjects are shown in Table 1 according to their baseline origin. Compared with western men, eastern men had higher total cholesterol and diastolic blood pressure levels in childhood. In adulthood, there was a significant difference in blood pressure levels, but the difference in total cholesterol level was no longer significant. Compared with western women, eastern women had higher total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, blood pressure levels, and lower smoking rates in childhood. In adulthood, eastern women had higher high-density lipoprotein (HDL) cholesterol and blood pressure levels compared with western women.
Eastern men and women used butter more frequently and ate vegetables less frequently in childhood. In adulthood, the difference in vegetable consumption was observed only in women, and butter usage was more common among western than eastern women in 2001 (Table 1). In childhood, eastern men had greater daily intake of saturated (20.3±3.9% versus 19.5±3.9% of daily energy [E%]; P=0.01) and smaller intake of polyunsaturated fat (4.2±1.8 E% versus 4.8±1.9 E%; P=0.0002). In adulthood, these differences were no longer observed, but eastern men had higher carbohydrate intake (45.5±7.4 E% versus 44.0±7.5 E%; P=0.03). Among women, eastern subjects had smaller intake of polyunsaturated fat (4.0±1.5 E% versus 4.4±1.8 E%; P=0.002) in childhood, but in adulthood, no differences in nutrient intake were observed.
Carotid IMT and Brachial FMD
Subjects with baseline origin in eastern Finland had greater IMT than western subjects (Table 1; Figure 2). This difference accentuated when family origin was taken into account. When subjects were compared according to their current residency, the east-west difference was slightly attenuated (Figure 2). The effects of baseline and family origin on IMT remained significant after adjustments for childhood and current environmental factors (Table 2). A direct dose-response relationship was seen between the number of grandparents born in eastern Finland and carotid IMT (Figure 3).
A significant east-west difference was seen in brachial FMD when subjects were compared according to their baseline origin, and the difference accentuated when family origin was taken into account (Figure 2). The effect of family east-west origin on FMD remained significant after adjustments for childhood and current risk factors (Table 2). An inverse relationship was seen between the number of grandparents born in eastern Finland and brachial FMD (Figure 3).
During the ischemic phase of the FMD test, vasoconstriction may occur in subjects at risk, whereas in normal subjects, there may be a trend toward vasodilatation.24 In our cohort as a whole, a minor vasodilatation of the brachial artery was observed during cuff occlusion (Table 1), with no east-west difference in absolute or relative diameter change during the ischemic phase (P for both >0.05).
There is a loss of ≤17% of individuals in multivariate models adjusted for childhood risk factors (Table 2). The main reason for this is that data on birth weight (n=1913) were collected in the second follow-up in 1983. Therefore, the multivariate models were examined in 3 different ways: (1) as shown in table 2; (2) in the same cohort as in Table 2 but without birth weight data; and (3) in the total cohort without birth weight data. In all 3 different analyses, the east-west differences in IMT and FMD remained essentially similar.
Effect of Blood Pressure on East-West Difference in IMT and FMD
Because eastern subjects have higher blood pressure values, and blood pressure is a correlate for IMT and FMD, we made a further subgroup analysis to examine whether the east-west difference in ultrasound variables is influenced by blood pressure values. To study this, IMT and FMD data were analyzed after exclusion of subjects with high blood pressure levels (above age- and sex-specific 75th percentile). The east-west difference between subjects with all grandparents from east or west remained highly significant in IMT (P=0.0002) and FMD (P=0.0003; P=0.0008 after adjustment for brachial diameter) in this subgroup without significant differences in blood pressure values between eastern and western subjects (P=0.23; Table I, available online at http://atvb.ahajournals.org).
We found significant differences among healthy young adults in markers of subclinical atherosclerosis between east and west Finland. These differences were independent of environmental factors and accentuated when taking into account the subjects’ family origin. Our results thus suggest that hereditable factors have a role in explaining the east-west difference in CHD mortality within Finland.
Regional differences in subclinical markers of atherosclerosis have been studied previously by Jartti et al,25 who found that middle-aged men born in eastern Finland had greater carotid IMT compared with men born in western Finland. Our study showing higher IMT in young adults originating from east Finland confirms these findings. We could also demonstrate lower FMD, indicating reduced endothelial function in eastern subjects. Vascular endothelium protects arteries against development of atherosclerosis,26 therefore, these regional phenotype differences in FMD may provide insight for the variations in the atherosclerosis susceptibility between eastern and western subjects.
Our findings are also interesting in light of the previous pathological studies that have shown greater intimal thickening in coronary arteries in infants who have died and whose families originated from eastern Finland.27 These early morphological alterations seen in infants of eastern origin may thus represent a difference in the vulnerability on the vascular wall to extrinsic deleterious factors and point to a morphological manifestation of hereditary predisposition to CHD. Together, these findings support the theory that eastern and western Finns have a different genetic origin. A number of considerations have led to a suggestion that genetic differences might exist between the people of the western and eastern parts of the country. Besides CHD mortality distribution, this dualism is supported by anthropology, dialects, and frequencies of blood groups.6 Recent analyses concerning Y-chromosomal haplotype frequencies have strengthened this dual-origin theory by proving evidence in support of 2 independent groups settling in Finland: 1 from Asia and the other from central Europe.8
Alternatively, the east-west difference could be attributable to differences in exposures acting during childhood. Socioeconomic circumstances and related environmental exposures during childhood and even before birth28 may be important for future atherosclerotic risk. Observations from the Young Finns study11 and other prospective population-based studies indicate9,10 that exposure to CHD risk factors in childhood may induce changes in arteries that contribute to the development of increased IMT in adulthood. In the present study, serum total cholesterol concentration and blood pressure values were significantly higher in the east when the subjects were children and adolescents. In adulthood, a difference was still seen in blood pressure values. Eastern subjects came from families that, on average, had lower socioeconomic status than western subjects. In addition, in childhood, eastern subjects had less favorable dietary habits. Nevertheless, the east-west differences in IMT and FMD remained significant after controlling for these potentially modifying factors. Forsen et al29 have suggested that the shorter stature in eastern subjects may partly explain the east-west difference in CHD risk. In the present study, men and women from eastern Finland had lower adult height, although the heights were similar in childhood. In men, the birth weight also tended to be lower in eastern subjects (P=0.06). However, adjustment for height and weight data did not dilute the east-west differences in IMT and FMD.
Young and healthy individuals with a positive family history of CHD, but without other major risk factors, have evidence of increased IMT and decreased FMD.30 We found increased IMT and decreased FMD in a population group of young adults originating from a geographic area characterized by excess CHD risk. These observations indicate that a genetic predisposition for CHD influences arterial structure and function before manifestation of CHD. The specific genetic determinants of IMT and FMD are inadequately known. We are currently conducting genetic analysis in this cohort in an attempt to provide more specific insight for the east-west difference.
In the present study, traditional risk factors did not correlate very strongly with brachial FMD. We reported recently in detail the interrelations between traditional risk factors and FMD in the Young Finns cohort.22 We found that FMD was directly related to HDL-cholesterol and BMI and inversely with systolic blood pressure. We could not demonstrate a significant correlation between FMD and LDL-cholesterol, nor between FMD and smoking. The direct correlation between FMD and BMI was an unexpected finding. During closer examination, this relationship seemed to be curvilinear, so that BMI was directly related to enhanced FMD only within nonobese range. The relationship was not explained by brachial artery diameter or any measured risk factor.22
In childhood, eastern subjects had higher cholesterol and blood pressure levels compared with western subjects. In adulthood, the east-west difference in serum cholesterol concentration was clearly diminished, but the difference in blood pressure levels was similar as in childhood. The diminishing regional contrast in serum cholesterol concentration is consistent with the changes in the dietary preferences between east and west Finland also observed in the present study (eg, reduction in butter use and saturated fat intake in the eastern subjects). Genetic differences have been suggested to partly explain regional differences in serum cholesterol concentrations within Finland. Therefore, the present observations may be in line with the notion that changes in environmental conditions may mask the effect of the genetic determinants.
Subjects’ family origin was assessed according to their grandparents’ birthplaces acquired by questionnaire. However, because most of the grandparents were born around 192031 and the migration between areas as large as the division used in this study was scarce before the 1920s,32 we believe that grandparents’ birthplaces reflect reliably the origin of the ancestors of the study subjects.
We found large variation in FMD measurements (CV 26%) but small variation in brachial artery diameter measurements (CV 3%). Thus, much of the long-term variation of FMD is attributable to physiological fluctuation in endothelial function and not to measurement error. We did not measure endothelium-independent nitrate-mediated vasodilatation that is often included as a control test for the FMD test to ensure that the decreased FMD capacity observed is a consequence of endothelial dysfunction not a reflection of underlying smooth muscle dysfunction. However, nitrate-mediated arterial relaxation also seems to attenuate in the process of atherosclerosis.33,34
We conclude that irrespective of risk factors levels, young adults originating from eastern Finland have higher carotid IMT and lower brachial FMD than those originating from western Finland. Consistent with a hereditable component predisposing or protecting from atherosclerosis, these differences accentuated when the subjects’ family origin was taken into account. These results support the dual-origin theory of Finns and suggest that genetic factors have a role in explaining the east-west difference in CHD mortality within Finland.
This study was financially supported the Academy of Finland (grants 53392 and 34316), special federal grants for the Turku University Hospital, the Social Insurance Institution of Finland, the Turku University Foundation, the Juho Vainio Foundation, the Finnish Foundation of Cardiovascular Research, the Lydia Maria Julin Foundation, the Research Foundation of Instrumentarium, the Research Foundation of Orion Corporation, the Maud Kuistila Foundation, and the Finnish Cultural Foundation.
- Received May 31, 2004.
- Accepted October 7, 2004.
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