References. 1. Personen E, Liuba P. Footprints of atherosclerotic coronary heart disease in children. Rev Port Cardiol 2004;23:

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1 IS FAMILY HISTORY OF PREMATURE CARDIOVASCULAR DISEASES APPROPRIATE FOR DETECTION OF DYSLIPIDEMIC CHILDREN IN POPULATION-BASED PREVENTIVE MEDICINE PROGRAMS? Roya Kelishadi, M.D., Associate Professor and Head, Preventive Pediatric Cardiology Department, Isfahan Cardiovascular Research Center, Isfahan University of Medical Sciences, Isfahan, Iran, s: ; According to multiple studies, the early stages of atherosclerosis begin in early life, and the extent of its lesions correlates positively with plasma low density lipoprotein cholesterol (LDL- C) levels and negatively with plasma high density lipoprotein cholesterol (HDL-C) levels, even in childhood and young adulthood [1]. Cardiovascular diseases (CVDs) are caused by interaction of genetic and environmental factors. Genetic component is believed to be more predominant when atherosclerosis presents in young age; in addition, premature CVDs tend to run in families. Many studies have demonstrated the association of family history with unfavorable serum lipid levels [2]. The current scientific guidelines of The American Academy of Pediatrics [3], the American Heart Association [4], and the National Cholesterol Education Program [5] emphasize the screening of those children with a positive family history of premature CVD. They define CVD as premature when it occurs in relatives, including parents, grandparents, uncles and/or aunts before the age of 55 years; and the current algorithms for screening and follow up of such children are based on their serum total and LDL-cholesterol levels. Nevertheless, controversy exists as to the effectiveness of these guidelines; it remains unclear whether they are appropriate for various ethnic groups having different genetic background and diversity in lifestyle. Consequently for the first time in Iran, and to the best of our knowledge in Asia, we performed the current population-based survey entitled Childhood & Adolescence Surveillance and PreventIon of Adult Non-communicable disease: CASPIAN study [6] to compare the serum lipid profile of a large national representative sample of children and adolescents, aged 6-18 years, with reference values, and to evaluate the usefulness of the existing guidelines to screen children and adolescents for dyslipidemia. As presented in Figure 1, we found that in both genders and in all age groups, the mean serum triglycerides (TG) and its percentiles were significantly higher, and the mean and percentiles of total, low-density, and high density cholesterol (TC, LDL-C, and HDL-C) were significantly lower than the Lipid Research Clinic (LRC) values [7]. In total, 45.7% of participants had dyslipidemia; the most frequent ones were low HDL-C (24.8%) and hypertriglyceridemia (24.5%), followed by hypercholesterolemia (6.4%), and high LDL-C (6.3%), respectively. The mean serum lipid levels and the anthropometric measures were not significantly different among those with or without positive FH. The sensitivity, specificity, and

2 positive and negative predictive values for family history in detecting those children with dyslipidemia were 28.4%, 70.3%, 44.7%, and 53.8%, respectively. The low sensitivity of positive family history is suggested as the main disadvantage of the current guidelines for screening lipid disorders among youths [8]. In our study, this sensitivity was 28.4%, which was nearly similar to that reported from Canada (33.1%) [9], but higher than the study in U.S. (21.6%) [10]. Consistent with some other population-based studies [11], we did not find any significant difference in the lipid profile of children with and without a self-reported family history of premature CVD. Whereas in many previous studies including ours, in which CVD risk factors have been more prevalent in children of patients hospitalized for premature CVD [12-15], we suggest that this controversy among population-based studies and the medical researches conducted in offspring of hospitalized patients, is mainly due to the inaccuracy of self-reports of family history. Although in general, the validity of such data is shown to be fairly good [16], but some other studies suggest that such self-reports are inaccurate [9,17]. Our finding about the high prevalence of high TG and low HDL-C among the children of our community might be of interest. In Western countries, the prevalence of high total and LDLcholesterol is reported to be considerably higher than in our study. In a recent study, rural children in the U.S. had high total and LDL-cholesterol levels (26% and 20%, respectively) [18]. In Brazil, this prevalence is reported to be 27.9% and 26.4%, respectively [19]. In our study, the prevalence of hypertriglyceridemia and low HDL-C, i.e. the components of the metabolic syndrome were higher than that reported from Western countries. In our population, the mean and the percentiles for TG were higher, and that of HDL-C were lower than in Western countries. The prevalence of the metabolic syndrome is high among Iranian youths [20], which confirms the supposed ethnic predisposition to this type of dyslipidemia among Asians [21]. In addition, a genetic-environment interaction might explain such difference between communities, and necessitate further studies. Diets high in trans-unsaturated fat may lower HDL-C, increase TG levels, and interfere with fatty acid metabolism; our previous study indicated that the improper quality of the consumed fat that is rich in saturated and trans-fatty acids correlated with the high prevalence of dyslipidemia in Iranian youths [22]. The current guidelines for screening dyslipidemia among youths are based on the total and LDL cholesterol levels; we suggest that the high varieties in the type of lipid disorders in different communities should be considered as well. In countries where the prevalence of hypertriglyceridemia and low HDL-C is reported to be high in the adult population, screening of these lipids might be of greater importance than that of total and LDL cholesterol recommended by Western countries. In conclusion, considering that in our study, self-reported family history had low sensitivity, as well as low positive and negative predictive value in identifying dyslipidemic children and adolescents, we suggest that family history has more value in medical research than in population-based studies. The common lipid disorder in our community was hypertriglyceridemia and low HDL-C, i.e. the metabolic syndrome components, but not hypercholesterolemia that is prevalent in Western countries; therefore, we suggest that the current guidelines for screening lipid disorders in youths should consider such ethnic differences. References 1. Personen E, Liuba P. Footprints of atherosclerotic coronary heart disease in children. Rev Port Cardiol 2004;23:

3 2. Greenlund KJ, Valdez R, Bao WH, Wattigney WA, Srinivasan SR, Berenson GS. Verification of parental history of coronary artery disease and associations with adult offspring risk factors in a community sample: The Bogalusa Heart Study. Am J Med Sci 1997;313: American Academy of Pediatrics, Committee on Nutrition. Cholesterol in childhood. Pediatrics 1998;101: Kavey RW, Daniels SR, Ronald M, et al. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation 2003;107: National Cholesterol Education Program (NECP) Expert Panel (ATPIII). Executive summary of the third report of the National Cholesterol Education Program (NECP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults. (Adult Treatment Panel III). JAMA 2001;285: Kelishadi R, Ardalan G, Gheiratmand R, Ramezani A. Is family history of premature cardiovascular diseases appropriate for detection of dyslipidemic children in population-based preventive medicine programs? CASPIAN Study. Pediatr Cardiol 2006;27(6): Tershakovec AM, Rader J. Disorders of lipoprotein metabolism and transport. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. 17 th ed. W.B. Saunders: Philadelphia, 2004: Pankow JS, Folsom AR, Province MA, et al. Family history of coronary heart disease and hemostatic variables in middle-aged adults. Thromb Haemost 1997;77: O Loughlin J, Lauzon B, Paradis G, et al. Usefulness of the American Academy of Pediatrics Recommendations for identifying youths with hypercholesterolemia. Pediatrics 2004;113: Muratova VN, Islam SS, Demerath EW, Minor VE, Neal WA. Cholesterol screening among children and their parents. Prev Med 2001;33: Bailleul S, Couderc R, Rossignol C, et al. Lipoprotein(a) in childhood: relation with other atherosclerosis risk factors and family history of atherosclerosis. Clin Chem 1995;41: Kelishadi R, Sarraf Zadegan N, Nadery GA, Asgary S, Bashardoust N. Atherosclerosis risk factors in children and adolescents with or without family history of premature coronary artery disease. Med Sci Monit 2002;8: Kelishadi R, Naderi Gh, Asgary S. Oxidized LDL metabolites in children with high family risk for premature CVD. Indian J Pediatr 2002;69: Kelishadi R, Sabet B, Khosravi A. Anticardiolipin antibody of adolescents and age of myocardial infraction in parents. Med Sci Monit 2003;9: Makedou A, Kourti M, Makedou K, Lazaridou S, Varlamis G. Lipid profile of children with a family history of coronary heart disease or hyperlipidemia: 9-year experience of an outpatient clinic for the prevention of cardiovascular diseases. Angiology 2005;56: Kee F, Tiret L, Robo JY, et al. Reliability of reported family history of myocardial infarction. Br Med J 1993;307: Martin LM, Leff M, Calonge N, Garrett C, Nelson DE. Validation of self-reported chronic conditions and health services in a managed care population. Am J Prev Med 2000;18: Davis CL, Flickinger B, Moore D, Bassali R, Domel Baxter S, Yin Z. Prevalence of cardiovascular risk factors in school children in a rural Georgia community. Am J Med Sci 2005;330: Prieto Albino L, Arroyo Diez J, Vadillo Machota JM, Mateos Montero C, Galan Rebollo A. Prevalence of hyperlipidemia in children and adolescents in the Province of Caceres. Rev Esp Salud Publica 1998;72: Kelishadi R, Ardalan G, Gheiratmand R, Adeli K, Delavari A, Majdzadeh R, For TheCaspian Study Group. Paediatric metabolic syndrome and associated anthropometric indices: The CASPIAN Study. Acta Paediatr 2006;95(12):

4 21. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases. Part II. Variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation 2001;104: Kelishadi R, Pour MH, Zadegan NS, et al. Fat intake and serum lipid profile in Iranian adolescents. Prev Med 2004; 39:760-6.

5 Figure1. Comparison of the mean serum lipids obtained in the current study versus the reference values [7]: CASPIAN Study Boys Girls