Pediatr Nephrol (1997) 11: 99 – 107  IPNA 1997

Invited review Atherosclerosis in youth: are hypertension and other coronary heart disease risk factors already at work? Margaret C. Oalmann, Jack P. Strong, Richard E. Tracy, and Gray T. Malcom Department of Pathology, Louisiana State University Medical Center, 1901 Perdido Street, New Orleans, Louisiana 70112, USA Received June 20, 1996; received in revised form July 11, 1996; accepted July 26, 1996

Abstract. The purposes of this review were to describe the natural history of atherosclerosis in youth, discuss the role of adult coronary heart disease (CHD) risk factors in the development of atherosclerosis – particularly in the young – and present the relationship between atherosclerosis and hypertension. Evidence is presented that, by age 15 years, 100% of the youth have aortic atherosclerosis and about one-half have coronary atherosclerosis. Risk factors for adult CHD, including lipoproteins, smoking, glycohemoglobin (a marker for diabetes), obesity, and hypertension, are associated with extent and prevalence of atherosclerosis in young people. Hypertension seems to play its role mainly by converting early atherosclerotic lesions (fatty streaks) to more advanced lesions (raised lesions).

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Key words: Atherosclerosis – Youth – Lipoprotein – Smoking – Glycohemoglobin – Obesity – Hypertension

Introduction The realization that atherosclerosis begins in childhood, and that young American adults have a high prevalence of advanced coronary atherosclerotic lesions [1 – 3], raised questions about: (1) whether the risk factors for adult clinically manifest coronary heart disease (CHD) exist in some form in children and (2) if they exist, whether they are associated with the preclinical arterial lesions of atherosclerosis. Until the middle of the twentieth century, age was considered the major determinant of atherosclerosis, and prevention was not discussed. However, investigators had recognized the early development of atherosclerosis, particularly in the aorta, for many years [4 – 7]. Zeek [8], in a 1930 review of the literature pertaining to juvenile arter-

Correspondence to: J. P. Strong

iosclerosis, concluded that arteriosclerosis may occur at any age. Atherosclerosis begins as intimal lipid deposits, called fatty streaks. Fatty streaks in some arterial sites are converted into fibrous plaques by continued accumulation of lipid, smooth muscle cells, and connective tissue. Fibrous plaques undergo a variety of changes – hemorrhage, ulceration, thrombosis, or calcification – some of which produce occlusion, ischemia, and clinical disease. Early quantitative studies in New Orleans led to a simplified diagrammatic concept of the natural history of atherosclerosis (Fig. 1) [9]. Typically, clinical disease occurs 30 or more years after the process begins as fatty streaks, but it may be greatly accelerated in persons with cardiovascular disease risk factors. Although deaths from the major clinical manifestations of atherosclerosis – CHD and stroke – seem to have reached their peak and began to decline after the midcentury, cardiovascular diseases remain the leading cause of death in the United States. It is difficult to unravel the etiology, pathogenesis, and temporal development of various stages of a complex chronic disease, whether cardiovascular or renal, by studying only the end-stage. This review describes atherosclerotic lesions in young subjects, the relationships among atherosclerotic lesions and cardiovascular risk factors, and why the investigators in the ongoing study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), chose to study subjects 15 through 34 years. Previous studies of the natural history of human atherosclerosis indicated that this period in life is when advanced lesions begin to appear with greater frequency in populations with high rates of CHD in middle age and later [10]. It became important to determine whether the risk factors for clinical disease influence the initiation or the progression of atherosclerosis, or both. For example, does hypertension affect only fatty streaks, does it affect progression to fibrous plaques, or does it precipitate plaque rupture and occlusive thrombosis? Answers to these questions determine which risk factors should be modified and when the modification should begin.

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International Atherosclerosis Project From the 21,302 subjects in the International Atherosclerosis Project (IAP), we examined aortic and coronary lesions in 4,737 young subjects,10 through 39 years of age, from six geographic-ethnic groups [13]. At the age of 10 years, practically 100% of the aortas from all geographicethnic groups had fatty streaks. Coronary fatty streaks, while not as frequent as aortic fatty streaks, occurred in some subjects from each geographic-ethnic group, even in those aged 10 – 14 years. Fatty streaks were present in the coronary arteries of all persons older than 20 years in New Orleans and in approximately 90% of persons in other location-race groups at 30 years of age. Fibrous plaques were present in some cases from each group before 20 years of age, and the prevalence increased rapidly in the following 2 decades. Microscopic studies

Fig. 1. Diagrammatic concept of the natural history of atherosclerosis (slightly modified from McGill et al. [9] and reprinted with permission of Academic Press)

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Natural history of atherosclerosis Early New Orleans studies Investigators in our laboratories described the origin of atherosclerosis in New Orleans children and showed that the early lesions of atherosclerosis progressed to more advanced plaques in some subjects during adolescence and young adulthood. These early studies were reviewed recently by Strong [11]. In a study of aortas from 526 necropsied individuals, 1 through 40 years of age, all individuals over 3 years of age had at least minimal sudanophilic intimal deposits [2]. Histological intracellular and extracellular lipid in the intima corresponded to the macroscopic sudanophilia. This observation led Holman [12] to propose the question, “is atherosclerosis a pediatric nutrition problem”? at the Ninth International Congress of Pediatrics in 1959. A study of atherosclerotic lesions in the coronary arteries of 548 necropsied subjects, 1 through 69 years, showed that coronary artery atherosclerosis followed aortic atherosclerosis by about 10 years [3]. Differences in prevalence and extent of coronary artery lesions among black and white and male and female subgroups appeared early in life, and paralleled the incidence of manifest clinical disease 20 years later.

Light and electron-microscopic studies of unopened pressure perfusion-fixed left coronary arteries of 691 male and female subjects who died between full-term birth and 39 years of age showed the early changes of atherosclerosis [14, 15]. Lesions in more than 50% of children aged 10 – 14 years were characterized by accumulations of macrophage foam cells, lipid-containing smooth muscle cells, and thinly scattered extracellular lipid. These changes represent the microscopic counterpart of gross fatty streaks. Lesions in approximately 8% of the subjects aged 10 – 14 years had larger accumulations of extracellular lipid and were thought to be in transition to atherosclerotic plaques, i.e., the lesions that are known to be associated with clinical disease in adults. These changes indicate a progression from fatty streaks through intermediate or transitional lesions to advanced atheromatous lesions (counterpart of gross fibrous plaques) in a segment of the left anterior coronary artery predisposed to clinically significant lesions. Pathobiological Determinants of Atherosclerosis in Youth This study of atherosclerotic lesions in the aortas and right coronary arteries of 1,532 subjects, ages 15 – 34 years, who died of external causes and were autopsied in forensic laboratories, confirms the early appearance of lesions and compares the prevalence and extent among black and white, males and females [16]. Lesions were classified in a central laboratory as fatty streaks, fibrous plaques, complicated lesions, or calcified lesions. Raised lesions were the sum of fibrous plaques, complicated and calcified lesions. All of the aortas and about half of the coronary arteries in the youngest age group (15 – 19 years) had lesions (fatty streaks or raised lesions). The prevalence of lesions in coronary arteries increased to about 75% in the 30- to 34-year age group and was greater in males than in females. The extent of atherosclerosis, expressed as mean percentage intimal surface covered by lesions, increased from age 15 through 34 years. Raised lesions increased with age in both extent and prevalence in the thoracic and abdominal aorta and in the right coronary arteries [16].

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Atherosclerosis in major renal arteries Renal arteries in kidneys without advanced parenchymal disease rarely display more than minimal atherosclerosis. When present, it is usually located near the renal ostia as it branches from the aorta. These renal atherosclerotic lesions do not seem to correlate with atherosclerotic lesions in other arterial segments within the same subjects [17, 18]. Diet-induced atherosclerotic lesions in rhesus monkeys, measured in ten arterial segments, show the major renal arteries have minimal involvement [19]. Therefore, the remainder of this review will relate to aortic and coronary atherosclerosis.

Risk factors and atherosclerosis

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Fig. 2. Bar graphs showing percentage of intimal surface involved with fatty streaks ( ) and raised lesions ( ) for the thoracic and abdominal aortas and the right coronary artery by sex, race, and 5-year age groups (modified from data in reference [16] and reprinted with permission of the American Heart Association). (Copyright, 1993, American Heart Association).

Fatty streaks, well established in both segments of the aorta by age 15 – 19 years, cover from 15% to 25% of the intimal surface of each segment (Fig. 2). In general, surface involvement with lesions is less in the right coronary artery than in the aortic segments. Black subjects had more extensive fatty streaks than white subjects in all three arterial segments. Young women had more extensive fatty streaks in the abdominal aorta, but young men had more in the thoracic aorta. The men had more extensive raised lesions in the right coronary artery than did the women. Black and white subjects did not differ significantly in extent of raised lesions. Among the three arterial segments, the right coronary had the least percentage of intimal surface involved with all types of lesions, but the greatest proportion of raised lesions among total lesions. These results confirm the origin of atherosclerosis in childhood and adolescence and show that the prevalence and extent of fatty streaks and fibrous plaques increase rapidly during this 15- to 34-year age span. Several subjects had lesions that were complicated, calcified, and stenotic – changes that are associated with clinically manifest disease.

Hypertension, long known to predispose to the clinical manifestations of atherosclerosis [20], emerged from the longitudinal epidemiological studies of the 1950s as one of the three major predictors, along with serum cholesterol concentration and smoking, of risk of CHD and stroke [21, 22]. The predisposition to atherosclerotic diseases of persons with diabetes mellitus [23, 24] and those with impaired glucose tolerance, but without clinically manifest diabetes [25], has long been known. Obesity, however, one of the most plausible – yet inconsistent – of the risk factors for CHD [26, 27], has been shown to contribute through its relationship with other risk factors. Gene polymorphisms that affect lipid metabolism, blood pressure, or other risk factors are emerging [28, 29]. In the early 1970s, to determine whether risk factors for adult clinically manifest CHD might exist in some form in children, several centers surveyed children and adolescents [30 – 33]. Although lower than in adults, there was considerable variability in prevalence and in average values and ranges. Smoking began by age 12 years and increased in prevalence to almost 40% by 20 years of age [34, 35]. Risk factors, such as hypertension, cholesterol, and obesity, tracked (high values tended to stay high, and the low, low) within childhood [36 – 38] and from childhood into young adulthood [39]. Serum lipid and lipoprotein levels were higher in children of parents who had experienced precocious CHD [40, 41]. Early studies of risk factor effects on lesions Early studies of atherosclerotic lesions were limited to the relationship of lesions to age, sex, ethnic origin, geographic population group, and clinical disease associated with the cause of death or autopsy findings. Relationships of lesions to suspected risk factors were mainly limited to correlations with average values in the population from which the autopsied persons were derived [42]. However, the IAP data offered an opportunity to test the effects of hypertension and diabetes on the lesions of atherosclerosis in a variety of populations [43]. Persons with hypertension or diabetes mellitus consistently had more atherosclerosis than persons without hypertension or diabetes, regardless of sex, age,

102 Table 1. Prevalence (%) of cases having only Age (years)

15 – 19 20 – 24 25 – 29 30 – 34

Blood pressure class

Normotensive Hypertensive Normotensive Hypertensive Normotensive Hypertensive Normotensive Hypertensive

$5% intimal surface area involved with lesions by age and blood pressure class, adjusted for race, males Abdominal aorta

Right coronary artery

No. of cases

Raised lesions (% positive)

No. of cases

Fatty streaks (% positive)

Raised lesions (% positive)

210 42 297 34 273 44 208 34

4.57 7.48 3.68 6.07 19.30 28.79 39.14 52.08 0.0251

202 40 286 31 267 45 201 34

10.04 11.33 19.81 22.05 27.93 30.74 45.03 48.40 0.5130

2.79 5.49 3.75 7.31 11.97 21.57 26.36 41.99 0.0052

P Adapted from reference (59)

race, or geographic location. Smoking, assessed by interviewing surviving relatives of over 1,300 autopsied New Orleans men, was associated with atherosclerotic lesions in the aorta and in the coronary arteries [44]. In another study of over 1,000 New Orleans men (black and white), measures of obesity and hypertension were associated with raised atherosclerotic lesions in the coronary arteries [45] and cholesterol was associated with coronary raised lesions in white but not in black men [46].

Longitudinal studies with autopsy follow-up

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Five reports appearing between 1979 and 1987 related risk factors measured during life, in longitudinal epidemiological studies, with atherosclerotic lesions measured after death and autopsy [47 – 51]. There was general agreement that serum cholesterol and elevated blood pressure were positively correlated with atherosclerosis, particularly raised lesions, in the coronary arteries. Smoking was associated with aortic lesions in all groups and with coronary lesions in one group. Relative body weight was associated with coronary artery lesions in only one group [52].

Angiographic studies Coronary artery angiography and quantitative evaluation techniques confirmed the association of coronary artery lesions with serum cholesterol, blood pressure, diabetes, smoking, and male sex [53]. However, the results were not always consistent. For example, one large study found no association with smoking, although the usual associations with other risk factors were present [54]. These scattered negative results did not negate the positive findings, however, because of the nature of the sample. Angiograms cannot be performed in randomly selected healthy individuals but only in persons suspected of having one or more manifestations of CHD.

Risk factors and atherosclerosis in childhood and youth Longitudinal studies Investigators in the Bogalusa Heart Study, an epidemiological study of cardiovascular risk factors in children from the biracial community of Bogalusa (Louisiana, USA), first assessed the relationship of risk factors to early atherosclerotic lesions in the aorta and coronary arteries of a small number of deceased study subjects aged 7 – 34 years [55, 56]. Aortic fatty streaks were positively associated with antemortem levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C), independent of race, sex, and age, and were negatively associated with the ratio of high-density lipoprotein cholesterol (HDL-C) to LDL-C plus very low-density lipoprotein cholesterol (VLDL-C). Coronary artery fatty streaks were positively correlated with levels of VLDL-C. Blood pressures measured during life had a positive (borderline significant) association with coronary artery fibrous plaques. In a later analysis with more study subjects, LDL-C levels had a significant, positive association with coronary artery fatty streaks; furthermore, there were significant relationships between LDL-C levels and the prevalence of both aortic and coronary artery fibrous plaques [57]. In a larger number of cases with measurements of blood pressure, there was an association of systolic blood pressure with coronary artery fatty streaks in white males [58].

Pathobiological Determinants of Atherosclerosis in Youth The risk factor-atherosclerosis findings of the PDAY study indicate that the risk factors for adult CHD are related to atherosclerosis in youth. Hypertension. Hypertension, as measured by the intimal thickness of small renal arteries, is associated with a twofold greater prevalence of raised lesions in the aortas and right coronary arteries of black and white male youth (Table 1) [59]. Prevalence of fatty streaks covering 5% or more of the abdominal aorta is 100%, therefore, data not shown.

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Fig. 3. Percent age intimal surface involved with fatty streaks ( ) and raised lesions ( ) for the abdominal aorta and right coronary artery by age and hypertensive classification, adjusted for race, males only (drawn from data presented in reference [59])

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Arterial changes associated with hypertension were measured in histological sections of kidney by a method developed by Tracy et al. [60]. The grader measured the outer diameter, from one outer media to the other, of the least axis of the elliptic profile of all arterial profiles with outer diameters of 80 – 300 µm. The grader then measured the thickness of the intima, also along the least axis. One observer made all measurements. Measurements were grouped into those derived from arteries with outer diameters of 80 through 149 µm (arteries remote from the heart) and those derived from arteries with outer diameters of 150 through 300 µm (arteries more proximal to the heart). Lipid deposits nor other manifestations of atherosclerosis were among the arterial changes found in these size ranges. Others have reported that atherosclerosis was not found at this level of the microvasculature in humans [61]. A renal measure of hypertension (RMH) was calculated by dividing the average thickness of the intima by the average diameter of the artery separately for the measurements made on the smaller (remote) arteries and the measurements made on the larger (proximal) arteries. Each case was classified as normotensive or hypertensive by an algorithm derived from an equation that predicted mean arterial pressure (MAP) from RMH and age [62]. The normotensive category included cases with a predicted MAP of less than 110 mmHg; hypertensive, those with a predicted MAP of 110 mmHg or greater. These cutoff points were selected on the basis of analysis of lengthy lifetime records of blood pressure measurements in persons whose kidneys were examined after autopsy [63]. Among hypertensive compared with normotensive cases, the extent of raised lesions (mainly fibrous plaques) was greater in the aortas, mainly in those of 30 – 34 years, and in the right coronary arteries, in those of 25 – 34 years (Fig. 3). These associations of hypertension with raised lesions were not accounted for by adjusting for glycohemoglobin level, body mass index (BMI), or thickness of panniculus adiposus. The effect of hypertension on ather-

Fig. 4. Total percentage of the intimal surface of the right coronary artery involved by atherosclerosis at two risk levels, predicted by multiple regression analysis of 351 men 15 – 34 years of age. The values are adjusted for race. The upper line represents the predicted extent of lesions at a high risk level with very low-density lipoprotein plus low-density lipoprotein cholesterol (VLDL+LDL-C) 1 SD above the mean, high-density lipoprotein cholesterol (HDL-C) 1 SD below the mean, and smoking status indicated by the serum thiocyanate concentration. The lower line represents the predicted extent of lesions at a contrasting low risk level with VLDL + LDL-C 1 SD below the mean, HDL-C 1 SD above the mean, and no smoking. The shaded bands represent 95% confidence intervals (reference [65], reprinted with permission of Lippincott-Raven)

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Fig. 5. Percentage intimal surface area involved with fatty streaks ( ) and raised lesions ( ) for the abdominal aorta and right coronary artery by age and glycohemoglobin level, adjusted for race and sex (drawn from data presented in reference [66])

osclerosis begins in the 2nd decade of life and accelerates atherogenesis primarily by accelerating the conversion of fatty streaks to fibrous plaques [59]. The lack of a positive association of heart weight, heart weight/height ratio, or ventricular wall thickness with predicted blood pressure classification among these young individuals (data shown in reference [59]) suggests that renal artery intimal thickness, which is strongly associated with atherosclerotic raised lesions, may be a marker for an early stage of elevated arterial blood pressure or a pre-

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Fig. 6. Percentage intimal surface involved with fatty streaks ( ) and raised lesions ( ) for the right coronary artery by sex, body mass index (BMI), and thickness of panniculus adiposus (PA), adjusted for race and age

cursor of elevated arterial pressure, as suggested by Tracy et al. [62].

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Lipoproteins and smoking. Serum cholesterol and HDL-C concentrations and serum thiocyanate levels are measured in postmortem serum. An early publication from PDAY on 390 young men showed that VLDL-C plus LDL-C levels were positively correlated and HDL-C negatively correlated with the extent of atherosclerotic lesions (principally fatty streaks) in the right coronary artery. Smoking, as indicated by the thiocyanate level, was positively associated with the extent of all lesions and with the prevalence of fibrous plaques in the right coronary artery [64]. Figure 4 shows the predicted difference in the extent of coronary atherosclerosis throughout the 15- to 34-year age group of these young males with a high VLDL-C plus LDL-C, low HDL-C, and smoking, compared with those young males with a low VLDL-C plus LDL-C, high HDL-C, and nonsmoking [65]. Glycohemoglobin and obesity. Glycohemoglobin levels equal to or greater than 8%, as determined by analysis of postmortem blood cells, were associated with substantially more extensive fatty streaks and raised lesions in the right coronary artery, especially in persons more than 25 years of age, and with more extensive raised lesions in the aorta in persons more than 30 years of age (Fig. 5). Thickness of the panniculus adiposus and the BMI (weight per height squared) were used as indicators of adiposity. BMI shows a strong association with the extent of fatty streaks in males but not in females (Fig. 6). Panniculus thickness is associated with more extensive fatty streaks and raised lesions in the right coronary artery, but there is no interaction with sex. The effects of elevated glycohemoglobin and of obesity on atherosclerosis are evident throughout this 15-to 34-year age group and they were not explained by a less-favorable lipoprotein profile or smoking. This was the first quantitative analysis of the relationship of glycohemoglobin levels, an objective marker for plasma glucose concentrations, to atherosclerotic lesions in young persons [66].

Several recent articles reviewed the potential mechanisms by which diabetes, hyperinsulinemia, and hyperglycemia augment atherogenesis [67 – 69]. Of the many mechanisms suggested, two seem most likely to be involved in the association of glycohemoglobin concentration in these young adults: the effects of dyslipoproteinemia and hyperinsulinemia in the prediabetic state, as suggested by Haffner et al. [70], and a direct effect of glycosylation of proteins on atherogenesis [71]. The association of obesity with atherosclerosis among young persons, who were the focus of this study, is particularly applicable for primary prevention programs in light of recent reports that obesity has greater predictive power for CHD after long follow-up periods [72 – 74] and that the prevalence of obesity is increasing in the United States [75]. Apolipoprotein polymorphisms. Two PDAY publications have described differences in arterial lesions according to apoprotein genotypes [76, 77]. Apo E genotypes containing E2 had the least, E3 intermediate, and E4 the greatest extent of lesions in the abdominal aorta. Genotypes with the Apo B signal peptide delete/delete had significantly more lesions in black but not white males. Although a number of apolipoprotein genotypes are associated with clinical manifestations of CHD, these are the only two genotypes which have been shown to be associated with arterial lesions. As knowledge accumulates regarding genetic polymorphisms, CHD, and atherosclerosis, it may become possible to describe a constellation of risk factors by analysis of DNA, even at birth. Summary and conclusions After her detailed review of juvenile arteriosclerosis, Zeek [8] in 1930 ended with this comment and these questions: “Perhaps more important than any conclusions to be drawn from this review are the unanswered questions that it has raised, a few of which are listed:” 1. What is the real incidence of arteriosclerotic lesions in children dying from any cause? This question can be answered only by a careful review of autopsy material, both gross and microscopic, from a large series of cases. 2. Under what conditions, if any, do chronic renal lesions occur in children without lesions in the vascular system? What is the real incidence of renal lesions in juvenile arteriosclerosis?... 5. Are vascular lesions any more numerous in children with poor heritage, many childhood diseases and faulty environment than in those showing an absence of these factors? 6. Is there a real peak in the incidence of arteriosclerosis around the onset of puberty? If so, why? 7. Would careful studies of metabolism reveal retention phenomena that would help explain the apparent frequency of association between renal lesions and arteriosclerosis, also between diabetes and vascular lesions? 8. Does hypertension without renal changes ever occur in childhood?“ [8]. These questions are very timely and are pertinent to this review. With data from the PDAY study, the questions re-

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garding the frequency of lesions in young persons, the relationships among hypertension, renal lesions, and juvenile atherosclerosis, and genetic and other “environmental” risk factors are being addressed. Reports from the PDAY study have provided valuable information on the relationship of CHD risk factors to the prevalence and extent of atherosclerosis in young subjects [59, 64, 66, 76 – 84]. The prevalence and extent of fatty streaks and fibrous plaques increase rapidly in this 15- to 34-year age span and confirm the origin of atherosclerosis in childhood and adolescence. These results also confirm the gender difference in the extent of advanced coronary lesions (males about twice that of females) at this early age. The associations among the CHD risk factors and atherosclerosis suggest that serum lipoprotein cholesterol concentrations, smoking, prediabetic or early diabetic states, obesity, and hypertension are important determinants of atherosclerosis in adolescents and young adults. The high prevalence of CHD risk factors in these young individuals – high cholesterol ( 200 mg/ml) 26.8%, smoking (thiocyanate 90 µmol/l) 49.2%, glycohemoglobin ( 8%) 2.1%, BMI ( 30) 11.4%, hypertension (MAP 110) 10.8% – indicate that primary prevention must begin prior to this age group, 15 – 34 years, if we are to reduce the prevalence and extent of atherosclerosis and ultimately reduce the risk of atherosclerotic disease later in life. We believe that there is much more potential for prevention among the young than among older adults.

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56. Freedman DS, Newman WP III, Tracy RE, Voors AW, Srinivasan SR, Webber LS, Restrepo C, Strong JP, Berenson GS (1988) Black-white differences in aortic fatty streaks in adolescence and early adulthood: the Bogalusa Heart Study. Circulation 77: 856 – 864 57. Newman WP III, Wattigney W, Berenson GS (1991) Autopsy studies in United States children and adolescents. Relationship of risk factors to atherosclerotic lesions. Ann NY Acad Sci 623: 16 – 25 58. Berenson GS, Wattigney WA, Tracy RE, Newman WP III, Srinivasan SR, Webber LS, Dalferes ER Jr, Strong JP (1992) Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons aged 6 to 30 years and studied at necropsy (the Bogalusa Heart Study). Am J Cardiol 70:851 – 858 59. McGill HC, Strong JP, Tracy RE, McMahan CA, Oalmann MC and the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group (1995) Relation of a postmortem renal index of hypertension to atherosclerosis in youth. Arterioscler Thromb Vasc Biol 15:2222 – 2228 60. Tracy RE, Velez-Duran M, Heigle T, Oalmann MC (1988) Two variants of nephrosclerosis separately related to age and blood pressure. Am J Pathol 131:270 – 282 61. Stoddard LD, Puchtler H (1969) Human renal vascular lesions and hypertension. Pathol Annu 4:253 – 268 62. Tracy RE, Berenson G, Wattigney W, Barrett TJ (1990) The evolution of benign arterionephrosclerosis from age 6 to 70 years. Am J Pathol 136:429 – 439 63. Tracy RE, Tabares Toca V (1974) Nephrosclerosis and blood pressure. I. Rising and falling patterns in lengthy records. Lab Invest 30:20 – 29 64. PDAY Investigators (1990) Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. A preliminary report from the Pathobiological Determinats of Atherosclerosis in Youth (PDAY) Research Group. JAMA 264:3018 – 3024 65. McGill HC Jr (1996) Overview. In: Fuster V, Ross R, Topol E (eds) Atherosclerosis and coronary heart disease. LippincottRaven, Philadelphia, pp 25 – 41 66. McGill HC Jr, McMahan CA, Malcom GT, Oalmann MC, Strong JP, and the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group (1995) Relation of glycohemoglobin and adiposity to atherosclerosis in youth. Arterioscler Thromb Vasc Biol 15:431 – 440 67. Brownlee M, Cerami A, Vlassara H (1988) Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315 – 1321 68. Bierman EL (1992) Atherogenesis in diabetes. Arterioscler Thromb 12:647 – 656 69. Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Cayatte AJ, Rozek MM (1992) Pathogenesis of the atherosclerotic lesion; implications for diabetes mellitus. Diabetes Care 15:1156 – 1167 70. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK (1990) Cardiovascular risk factors in confirmed prediabetic individuals; does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 263:2893 – 2898 71. Vlassara H, Bucala R, Striker L (1994) Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest 70:138 – 151 72. Garrison RJ, Castelli WP (1985) Weight and thirty-year mortality of men in the Framingham Study. Ann Intern Med 103: 1006 – 1009 73. Rissanen A, Heliovaara M, Knekt P, Aromaa A, Reunanen A, Maatela J (1989) Weight and mortality in Finnish men. J Clin Epidemiol 42:781 – 789 74. Lee I-Min, Manson JE, Hennekens CH, Paffenbarger RS (1993) Body weight and mortality. A 27-year follow-up of middle-aged men. JAMA 270:2823 – 2828 75. Kuczmarski RJ, Flegal KM, Campbell, Johnson CL (1994) Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys. JAMA 272:205 – 211

107 76. Hixson JE, PDAY Investigators (1991) Apolipoprotein E polymorphisms affect atherosclerosis in young males. Arterioscler Thromb 11:1237 – 1244 77. Hixson JE, McMahan CA, McGill HC Jr, Strong JP, Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group (1992) Apo B insertion/deletion polymorphisms are associated with atherosclerosis in young black but not young white males. Arterioscler Thromb 12:1023 – 1029 78. Strong JP, Malcom GT, Newman WP III, Oalmann MC (1992) The early lesions of atherosclerosis in childhood and youth: natural history and risk factors. J Am Coll Nutr 11:51S – 54S 79. Strong JP, Oalmann MC, Malcom GT, Newman WP, McMahan CA, and the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group (1992) Pathobiological determinants of atherosclerosis in youth (PDAY): rationale, methodology, and selected risk factor findings. Cardiovasc Risk Factors 2:22 – 30 80. Strong JP, Oalmann MC, Malcom GT, Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group (1994) Atherosclerosis in youth: relationship of risk factors to arteiral

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Literature abstracts J Pediatr (1996) 129: 208 – 213

Sexual maturation and racial differences in blood pressure in girls: the National Heart, Lung, and Blood Institute Growth and Health Study Stephen R. Daniels, Eva Obarzanek, Bruce A. Barton, Sue Y. S. Kimm, Shari L. Similo, and John A. Morrison

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Objective: To evaluate racial differences in blood pressure in girls aged 9 to 10 years in the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) and to evaluate the extent to which racial differences in blood pressure are explained by other factors, including sexual maturation and body size. Methods: The NGHS enrolled 539 black and 616 white girls aged 9 years, and 674 black and 550 white girls aged 10 years. Racial differences in blood pressure were examined. Relationships of stage of sexual maturation, height, and skinfold thickness with systolic and diastolic blood pressure were evaluated by multiple regression analysis. Results: The black girls had significantly higher systolic (102.0 8.90 vs 100.5 9.42 mmHg, p 0.001) and diastolic (58.0 12.0 vs 56.5 12.51 mmHg, p 0.01) blood pressures than the white girls. The black girls were also more advanced in sexual maturation and were taller (142.9 7.94 vs 139.6 7.05, p 0.001)

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and heavier (39.6 11.24 vs 35.3 8.73 kg, p 0.001) than the white girls. Both systolic and diastolic blood pressure were significantly correlated with level of maturation height, weight, and sum of skinfolds. Stage of maturation was found to account for the difference in blood pressure between black girls and white girls. In a multiple regression analysis, controlling for height (for diastolic blood pressure) and for both height and sum of skinfolds (for systolic blood pressure) eliminated the effects of race and stage of maturation on blood pressure. Conclusion: Racial differences in blood pressure were observed for 9- and 10-year-old girls and are explained by the fact that black girls were more mature than white girls. The effect of sexual maturation on blood pressure appears to operate through height and body fat. The effect of obesity may be more important for systolic than for diastolic blood pressure. Continuation of racial differences in blood pressure may result in a higher prevalence of hypertension for black women.

Am J Kidney Dis (1996) 28: 14 – 22

Superoxide dismutase activity in human glomerulonephritis Abul Kashem, Masayuki Endoh, Fumio Yamauchi, Naohiro Yano, Yasuo Nomoto, Hideto Sakai, Laszlo Pronai, Masao Tanaka, and Hiroe Nakazawa Superoxide dismutase (SOD) in renal tissue biopsy specimens obtained from patients with immunoglobulin A nephropathy (13 cases) and nonimmunoglobulin A mesangial proliferative glomerulonephritis (nine cases) was studied at the protein level by an enzyme-linked immunosorbent assay method and at the mRNA level by the reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Total SOD activity in the tissue supernatant was measured by applying an electron paramagnetic resonance/spin trapping method. Normal renal tissues obtained from kidneys removed for malignancies (six cases) were included as healthy controls. The copper and zinc form of SOD (Cu, ZnSOD) activity at both the protein and mRNA levels was lower in the moderately or severely damaged tissues compared with that in the normal or mildly damaged tissues. On the other hand, manganese SOD

(Mn-SOD) values at either the protein level or the mRNA level did not differ significantly between control and patient samples. In the histochemical study using a polyclonal rabbit anti-Cu, Zn-SOD antibody, the staining intensity for Cu, Zn-SOD antigen was lower in the areas with advanced histologic damage than in the intact tissues. A followup study showed that renal function deterioration was proportionately slower in patients whose SOD activity was within the range of healthy tissue levels at the time of biopsy. Our data suggest that a lower level of SOD activity, whether as a cause or a consequence of the disease process, might induce a decrease in the scavenger reaction of superoxide (O2–), thus causing the tissue to become more vulnerable to oxidative stress.