Childhood risk factors predict adult risk associated with subclinical cardiovascular disease

Childhood risk factors predict adult risk associated with subclinical cardiovascular disease

Childhood Risk Factors Predict Adult Risk Associated with Subclinical Cardiovascular Disease: The Bogalusa Heart Study Gerald S. Berenson, MD, for t...

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Childhood Risk Factors Predict Adult Risk Associated with Subclinical Cardiovascular Disease: The Bogalusa Heart Study Gerald S. Berenson,

MD,

for the Bogalusa Heart Study Research Group

Cardiovascular risk factors begin in childhood and are predictive of cardiovascular risk in adulthood. Observations in the Bogalusa Heart Study have shown an important correlation of clinical risk factors in early life with anatomic changes in the aorta and coronary vessels with atherosclerosis and cardiac and renal changes related to hypertension. These observations have been extended by echo Doppler studies of carotid artery intima media thickness (IMT). A close association of risk factors in young adults, 20 –38 years of age, occurs with

IMT, and a marked increase is noted as numbers of risk factors increase. More extensive changes seem to occur in the bulb or bifurcation area. This area may be an earlier marker of disease. Observations of risk factors in young individuals and noninvasive studies of structural changes of the cardiovascular system have strong implications for prevention by cardiologists. 䊚2002 by Excerpta Medica, Inc. Am J Cardiol 2002;90(suppl):3L–7L

is now well established that cardiovascular risk are definable in childhood and are predictive Iof tfactors future cardiovascular risk. Although clinical car-

biracial (65% white, 35% black), semirural community. The study began in 1973 and has continued with multiple cross-sectional and longitudinal surveys. Extensive cardiovascular risk factor data have been collected on approximately 16,000 individuals from birth to 38 years of age, many of them with multiple observations.

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diovascular heart disease occurs in later life, evidence of atherosclerosis and traits of hypertension and diabetes mellitus are clearly present in childhood. The precise initiating factors of these diseases are still being investigated, but by identifying the earliest determinants of cardiovascular risk, we can achieve a great deal in determining susceptibility (risk) to complex traits, such as coronary artery disease. The clinical physiologic risk factors are governed by both genes and environment, and what is observed is a genetic– environmental interaction. The long-term burden of cardiovascular risk factors and lifestyle behaviors developing from childhood interacting with a genetic basis is important to ultimate clinical events. Risk factor levels at any early age relate to beginning anatomic changes of the cardiovascular–renal system. Unhealthy lifestyles, such as high-fat, high-calorie diet, tobacco use, and physical inactivity leading to obesity, begin in childhood and are controllable. Cardiologists now have the opportunity to study cardiovascular risk and determine its effect on underlying cardiac and vascular changes early in life.

POPULATION UNDER STUDY The Bogalusa Heart Study is a comprehensive study of early natural history of cardiovascular disease in a population of children and young adults from a

PERSISTENCE AND PREDICTABILITY OF CHILDHOOD RISK FACTORS Levels of risk factor variables for an individual tend to remain over time in a given rank relative to their peers. “Tracking,” based on findings beginning in early life, is important for predicting adult cardiovascular risk factors and clinical disease. Risk factors track to varying degrees, with measures of obesity tracking the most.5 Obesity, which begins in infancy and childhood, persists into adulthood. Serum total cholesterol and low-density lipoprotein (LDL) cholesterol track almost as well. The magnitude of tracking of triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure is relatively low, probably due to biologic and/or measurement variability. Of note, clusters of multiple risk factors persist strongly from childhood to adulthood, especially among those with increased body fatness.6 The persistence of risk factors from childhood indicates that precursors of atherosclerosis and essential hypertension begin early and progress into adulthood.

SECULAR TRENDS From the Tulane Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA. Supported by Grant Nos. HL38844 from the National Heart, Lung, and Blood Institute and AG16592 from the National Institute on Aging. Address for reprints: Gerald S. Berenson, MD, Director, Tulane Center for Cardiovascular Health, 1440 Canal Street, Suite 1829, New Orleans, Louisiana 70112, USA. E-mail: [email protected] ©2002 by Excerpta Medica, Inc. All rights reserved.

Repeated surveys in this biracial community have allowed observations of secular trends over several decades. Of particular importance is the dramatic increase of obesity over time, especially in black females. Since 1973, children on average gained 5 kg of body weight without increases in height.7 This upward secular trend in childhood obesity reflects the national 0002-9149/02/$ – see front matter PII S0002-9149(02)02953-3

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FIGURE 1. The effect of multiple risk factors on the extent of atherosclerosis in the aorta and coronary arteries in children and young adults. Values shown are the percentages of the intimal surface covered with lesions in subjects with 0, 1, 2, and 3 or 4 risk factors. Risk factors were elevated values for body mass index, systolic blood pressure, and serum triglycerides and low-density lipoprotein cholesterol concentrations, defined as values above the 75th percentile for the study group (specific for study period, race, sex, and age). There were 52 subjects with no risk factors, 20 with 1, 14 with 2, and 7 with 3 or 4. The p-value is based on the analysis of trend. A marked increase in the percentage of the intimal surface covered by fibrous plaques is evident in the coronary vessels of subjects with multiple risk factors.17

trend seen in the general population of children and, consequently, in adults.8 With this increasing obesity there is a notable increase in the incidence of type 2 diabetes mellitus, with an increase in early onset of diabetes, even during adolescence.

CLUSTERING OF MULTIPLE RISK FACTORS Individual risk factors correlate with other risk factors in children and young adults alike, for example, obesity and high blood pressure levels. Consequently, risk factors tend to occur in constellations. This is consistent with the findings of adult epidemiologic studies, such as the Framingham Study and the Multiple Risk Factor Intervention Trial (MRFIT). Coexistence of multiple risk factors in the young has strong implications for adult heart disease. Central obesity and the attendant insulin resistance/hyperinsulinemia occurring in childhood are the driving force of the multiple metabolic syndrome X, insulin resistance syndrome, or the “deadly quartet.” In particular, childhood obesity precedes insulin resistance/hyperinsulinemia and strongly predicts the risk of developing a constellation of metabolic, hemodynamic, thrombotic, and inflammatory disorders of syndrome X.9 Of considerable importance, the burden of multiple risk factors from childhood on the cardiovascular system can now be evaluated by noninvasive imaging procedures. That is, we now have the opportunity of addressing “silent” cardiovascular disease and can begin to learn rational approaches to prevention. 4L THE AMERICAN JOURNAL OF CARDIOLOGY姞

AUTOPSY STUDIES AS A BASIS FOR NONINVASIVE IMAGING STUDIES Autopsy studies in youth from Bogalusa have provided the most compelling evidence that an unusually high prevalence (90%) of coronary atherosclerosis occurs by the third decade of life. The early occurrence of atherosclerosis was found in autopsy studies of the International Atherosclerosis Study emphasized by McGill10 and in soldiers dying in the Korean and Vietnamese wars.11,12 Fatty streaks begin to appear in the aorta even earlier than 3 years of age. It has been recently reported that anatomical changes in the fetal arterial wall are conditioned by maternal hypercholesterolemia during pregnancy and adversely influence the rate of progression of early lesions throughout childhood.13 Lesions appear in other vascular beds early, and beginning in adolescence progressive lesions involve the coronary arteries.14 Coronary vessels demonstrate both fatty streaks and fibrous plaques of raised, collagen-capped lesions that are precursors of more advanced disease. There are also race–sex differences, with a definite lag in the development of lesions in females versus males at this young age. Blacks show more aorta fatty streaks and white males more coronary fibrous plaques.15,16 Of importance is the striking relation of antemortem cardiovascular risk factors to the extent of lesions, with the severity increasing curvilinearly as the number of multiple risk factors increases (Figure 1).17 The Pathobiologic Determinants of Atherosclerosis in Youth (PDAY) study has confirmed and extended these autopsy findings showing the importance of multiple risk factors in

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young adulthood.18 These observations are in concert with the multiple risk factor concept of the Framingham risk score for predicting morbidity and mortality. It is also important to note that autopsy studies have shown atherosclerosis developing at various vascular sites, including carotid and renal vessels at a young age, indicating the systemic effects of atherosclerosis.19

CAROTID ARTERY STUDIES Although a profile of cardiovascular risk factors is useful in predicting cardiovascular events, inclusion of measurements of subclinical atherosclerosis by noninvasive imaging techniques in this paradigm can be a powerful approach to determining the extensiveness and severity of asymptomatic disease and potential future risk. Recently, there has been considerable interest in imaging for calcification of coronary arteries, but these observations are often limited in determining the extensiveness of coronary atherosclerosis of noncalcified types, even in individuals with known coronary artery disease. The Muscatine Study showed a relation of obesity from childhood with coronary calcification,20 although coronary calcification shows a limited relationship to cardiovascular risk factors. Other methods, such as coronary arteriography and intravascular coronary ultrasound studies, even though they confirm disease at a young age, are not applicable for large population studies nor can they be recommended for asymptomatic individuals. On the other hand, echo Doppler studies of the carotid arteries do provide a noninvasive and readily available tool for evaluating large numbers of asymptomatic individuals. We measured intima-media thickness (IMT) of carotid arteries by B-mode duplex ultrasonography in 517 black and white subjects, aged 20 to 38 years, enrolled in the Bogalusa Heart Study. The risk factor variables included parental history, blood pressure, obesity measures, lipoproteins, insulin, glucose, and cigarette smoking.21 The means of 3 values each for right and left far wall were used for the common, the bulb or bifurcation, and internal carotid segments. IMT of the common carotid and the bulb segments were significantly greater in blacks, men, and older individuals. Internal carotid IMT was greater only in men. Lumen narrowing by encroaching atherosclerotic plaques is not expected to occur at this young age. However, marked individual differences occur in IMT. The top 5% of the carotid artery at the common segment showed a range of 0.84 to 1.1 mm IMT, with a mean of 0.68 mm, and for the carotid bulb 0.90 to 2.1 mm, with a mean of 0.87 mm. Earlier, in a related study regarding vascular (carotid artery) distensibility measured in 10- to 17-year-olds, we were able to show an association of increased stiffness in terms of pressure–strain elastic modulus (Ep), with elevated levels of both serum total cholesterol and systolic blood pressure, and a positive parental history of myocardial infarction.22 It is possible that studies of compliance and distensibility may show functional changes even

preceding detectable structural disease of the arterial wall. The association among different segments of carotid IMT and risk factor variables occurred in the expected direction. Systolic blood pressure, race, age, LDL cholesterol, and HDL cholesterol explained 16% variance in the common carotid IMT; age, systolic blood pressure, HDL cholesterol LDL cholesterol, race, and insulin explained 19.4% variance in the carotid bulb IMT; and sex and body mass index explained 4.7% variance in the internal carotid IMT. Increases in IMT with increasing numbers of risk factors (0, 1, 2, 3, or more), similar to the Framingham multivariate risk score, were noted for the common carotid and the carotid bulb segments (Figure 2). These observations are consistent with the notion that the carotid bulb or bifurcation area is more susceptible to atherosclerotic damage than the common carotid or internal carotid segments. Zarins et al showed the importance of pulsatile hemodynamic forces on arterial wall structure, which led him later to the concept of remodeling.23 This may be the basis of thicker IMT of the bulb and stronger association of risk factors similar to that noted for coronary arteries. The subclinical underlying lesions in the carotid arteries, especially at the bulb site, by relating to multiple cardiovascular risk factors in young individuals, could help identify those at particular risk for future cardiovascular events. Carotid ultrasound measurements are relatively easy to obtain and can be a marker for the intensity of the long-term burden of cardiovascular risk factors beginning at a young age. Understanding risk factors at a young age and observing their effects on the cardiovascular system can guide early prevention modalities.

APPROACHES FOR PREVENTION The importance of beginning prevention in early life has to be emphasized by cardiologists being confronted with the daily problem of morbidity and mortality from heart diseases. Although the effectiveness of drug therapy has been demonstrated in many clinical trials, primary intervention by altering lifestyles plays a major role in managing patients and families at cardiovascular risk.24 To establish effectiveness of primary prevention alone at a population level is almost impossible, because it would require a largescale population study over many years. As a population approach for the young, we have developed an effective comprehensive health education program (Health Ahead/Heart Smart) for elementary school children.25 This involves the classroom, cafeteria, physical education, lifestyles of teachers, and parents. Lifestyles and behaviors that influence cardiovascular risk factors are learned in childhood. Healthy lifestyles need to be adopted early because they are critical to modulating risk factors in adult life. Cardiologists and primary care physicians have a tremendous opportunity to guide and propagate prevention programs for the young, destined to be our next generation of cardiac patients.26 A SYMPOSIUM: SECOND INTERNATIONAL SAI MEETING

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FIGURE 2. Mean intima media thickness (IMT) of 3 segments of the carotid artery related to the number of risk factors. *Total cholesterol to high-density lipoprotein cholesterol ratio, waist circumference, systolic blood pressure, insulin (>75th percentile specific for age, race, and sex), and smoking.21

Acknowledgment: The Bogalusa Heart Study is a joint effort of many individuals whose cooperation is gratefully acknowledged. We are especially grateful for the children who grew up contributing to this research.

1. Lauer RM, Shekelle RB, eds. Childhood Prevention of Atherosclerosis and Hypertension. New York: Raven Press, 1980:484. 2. Berenson GS, McMahan CA, Voors AW, Webber LS, Srinivasan SR, Frank GC, Foster TA, Blonde CV. Cardiovascular Risk Factors in Children—The Early Natural History of Atherosclerosis and Essential Hypertension. New York: Oxford University Press, 1980:450. 3. Berenson GS, ed. Causation of Cardiovascular Risk Factors in Children: Perspectives on Cardiovascular Risk in Early Life. New York: Raven Press, 1986:408. 4. Akerblom HK, Uhari M, Pesonen E, Dahl M, Kaprio EA, Nuutinen EM, Pietikanen M, Sala MK, Aromaa A, Kannas L, et al. Cardiovascular risk in young Finns. Ann Med 1991;23:35–39. 5. Srinivasan SR, Bao W, Wattigney WA, Berenson GS. Adolescent overweight is associated with adult overweight and related multiple cardiovascular risk factors. The Bogalusa Heart Study. Metabolism 1996;45:235–240. 6. Boa W, Srinivasan SR, Wattigney WA, Berenson GS. Persistence of multiple cardiovascular risk clustering related to syndrome X from childhood to young adulthood. Arch Intern Med 1994;154:1842–1847. 7. Gidding SS, Bao W, Srinivasan SR, Berenson GS. Effects of secular trends in obesity on coronary risk factors in children. The Bogalusa Heart Study. J Pediatr 1995;127:868 –874.

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8. Mohdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991–1998. JAMA 1999; 282:1519 –1522. 9. Srinivasan SR, Myers L, Berenson GS. Temporal association between obesity and hyperinsulinemia in children, adolescents, and young adults: the Bogalusa Heart Study. Metabolism 1999;48:928 –934. 10. McGill HC Jr. Persistent problems in the pathogenesis of atherosclerosis. Arteriosclerosis 1984;4:443–451. 11. Enos WF, Beyer JC, Holmes RH. Pathogenesis of coronary disease in American soldiers killed in Korea. JAMA 1955;158:912–914. 12. McNamara JD, Molot MA, Stremple JF, Cutting RT. Coronary artery disease in combat casualties in Vietnam. JAMA 1971;216:1185–1187. 13. Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP. Influences of maternal hypercholesterolemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 1999;354:1234 –1241. 14. Stary HC, Blankenhorn DH, Chandler AB, Glagov S, Insull W Jr, Richardson M, Rosenfeld ME, Schaeffer SA, Schwartz CJ, Wagner WD, et al. A definition of the intima of human arteries and of its atherosclerosis-prone regions. Circulation 1992;85:391–405. 15. Freedman DS, Newman WP III, Tracy RE, Voors AW, Srinivasan SR, Webber LS, Restrepo C, Strong JP, Berenson GS. Black/white differences in aortic fatty streaks in adolescence and early childhood: the Bogalusa Heart Study. Circulation 1988;77:856 –864. 16. Berenson GS, Wattigney WA, Tracy RE. Atherosclerosis of aorta and coronary arteries and cardiovascular risk factors in persons aged 6 –30 years studied at necropsy: the Bogalusa Heart Study. Am J Cardiol 1992;70:851–858. 17. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney W, for the Bogalusa Heart Study. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 1998;338:1650 –1656.

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18. McGill HC Jr, McMahan CA, Malcom RT, Oalmann MC, Strong JP. Effect of serum lipoproteins and smoking on atherosclerosis in young men and women. Arterioscl Thromb Vasc Biol 1997;17:95–106. 19. McGarry P, Solberg LA, Guzman MA, Strong JP. Cerebral atherosclerosis in New Orleans. Comparison of lesions by age, sex, and race. Lab Invest 1985;52: 533–539. 20. Mahoney LT, Burns TL, Stanford W, Thompson BH, Witt JD, Rost CA, Lauer RM. Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study. J Am Coll Cardiol 1996;27:277–284. 21. Urbina EM, Srinivasan SR, Tang R, Bond MG, Kieltyka L, Berenson GS. Impact of multiple coronary risk factors on the intima-media thickness of different segments of carotid artery in healthy, young adults: the Bogalusa Heart Study. Am J Cardiol 2002;90:953–958. 22. Riley WA, Freedman DS, Higgs NA, Barnes RW, Zinkgraf SA, Berenson

GS. Decreased arterial elasticity associated with cardiovascular disease risk factors in the young: the Bogalusa Heart Study. Arteriosclerosis 1986;6:377–386. 23. Zarins CK, Giddens DP, Bharadvaj BK, Sottiurai VS, Mabon RF, Glagov S. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and with shear stress. Circ Res 1983;53:502–511. 24. Johnson CC, Nicklas TA, Arbeit ML, Harsha DW, Serpas DC, Hunter SM, Wattigney W, Berenson GS. Cardiovascular intervention for high-risk families: the Heart Smart Program. South Med J 1991;84:1305–1312. 25. Arbeit ML, Johnson CC, Mott DS, Harsha DW, Nicklas TA, Webber LS, Berenson GS. The Heart Smart cardiovascular school health program. Behavior correlates of risk factor change. Prev Med 1992;21:18 –32. 26. Downey AM, Cresanta JL, Berenson GS. Cardiovascular health promotion: “Heart Smart” and the changing role of the physician. Am J Prev Med 1989;5: 279 –295.

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