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In myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN), bone marrow (BM) histopathology is assessed to identify dysplastic cellular morphology, cellularity, and blast excess. Yet, other morphologic findings may elude the human eye. We used convolutional neural networks to extract morphologic features from 236 MDS, 87 MDS/MPN, and 11 control BM biopsies. These features predicted genetic and cytogenetic aberrations, prognosis, age, and gender in multivariate regression models. Highest prediction accuracy was found for TET2 [area under the receiver operating curve (AUROC) = 0.94] and spliceosome mutations (0.89) and chromosome 7 monosomy (0.89). Mutation prediction probability correlated with variant allele frequency and number of affected genes per pathway, demonstrating the algorithms' ability to identify relevant morphologic patterns. By converting regression models to texture and cellular composition, we reproduced the classical del(5q) MDS morphology consisting of hypolobulated megakaryocytes. In summary, this study highlights the potential of linking deep BM histopathology with genetics and clinical variables., Significance: Histopathology is elementary in the diagnostics of patients with MDS, but its high-dimensional data are underused. By elucidating the association of morphologic features with clinical variables and molecular genetics, this study highlights the vast potential of convolutional neural networks in understanding MDS pathology and how genetics is reflected in BM morphology. See related commentary by Elemento, p. 195., (©2021 American Association for Cancer Research.)

The pathogenetic mechanisms behind familial combined hyperlipidemia (FCHL) are unknown. However, exaggerated postprandial lipemia and excessive serum free fatty acid (FFA) concentrations have drawn attention to altered lipid storage and lipolysis in peripheral adipose tissue. Hormone-sensitive lipase (HSL) is the enzyme responsible for intracellular lipolysis in adipocytes and a decrease of adipocyte HSL activity has been demonstrated in Swedish FCHL subjects. The aim of the study was to investigate if adipose tissue HSL activity had any effect on lipid phenotype and if low HSL activity and FCHL were linked in Finnish FCHL families. A total of 48 family members from 13 well-characterized Finnish FCHL families and 12 unrelated spouses participated in the study. FCHL patients with different lipid phenotypes (IIA, IIB, IV) did not differ in adipose tissue HSL activity from each other or from the 12 normolipidemic spouses (P = 0.752). In parametric linkage analysis using an affecteds-only strategy the low adipose tissue HSL activity was not significantly linked with FCHL phenotype. However, we found a significant sibling-sibling correlation for the HSL trait (0.51, P < 0.01). Thus, a modifying or interacting role of HSL in the pathogenesis of FCHL could not be excluded.

The socioeconomic status (SES) of the family influences the cardiovascular risk status of children and adolescents; however, it is not as well known whether parental SES has any effect on the risk factor profile of young adults. The aim of the present study was to investigate the relations of different aspects of parental SES, namely occupation, education, income and living area, to the common cardiovascular risk factors of their offspring (n = 919) aged 18, 21 and 24 years as a part of the Cardiovascular Risk in Young Finns Study in 1986. Subjects from farming families and rural areas had the highest serum total and low-density lipoprotein cholesterol values, and the lowest diastolic blood pressure compared with subjects from other occupational groups and subjects from urban regions. The diet of young adults from farming families and from rural areas contained more saturated fatty acids and less monounsaturated and polyunsaturated fatty acids. In addition, the body mass index was lower in subjects from urban regions compared with rural regions, and physical inactivity was less common in the urban group. Subjects with the highest parental occupational status smoked less compared with those with the lowest status. Parental education related inversely to physical inactivity and directly to dietary polyunsaturated fatty acids. The income level of the family associated positively with frequent inebriation by alcoholic beverages and inversely with the percentage of dietary energy from fat. In conclusion, there were modest inverse associations between different indicators of the SES of parents and some of the traditional risk factors of their offspring in young adulthood, which may contribute to the future risk of cardiovascular diseases.

Background: Low educational level is associated with an increased risk of coronary heart disease. The aim of the present study was to examine the relationships between education and common cardiovascular risk factors in young adults., Methods: Trends in conventional risk factors of young adults aged 21, 24, 27 and 30 years in 1992 (n = 443) were examined across the educational groups as part of a 12-year follow-up study, the Cardiovascular Risk in Young Finns Study. Education was determined as participants' own educational level and as parental years of schooling., Results: In males, subject's own education was related inversely and independently of parental school years to serum total and low density lipoprotein (LDL) cholesterol concentration, smoking and body mass index. In females, participant's own educational level associated inversely with smoking and physical inactivity. Parental school years was associated inversely and independently of one's own educational level with serum total and LDL cholesterol values and waist-hip ratio in females. In both genders, parental education was a stronger determinant of diet (butter use) than one's own educational level., Conclusions: The least educated young adults have adopted a more adverse lifestyle than the more educated. The risk factor profile in young adulthood, especially in females, is still affected by parental education. The influences of one's own and parental educational level on vascular risk profile should be taken into consideration when planning public health campaigns among young adults.

Complex disorders are caused by several environmental factors that interact with multiple genes. These diseases are common at the population level and constitute a major health problem in Western societies. Familial combined hyperlipidemia (FCHL) is characterized by elevated levels of serum total cholesterol, triglycerides, or both. This disorder is estimated to be common in Western populations with a prevalence of 1% to 2%. In addition, 14% of patients with premature coronary heart disease (CHD) have FCHL, making this disorder one of the most common genetic dyslipidemias underlying premature CHD. Both genetic and environmental factors are suggested to affect the complex FCHL phenotype, but no specific susceptibility genes to FCHL have been identified. It is hoped that further analysis of the first FCHL locus and other new loci obtained in genome-wide scans will guide us to genes predisposing to this complex disorder.

More than half of the patients with angiographically confirmed premature coronary heart disease (CHD) have a familial lipoprotein disorder. Familial combined hyperlipidaemia (FCHL) represents the most common genetic dyslipidemia with a prevalence of 1.0-2.0%. FCHL is estimated to cause 10-20% of premature CHD and is characterized by elevated levels of cholesterol, triglycerides, or both. Attempts to characterize genes predisposing to FCHL have been hampered by its equivocal phenotype definition, unknown mode of inheritance and genetic heterogeneity. In order to minimize genetic heterogeneity, we chose 31 extended FCHL families from the isolated Finnish population that fulfilled strictly defined criteria for the phenotype status. We performed linkage analyses with markers from ten chromosomal regions that contain lipid-metabolism candidate genes. One marker, D1S104, adjacent to the apolipoprotein A-II (APOA2) gene on chromosome 1, revealed a lod score of Z = 3.50 assuming a dominant mode of inheritance. Multipoint analysis combining information from D1S104 and the neighbouring marker D1S1677 resulted in a lod score of 5.93. Physical positioning of known genes in the area (APOA2 and three selectin genes) outside the linked region suggests a novel locus for FCHL on 1q21-q23. A second paper in this issue (Castellani et al.) reports the identification of a mouse combined hyperlipidaemia locus in the syntenic region of the mouse genome, thus further implicating a gene in this region in the aetiology of FCHL.

Background: Familial combined hyperlipidaemia (FCHL) is a common hereditary disorder. Hypertriglyceridaemia is associated with glucose intolerance and insulin resistance., Methods: To study glucose tolerance in FCHL patients with different lipid phenotypes [hypercholesterolaemia (IIA), mixed hyperlipidaemia (IIB), hypertriglyceridaemia (IV)], we investigated 253 family members and 92 spouses arising from 33 well-defined Finnish FCHL pedigrees., Results: In oral glucose tolerance tests the affected family members had higher values for glucose area under the curve than did non-affected family members [673+/-127 min mmolL(-1), 754+/-145 min mmol L(-1), 846+/-180 min mmol L(-1) and 838+/-183 min mmol L(-1) for phenotypes normal, IIA, IIB and IV respectively; P < 0.001 after adjustment for body mass index, waist circumference and age]. Impaired glucose tolerance and diabetes were more common among affected than non-affected family members (prevalences of normal glucose tolerance 94.0%, 80.0%, 54.3% and 58.5% for phenotypes normal, IIA, IIB and IV)., Conclusion: Affected FCHL family members were more glucose intolerant than non-affected family members. In men, this disturbance was not related to lipid phenotype nor was it explained by obesity.

Familial combined hyperlipidaemia (FCHL) is one of the most common hereditary disorders predisposing to early coronary death. The affected family members have elevations of serum total cholesterol, triglycerides or both. Despite intensive research efforts the genetic and metabolic defects underlying this complex disorder are still unknown. To dissect the metabolism and genetics of FCHL the phenotype of an individual must be precisely defined. We assessed the influence of different diagnostic criteria on the phenotype definition and studied factors affecting the phenotype expression in 16 large Finnish families (n = 255) with FCHL. The fractile cut-points used to define abnormal lipid values had a profound influence on the diagnosis of FCHL. If the 90th percentile cut-point was used, approximately 45% of the family members were affected, in concord with the presumed dominant mode of transmission for FCHL. If the 95th percentile was used only 22% of study subjects were affected. To characterize the metabolic differences or similarities between the different lipid phenotypes, we determined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles separated by ultracentrifugation. In linkage analysis no single ultracentrifugation variable could discriminate reliably affected family members from non-affected family members. Our data emphasizes the need for re-evaluation of FCHL diagnostic criteria. Preferably, the diagnosis should be based on a single, reliable metabolic marker.

Risk factors such as high serum cholesterol concentration measured in young adulthood predict premature coronary heart disease (CHD) in the middle-aged. The objective of this study was to analyze the associations between physical activity and CHD risk factors--body composition, blood pressure, serum lipids, apolipoproteins, and insulin--in children and young adults. The design was a cross-sectional study of atherosclerosis precursors in children and young adults using a cohort of children and young adults (N = 2,358) aged 9 to 24 years to determine indices of physical activity, measurements of anthropometric characteristics, blood pressure, serum lipids, apolipoproteins A-I and B, and insulin. The results show that a high level of physical activity was associated with high serum high density lipoprotein cholesterol (HDL-C) and HDL2-C concentrations, and low levels of serum triglycerides (TG), apolipoprotein B and insulin in males. However, in females, the influence of physical activity was evident only on TG level. In both genders, physical activity was inversely associated with obesity. In all these associations, a significant dose-related relationship was observed. We found no association between physical activity and blood pressure. In conclusion, physical activity is associated with a favorable serum lipid profile already during childhood and early adulthood in a dose-related manner, particularly in males. The promotion of physical activity is important in childhood in preventing obesity and premature cardiovascular disease.

To assess secular trends in serum lipid levels in Finnish children and young adults, the authors examined a total of 3,517, 2,769, 2,392, 352, and 880 subjects who had complete data on serum lipids in 1980, 1983, 1986, 1989, and 1992, respectively, in a longitudinal follow-up study. Trend analyses were carried out among subjects aged 15 (n = 1,835) or 18 (n = 1,562) years to exclude the confounding effect of age on the study variables. Data on obesity, physical activity, smoking, and alcohol use were available from each study year, and data on diet were available for the study years 1980, 1986, and 1992. Between 1980 and 1992, mean total cholesterol levels decreased from 4.88 to 4.47 mmol/liter (from 189 to 173 mg/dl), and low density lipoprotein cholesterol levels decreased from 3.06 to 2.85 mmol/liter (from 119 to 110 mg/dl). The mean high density lipoprotein cholesterol levels decreased by 19%, from 1.43 to 1.15 mmol/liter (55.2 to 44.6 mg/dl). During 1986-1992, triglyceride levels increased by 15%, from 0.88 to 1.01 mmol/liter (78.2 to 89.9 mg/dl). During 1980-1992, body mass index values increased from 20.8 to 21.8 kg/m2, parallel to increases in skinfold thickness. In the diet, the ratio of polyunsaturated to saturated fatty acids increased from 0.26 to 0.39. Alcohol and oral contraceptive use became more frequent, and the subjects tended to become less physically active. In conclusion, a change in the lipid profile in Finnish adolescents aged 15 and 18 years and young adults during 1980-1992 was observed, characterized by a decrease in low density lipoprotein cholesterol and high density lipoprotein cholesterol levels and an increase in triglyceride level. Possible determinants for these changes include alterations in diet and a trend toward increased obesity.

The effect of diet on blood lipids has been under intensive study during recent decades. However, diet in the context of the hyperapobetalipoproteinemia (hyperapoB) phenotype has received less attention. The hyperapoB phenotype is commonly encountered in patients with premature coronary heart disease. It is defined as a combination of an increased concentration of apolipoprotein B (apo B), a normal concentration of LDL cholesterol (LDL-C), and as a result, a low LDL-C/apo B ratio. We studied the associations between diet and blood lipids in a cohort of 534 children and young adults 9 to 24 years old. The ratio of polyunsaturated to saturated fats (P/S ratio) correlated (r=-0.19, P<.001) with the LDL-C/apo B ratio. This association was also found when the model was adjusted with triglycerides (r=-0.24, P<.001). A change in the P/S ratio from 0.10 to 0.60 corresponded to a decrease of 0.12 in the LDL-C/apo B ratio, and in the highest apo B decile, the P/S value was higher in hyperapoB individuals (0.33) than in others (0.28, P=.019). Our results imply that the fatty acid composition of the diet may be one of the environmental factors that influence the hyperapoB phenotype expression.

Familial combined hyperlipidemia (FCHL) is characterized by different lipid phenotypes (IIa, IIb, IV) and elevated apolipoprotein B (apo B) levels in affected family members. Despite intensive research, the genes involved in the expression of this complex disorder have not been identified, probably because of problems associated with phenotype definition, unknown mode of inheritance, and most probably genetic heterogeneity. To explore the genetics of FCHL in the genetically homogeneous Finnish population, we collected 14 well-documented Finnish pedigrees with premature coronary heart disease and FCHL-like dyslipidemia. The lipolytic enzymes lipoprotein lipase (LPL), hepatic lipase (HL), and hormone-sensitive lipase (HSL) were selected as initial candidate genes because of their central roles in apo B and triglyceride metabolism. On the basis of the pedigree structures, a dominant mode of inheritance was adopted for linkage analyses, and serum total cholesterol and/or triglyceride levels exceeding the 90th percentile level were set as diagnostic criteria (criterion 1). In pairwise linkage analyses with intragenic markers, no evidence for linkage was found. Instead, the significantly negative LOD scores suggested exclusion of all three loci for single major gene effect. LOD scores were -14.63, -5.03, and -5.70 for the three LPL polymorphisms (theta=0.00); -9.40, -6.30, and -4.74 for the three HL polymorphisms (theta=0.00); and -15.29 for the HSL polymorphism (theta=0.00). The results were very similar when apo B levels over the 90th percentile were used as criteria for affected status (criterion 2). Also, when linkage calculations were carried out using an intermediate or recessive mode of inheritance, the results of pairwise linkage analysis remained negative. Furthermore, when haplotypes were constructed from multiple polymorphisms of the LPL and HL genes, no segregation with the FCHL phenotype could be observed in the 14 Finnish families. Data obtained by the affected sib-pair method supported these findings, suggesting that the LPL, HL, or HSL genes do not represent major loci influencing the expression of the FCHL phenotype.

Familial combined hyperlipidemia (FCHL) is one of the most common inherited lipid disorders. Resistance of adipocytes to the effects of acylation stimulating protein (ASP) may contribute to ineffective triglyceride synthesis and thereby prolonged postprandial lipemia and increased fatty acid flux to the liver seen in FCHL patients. Interestingly, ASP is identical to C3a-desArg, fragment of the third component of complement. We examined the relationships between serum levels of complement components C3 and C4 and markers of lipid and glucose metabolism in 11 large FCHL families (n = 53). Median serum C3 levels were 38% higher in affected compared to non-affected male FCHL family members (1.90 g/l vs. 1.38, P = 0.0027). The strongest correlations were observed between serum complement C3 and apolipoprotein B levels, reaching 0.77 in males. These relations were not confounded by obesity or impaired glucose tolerance. In conclusion, serum levels of the main complement components C3 and C4 correlated significantly with serum lipid levels. Further studies are needed to clarify the importance of disturbances in the complement system on the pathogenesis of FCHL and other lipid disorders.

Background: The influence of parental occupation on selected coronary heart disease risk factors was studied in a cohort of Finnish children aged 9, 12 and 15 years (n = 1211) as part of the Cardiovascular Risk in Young Finns Study in 1986., Methods: The relationships of parental occupation to serum lipid and apolipoprotein concentrations, blood pressure, obesity, smoking, physical activity, diet and birthweight were examined. The occupation of the parents was obtained by a questionnaire and classified as I: upper non-manual (22%), II: lower non-manual (26%), III: upper manual (32%), IV: lower manual (5%) and F: farmers (15%)., Results: Highest serum total and how density lipoprotein cholesterol concentrations were found in classes IV and F. Boys from class IV had 7.1% higher total cholesterol concentrations compared to class I (4.98 mmol/l versus 4.65 mmol/l, P = 0.0033), whereas farmers' girls had 10.4% higher concentrations than girls from class III (5.31 mmol/l versus 4.81 mmol/l, P = 0.0057). Blood pressure was related to parental occupation only in boys, and the values were highest in class F. Boys from class IV smoked most often, and they also had lowest values for physical activity index and highest obesity indices. Farmers' children consumed significantly more saturated fat and cholesterol than children from other classes. In boys, the percentage of subjects with a low birthweight (< or = 10th percentile) was smallest in class I and greatest in class IV (7.1% versus 20.7%, P = 0.0330)., Conclusions: Socioeconomic status based on parental occupation is associated with several coronary heart disease risk factors already present in children. These differences should be taken into account in prevention programmes aimed at children at an increased risk for developing coronary heart disease as adults.

Serum lipoproteins are related to vascular atherosclerotic changes as seen in necropsy studies of child fatal accident victims; therefore, efforts have been made to reveal the determinants of lipoprotein metabolism in children and young adults. Recent data emphasize the adverse effects of obesity, insulin resistance and high fat intake on lipid profiles of children, and currently many lifestyle and dietary intervention studies are in progress. Detection of hereditary dyslipidemias in childhood is presently hampered by diagnostic problems. However, with the advent of efficient tools for genetic mapping, early diagnosis of common genetic dyslipidemias will probably be possible in the near future.

Apolipoprotein E (apo E) determines serum total (TC) and low-density lipoprotein (LDL-C) cholesterol concentrations and is thus associated with coronary heart disease (CHD) risk. We studied if the effect of physical activity (PA) on serum TC and LDL-C concentrations varies with apo E phenotype in a population-based sample of children and young adults with regular PA. The study cohort consisted of subjects aged 9, 12, 15, 18, 21, and 24 years in 1986 (N = 1,498) participating in a large multicenter study of cardiovascular risk factors in children and young adults. Serum lipid concentrations were determined enzymatically, and apo E phenotypes by isoelectric focusing and immunoblotting. The composition of the diet was determined by a 48-hour recall method, and a PA index was calculated on the basis of frequency, intensity, and duration of activity assessed by a questionnaire. LDL-C (P = .0082), TC (P = .014), and the high-density lipoprotein cholesterol (HDL-C)/TC ratio (P = .0004) responses to exercise varied with apo E phenotype. The effect of PA on LDL-C, TC, or HDL/TC was not found in apo E phenotype E4/4. A moderate inverse effect of PA on TC and LDL-C and a positive effect on HDL/TC was found in subjects with E4/3 and E3/3 phenotypes. Similar but stronger associations were found between these variables within the group of E3/2 males. The effect of PA on serum lipid levels was strongest within the phenotype E3/2. These associations were not explained by dietary habits. Apo E phenotype partly determines the effect of PA on serum TC and LDL-C in Finnish male children and young adults with regular PA.

Daily smoking and use of alcohol have a many-fold influence on lipid metabolism. The relations between HDL-cholesterol, alcohol use and smoking are well known. During recent years, the influence of smoking on postprandial lipid and glucose metabolism, and on insulin sensitivity in particular, has gained increasing attention. In addition, new data have emerged about the oxidative properties of alcohol use and smoking. As life habits tend to show clustering, isolating mechanisms responsible for the lipid changes induced by smoking or alcohol per se is difficult and is one factor causing contradiction in this study area.

In adults, the high-density lipoprotein cholesterol (HDL-C) level is higher among physically active subjects. However, the association of physical activity and HDL-C is less well studied in adolescents and young adults. Furthermore, it is not known whether the effect of physical activity on HDL-C levels is independent, or whether it is mediated by other physiological changes seen in exercise, such as weight loss or increased insulin sensitivity. In order to study the effects of leisure-time physical activity on the levels of serum HDL-C concentration, we analysed longitudinal data from a follow-up study of adolescents and young adults. The study subjects were participants of a large multicentre study of cardiovascular risk factors, aged 15-21 years at the beginning of the study (n = 714). HDL-C was measured from the serum supernatant after precipitation with dextran sulphate and MgCl2. A physical activity index was calculated on the basis of frequency, intensity, and duration of leisure-time activity assessed by a questionnaire. In males, an increase in the physical activity level predicted an increase in HDL-C concentration, and this association persisted after simultaneously controlling for changes in body mass index (kg/m2), subscapular skinfold thickness, serum insulin and triglyceride concentrations, and smoking. For example, an increase in the physical activity level corresponding to approximately 1 hour of intensive exercise weekly lead to an increase of 42 mumol/L in HDL-C as calculated from the regression equation. In conclusion, physical activity seems to have a direct effect on HDL-C levels among young male subjects within the usual range of physical activity levels.

Hyperapobetalipoproteinemia (hyperapoB) is one of the most common phenotypes in patients with premature coronary heart disease. In this study the factors that affect the expression of the hyperapoB phenotype were evaluated in young individuals. A cohort of 1125 children and young adults aged 9-24 years was classified into three groups by sex: (1) normal serum apolipoprotein B (apoB), (2) high apoB (> or = 90th percentile) and normal low density lipoprotein cholesterol (LDL-C < 90th), (3) high apoB and high LDL-C (> or = 90th percentile). In females, alcohol use (11, 33, 0%, in groups 1-3, P < 0.05) and oral contraceptive use (35, 83, 47%, P < 0.01) were significantly different between the groups and the highest frequencies were seen in the hyperapoB group (group 2). In both sexes smoking tended to be more common in the hyperapoB group (29, 43, 18%, P < 0.14). The two hyperapoB definition criteria (high apoB and low LDL-C/apoB ratio) were studied with multiple linear regression analyses. Oral contraceptive use correlated positively with apoB values (coefficient beta = 0.101, R2 = 2.1%, P < 0.01) and negatively with LDL-C/apoB ratio (beta = -0.134, R2 = 3.3%, P < 0.001). Alcohol use (beta = -0.072, R2 = 2.9%, P < 0.001) and smoking (beta = -0.050, R2 = 1.0%, P < 0.05) correlated negatively with LDL-C/apoB ratio. Prevalence of the hyperapoB phenotype was 4.4%. According to the results, the expression of the hyperapoB phenotype may be influenced by common lifestyle habits. This should be considered if high risk young individuals are identified through the expression of the hyperapoB phenotype.

Previous studies have reported increasing trends in physical activity in the Finnish population. These reports have not, however, included the perspective of cardiorespiratory stress in adolescent and young adults. We examined the present patterns of physical activity among Finnish adolescents and young adults in 1992. We specifically assessed whether the young people experience the volume of physical activity that is believed to stress the cardiorespiratory system appropriately in order to increase the level of fitness. The subjects in the present study were participants of a large multicenter study of atherosclerosis precursors in children and young adults. Physical activity was measured with a self-administered questionnaire in 2255 adolescents and young adults (1015 males and 1240 females). The proportion of subjects undertaking the volume of physical activity believed to benefit the cardiorespiratory system appropriately was 19%. The proportion was higher in males than in females (26 vs 13%). The proportion of active subjects became smaller in older age groups in both sexes. Half the study population (51% of the males; 48% of the females) reported frequent leisure-time physical activity less than once a month. In conclusion, Finnish adolescents and young adults have low levels of physical activity on the average, and many young Finns seldom undertake the volume of physical activity believed to benefit the cardiopulmonary system. Young males seem to be physically more active than females.

In adults hyperinsulinaemia is associated with an atherogenic risk profile including obesity, low levels of HDL-cholesterol, high levels of triglycerides and elevated blood pressure. To examine these associations in the young we studied the cross-sectional relationships of insulin with obesity indices (body mass index, subscapular skinfold thickness), serum lipids and blood pressure in 1,865 children, adolescents and young adults aged 6-24 years. We also used longitudinal data to study the value of a single insulin measurement to predict high risk factor levels and clustering of multiple risk factors after a 6-year follow-up. In cross-sectional analyses the levels of triglycerides, HDL-cholesterol, systolic blood pressure and obesity indices were usually significantly different across the quartiles of fasting insulin in both sexes among children, adolescents and young adults. In general, no associations were seen with total cholesterol or LDL-cholesterol. In prospective analysis elevated baseline insulin was related to the incidence of hypertriglyceridaemia (> or = 95th percentile) at the follow-up. This relationship persisted even after adjustments for baseline obesity or 6-year change in obesity status. Moreover, baseline insulin concentration was higher in subjects who subsequently showed clustering of high triglycerides, low HDL-cholesterol and high systolic blood pressure levels at the follow-up. We conclude that high fasting insulin levels measured in children and adolescents predict the development of hypertriglyceridaemia years later. In addition, high insulin levels seem to precede the development of a potentially atherogenic risk factor profile including low HDL-cholesterol, high triglycerides and high systolic blood pressure.

The authors studied the occurrence of common lifestyle risk factors, namely, nonprudent diet, smoking, physical inactivity, and frequent inebriation by alcohol in a cohort of young adults aged 18, 21, and 24 years (n = 484) as part of the Cardiovascular Risk in Young Finns Study in 1986. Risk habits showed significant clustering; the number of subjects was greater than expected in groups with zero and three of four risk habits and less than expected in the group with only one or two risk habits. Stepwise logistic regression analysis was used to find independent determinants for this clustering from a set of socioeconomic, demographic, and behavioral (type A components) determinants. The logistic model suggested several independent risk factors for risk habit clustering. These included male sex, aggressiveness, and past unemployment. Paying a lot of attention to health habits, higher education (being a student), good self-perceived health, and a high sense of responsibility seemed to be protective factors against risk habit clustering. The accumulation of risk habits was also associated with an atherogenic lipid and blood pressure profile (clustering of high density lipoprotein cholesterol/total cholesterol ratio, triglycerides, and diastolic blood pressure in their extreme tertiles). These findings show that common risk habits cluster among young adults. Knowledge about the determinants of this clustering will aid in the planning of future preventive strategies against cardiovascular diseases in young people.

We have studied the influence of oral contraceptive use on lipoprotein (a) levels in a cohort of women aged 18, 21 and 24 years (n = 559). Data was available on oral contraceptive formulation and dosage, anthropometric variables, exercise, serum lipoprotein (a), insulin, lipid and apolipoprotein levels. Lipoprotein (a) was determined by radioimmunoassay. Differences were assessed with non-parametric statistical methods. Forty per cent of the study women used oral contraceptives. The use of desogestrel-containing monophasic preparations was associated with lower levels of lipoprotein (a) compared to triphasic/levonorgestrel formulations or to non-users (P = 0.005). This effect was seen only in non-smoking women. Oral contraceptive users had higher levels of serum apolipoprotein B, HDL3-cholesterol, apolipoprotein A-I, triglycerides and systolic blood pressure, and lower serum lecithin:cholesterol acyltransferase activity. Lifestyle factors (smoking, exercise) showed no significant influence on lipoprotein levels. In conclusion, the use of desogestrel-containing oral contraceptives has a marked lowering effect on lipoprotein levels. Prospective studies will be needed to assess the net influence of oral contraceptive use on cardiovascular health.

We studied tracking of serum lipids in children and young adults (n = 248) during a 12-year follow-up. A novel method was developed for assessing tracking. It was based on the calculation of the absolute width of the individual track consisting of 5 serum lipid determinations. The total cholesterol (TC) track width tended to be broader in females compared to males (1.33 versus 1.24 standard deviation (SD) units). Approximately 35, 39, 24 and 13% of subjects had all 5 measurements within 1 SD (of the cohort mean) from serum TC, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglycerides, respectively. However, variations in excess of 2.5 SDs were not rare. We also assessed the dependence of tracking on the absolute lipid level by calculating the SD of the standardized 6-year change in a cohort of 2236 children. In each serum lipid variable studied, lowest degree of tracking was found in highest lipid values. The mean changes were also largest in extreme values due to regression toward mean phenomenon. Our findings indicate that the width of longitudinal track of serum lipids may be two wide to reliably detect high risk children. Further, the track width was even broader in subjects with extreme serum lipid values.

The authors analyzed tracking and predictiveness of serum lipid and lipoprotein measurements in Finnish children and young adults over a 12-year follow-up period. A representative sample of 3,596 healthy subjects aged 3-18 years was examined in 1980. The follow-up studies were done in 1983, 1986, 1989, and 1992. Data were available on serum lipids and lipoproteins, anthropometric measurements, dietary and smoking habits, and use of oral contraceptives. Complete data on serum lipids in 1980 and 1992 were available for 883 subjects (47% males), and they comprised the study cohort for this analysis. Significant tracking was found in each of the serum lipid variables studied. The range of 12-year correlations was 0.48-0.58, 0.53-0.58, 0.53-0.58, 0.57-0.59, and 0.33-0.37 for serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, the LDL:HDL cholesterol ratio, and triglycerides, respectively. Males showed more tracking than females; there was no clear age trend. Tracking of HDL2 cholesterol was better than that of HDL3 cholesterol (0.64 vs. 0.43, respectively; 3-year tracking). Apolipoproteins A-I and B showed similar amounts of tracking compared with HDL and LDL cholesterol, respectively. Approximately 50% of subjects who initially fell into the extreme quintiles of total cholesterol, LDL cholesterol, and HDL cholesterol were in the same quintiles after 12 years. In multiple regression analyses, childhood obesity, exercise, diet, and smoking habits did not markedly aid the prediction of adult serum lipid values. However, the use of two childhood measurements increased the amount of adult serum lipid variability explained. Although universal screening cannot be endorsed, these findings emphasize the importance of serum lipid measurements in the early detection of familial lipoprotein disorders and in the initial evaluation of coronary heart disease risk in childhood.

The associations of life-style variables, namely type of dietary fat, alcohol use, smoking, obesity, physical activity and oral contraceptive use with serum lipids, insulin and blood pressure were studied in 1398 adolescents and young adults aged 15-24 years. Smokers were more often physically inactive and regular users of alcohol compared to non-smokers. In females, smoking and alcohol use were more prevalent among oral contraceptive users. Independent effects of life-style variables on lipids, blood pressure and insulin were assessed with multiple linear regression models. In both sexes, body mass index was positively related to low density lipoprotein cholesterol (LDL-C), triglycerides (TG), systolic (SBP) and diastolic (DBP) blood pressure and insulin, and negatively with high density lipoprotein cholesterol (HDL-C). Leisure time physical activity was associated with lower levels of insulin among males. Smoking was related with 0.07 mmol/l lower HDL-C levels and about 0.09 mmol/l higher TG levels in males. In both sexes, smoking was related with lower levels of SBP. In males, alcohol use was associated with 0.05 mmol/l higher level of HDL-C (P = 0.06). In females, alcohol use was associated with lower levels of LDL-C and TG. Oral contraceptive use was associated with approximately 0.15 mmol/l higher levels of TG and about 4.0 mmHg higher SBP. Preferring butter over margarine as dietary fat was associated with 0.26 and 0.19 mmol/l higher levels of LDL-C in males and females, respectively. Accumulation of adverse life-habits contributed to the clustering of an atherogenic lipid profile and high blood pressure. In males, those with 4 selected life-habits present, namely obesity, smoking, inactivity and the use of butter, had 5.5 times greater risk (95% confidence interval 1.4-20.7) of belonging to the group with high LDL-C, low HDL-C and high DBP compared to those with zero or one life-habits present. These data demonstrate that life-habits show clustering in adolescents and young adults. Individuals with many adverse life-style risk factors present are at increased risk of having an atherogenic lipid and blood pressure profile.

A high lipoprotein(a) (Lp(a)) level is an independent and predominantly genetically determined risk factor for coronary heart disease and other vascular diseases. We studied the levels of Lp(a) and the influence of physical activity on Lp(a) in the young Finnish population. The study cohort comprised children and young adults aged 9, 12, 15, 18, 21 and 24 years (n = 2464) participating in a large multicenter follow-up study of cardiovascular risk factors in children and young adults. Data were available on physical activity, anthropometric variables, serum Lp(a), insulin and lipid levels. A physical activity index was calculated based on several physical activity variables. Lp(a) was determined by radioimmunoassay with a detection threshold of 3 mg/dl. Differences were assessed with non-parametric statistical analyses. The observed range of Lp(a) was from < 3 to 90.8 mg/dl. The distribution of Lp(a) was highly skewed as 88% of the population (89% males and 87% females) had Lp(a) concentrations less than 25 mg/dl. A total of 35% of the subjects had Lp(a) levels less than 3 mg/dl. There were no significant differences in Lp(a) levels with respect to age or gender. The serum concentration of Lp(a) was statistically significantly correlated with the level of physical activity. Other behavioral variables studied did not have a significant contribution to the variability of Lp(a) levels. These results demonstrate that levels of Lp(a) are not related to age, gender or many of the known coronary heart disease risk factors. However, physical activity is associated with favorable Lp(a) levels, as high levels of Lp(a) (> 25 mg/dl) were less frequent in the physically most active subjects.

Clustering and tracking of serum total cholesterol, high-density lipoprotein cholesterol (HDL-C) and diastolic blood pressure were studied in children and young adults. "High-risk" individuals were defined as those having these risk factors at the age and sex specific upper tertile (lowest tertile for HDL-C). Among older boys risk factors occurred at adverse levels more often than expected by chance. Cluster-tracking was assessed as the probability of remaining in the extreme tertiles during follow-up. Approximately 25% of subjects initially at "risk" remained there for 6 years. Subjects who became high-risk individuals during the follow-up expressed greater increase in obesity indices, started to consume more saturated fat and cholesterol and became physically active less often compared to those subjects who were initially at risk, but no longer at the follow-up.

Clustering of selected coronary heart disease (CHD) risk factors was studied in a cohort of 3457 children and adolescents, aged 3-18 years. Subjects were defined as "high-risk" individuals if their values for serum LDL cholesterol, systolic blood pressure and obesity index (sum of biceps, triceps and subscapular skinfolds) exceeded the age- and gender-specific 75th percentile of the present study cohort. Clustering was studied by using the observed/expected ratio (O/E ratio). Statistically significant clustering was observed as 3.1% of all subjects belonged to the high-risk group (O/E ratio = 2.0, p < 0.001). Under the assumption of no association, only 1.56% would have been expected. Clustering was stronger in boys (3.6%) than in girls (2.6%). When other lipid variables (total cholesterol, HDL cholesterol, triglycerides) or obesity indices (subscapular, biceps, triceps skinfolds, the subscapular/triceps ratio and BMI) were used in the analyses, the degree of clustering remained essentially the same. The tendency of risk factors to cluster increased with age in boys, whereas in girls the strongest clustering was usually seen in the age group 9-12 years. When a fourth risk factor (low HDL cholesterol) was added to the analyses, the tendency of risk factors to occur simultaneously became even greater. Aggregation of multiple risk factors was strongest in boys who presented the highest levels of these risk factors. Common risk factors for CHD cluster in children and adolescents. The gender differences observed here may partly explain why males develop CHD more often than females in adulthood.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary heart disease (CHD) has its origin in childhood. High cholesterol levels measured in children and adolescents are indicative of concurrent atherosclerotic changes and probably predict adult coronary heart disease. We review here the relevance of screening children, adolescents or young adults for serum lipid levels in order to efficiently prevent premature adult coronary heart disease. Data is presented in the light of the large Cardiovascular Risk in Young Finns study and other studies. The authors do not recommend universal screening strategies because of (i) the limited predictive power of serum lipid levels on an individual level, (ii) the limited knowledge on the safety of interventive measures on the growing child, and (iii) the limited knowledge on the ethical aspects of screening (labelling). However, the importance of measuring serum lipids to detect familial dyslipidaemic disorders such as familial hypercholesterolaemia, is stressed. The selection of children or adolescents for serum lipid measurements should be made on the basis of family history of early CHD or dyslipidaemia.

We present fractile data on serum lipids and apolipoproteins A-l and B for children and young adults from the cardiovascular risk in young Finns study cohort of 1986. The sample comprised 2370 fasting children and young adults (1114 males and 1256 females) aged 9, 12, 15, 18, 21 and 24 years. The determinations were performed in duplicate with standard methods. LDL-cholesterol values were calculated. The limits for clearly pathological values (exceeding the 97.5th percentile) irrespective of age and gender were 7.5 mmol/l, 5.0 mmol/l, 3.5 mmol/l and 1.4 g/l for serum total cholesterol, LDL-cholesterol, triglycerides and apolipoprotein B, respectively. Corresponding values (below the 2.5th percentile) for HDL-cholesterol, apolipoprotein A-l, HDL2- and HDL3-cholesterol were 0.80 mmol/l, 1.0 mg/l, 0.20 mmol/l and 0.70 mmol/l, respectively. Approximately 79%, 33% and 7% of males had serum total cholesterol values greater than 4.0 mmol, 5.0 mmol/l and 6.0 mmol/l, respectively. Corresponding percentages for females were 87%, 43% and 10%. However, age-related differences were marked. The prevalence of values, e.g. greater than 6 mmol/l according to age, ranged from 6 to 13% in females and from 3 to 12% in males, emphasizing the need for age-specific reference values. Additionally, postpubertal values for total and LDL-cholesterol tended to be slightly lower compared to prepubertal values, indicating that the reference values for adults do not apply to adolescents and young adults. The age-related changes in lipid levels were evident in each fractile and were especially accentuated in higher fractiles. Fluctuations with age were more pronounced in males than in females. These results are intended to be applied as reference values for diagnosing dyslipidemias.

The tracking of physical activity and its influence on selected coronary heart disease risk factors were studied in a 6-year (original survey in 1980, with follow-ups in 1983 and 1986) study of Finnish adolescents and young adults as part of the Cardiovascular Risk in Young Finns Study. The subjects in this analysis were aged 12, 15, and 18 years at baseline. Physical activity was assessed with a standardized questionnaire, and a sum index was derived from the product of intensity, frequency, and duration of leisure time physical activity. Complete data on physical activity index from each study year were available on 961 participants. Significant tracking of physical activity was observed with 3-year correlations of the index ranging from 0.35 to 0.54 in boys and from 0.33 to 0.39 in girls. Tracking was better in older age groups. Two groups of adolescents (active and sedentary groups) were formed at baseline according to high and low values of the index, respectively. Approximately 57% of those classified as inactive remained inactive after a 6-year follow-up. The corresponding value for active subjects was 44% (p < 0.01, active vs. inactive). The long-term effects of physically active and sedentary life-styles were studied by comparing groups of young adults who had remained active or inactive in every three examinations. Serum insulin and serum triglyceride concentrations were significantly lower in active young men. They had a more beneficial high density lipoprotein to total cholesterol ratio and thinner subscapular skinfolds. Among young women, significant differences were seen in adiposity (subscapular skinfold) and in serum triglyceride concentration. Physical activity was also related to less smoking in both sexes and, among young men, to lower consumption of saturated fatty acids and to higher polyunsaturated to saturated fatty acids ratio of the diet. In regression analyses adjusted for the 6-year change in obesity, smoking status, and diet, the change in physical activity was inversely associated with changes in serum insulin and triglycerides in boys. Independent association with triglycerides disappeared when insulin change was added to the model, suggesting that the effect may partly be mediated through insulin metabolism. The authors conclude that the level of physical activity tracks significantly from adolescence to young adulthood. Physical inactivity shows better tracking than does physical activity, and subjects who are constantly inactive express a less beneficial coronary risk profile compared with those who are constantly active.(ABSTRACT TRUNCATED AT 400 WORDS)

We studied the influence of selected genetic markers on the intra-individual long-term variability in serum lipid levels. The study cohort consisted of a sub-sample from a large follow-up study of atherosclerosis precursors in children and young adults. A total of 320 subjects had determinations of apo B XbaI RFLP genotypes, 305 subjects had apo AI/CIII SstI RFLP genotype determinations and 1581 subjects had their apo E phenotypes determined. Complete data on serum lipids were available at 3-year intervals over a 6-year follow-up period. The subjects were healthy and aged 3-18 years at baseline. Intra-individual variability was assessed with a nested analysis of variance procedure. Each of the genetic markers studied here significantly affected intra-individual variability of serum lipid levels. No clear sex influence was observed, although the differences in variability tended to be more significant in males. Apo B XbaI genotypes significantly influenced intra-individual variability of total and LDL-cholesterol levels in both sexes. A marked effect of the XbaI genotype was also found on triglyceride variability. In males the standardized intra-individual triglyceride variances were 0.71 and 0.34 in genotypes X1X1 and X2X2, respectively (p < 0.001), with a clear gene dosage effect. The apo AI/CIII genotype had an influence only on the variability of total cholesterol and LDL-cholesterol levels and only in males. The apo E phenotypes were associated with intra-individual variability in total and LDL-cholesterol levels but again, only in males.(ABSTRACT TRUNCATED AT 250 WORDS)

We have studied the short-term intra-individual variation and long-term tracking until early adulthood of serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglyceride levels in 9-year-old Finnish boys. The study was based on two different cohorts; one to study short-term tracking and another to study long-term tracking. The short-term tracking cohort consisted of 57 healthy Finnish 9-year-old boys with serum lipid determinations 2 and 7 days apart in 1984. The other cohort consisted of 40 healthy Finnish 9-year-old boys and the serum lipid determinations were made in 3-year intervals from 1980 to 1989. Tracking was expressed as Spearman's rank order correlation coefficients between subsequent measurements. Tracking was weaker as the time between measurements became longer. For serum total cholesterol the correlation coefficients were 0.92, 0.77, 0.70, 0.73, and 0.59 for measurements made 2 days, 7 days, 3 years, 6 years, and 9 years apart, respectively. Other lipid variables behaved quantitatively in a similar manner. The dependence of tracking on time was not linear. The greatest relative decrease in correlations took place during the determination periods of 2 and 7 days, whereafter the decline was only moderate. In conclusion, short-term intra-individual variation of serum lipid levels in children, which is mainly due to biological variation, has a major influence on their long-term tracking. Our findings emphasize the need for several independent serum lipid determinations, performed at least one week apart, in the assessment of a child's true serum lipid level.

Background: We have studied the tracking (i.e., the correlation between subsequent measurements) of serum lipids in a cohort of 2,236 children and adolescents (ages initially 3-18 years)., Methods: Determinations of the serum variables were made 3 and 6 years apart. Six-year tracking values (Spearman's r) were 0.63, 0.66, 0.58, and 0.36 for serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, respectively. Boys were found to track better than girls. Subjects who remained persistently in the highest (total cholesterol, low-density lipoprotein cholesterol, and triglycerides) or lowest (high-density lipoprotein cholesterol and high-density lipoprotein ratio) quintile tended to become obese and smoked cigarettes more frequently than the others., Conclusion: The tracking of high-density lipoprotein cholesterol was higher than in previous studies, but differences in methodology may account for this. We conclude that total cholesterol and low-density as well as high-density lipoprotein cholesterol measurements in childhood and adolescence are predictive of adult values.

Patients with obstructive sleep apnea (OSA) and heavy snorers without apnea both show intrathoracic suction pressures during sleep that exceed their static upper airway closing pressures. Complete airway occlusion, however, occurs only in the former patient group. We hypothesized that the kinetic properties of the airflow would be different in these two types of patients because of differences in upper airway morphology. The pharyngeal computed tomography (CT) was used to measure the cross-sectional areas of the upper airways in 15 patients with OSA, 25 nonapneic heavy snorers, and 14 control subjects while they were awake. Nocturnal breathing was monitored with the static charge-sensitive bed (SCSB). The patients with OSA had a narrower airspace at the velopharyngeal (VP) level than the controls (p less than 0.01); the nonapneic snorers did not differ from the other groups. At the tongue base (TB) and the hyoid bone (HB) levels there was no difference between the OSA and the control groups, but the nonapneic snorers had narrower airways at both of these levels compared with control subjects (p less than 0.01) and at the hyoid bone level compared with the OSA group (p less than 0.05). The VP/HB ratio was the parameter that best distinguished the patients with OSA from the nonapneic snorers (lower in the OSA group, p less than 0.001). We suggest that airway collapse during sleep is favored by a narrow velopharynx associated with large hypopharynx. Some heavy snorers may not have an oropharyngeal collapse because the peak inspiratory suction pressure could already be damped down at the level of the relatively narrow hypopharyngeal airways.