REVIEW Print ISSN 1738-5520 / On-line ISSN 1738-5555 DOI 10.4070 / kcj.2010.40.1.1 Copyright ⓒ 2010 The Korean Society of Cardiology Open Access Atherosclerotic Cardiovascular Disease Beginning in Childhood Young Mi Hong, MD Department of Pediatrics, School of Medicine, Ewha Womans University, Seoul, Korea ABSTRACT Although the clinical manifestations of cardiovascular disease (CVD), such as myocardial infarction, stroke, and peripheral vascular disease, appear from middle age, the process of atherosclerosis can begin early in childhood. The early stage and progression of atherosclerosis in youth are influenced by risk factors that include obesity, hypertension, dyslipidemia, and smoking, and by the presence of specific diseases, such as diabetes mellitus and Kawasaki disease (KD). The existing evidence indicates that primary prevention of atherosclerotic disease should begin in childhood. Identification of children at risk for atherosclerosis may allow early intervention to decrease the atherosclerotic process, thereby preventing or delaying CVD. This review will describe the origin and pro- gression of atherosclerosis in childhood, and the identification and management of known risk factors for athe- rosclerotic CVD in children and young adults. (Korean Circ J 2010;40:1-9) KEY WORDS: Atherosclerosis; Cardiovascular diseases; Child; Adolescent; Primary prevention. Introduction cells) and T lymphocytes in the intima of the arteries. Fatty streaks may or may not progress, and may regress. Although atherosclerosis manifests clinically in mid- In some people, lipid accumulation is more pronounc- dle and late adulthood, it is well-known that it has a ed with time, and the accumulated lipid becomes co- long asymptomatic phase of development, which begins vered by a fibromuscular cap to form what is termed a early in life, often during childhood. In most children, fibrous plaque. Temporally, between the fatty streak and atherosclerotic vascular changes are minor and can be the fibrous plaque, transitional stages of atherosclero- minimized or prevented with a healthy lifestyle. How- sis exist that are not identifiable by gross examination ever, in some children the process is accelerated because alone. With time, fibrous plaques enlarge and undergo of risk factors or specific diseases. Identification of child- calcification, hemorrhage, ulceration or rupture, and ren who are at risk for atherosclerosis may allow early thrombosis. Thrombotic occlusion precipitates clinical intervention to decrease the atherosclerotic process, pre- disease such as myocardial infarction, stroke, or gan- venting or delaying cardiovascular diseases (CVD), such grene depending on which artery is affected (Fig. 1).1) as myocardial infarction, stroke, and peripheral vascular As detailed below, autopsy studies in children and disease. young adults who had died of non-cardiovascular cau- ses have conclusively demonstrated early development Atherosclerotic Changes in Childhood of atherosclerosis. Attention was first drawn to the early origin of athe- Atherosclerosis begins in childhood as an accumula- rosclerosis by an autopsy study conducted on young tion of fatty streaks-lipid-engorged macrophages (foam soldiers killed in the Korean War.2) Their average age was 22 years, and over 70% of them had evidence of Correspondence: Young Mi Hong, MD, Department of Pediatrics, School of atherosclerosis in their coronary arteries. Postmortem Medicine, Ewha Womans University, 911-1 Mok-dong, Yangcheon-gu, Seoul 158-710, Korea coronary angiography and dissection of hearts from Tel: 82-2-2650-2841, Fax: 82-2-2653-3718 105 United States soldiers killed in Vietnam demon- E-mail: [email protected] strated that 45% had some evidence of atherosclerosis ○cc This is an Open Access article distributed under the terms of the Creative and 5% had gross evidence of severe coronary athe- Commons Attribution Non-Commercial License (http://creativecommons. rosclerosis.3) Another study demonstrated a very high org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is incidence of lipid-laden macrophages in the intima of properly cited. the aorta and coronary arteries of young American 1 2·Atherosclerosis in Childhood Natural history of atherosclerosis tely 30% of those aged 30-34 years at the time of death. 70 Infarct Stroke Gangrene Aneurysm The percent of intimal surface involved with raised fat- ty streaks increased with age and was associated with a high level of non-high-density lipoprotein cholesterol 60 (HDL-C) and low HDL-C, hypertension, obesity, and impaired glucose tolerance. An intravascular ultrasound study determined that 17% of otherwise healthy heart 50 donors <20 years of age, 37% of those aged 20-29 years, Clinical horizon 60% of those aged 30-39 years, 71% of those aged 40- Calcification ≥ - - - - 40 Complicated lesion: 49 years, and 85% of those 50 years of age had evid 9) Hemorrhage, Ulceration, ence of coronary atherosclerosis. Thrombosis 30 Age in years Noninvasive Assessment of Preclinical Atherosclerosis Fibrous plaque 20 Until recently, our understanding of the childhood Fatty streak antecedents of adult CVD was limited mainly to auto- 10 psy studies and pathologic findings in teenagers and young adults who died from accidental causes. Recent advances in noninvasive techniques have allowed de- 0 tection of early changes in physiology and visualization Fig. 1. Natural history of atherosclerosis. of anatomical and mechanical abnormalities that re- flect the preclinical biology of atherogenesis. children killed in motor accidents, with over 50% of In adults, noninvasive measures of atherosclerosis children aged 10-14 years having some evidence of early have become established as valid and reliable tools for atherosclerosis.4) A nation-wide autopsy-based study of refining the cardiovascular risk to target individuals who atherosclerosis in young Japanese (1 month-39 years) need early intervention. Noninvasive ultrasound studies disclosed the presence of fatty streaks in 29% of aortas of the neonatal aorta and fetal and early childhood in those aged <1 year and in 3.1% of coronary arteries postmortem studies indicate that impaired fetal growth, of children aged 1-9 years.5) Another examination 13 in utero exposure to maternal hypercholesterolemia, and years later revealed an increased prevalence and extent diabetic macrosomia may all be important risk factors of coronary artery lesions in autopsied subjects who for vascular changes consistent with the earliest physi- died in their third and fourth decade of life.6) In the cal signs of atherosclerosis.10) With limited pediatric data, Bogalusa Heart Study,7) the extent of fatty streaks and the use of these techniques in children and adolescents fibrous plaques in the aorta and coronary arteries were largely has been reserved for research purposes.11) examined in 204 young patients 2-39-years-of-age. The prevalence of fatty streaks in the coronary arteries in- Functional measures creased with age from approximately 50% at 2-15-years- Endocardial function can be evaluated by measuring of-age to 85% at 21-39-years-of-age, and the prevalence changes in blood vessel diameter in response to speci- of raised fibrous-plaque lesions increased with age from fic stimuli using the technique of flow-mediated dila- 8% at 2-15-years-of-age to 69% at 26-39-years-of-age. tion (FMD). FMD measures the nitric oxide-mediated The prevalence and the extent of atherosclerosis was gr- vasodilation produced by increased flow after a period eater with increasing age, body mass index (BMI), blood of ischemia (e.g., ischemia induced by an inflated blood pressure, and levels of serum total cholesterol (TC) and pressure cuff) by brachial artery ultrasonography. Ab- low-density lipoprotein cholesterol (LDL-C). The degree normalities in endothelial function have been noted in of involvement increased with worsening severity and children affected with a variety of conditions. Decreas- greater numbers of risk factors. In the Pathobiological ed FMD has been observed in children with type 1 dia- Determinants of Atherosclerosis in Youth (PDAY) st- betes mellitus, a family history of premature coronary udy,8) the right coronary arteries and aortas were ex- disease,12) and Kawasaki disease (KD).13)14) amined during autopsy in 2,876 individuals aged 15-34 years. Raised fatty streaks were present in the abdomi- Structural measures nal aortas of approximately 20% of those aged 15-19 Carotid intima-media thickness (cIMT) has been used years and approximately 40% of subjects 30-34-years- extensively in children and young adults with risk fac- of-age, and in the right coronary arteries of approxi- tors for CVD. Several large studies have shown that in- mately 10% of 15-19-year-old subjects and approxima- creased IMT correlates well with traditional cardiovas- Young Mi Hong·3 cular risk factors that include excess weight, dyslipide- Risk Factors for Atherosclerosis mia, and hypertension.15-17) In addition, increased IMT in Children is found in adolescents with familial hyperlipidemia and in children with a parent with a history of premature In adults, large prospective population-based studies myocardial infarction.12)18) Young adults with increased have shown that a higher risk of CVD is associated with IMT have an increased likelihood of a cardiovascular multiple risk factors that include obesity, hypertension, events that include myocardial infarction and stroke.