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Time-Course of Adiposity and Fasting Insulin from Childhood to Young Adulthood in Offspring of Parents with Coronary Artery Disease
Time-Course of Adiposity and Fasting Insulin from Childhood to Young Adulthood in Offspring of Parents with Coronary Artery Disease: The Bogalusa Heart Study ADEL A.YOUSSEF, MD, PHD, RUDOLFO VALDEZ, PHD, ABDALA ELKASABANY, MD, PHD, SATHANUR R. SRINIVASAN, PHD, AND GERALD S. BERENSON, MD
PURPOSE: Obesity and the attendant insulin resistance/hyperinsulinemia related to coronary artery disease (CAD) morbidity and mortality are well documented. However, information is lacking on the time-course relation of adiposity and fasting insulin from childhood to young adulthood in offspring of parents with CAD, a surrogate measure of future risk. METHODS: Longitudinal analysis was performed on data collected from the Bogalusa Heart Study cohort with (n 271) and without (n 805) a parental history of CAD followed since childhood by repeated surveys from 1973 to 1991. RESULTS: Lowess smoothing and multivariate analyses using Generalized Estimating Equations revealed that body mass index, triceps, and subscapular skinfolds were consistently higher from childhood to adulthood in offspring of parents with CAD history. Insulin levels during childhood and adolescence were lower in the offspring with affected parents. On the other hand, higher levels of fasting insulin from offspring were associated with positive parental history of CAD after age 20 and this association remained significant even after adjusting for body mass index. There was no significant interaction with race or sex in these relationships. CONCLUSION: These results indicate that the offspring at high risk for CAD develop excess body fatness beginning in childhood and then later manifest hyperinsulinemia in young adulthood. These observations have important implications for prevention. Ann Epidemiol 2002;12:553–559. © 2002 Elsevier Science Inc. All rights reserved. KEY WORDS:
Coronary Artery Disease Risk, Adiposity, Insulin, Childhood, Young Adulthood, TimeCourse Obesity.
INTRODUCTION The association between obesity and coronary artery disease (CAD) has been well documented (1, 2). Moreover, obesity among adolescents and young adults is related to asymptomatic atherosclerotic lesions in coronary arteries (3– 5). The association of obesity and CAD is thought to be mediated through the development of insulin resistance/ hyperinsulinemia and the attendant adverse changes in lipoproteins, blood pressure, and glucose tolerance. This cluster and central obesity has become recognized as insulin resistance syndrome or Syndrome X (6, 7). It is becoming increasingly evident that the genesis of adult obesity begins
From the Tulane Center for Cardiovascular Health, Department of Epidemiology, Tulane School of Public Health & Tropical Medicine, New Orleans, LA. Address reprint requests to: Gerald S. Berenson, M.D., Director, Tulane Center for Cardiovascular Health, Tulane School of Public Health & Tropical Medicine, 1440 Canal Street, Suite 2140, New Orleans, LA 70112–2824. Received March 23, 2001; revised August 6, 2001; accepted August 22, 2001. © 2002 Elsevier Science Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
in childhood and the cluster of risk factors of Syndrome X also begins in childhood (8–11). Familial aggregation of CAD, obesity and insulin resistance is also known to occur (12–14). Therefore, knowledge of obesity and insulin status during childhood and young adulthood in offspring with parental CAD may be useful in predicting future CAD. Previous observations from the Bogalusa Heart Study have supported the relationship between parental CAD and different cardiovascular risk variables in their offspring (15). This relationship becomes apparent at different ages during childhood and young adulthood when comparisons were made in a crosssectional manner. However, there is a lack of information on the course of development of adverse levels of body fatness and insulin levels in a continuous (longitudinal) time scale from childhood to young adulthood in the offspring of parents with CAD compared to those without CAD. The current analyses examine the association of parental CAD with various anthropometric measures, body mass index (BMI), subscapular and triceps skinfolds, and fasting insulin, an indicator of insulin resistance (16, 17), in a longitudinal cohort being followed from childhood to young adulthood. 1047-2797/02/$–see front matter PII S1047-2797(01)00286-1
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Selected Abbreviations and Acronyms CAD coronary artery disease BMI body mass index GEE generalized estimation equations
METHODS Study Population The Bogalusa Heart Study is a long-term epidemiologic study of cardiovascular risk factors in children and young adults residing in a biracial (65% white, 35% black), semirural community of Bogalusa, Louisiana (18). Six cross-sectional surveys of children, ages 4–17 years, were conducted between 1973 and 1988. In addition, five cross-sectional surveys of young adults, who have been previously examined as children and accessible, were conducted between 1977 and 1991. The cross-sectional and longitudinal nature of the study design resulted in multiple observations during childhood and young adulthood required for the longitudinal analyses. However, since this was not a prospective cohort study by design, not every participant has been examined at all surveys. Offspring with and without parental CAD for this study were selected from 1930 young adults, ages 18–32 years, participated in the 1988–1991 cross-sectional survey. Three hundred seventy-one young adults reported that one or both parents had CAD. The confirmation process on these self-reported cases of parental CAD has been detailed in a previous report (19). Briefly, the parents (or close relatives, if the affected parent was deceased) were contacted to confirm symptoms, specific procedures or treatment that the affected parent TABLE 1. Number of subjects examined at various ages by parental CAD: The Bogalusa Heart Study
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might have undergone, related to CAD. Medical records or interviews with subjects or close relatives were used to verify the occurrence of CAD in cases. The interview requested information on angina, myocardial infarction, balloon angioplasty, bypass surgery, and medications or the cause of death. Parental CAD was confirmed in 271 individuals. Parents with no CAD history were included in the study only if offspring consistently acknowledged no history of parental CAD in all previous surveys. Of those with no parental history of parental CAD in the 1988–1991 survey (n 894), 89 reported positive parental CAD in a subsequent 1995–1996 survey. These 89 individuals were excluded from the current analysis resulting in 805 individuals with no parental history of CAD to make the classification of controls more specific. The number of examinations, totaling 5022, made on this 1076 study cohort by age and status of parental CAD is given in Table 1. Among those 1076 included in the study 65% were examined at least four times. Anthropometry Subjects were examined by trained observers according to protocols previously published (18). Subjects were instructed to fast for 12 hours and compliance with fasting was determined by an interview on the morning of the examination. Blood was obtained by venipuncture for serum and plasma. Height and weight were measured twice to 0.1 cm and 0.1 kg, respectively. As a measure of general body fatness, body mass index (BMI weight in kilograms divided by the square of height in meters) was used. Triceps and subscapular skinfolds were measured to the nearest mm using a Lange skinfold caliper. Means of replicates were used in all analyses. The reproducibility of anthropometric measurements was assessed in a 10% random sample in each survey, and the intra-class coefficients were 0.99 for height and weight; 0.90 for each skinfold thickness.
Sample Sizea Age (years) 7 7–9 9–11 11–13 13–15 15–17 17–19 19–21 21–23 23–25 25–27 27 Total a
With parental CAD Without parental CAD Total N 271 N 805 N 1076 20 53 86 114 157 140 96 91 106 92 88 141 1184
129 254 362 413 482 435 283 332 338 304 229 277 3838
149 307 448 527 639 575 379 423 444 396 317 418 5022
The values represent observations made on 271 individuals with parental CAD and 805 without parental CAD from childhood to young adulthood.
Insulin Assay Plasma immunoreactive insulin levels were measured by a commercial radioimmunoassay kit (Phadebas, Pharmacia Diagnostics, Piscataway, NJ). The reproducibility in terms of the intra-class correlations between blind duplicate values ranged from 0.94 to 0.98. Statistical Analysis A curve fitting method, Lowess smoothing (20), was used to highlight the change in anthropometric and insulin variables over various ages by parental history of CAD. Lowess is a non-parametric regression method where weighted least-squares line is fitted for multiple windows (groups) of the data. More weight is given to observations close to the middle of the window, and less weight is given to outliers.
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In order to investigate the association and change over years of follow-up of different risk factors by parental history of CAD, generalized estimation equations (GEE) analysis was used (21). Using this longitudinal data analysis method, adjustments can be made for the correlation between observations taken on the same individual repeatedly. Further, GEE analysis is suitable for handling longitudinal data on individuals with varying number and unequal spacing of observations. Multivariate models including interaction with age, race, and sex were fitted to the data. To study the role of BMI in this association, body mass was included in a separate model. Beta coefficient and confidence interval for each of these models was also determined. Stata Statistical Software (STATA) were used for additional analyses (22).
The results of multivariate analysis, also reflected in Figure 1, show that BMI, triceps skinfold, and subscapular skinfold were consistently higher in offspring of parents with CAD history from childhood to adulthood (p 0.05). When BMI was included in the second model the positive association of parental CAD with subscapular and triceps skinfolds disappeared. Fasting insulin showed a significant interaction between parental history and age (p 0.01), with values significantly lower approximately to around age 20 (p 0.01) and higher after age 20 (p 0.01) in offspring with parental CAD (data not shown). The trend for insulin continued to be significant even after controlling for the confounding effect of BMI. There was no significant interaction with race and sex, denoting that the association between parental CAD history and the different risk variables was consistent regardless of race and sex.
RESULTS Means and longitudinal trends of body fatness measures and fasting insulin during childhood, adolescence, and young adulthood are shown in Table 2 along with longitudinal trends by age in Figure 1 by parental history of CAD. It is clear that trends of BMI, subscapular skinfold, and triceps skinfold were consistently higher for offspring with parental history of CAD beginning in childhood. Observations of fasting insulin, however, showed lower values in childhood and higher values in adulthood for offspring of parents with CAD compared to offspring without parental history of CAD. BMI and subscapular skinfold markedly increased with age in an almost linear fashion, while triceps skinfold showed a similar trend only up to age 20 in both groups. Table 3 shows results of a multivariate analysis, examining the association between parental CAD and longitudinal changes in these risk factors, being adjusted for race and sex.
DISCUSSION Prospective epidemiologic studies have established an independent relationship between obesity, especially central adiposity, and CAD morbidity and mortality (1, 23–25). Moreover, excess body fatness is associated with coronary atherosclerosis in healthy adolescents (3–5) and even with increased cardiac left ventricular dimensions. Both relationships would carry a poor cardiovascular prognosis in the future (26). The present study examined the time-course relation of parental history of CAD, as a surrogate indicator of future cardiovascular risk, with obesity and fasting insulin in their offspring from childhood to young adulthood. The results show that even in childhood offspring of parents with CAD already demonstrated excess generalized and truncal body fatness. The obesity persisted into young adulthood. On the
TABLE 2. Levels (mean) of body fatness measures and fasting insulin during childhood, adolescence, and young adulthood in offspring by parental history of CAD: The Bogalusa Heart Study Variables BMI (kg/m2) Without CAD history With CAD history Triceps skinfold (mm) Without CAD history With CAD history Subscapular skinfold (mm) Without CAD history With CAD history Fasting insulin (µU/ml) Without CAD history With CAD history a
Childhooda Ages 5–11 years
Adolescencea Ages 12–18 years
Young adulthooda Ages 19–32 years
16.7 17.1
20.3 21.1
13.0 13.8
P-value CAD
Age
CAD Age
23.9 25.2
0.00
0.00
0.15
16.2 16.9
17.3 18.6
0.00
0.00
0.42
9.1 13.4
11.6 12.6
16.6 18.4
0.00
0.00
0.30
2.3 2.2
8.5 6.1
10.9 12.7
0.61
0.00
0.00
Mean values were derived from observations made on 271 individuals with parental CAD and 805 individuals without parental CAD by age category.
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FIGURE 1. Longitudinal trends in body fatness and fasting insulin in the offspring of parents with (N 271) and without (N 805) a history of coronary artery disease: The Bogalusa Heart Study.
other hand, higher fasting insulin levels in the offspring of parents with CAD compared with offspring of parents without such history became evident only after age 20, after completion of growth and sexual maturation. The adverse insulin profile, however, persisted even after controlling for adiposity (BMI). Although BMI does not reflect body fatness distribution, the offspring with parental CAD in the current study also displayed increased subscapular skinfold thickness, a measure of truncal fatness. Truncal body fat is known to increase during adolescence (27, 28), and this measure of obesity persists throughout adulthood (8, 29, 30). This childhood central obesity with a familial history of CAD becomes an additional marker of future CAD risk. Obesity is commonly associated with insulin resistance/ hyperinsulinemia as part of the Syndrome X or metabolic syndrome that includes dyslipidemia, hypertension, and glucose intolerance (6, 7, 31). Several prospective studies have demonstrated that elevated insulin levels is an independent predictor of subsequent CAD in non-diabetic subjects (32–36). In addition, insulin resistance has been directly and independently related to asymptomatic atherosclerosis measured as intimal-medial thickness of the carotid artery (37, 38). The current finding that insulin levels become markedly higher after age 20 in the offspring of parents with CAD is in concert with an increased CAD risk in this group. The observed excess insulin level during young adulthood in those with affected parents may be the mani-
festation of long standing burden of obesity beginning in childhood. Although the association between obesity and hyperinsulinemia/insulin resistance is well known, studies have shown temporal sequence of obesity and hyperinsulinemia to occur in both directions (39–43). Conceptionally, potential mechanisms have been proposed to explain the causality either way (44, 45). It has been hypothesized that populations genetically predisposed to obesity and type 2 diabetes are endowed with the thrifty genotype, which was intended to facilitate efficient fat storage in times of food abundance through a high insulin response to provide an energy buffer in times of scarcity (46). Obesity and type 2 diabetes ensue in such populations when a rapid transition occurs from a traditional subsistence lifestyle to a western diet and low-activity lifestyle. In this context hyperinsulinemia may precede obesity, as seen in the case of Pima Indians (43). However, the thrifty genotype metabolic sequelae may not be applicable to the general population. Our earlier observations in the Bogalusa Heart Study population showing a temporal relationship between the degree of baseline obesity and the incidence of hyperinsulinemia at follow-up, independent of baseline insulin levels, support the role of obesity in the development of hyperinsulinemia/ insulin resistance (47). The current study also showed an interacting effect of growth and development on the insulin-parental CAD relationship. Insulin levels during childhood and adolescence
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TABLE 3. Independent association of longitudinal changes of body fatness variables and fasting insulin with parental CAD in the study cohort: The Bogalusa Heart Study Model 1 Risk Factor
Model 2
P-value
95% CI
0.44, 1.48
—
—
—
0.04
0.06, 1.51
0.32
0.15
0.75, 0.11
1.33
0.01
0.33, 2.34
0.20
0.43
0.70, 0.30
2.46 0.15
0.04 0.01
4.78, 0.14 0.04, 0.25
3.10 0.14
0.01 0.01
5.29, 0.90 0.70, 0.83
a
P-value
95% CI
0.96
0.00
0.78
b
2
BMI (kg/m ) Parental CAD Triceps skinfold (mm) Parental CAD Subscapular skinfold (mm) Parental CAD Fasting insulin (µU/ml) Parental CAD Parental CAD Age a
Generalized Estimation Equation Regression Coefficient. 95% confidence interval. Model 1: Parental CAD race, sex, age, and age interaction. Model 2: Model 1 BMI. b
were, unexpectedly relatively, lower in the offspring with affected parents, although the levels increased dramatically in both groups during this period. It is of interest that the offspring with parental CAD began to display elevated insulin levels after reaching adulthood. The increase in insulin levels during adolescence has been linked to decreases in insulin sensitivity (48–50) and to compensate this insulin secretion may increase. Our earlier studies in this regard have shown that both increased insulin secretion and decreased insulin clearance contribute to hyperinsulinemia in obese adolescents (51). However, the basis for the relatively lower levels in young offspring of parents with CAD, despite being relatively overweight during the sexual maturation period is not clear. It should be noted that the sexual maturation process is characterized by a complex interplay among various gonadal and adrenal hormones, growth hormones, and growth factors that rise dramatically during this period (52, 53). Higher insulin resistance during puberty has been found to be mediated by these factors, independent of body fatness (54, 55). Therefore, adiposity may not be the only determining factor of hyperinsulinemia/insulin resistance during sexual maturation. In conclusion, offspring of parents with CAD develop excess body fatness beginning in childhood and manifest hyperinsulinemia in young adulthood. Since over nutrition, characterized by positive energy balance plays a major role in the development of obesity, a prudent diet and exercise, if undertaken beginning in childhood, should have a salutary effect on adult health. The Bogalusa Heart Study is a joint effort of many investigators and staff members whose cooperation is gratefully acknowledged. We are also quite appreciative of the subjects in Bogalusa without whom this research could not be conducted. Supported by grants HL-38844 from the National Heart, Lung and Blood Institute and HL-32194 from the National Institute of Child Health and Human Development, and AG-16592 from the National Institutes on Aging.
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PURPOSE: Obesity and the attendant insulin resistance/hyperinsulinemia related to coronary artery disease (CAD) morbidity and mortality are well documented. However, information is lacking on the time-course relation of adiposity and fasting insulin from childhood to young adulthood in offspring of parents with CAD, a surrogate measure of future risk. METHODS: Longitudinal analysis was performed on data collected from the Bogalusa Heart Study cohort with (n 271) and without (n 805) a parental history of CAD followed since childhood by repeated surveys from 1973 to 1991. RESULTS: Lowess smoothing and multivariate analyses using Generalized Estimating Equations revealed that body mass index, triceps, and subscapular skinfolds were consistently higher from childhood to adulthood in offspring of parents with CAD history. Insulin levels during childhood and adolescence were lower in the offspring with affected parents. On the other hand, higher levels of fasting insulin from offspring were associated with positive parental history of CAD after age 20 and this association remained significant even after adjusting for body mass index. There was no significant interaction with race or sex in these relationships. CONCLUSION: These results indicate that the offspring at high risk for CAD develop excess body fatness beginning in childhood and then later manifest hyperinsulinemia in young adulthood. These observations have important implications for prevention. Ann Epidemiol 2002;12:553–559. © 2002 Elsevier Science Inc. All rights reserved. KEY WORDS:
Coronary Artery Disease Risk, Adiposity, Insulin, Childhood, Young Adulthood, TimeCourse Obesity.
INTRODUCTION The association between obesity and coronary artery disease (CAD) has been well documented (1, 2). Moreover, obesity among adolescents and young adults is related to asymptomatic atherosclerotic lesions in coronary arteries (3– 5). The association of obesity and CAD is thought to be mediated through the development of insulin resistance/ hyperinsulinemia and the attendant adverse changes in lipoproteins, blood pressure, and glucose tolerance. This cluster and central obesity has become recognized as insulin resistance syndrome or Syndrome X (6, 7). It is becoming increasingly evident that the genesis of adult obesity begins
From the Tulane Center for Cardiovascular Health, Department of Epidemiology, Tulane School of Public Health & Tropical Medicine, New Orleans, LA. Address reprint requests to: Gerald S. Berenson, M.D., Director, Tulane Center for Cardiovascular Health, Tulane School of Public Health & Tropical Medicine, 1440 Canal Street, Suite 2140, New Orleans, LA 70112–2824. Received March 23, 2001; revised August 6, 2001; accepted August 22, 2001. © 2002 Elsevier Science Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
in childhood and the cluster of risk factors of Syndrome X also begins in childhood (8–11). Familial aggregation of CAD, obesity and insulin resistance is also known to occur (12–14). Therefore, knowledge of obesity and insulin status during childhood and young adulthood in offspring with parental CAD may be useful in predicting future CAD. Previous observations from the Bogalusa Heart Study have supported the relationship between parental CAD and different cardiovascular risk variables in their offspring (15). This relationship becomes apparent at different ages during childhood and young adulthood when comparisons were made in a crosssectional manner. However, there is a lack of information on the course of development of adverse levels of body fatness and insulin levels in a continuous (longitudinal) time scale from childhood to young adulthood in the offspring of parents with CAD compared to those without CAD. The current analyses examine the association of parental CAD with various anthropometric measures, body mass index (BMI), subscapular and triceps skinfolds, and fasting insulin, an indicator of insulin resistance (16, 17), in a longitudinal cohort being followed from childhood to young adulthood. 1047-2797/02/$–see front matter PII S1047-2797(01)00286-1
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Selected Abbreviations and Acronyms CAD coronary artery disease BMI body mass index GEE generalized estimation equations
METHODS Study Population The Bogalusa Heart Study is a long-term epidemiologic study of cardiovascular risk factors in children and young adults residing in a biracial (65% white, 35% black), semirural community of Bogalusa, Louisiana (18). Six cross-sectional surveys of children, ages 4–17 years, were conducted between 1973 and 1988. In addition, five cross-sectional surveys of young adults, who have been previously examined as children and accessible, were conducted between 1977 and 1991. The cross-sectional and longitudinal nature of the study design resulted in multiple observations during childhood and young adulthood required for the longitudinal analyses. However, since this was not a prospective cohort study by design, not every participant has been examined at all surveys. Offspring with and without parental CAD for this study were selected from 1930 young adults, ages 18–32 years, participated in the 1988–1991 cross-sectional survey. Three hundred seventy-one young adults reported that one or both parents had CAD. The confirmation process on these self-reported cases of parental CAD has been detailed in a previous report (19). Briefly, the parents (or close relatives, if the affected parent was deceased) were contacted to confirm symptoms, specific procedures or treatment that the affected parent TABLE 1. Number of subjects examined at various ages by parental CAD: The Bogalusa Heart Study
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might have undergone, related to CAD. Medical records or interviews with subjects or close relatives were used to verify the occurrence of CAD in cases. The interview requested information on angina, myocardial infarction, balloon angioplasty, bypass surgery, and medications or the cause of death. Parental CAD was confirmed in 271 individuals. Parents with no CAD history were included in the study only if offspring consistently acknowledged no history of parental CAD in all previous surveys. Of those with no parental history of parental CAD in the 1988–1991 survey (n 894), 89 reported positive parental CAD in a subsequent 1995–1996 survey. These 89 individuals were excluded from the current analysis resulting in 805 individuals with no parental history of CAD to make the classification of controls more specific. The number of examinations, totaling 5022, made on this 1076 study cohort by age and status of parental CAD is given in Table 1. Among those 1076 included in the study 65% were examined at least four times. Anthropometry Subjects were examined by trained observers according to protocols previously published (18). Subjects were instructed to fast for 12 hours and compliance with fasting was determined by an interview on the morning of the examination. Blood was obtained by venipuncture for serum and plasma. Height and weight were measured twice to 0.1 cm and 0.1 kg, respectively. As a measure of general body fatness, body mass index (BMI weight in kilograms divided by the square of height in meters) was used. Triceps and subscapular skinfolds were measured to the nearest mm using a Lange skinfold caliper. Means of replicates were used in all analyses. The reproducibility of anthropometric measurements was assessed in a 10% random sample in each survey, and the intra-class coefficients were 0.99 for height and weight; 0.90 for each skinfold thickness.
Sample Sizea Age (years) 7 7–9 9–11 11–13 13–15 15–17 17–19 19–21 21–23 23–25 25–27 27 Total a
With parental CAD Without parental CAD Total N 271 N 805 N 1076 20 53 86 114 157 140 96 91 106 92 88 141 1184
129 254 362 413 482 435 283 332 338 304 229 277 3838
149 307 448 527 639 575 379 423 444 396 317 418 5022
The values represent observations made on 271 individuals with parental CAD and 805 without parental CAD from childhood to young adulthood.
Insulin Assay Plasma immunoreactive insulin levels were measured by a commercial radioimmunoassay kit (Phadebas, Pharmacia Diagnostics, Piscataway, NJ). The reproducibility in terms of the intra-class correlations between blind duplicate values ranged from 0.94 to 0.98. Statistical Analysis A curve fitting method, Lowess smoothing (20), was used to highlight the change in anthropometric and insulin variables over various ages by parental history of CAD. Lowess is a non-parametric regression method where weighted least-squares line is fitted for multiple windows (groups) of the data. More weight is given to observations close to the middle of the window, and less weight is given to outliers.
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In order to investigate the association and change over years of follow-up of different risk factors by parental history of CAD, generalized estimation equations (GEE) analysis was used (21). Using this longitudinal data analysis method, adjustments can be made for the correlation between observations taken on the same individual repeatedly. Further, GEE analysis is suitable for handling longitudinal data on individuals with varying number and unequal spacing of observations. Multivariate models including interaction with age, race, and sex were fitted to the data. To study the role of BMI in this association, body mass was included in a separate model. Beta coefficient and confidence interval for each of these models was also determined. Stata Statistical Software (STATA) were used for additional analyses (22).
The results of multivariate analysis, also reflected in Figure 1, show that BMI, triceps skinfold, and subscapular skinfold were consistently higher in offspring of parents with CAD history from childhood to adulthood (p 0.05). When BMI was included in the second model the positive association of parental CAD with subscapular and triceps skinfolds disappeared. Fasting insulin showed a significant interaction between parental history and age (p 0.01), with values significantly lower approximately to around age 20 (p 0.01) and higher after age 20 (p 0.01) in offspring with parental CAD (data not shown). The trend for insulin continued to be significant even after controlling for the confounding effect of BMI. There was no significant interaction with race and sex, denoting that the association between parental CAD history and the different risk variables was consistent regardless of race and sex.
RESULTS Means and longitudinal trends of body fatness measures and fasting insulin during childhood, adolescence, and young adulthood are shown in Table 2 along with longitudinal trends by age in Figure 1 by parental history of CAD. It is clear that trends of BMI, subscapular skinfold, and triceps skinfold were consistently higher for offspring with parental history of CAD beginning in childhood. Observations of fasting insulin, however, showed lower values in childhood and higher values in adulthood for offspring of parents with CAD compared to offspring without parental history of CAD. BMI and subscapular skinfold markedly increased with age in an almost linear fashion, while triceps skinfold showed a similar trend only up to age 20 in both groups. Table 3 shows results of a multivariate analysis, examining the association between parental CAD and longitudinal changes in these risk factors, being adjusted for race and sex.
DISCUSSION Prospective epidemiologic studies have established an independent relationship between obesity, especially central adiposity, and CAD morbidity and mortality (1, 23–25). Moreover, excess body fatness is associated with coronary atherosclerosis in healthy adolescents (3–5) and even with increased cardiac left ventricular dimensions. Both relationships would carry a poor cardiovascular prognosis in the future (26). The present study examined the time-course relation of parental history of CAD, as a surrogate indicator of future cardiovascular risk, with obesity and fasting insulin in their offspring from childhood to young adulthood. The results show that even in childhood offspring of parents with CAD already demonstrated excess generalized and truncal body fatness. The obesity persisted into young adulthood. On the
TABLE 2. Levels (mean) of body fatness measures and fasting insulin during childhood, adolescence, and young adulthood in offspring by parental history of CAD: The Bogalusa Heart Study Variables BMI (kg/m2) Without CAD history With CAD history Triceps skinfold (mm) Without CAD history With CAD history Subscapular skinfold (mm) Without CAD history With CAD history Fasting insulin (µU/ml) Without CAD history With CAD history a
Childhooda Ages 5–11 years
Adolescencea Ages 12–18 years
Young adulthooda Ages 19–32 years
16.7 17.1
20.3 21.1
13.0 13.8
P-value CAD
Age
CAD Age
23.9 25.2
0.00
0.00
0.15
16.2 16.9
17.3 18.6
0.00
0.00
0.42
9.1 13.4
11.6 12.6
16.6 18.4
0.00
0.00
0.30
2.3 2.2
8.5 6.1
10.9 12.7
0.61
0.00
0.00
Mean values were derived from observations made on 271 individuals with parental CAD and 805 individuals without parental CAD by age category.
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FIGURE 1. Longitudinal trends in body fatness and fasting insulin in the offspring of parents with (N 271) and without (N 805) a history of coronary artery disease: The Bogalusa Heart Study.
other hand, higher fasting insulin levels in the offspring of parents with CAD compared with offspring of parents without such history became evident only after age 20, after completion of growth and sexual maturation. The adverse insulin profile, however, persisted even after controlling for adiposity (BMI). Although BMI does not reflect body fatness distribution, the offspring with parental CAD in the current study also displayed increased subscapular skinfold thickness, a measure of truncal fatness. Truncal body fat is known to increase during adolescence (27, 28), and this measure of obesity persists throughout adulthood (8, 29, 30). This childhood central obesity with a familial history of CAD becomes an additional marker of future CAD risk. Obesity is commonly associated with insulin resistance/ hyperinsulinemia as part of the Syndrome X or metabolic syndrome that includes dyslipidemia, hypertension, and glucose intolerance (6, 7, 31). Several prospective studies have demonstrated that elevated insulin levels is an independent predictor of subsequent CAD in non-diabetic subjects (32–36). In addition, insulin resistance has been directly and independently related to asymptomatic atherosclerosis measured as intimal-medial thickness of the carotid artery (37, 38). The current finding that insulin levels become markedly higher after age 20 in the offspring of parents with CAD is in concert with an increased CAD risk in this group. The observed excess insulin level during young adulthood in those with affected parents may be the mani-
festation of long standing burden of obesity beginning in childhood. Although the association between obesity and hyperinsulinemia/insulin resistance is well known, studies have shown temporal sequence of obesity and hyperinsulinemia to occur in both directions (39–43). Conceptionally, potential mechanisms have been proposed to explain the causality either way (44, 45). It has been hypothesized that populations genetically predisposed to obesity and type 2 diabetes are endowed with the thrifty genotype, which was intended to facilitate efficient fat storage in times of food abundance through a high insulin response to provide an energy buffer in times of scarcity (46). Obesity and type 2 diabetes ensue in such populations when a rapid transition occurs from a traditional subsistence lifestyle to a western diet and low-activity lifestyle. In this context hyperinsulinemia may precede obesity, as seen in the case of Pima Indians (43). However, the thrifty genotype metabolic sequelae may not be applicable to the general population. Our earlier observations in the Bogalusa Heart Study population showing a temporal relationship between the degree of baseline obesity and the incidence of hyperinsulinemia at follow-up, independent of baseline insulin levels, support the role of obesity in the development of hyperinsulinemia/ insulin resistance (47). The current study also showed an interacting effect of growth and development on the insulin-parental CAD relationship. Insulin levels during childhood and adolescence
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TABLE 3. Independent association of longitudinal changes of body fatness variables and fasting insulin with parental CAD in the study cohort: The Bogalusa Heart Study Model 1 Risk Factor
Model 2
P-value
95% CI
0.44, 1.48
—
—
—
0.04
0.06, 1.51
0.32
0.15
0.75, 0.11
1.33
0.01
0.33, 2.34
0.20
0.43
0.70, 0.30
2.46 0.15
0.04 0.01
4.78, 0.14 0.04, 0.25
3.10 0.14
0.01 0.01
5.29, 0.90 0.70, 0.83
a
P-value
95% CI
0.96
0.00
0.78
b
2
BMI (kg/m ) Parental CAD Triceps skinfold (mm) Parental CAD Subscapular skinfold (mm) Parental CAD Fasting insulin (µU/ml) Parental CAD Parental CAD Age a
Generalized Estimation Equation Regression Coefficient. 95% confidence interval. Model 1: Parental CAD race, sex, age, and age interaction. Model 2: Model 1 BMI. b
were, unexpectedly relatively, lower in the offspring with affected parents, although the levels increased dramatically in both groups during this period. It is of interest that the offspring with parental CAD began to display elevated insulin levels after reaching adulthood. The increase in insulin levels during adolescence has been linked to decreases in insulin sensitivity (48–50) and to compensate this insulin secretion may increase. Our earlier studies in this regard have shown that both increased insulin secretion and decreased insulin clearance contribute to hyperinsulinemia in obese adolescents (51). However, the basis for the relatively lower levels in young offspring of parents with CAD, despite being relatively overweight during the sexual maturation period is not clear. It should be noted that the sexual maturation process is characterized by a complex interplay among various gonadal and adrenal hormones, growth hormones, and growth factors that rise dramatically during this period (52, 53). Higher insulin resistance during puberty has been found to be mediated by these factors, independent of body fatness (54, 55). Therefore, adiposity may not be the only determining factor of hyperinsulinemia/insulin resistance during sexual maturation. In conclusion, offspring of parents with CAD develop excess body fatness beginning in childhood and manifest hyperinsulinemia in young adulthood. Since over nutrition, characterized by positive energy balance plays a major role in the development of obesity, a prudent diet and exercise, if undertaken beginning in childhood, should have a salutary effect on adult health. The Bogalusa Heart Study is a joint effort of many investigators and staff members whose cooperation is gratefully acknowledged. We are also quite appreciative of the subjects in Bogalusa without whom this research could not be conducted. Supported by grants HL-38844 from the National Heart, Lung and Blood Institute and HL-32194 from the National Institute of Child Health and Human Development, and AG-16592 from the National Institutes on Aging.
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