The genesis of atherosclerosis in pediatric age-group.

PEDIATRIC DISEASES THE GENESIS OF ATHEROSCLEROSIS IN PEDIATRIC AGE-GROUP

M. Daria Haust, MD

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Departments of Pathology and Paediatrics, Children’s

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Chulalongkorn University on 12/29/14 For personal use only.

Psychiatric Research Institute, and University of Western Ontario, London, Ontario, N6A 5C1, Canada

0 The three forms of origin ofthe atherosclerotic plaque of adults, that is, the fatty streaks, gelatinous elevations, and microthrombi, all occur in arteries o f normal infants and children. Some of these may become arrested or regress, but many progress to the prominent lesions that precipitate various clinical catastrophies. The aim of modem medicine is to modifr or eliminate many of the factors known to advance the atherosclerotic process and thus decrease the incidence of this disease, which ranks highest on the list of causes of morbidity and mortality in the Wslern world. Of these factors, some may be controlled by dietary means (low salt; low total fat and cholesterol; appropriate ratios o f saturated to mono- and polyunsaturated fatty adds; high content of complex carbohydrates and fiber); controlling hypertension, diabetes, and obesity; abstaining from cigarette smoking; and v~oroo7ousphysical activities. Because pattern of life-style are determined in childhood and adolescence, and because it is o n b during that period of life that measures to prevent progression of atherosclerosis may be predictably effective, it becomes increasingly apparent that atherosclerosis is, indeed, a pediatric problem.

KEY WORDS: childhood atherosclerosis, prevention of atherosclerosis, risk faciors, ultrastructure of lesions.

INTRODUCTION Atherosclerosis remains the principal cause of morbidity and mortality in the industrialized Western societies, although a moderate reduction in the clinical manifestations has been registered in the past 2 decades (1, 2). Since the clinical consequences of this disease usually manifest themselves in midlife, or later, attempts at prevention and treatment have been designed for or aimed at the adult population. And yet, many facts indicate strongly that atherosclerosis begins in early life (3-19). Thus the pediatrician, who traditionally has practiced preventive medicine, should adopt a similar approach to atherosclerosis, which takes it toll in the adult population but whose inception occurs in childhood. Supported by a grant-in-aid T.3-11 from the Heart and Stroke Foundation of Ontario, Toronto, Ontario, Canada. The author acknowledges the skillful technical assistance of Ms. Irena Wojewodzka, Mr. Roger Dewar, and Mrs. Renate Feulgen, and the efficient typing of the manuscript by Mrs. Joanne Weir. Address reprint requests to M. Daria Haust, MD, Department of Pathology, University of Western Ontario, London, Ontario N6A 5C1, Canada.

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The problem of prevention in childhood is by no means a simple matter, nor do all experts (both in pediatrics and atherosclerosis) agree entirely on the course of action. This state of affairs reflects several existing uncertainties. Despite the enormous advances in the field of atherosclerosis, the most reliable predictors of this multifaceted disease have not been identified. Moreover, too few well-designed epidemiological and prospective studies have been undertaken in the pediatric age group (20, 21) to justify the institution of all measures recommended for the adult population. I n considering such steps in early life, the knowledgeable pediatrician must weigh the presumptive or real benefits of preventing atherosclerosis against those nutritional measures that may interfere with optimal growth, maturation, and mental status of the patients (20). Herein perhaps lies a partial explanation for some delay in the willingness of pediatricians to involve themselves in this field. Furthermore, in the minds of some pediatricians, the recommendations that exist today are based on shaky grounds (21). The purpose of this article is to illustrate briefly the early forms of atherosclerotic lesions encountered in children and in youth; to emphasize that these are potential precursors of the atherosclerotic plaque (i.e., the lesion that ultimately underlies the clinical manifestations of atherosclerosis in adult life) (Fig. 1); to provide arguments in support of the belief that not all early lesions necessarily progress to clinically important atherosclerotic plaque; to review briefly the known risk factors for the adult population and consider their

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FIGURE 1. Schematic representation of the progression of three forms of early lesions to atherosclerotic plaque, which may then proceed to a complicated lesion. Clinical manifestations are associated only with the advanced and complicated lesions. FS fatty streak; GE gelatinous elevation; MTh miulceration; CALC calcification; HEM hemorrhage. crothrombus; THR thrombosis; ULC Modified from Table 1.3 in Haust and More (97).

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possible role in childhood; and to summarize the prevailing position regarding preventive measures that could justifiably be introduced in childhood and youth in the light of existing knowledge.


ATHEROSCLEROTIC LESIONS OF EARLY LIFE With the exception of some uncommon heritable disorders (e.g., type I1 hyperlipoproteinemia, Hurler syndrome), the atherosclerotic plaque is rarely, if ever, well developed in arteries before the end of the 2nd decade. The lesions observed until that time are innocuous arterial changes that have no clinical consequences. They are confined to focal areas of the intima and are, in order of frequency, of three varieties, which may occur concomitantly in the same artery: (a) fatty dots and streaks, (b) gelatinous lesions (elevations), and (c) microthrombi. All these lesions have been analyzed morphologically in detail in the past (3, 4, 22-24), and new observations were reported recently (25, 26). To avoid repetition, the following account provides an illustrated summary of the three types of lesion in order to assist in the understanding of the genesis of the disease and its progression. The interested reader is referred to other accounts for morphological details (3, 4, 22-26).

Fatty Dots and Streaks Basically, these lesions are easily detectable on examination of the arterial luminal surface because of their yellow color, and because they reflect focal cellular and extracellular lipid accumulation in the intima. The smallest lesions, and particularly those present in infancy, are considered to represent the earliest forms (Fig. 2). Microscopic appearance depends upon the size of the lesion and its stage of development. Thus, a tiny fatty dot contains a few intimal smooth muscle cells (SMCs) with a small to moderate number of cytoplasmic lipid droplets (Fig. 2). The extracellular compartment is not noticeably altered, as it contains only a small amount of finely dispersed lipid resembling that present in normal intima. In larger lesions, the number of lipid droplets in an individual SMC and the number of fat-containing cells increase, as does the amount of finely dispersed lipid. At a certain stage, when the lipid droplets occupy much of the cytoplasm of a SMC, the latter assumes a foam cell appearance (myogenic foam cell) (3). It is believed that such a cell is no longer capable of metabolizing the accumulated fat droplets, and the lesion has thus entered a nonreversible stage and will advance to an atherosclerotic plaque. In large fatty streaks, this is signaled by the presence of necrotic myogenic foam cells, which release their fat droplets into the extracellular compartment. The conse-

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FIGURE 2. Small fatty streak. Lipid droplets (L), some with lucent core, in endothelium (top) and in an intimal smooth muscle cell. A few granules of finely dispersed lipids lie in the interstitium (arrows). Routine processing and double staining for electron microscopy. X 15,300.



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quences thereof include the migration of local and blood-derived macrophages into the affected area for phagocytosis of fat and cellular debris, with the formation of macrophage foam cells; replication of SMCs; and induced permeability changes of the overlying endothelium with consequent influx of blood constituents into the intima and/or the deposition of microthrombi. With the exception of the appearance of the macrophages and new SMCs, the other features are not commonly observed in the advanced fatty streaks before the end of the 2nd decade of life. Mitogenic stimuli for SMC replication are derived from signals liberated by necrotic cells, from the autocrine secretion of mitogenic factors from intact SMCs (27), and also from factors originating from other sources such as serum, platelets, endothelium, and macrophages

(27). Gelatinous Elevations On gross inspection, these gray lesions may be overlooked because they blend with the adjacent tissue. They represent focal edema of the arterial intima from insudation of blood constituents (3, 4). When the lesions are small, the insudate is usually serous and affects only the superficial intimal layers by separating and distorting the collagen fibers and elastic tissue and causing swelling of the proteoglycan-containing ground substance (3, 4). At the electron microscopic level, it is possible to demonstrate by special techniques that the normal structural pattern of the proteoglycans is considerably altered (Fig. 3a, b). In larger lesions the insudate is usually of a serofibrinous nature (3, 4) and involves the deep intimal layers as well. The large lesions may represent repeated episodes of serofibrinous insudation into the same area, the hallmarks of which are remnants of fibrinoid often surrounded by foam cells (3). Whereas it is plausible that serous edema may be absorbed and small lesions regress, the admixture of fibrinogen in the insudate makes regression less likely. Moreover, the entry of the fibrinogen into the intima is usually accompanied or followed by the deposition of lipoproteins derived from the blood. The local conversion of fibrinogen to fibrin may secondarily affect the integrity of the intimal SMCs. Thus, processes similar to those induced in large fatty streaks, but in a different sequence, may culminate in the formation of the atherosclerotic plaque beyond the 2nd decade of life.

Microthrombi These lesions are identifiable almost exclusively on microscopic examination and probably, therefore, are the least commonly reported (3, 22, 28). Tiny mural thrombi may consist of fibrin or platelets but most often contain

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FIGURE 3. (a) Gelatinous elevation (aorta). The network of interconnected granules of proteoglycans in the intercellular space is disrupted. Ruthenium red method for electron microscopy. X 29,000. (b) Larger than normal granules (arrows) represent sulphated glycosaminoglycans that lack interconnecting filaments (hyaluronic acid). X 68,000.



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both. They may be found in the aorta and coronary arteries of young children. As long as these tiny formations are not overgrown by endothelium from the adjacent intima, they may be lysed by fibrinolytic systems of the circulating blood or the underlying endothelium (3, 4) and the lesions are reversible. Endothelialization of the microthrombus initiates its organization and incorporation into the intima (Fig. 4). Whereas some tiny organized thrombi may be molded into and become a functional part of the arterial intima, the larger variety may induce further changes and alterations to the underlying intima. These secondary changes may ultimately provide a nidus for the development of clinically important atherosclerotic plaque beyond the 2nd decade of life (28).

NOT ALL EARLY LESIONS PROGRESS TO ATHEROSCLEROTIC PLAQUES Evidence exists that not all early lesions progress to atherosclerotic plaques and that some instead regress or are arrested at a certain stage of development. Whereas the belief that this is true of the human gelatinous lesions and microthrombi is largely based on extrapolation from animal experimentation and from knowledge of general tissue reactions, epidemiological and other data strongly support such a contention with respect to the human fatty dots and streaks. That fatty dots and streaks occur in the aortic intima of very young children was recognized in the last century. It was uncertain at that time, however, whether these represented precursors of atherosclerotic plaques. The early publications and the problems relevant to this question were discussed in detail by Jores (29) and by several other investigators later in this century (5, 6, 17-19, 30-35). Holman et al. (6) found that many children under 3 years of age had fatty streaks in the aorta and that some degree of fatty streaking was present in every person over that age. By the age of 1 year, all children exhibit some degree of fatty streaking at one or more areas of the aortic intima (35). A study involving 19 racial or geographical population groups from different areas of the world (17, 34) showed that initially the fatty streaks were similar with respect to extent and location. This feature did not differ among the various geographic areas or races and was not related to socioeconomic strata, nutrition, or dietary habits. The percentage of surface involvement by fatty streaks increased with age (5, 6). The fatty lesions are present in the aorta throughout life, but the pattern of distribution changes with age. In the neonatal period the lesions are restricted to an area just above the aortic valve ring and to the region of the scar of the ductus arteriosus. Later in childhood they may occupy large areas of the ascending aorta and arch (35), and subsequently lesions appear in the de-

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FIGURE 4. Ultrastructure of an organizing microthrombus. Central masses of fibrin (F) covered by endothelium (E) are invaded by migrating intimal smooth muscle cells (arrows). Tissue preparation as in Fig. 2. X 11,300.



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scending thoracic aorta at the distal lip of the orifices of the intercostal arteries. Similar lesions develop in the abdominal aorta late in the first decade, and the extent of involvement here increases steadily (24, 35). By the end of the 2nd decade, the abdominal segment may be markedly involved, with large surface areas showing fatty streaking (24). It was this feature, the shifting pattern of involvement from the thoracic to the abdominal aorta, as well as the knowledge that in adult life atherosclerotic plaques affect the abdominal aorta much more severely than the more proximal segments, that raised the question as to whether the fatty streaks were really precursor lesions of atherosclerotic plaques. If they were, argued some investigators, why didn’t all precursor lesions develop into the clinically important atherosclerotic lesions? Was it because there are two distinct forms of fatty streaks, only one of which represents an early precursor lesion? Or, alternatively, do some fatty streaks disappear because they are arrested at a reversible stage in their development? Qualitative morphological differences of fatty streaks in normal individuals have not been identified to date, and there is no reason to believe that two distinct types of lesion exist. One may surmise that some fatty streaks regress once the SMCs metabolize the fat droplets accumulated in their cytoplasm. In addition, recent morphological studies of aortas of infants and older children indicate that even when fat-containing SMCs disintegrate and cholesterol crystals accumulate within the intima, the process may be arrested. The arterial wall is apparently capable of repairing itself and such crystals do not necessarily create the nidus of an atherosclerotic plaque (36). This is important with respect to preventive measures of atherosclerosis in the first 2 decades of life.

RISK FACTORS IN ATHEROSCLEROSIS Many factors have been shown to play a role in atherogenesis (37, 38), and the numerous studies emphasize the importance of hypertension; cigarette smoking; family history; age; sex; diabetes mellitus; obesity; and the intake of salt, total fat, cholesterol, and saturated and unsaturated fatty acids (37-41). Of the identified factors, none has been more extensively studied than the plasma lipids, especially cholesterol. In the fasting state, most of the plasma cholesterol in humans, in the absence of genetic diseases, is carried in the fraction of low-density lipoproteins (LDL); the high-density lipoproteins (HDL) and the very low-density lipoproteins (VLDL) carry the remaining plasma cholesterol. Most of the endogenous triglycerides are also carried in the VLDL fraction. The risk of coronary atherosclerosis and subsequent heart disease is increased with high levels of LDL cholesterol or low levels of HDL cholesterol, with each of the above being an independent predictor (39, 40). Thus, the


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ratios of total cholesterol to HDL and of LDL to HDL have been used as additional parameters in the assessment of risks for coronary heart disease (8). Elevated levels of triglycerides and VLDL have been shown to be associated with disease but not as separate risk factors (42). Moreover, it has been reported that in children, antemortem VLDL cholesterol levels correlated best with the extent of fatty streaks in the coronary arteries, whereas in the aorta, these lesions were strongly associated with both the plasma total cholesterol and LDL cholesterol and inversely related to the ratio of H D L cholesterol to the sum of LDL and VLDL cholesterol (43). Determining the levels of total plasma cholesterol, LDL, HDL, and VLDL may not always provide all the information necessary for risk assessment, because the apoproteins, the carrier proteins of the plasma lipids, play an important role in atherosclerosis. There is an increased risk of premature coronary heart disease in the presence of normal plasma total cholesterol with prevailing hyperapo-@-lipoproteinemia (44) or hypo-a-lipoproteinemia (4548), and a reduced risk, despite high levels of plasma cholesterol, in “hyper-alipoproteinemia” (49-5 1). The studies on the absolute and relative values of plasma lipoproteins and their classes and profiles have been extended, with relevance to atherosclerosis, to factors capable of influencing these parameters. Those factors that tilt the scale in favor of atherogenesis or acceleration of the atherosclerotic process and its clinical manifestations may themselves be considered to be risk factors. For example, it is the fatty acid (FA) composition of consumed fats and not only the total amount of cholesterol and fat consumed that has been shown to influence the profile and level of plasma lipids (52). Saturated FAs elevate the total plasma cholesterol level, whereas unsaturated FAs have the opposite effect (8, 53, 54). The intake of fats rich in poly- or monounsaturated FAs raises the level of plasma H D L (55, 56). Lipids rich in the omega-3 (n-3) FAs, which abound in fish oil, not only decrease the cholesterol-induced rise in plasma lipoprotein cholesterol level (52), but also indirectly decrease the propensity for blood clotting. The long-chain derivatives of the omega-3 FAs (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) are capable of inhibiting the formation and actions of prostaglandins, leukotriene, and arachidonic acid, factors which promote blood clotting (53, 54). Since thrombosis is involved not only at the inception (Fig. 4) but also in the progression and complication of atherosclerotic lesions (24, 28), the amount and nature of consumed fats may influence these processes by affecting clotting. That dietary lipids may relate to atherosclerosis by diverse mechanisms has been known for several decades. Their links to atherogenic or risk factors in addition to thrombosis, such as hypertension, cigarette smoking, and stress, have been documented repeatedly in the past (see Ref. 37). The many factors that are known or assumed to play a role in the incep-



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tion and progression of atherosclerosis relate to the blood (constituents and elements in transit, e.g., toxins, hormones, vitamins, pharmacological agents, nicotine, catecholamines, and other active principles), to the hemodynamics of the circulation (hypertension, turbulence, decreased velocity, increased viscosity, shearing forces, neurovascular control), or to the constituents and status of the arterial wall itself (37). Lipids were singled out for the preceding discussion, not because they are considered to be the only important factors, but because a great amount of clinical, genetic, epidemiological, pathological, and experimental data has accumulated in this specific area, that justifies the recommended preventive and therapeutic measures (57-81). The account also serves to illustrate the interdependence of several seemingly unrelated factors implicated in atherogenesis. Not all risk factors affect all arteries to the same extent. Whereas lipids play an important role in coronary heart disease, hypertension is the prevalent factor in stroke. Lowering of high blood pressure by drug treatment does not convincingly reduce the incidence of myocardial infarction, but its beneficial effects on the incidence of stroke are well documented. The question arises whether evidence exists that risk factors related to coronary heart disease in the adult population are relevant to the pathogenesis of atherosclerotic lesions in children. Until the early seventies, the evidence was at best circumstantial, based on retrospective and postmortem studies. Nevertheless, these studies were important because they stimulated interest in atherosclerosis of childhood. Moreover, they documented that, in the coronary arteries, fatty streaking in childhood was more extensive in populations with a prevalence of advanced, severe atherosclerotic lesions in middle age (17). Clinical and laboratory studies in children in the past had to overcome the fact that norms and standards for plasma cholesterol, lipoproteins, and even blood pressure were nonexistent for the first 2 decades of life. Today, these data are available but their standardization is not yet uniform, even in North America. Physicians who attend to children must be made aware that values differ at various ages and also between boys and girls. There is accumulating evidence that lipids as risk factors for coronary heart disease in the adult population are relevant to atherogenesis in early life. Fewer data are available pertinent to other risk factors in childhood, but in this area, too, there has been progress in the past 15 years (for review, see Ref 8).

PREVENTION OF ATHEROSCLEROSIS IN THE FIRST 2 DECADES OF LIFE: THE CURRENT APPROACH Any rational strategy of prevention or therapy must be based on concrete knowledge of etiology and pathogenesis of the disease in question. Some as-


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pects of atherosclerosis have not yet been unravelled, but recent advances have been convincing enough to promote a consensus regarding aspects of prevention and treatment. A summary of current views on the applicability of preventive measures to early life and on the role of the pediatrician in this area follows. The role of the pediatrician in preventing atherosclerosis is envisaged as being threefold: (a) to recommend optimal nutrition for infants, children, and adolescents; (b) to recommend adoption of life-styles believed to prevent or retard advancing atherosclerosis; and (c) to identify children at risk and recommend appropriate treatment for them.

Nutrition There are three periods regarding nutritional needs for optimal amounts of fats, including the fatty acids, and cholesterol: from birth until 1 to 2 years of age; the interval ending with puberty; and adolescence. Infancy and up to I to 2 Years of Age. In this period human breast milk (82) is considered to have optimal nutritional value. It contains 40-50% of calories as fat, with the level of cholesterol being approximately 150 mg/dL (15). For infants brought up on formulas, it seems desirable to design the composition to resemble closely that of breast milk. This applies not only to the levels of cholesterol and the amount of total fat but also to the content and nature of the fatty acids. Whereas the American Heart Association (80) recommends that the ratio of saturated (S):monounsaturated (MU):polyunsaturated (PU) fatty acids be l : l : l , a ratio of 2:3:1 for SFAs:MUFAs:PUFAs has been more recently suggested (15). This recommendation was made on two grounds. First, high concentrations of dietary MUFAs increase the level of HDL (in adults) (55). Second, a study carried out on the phospholipids of red blood cells in infants indicated that the highest level of HDL was obtained when PUFAs amounted to half the levels of SFAs (56). Human milk contains two important PUFAs that must be added to the formulas, linoleic acid and alpha-linolenic acid (83). Linoleic acid is the parent FA of the omega-6 (n-6) family, whose members are important constituents of cell membrane phospholipids (e.g., arachidonic acid) and precursors of various biologically active eicosanoids (prostaglandin, prostacyclin, leukotriene, and thromboxane) (53, 54, 84, 85). Linoleic acid must be added to formulas because animal tissues are unable to synthesize this parent FA (18:2, n-6). It has been recommended recently that the n-6 FAs added to formulas not exceed 20% of total FAs or 10% of dietary energy (83). Since the n-6 FAs are the precursors of many biologically active eicosanoids, levels that are higher than recommended may have undesirable effects. The enzymes that catalyze the conversion (86) of linoleic acid into its



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derivatives are the same that convert alpha-linolenic acid, the parent FA of the omega-3 (n-3) family (another important FA not synthesized by animal tissues), into its biologically important derivatives (i.e., EPA and DHA). Since both the omega-6 and omega-3 families compete for the same enzymes, and the amount of one will affect the requirements for the other in diet, a certain balance may be optimal (from 5:l to 15:l) (83). Thus, in standard infant formulas, alpha-linolenic acid should not exceed 3% and the sum of its derivatives EPA and DHA should be approximately 1% of all FAs, or the total amount of n-3 FAs should not exceed 2 % of energy (83). Of the total FAs, 0.5% as DHA and 0.8% as EPA are sufficient to maintain the required levels for tissue phospholipids in infants (87). The susceptibility of DHA and EPA to autoxidation (88) and their effects on inhibiting blood coagulation (53, 54) are the main limiting factors in increasing their content in infant formulas. Many recent data support the previous, largely epidemiological, observations that diets rich in n-3 FAs, which are contained in vegetable (soybean and canola) oils, and in fish (89) and other marine oils, prevent clinical manifestations of atherosclerosis by a variety of mechanisms. Thus, inclusion of the sources of the n-3 FAs in the nutrition of older children and adolescents is highly recommended. From Infancy to Puberty. There are committee and society reports with recommendations for optimal nutrition, including lipids, specifically for children older than 2 years or for the general population but with special consideration given to that age group. Such reports have been put out by the Nutrition Committee of the American Heart Association (80), the National Institutes of Health (59), the Senate Select Committee on Nutrition and Human Needs (go), the Nutrition Committee of the Canadian Paediatric Society (91), the Committee on Nutrition of the American Academy of Pediatrics (20), and the British Cardiac Society Working Group (92). The most recent report was issued by the Canadian Consensus Conference on Cholesterol (93). Most of the reports recommend that the fat intake be restricted to 30% (some favor 35% [92, 931) of the calories. Reducing dietary fat to this level is generally believed to be sufficient to lower the cholesterol level. Undernutrition as well as obesity should be avoided by proper caloric adjustment. The recommendations from the United Kingdom are at some variance with the above: “Particular attention should be given to the provision of a healthy diet, as outlined above [for adults], to children over the age offive.” (No reference is made regarding the recommendation for the group 2-5 years of age.) Furthermore, no more than 15% of food energy should be derived from saturated FAs. The ratio of polyunsaturated to saturated FAs should be 0.45 (92). The report stresses that the more stringent recommendations of the World Health Organization in 1982 (which recommended that food energy be


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derived from less total and saturated fat) are not being endorsed for the general population (presumably this includes the children over the age of 5 (92). Adolescence. In normal adolescent subjects, deliberate lowering of the cholesterol level by diet or by other means is not recommended, largely because cholesterol is required as a precursor of hormone production-an active process at this age. Dietary recommendations for the first 2 decades of life for healthy children (older than 2 years of age) are conveniently summarized in Table 4 of an article by Kwiterovich (8) and are based on (or consistent with) the several guidelines mentioned above. In the same article, Table 2‘ provides, separately for boys and girls, normal plasma values for cholesterol and triglycerides, and in Table 3 normal plasma lipoprotein concentrations for boys and girls are provided for the first 2 decades of life (after the age of 2). These values were calculated on the basis of data obtained from seven North American Lipid Research Clinics, all using common protocols and standardized laboratory methodology (1 1,219 children were studied for plasma lipid levels and 1,415 children for plasma lipoprotein concentrations) (94). Whereas the values provided are not absolute, nor can they be, they should serve the practitioner attending children as an excellent guide. Such data based on uniform procedures and the experience of experts were not available in the past.

Life-style Certain factors are known to be of particular importance in the advancement and precipitation of clinical manifestations of atherosclerosis in adult life, but the pediatrician should be concerned with these risk factors early in life. This is important, because dietary patterns, habits, and general life-style are established in childhood and adolescence. In addition to making suitable recommendations for proper nutrition, physicians attending to subjects in the first 2 decades of life should also concern themselves with preventing and treating obesity, controlling diabetes, assessing blood pressure status periodically and instituting appropriate treatment, discouraging cigarette smoking and the use of salt, and promoting physical activity with high-energy output.

Children at High Risk Prenatal and early identification of children at high risk (i.e., those from families with known hypercholesterolemia or a history of premature coronary heart disease) is very important for intervention (95). It is crucial to obtain a detailed family history that includes the parents, grandparents, and all first-



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degree relatives. When the family history is positive, it is recommended that a complete lipid profile (cholesterol, triglycerides, lipoproteins) be determined on fasting blood samples and that rigorous dietary modification be instituted for the child. Some recommend that the dietary trial period be 3-6 weeks (15), and others suggest that it last as long as 6 months (93). Diet alone may be quite effective (76), and even in children with heterozygous familial hypercholesterolemia, the total plasma and LDL-cholesterol levels may be reduced, on average, by 10-15% (8). If dietary measures alone fail to reach the goals of treatment, drugs are then required. However, the dietary therapy should continue. The choice of drugs will depend on the nature of the hyperlipidemia (93). The many as yet unresolved problems of treatment in children at risk is reflected by the following statement in a recent recommendation: “The panel could not reach a consensus about guidelines for the treatment of mild to moderate hypercholesterolemia in this age group [children and adolescents under age 181” (93; p. 6). Routine screening for plasma lipids (96) in infants and children with a negative family history is not considered to be justified at present.

CONCLUSIONS It has been established by many morphological studies that all three precursor forms of adult and clinically significant atherosclerotic plaque occur ubiquitously in infants and children. What really qualifies atherosclerosis as a pediatric problem is the accumulating knowledge that the process depends upon many factors present during the first 2 decades of life that will singly or in combination determine whether or not the innocuous intimal lesions will progress to the more serious atherosclerotic plaques of adulthood (3, 97). These factors include the total amount of dietary fat (and its content of saturated and mono-and polyunsaturated fatty acids), cholesterol, salt, complex carbohydrates and fiber; sex; age; hypertension; diabetes; obesity; cigarette smoking; habits of exercise; and the family history of coronary heart disease. Whereas some of the above factors cannot be altered (e.g., age and sex), others may be modified by appropriate measures. Attempts to do so may be more meaningfully contemplated in the first 2 decades of life than at any other time. In this context, it may be mentioned that much has been written on the subject of regression of atherosclerotic lesions in adult life and the treatment of atherosclerosis after the clinical event. Whether the advanced, prominent atherosclerotic lesions that precipitate clinical events may ever truly regress remains a controversial issue. From a clinical point of view, it makes little sense to allow atherosclerosis to progress to a stage culminating in permanent dam-


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age to vital organs before treating the underlying process. What is treated at that point are the consequences of the disease. At best, preventive measures undertaken in the adult may slow the progression of lesions at other sites of the arterial tree. The same measures, were they instituted in childhood and adolescence, might have altered the natural history of the early disease. Pediatricians and other physicians attending to normal young people are in a unique position to institute and direct such modifications of life-style as will reduce the incidence of atherosclerosis in the adult population.

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Pediatric aspects of atherosclerosis and hypertension.

The genesis of microarrays.

The genesis of tyrosine phosphorylation.

The genesis of intravenous hyperalimentation.

GENESIS OF PAIN IN ARTHROSIS.

Is the serum level of salusin-β associated with hypertension and atherosclerosis in the pediatric population?

Genesis of EDCTP2.

The Potential of ACTH in the Genesis of Primary Aldosteronism.

Epinephrine and the genesis of hypertension.

The Genesis of Ideas in the Blind Deaf Mute.

Role of GABA in the genesis of chemoconvulsant seizures.

Genesis of a replantation program.

[Vitreous hemorrhage of unusual genesis].

Prevalence and genesis of endometriosis.

Ouabain--a link in the genesis of high blood pressure?

Anisotropic structural complexities in the genesis of reentrant arrhythmias.

Genesis of the 14q+ marker in Burkitt's lymphoma.

[Genesis of merozoites in the coccidia, Eimeria necatrix. Ultrastructural study].

Letter: Psychologic factors in the genesis of myocardial infarction.

Zooming in on the genesis of atherosclerotic plaque microcalcifications.

Functional MRI: Genesis, State of the art and the Sequel.

The subependymal plate and the genesis of gliomas.

The "Genetic Program": Behind the Genesis of an Influential Metaphor.

Community analysis in community health nursing practice: the GENESIS model.