Although the clinical complications of atherosclerosis do not usually occur until adulthood, it is now appreciated that the underlying arterial pathology begins much earlier. Over the last two decades, there have been substantial advances in the understanding of the disturbed vascular biology involved in the initiation and progression of atherosclerosis and its late sequels, with identification of several risk factors on the causal pathway.
In developed countries, better treatment of adults with clinical cardiovascular disease, including reduction of risk factors, has resulted in substantial decrease in morbidity and mortality. This downward trend is slowing, and in developing countries there has been a huge increase in the burden and consequences of atherosclerosis, largely due to a deterioration in the levels of risk factors in the population. 1,2 This has led to increasing interest in the understanding and treatment of the adverse influences promoting atherosclerosis during its long preclinical stage, rather than merely attempting to reverse long-standing atherosclerosis by complex and often expensive interventions which do not fully reverse risk.
The need for identification and treatment of risk factors from childhood is supported by a number of key observations:
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In autopsy studies, atheroma is prevalent in children and young adults who died of non-cardiac causes, from the first decade of life. This has recently been confirmed using intravascular ultrasound, with almost one-fifth of teenagers in the United States being found to have early lesions in their coronary arteries ( Fig. 59-1 ). 3,4
Figure 59-1
The images provide the evidence that atherosclerosis begins in childhood. Coronary atherosclerotic plaques were found in young American soldiers in their teens and early 20s who died in action in the Korean war. 3 The arrow in panel A highlights the presence of significant plaque. The intravascular ultrasonic image of the coronary artery of a 17-year-old boy shown in panel B , who died of non-cardiac causes, shows the distinct mural thickening of the coronary artery ( arrow ). 4
(A, Reproduced with permission from Enos WF, Holms RH, Beyer J: Coronary disease among United States soldiers killed in action in Korea; preliminary report. JAMA 1953;152:1090–1093. Copyright © 1953 Massachusetts Medical Society. All rights reserved. B, Reproduced with permission from Tuzcu EM, Kapadia SR, Tutar E, et al: High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: Evidence from intravascular ultrasound. Circulation 2001;103:2705–2710.)
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The interaction between risk factors and the vessel wall in early life has a strong influence on later cardiovascular outcome. In a recent reanalysis of the Framingham cohort, the risk factor profile at 50 years was associated with a tenfold variation in later event rates. 5
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Risk factors in early years, such as blood pressure and adiposity, track into adulthood and predict higher rates of events produced by coronary arterial disease. 5
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Reduction of risk factors in the young, by modification of lifestyle and/or medication, can improve dysfunctional vascular biology, such as endothelial function, and reverse structural changes in the arterial wall, such as the thickness of the carotid intimal and medial layers. 6
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Early intervention to reduce risk factors is likely to produce greatly leveraged gains in cardiovascular outcome, so that duration of exposure is crucial. In the ARIC study, a genetically determined 28% reduction in lifetime levels of low-density lipoprotein cholesterol levels in subjects with a polymorphism of the PCSK9 gene was associated with a reduction of almost nine-tenths in cardiovascular events. 7
The study of arterial disease in childhood has been greatly facilitated by the development of non-invasive tests of vascular function and structure using ultrasound, and more recently magnetic resonance. In this chapter, we will review the range of factors which can interact with the arterial wall from early in life, discussing the evidence for a causal role and the opportunity for intervention. This approach to prevention is relevant, not only for the management of children who are at high risk, but also as a population-based strategy to reduce morbidity and mortality from atherosclerosis in later life.
CLASSICAL RISK FACTORS
Classical risk factors identified from adult studies, including hypercholesterolemia, hypertension, cigarette smoking, diabetes, and family history, all have adverse effects on the arterial wall from childhood. Originally it was thought that this occurred only in selected groups with high cardiovascular risk, such as those with familial hypercholesterolaemia, diabetes mellitus types 1 and 2, chronic renal disease, or chronic inflammatory conditions. Large epidemiological studies, however, such as the Bogalusa Heart Study, the Muscatine study, and the Cardiovascular Risk in Young Finns Study in childhood and adolescence, have demonstrated the impact of risk factors even in the general paediatric population. Furthermore, these risk factors tend to tend to track into adulthood. 8–13
Dyslipidaemia
Cholesterol is absorbed from the intestine, transported to the liver, and taken up by low-density lipoprotein-related proteins. 14 Hepatic cholesterol enters the circulation as very low density lipoprotein, and is metabolised to remnant lipoproteins. Reverse transport of cholesterol from peripheral tissues to the liver is mediated by high-density lipoproteins. 15–17 Cholesterol is recycled to low-density lipoproteins and very low density lipoproteins by cholesteryl-ester transport proteins, or is taken up in the liver by hepatic lipase. 14 Defects in this pathway translate into a range of disordered lipid profiles.
Cholesterol was first postulated to be related to atherosclerosis because it is the major component of advanced atherosclerotic lesions. The causal relationship between cholesterol and the formation of atherosclerotic plaques is now well established, and the impact of cholesterol both in initiation and progression of arterial disease is understood. 18,19 Once lipid subfractions are retained in the intimal layers of the arterial walls, they undergo oxidative modification, and acquire pro-inflammatory actions. 20 Oxidised low-density lipoprotein stimulates the expression of adhesion molecules, such as vascular cell adhesion molecule–1, on endothelial cells, increasing the expression of monocyte chemotactic protein–1 by vascular cells. This promotes infiltration of myocytes into the vascular wall, and proliferation of macrophages. Apart from these initial steps in atherogenesis, oxidised low-density lipoproteins are involved in the progression of atherosclerosis. 20 They promote proliferation of macrophages and smooth muscle cells, as well as the expression and secretion of a variety of growth factors and cytokines from vascular cells. The resulting injury, apoptosis, and necrosis of vascular cells leads to the formation of the lipid core seen in established atherosclerotic lesions. 19
The association between levels of cholesterol and cardiovascular risk is strong, continuous, and dependent on concentration, even at low levels of cholesterol, from childhood onwards. It is amenable to reversion. 21 Large randomised trials in adults, predominantly using statins, have shown that significant reductions in levels of cholesterol are associated with a tremendous decrease in clinical events. 22–24 A drop of no more than 1% in the level of cholesterol in the serum reduces the risk for coronary arterial disease by 2%. 25
In children, extreme elevations in the levels of lipids are usually encountered as a result of genetic hyperlipidaemias, whereas modest increases are seen in relation to dietary habits and a sedentary type of life. 26 Reference values for the total concentrations of cholesterol in the serum are available for both sexes from the first few months of life up to 1 year of age, and every 2 years afterwards up to 18 years. At birth, levels of cholesterol are low. They then rise over the first year of life to the level for the rest of childhood before puberty. These normal values in Western societies, even in childhood, are markedly higher than in countries with healthier diets and lifestyles. They may not be therefore healthy and appropriate for prevention of atheroma ( Fig. 59-2 ). 27,28
Strategies for screening children to establish levels of cholesterol have been reviewed recently in the light of the increasing evidence for the risk in the population, and to identify subjects with familial hypercholesterolaemia. Recent guidelines produced by the National Cholesterol Educational Program, designed to increase sensitivity and specificity of screening programmes, are outlined in Table 59-1 . 26 Implementation of national strategies for cascade screening of families, once an index case has been identified, should greatly improve the rate of detection and lead to early and more active treatment from childhood. Family education is important, as eating habits in childhood influence behaviour in later life. The use of drugs, usually statins, in children remains controversial. According to the guidelines, they are not usually advocated until after the first decade of life, and only in children with hyperlipidaemia and two or more other cardiovascular risk factors. Over the past few years, however, a number of randomised controlled trials have demonstrated that treatment with statins is effective and safe in children, albeit with the short-term follow up 29 (see Fig. 59-2 ). For example, it was shown that, in children with familial hypercholesterolaemia, early treatment from the age of 8 years was associated with delay in progression of carotid intimal and medial thickness in adolescents and young adults. 30 As far as combined hyperlipidaemias are concerned, no specific guidelines exist for children with persisting hypertriglyceridaemia or low levels of high-density lipoproteins. In such cases, a diet restricted in terms of fat and cholesterol is important, and extra caution is needed in the setting of extreme elevations of triglycerides so as to prevent pancreatitis. 26
Original Recommendations of the National Cholesterol Education Program Expert Panel
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2007 Modifications to National Cholesterol Educational Program recommendations
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Hypertension
Hypertension is the most common risk factor for clinical cardiovascular disease in both men and women, irrespective of age. Both diastolic and systolic levels of pressure have been associated in a continuous and dose-dependent manner with incidence of stroke, coronary arterial, and peripheral vascular events. 31 The pathophysiology that contributes to cardiovascular risk involves changes in resistance vessels, conduit arteries, and the heart, with alterations in shear stress in the arterial wall, endothelial dysfunction, a procoagulant state, increased oxidative stress, and inflammation.
Recent population studies emphasise the continuous relationship between blood pressure and cardiovascular outcome at levels previously considered safe and effective. This has been termed prehypertension by some, and an excessive response in the levels of blood pressure to exercise has also been shown to predict future cardiovascular events, further broadening the hypertensive phenotype. A wealth of clinical studies have shown that reduction in blood pressure by lifestyle or antihypertensive medication results in substantial fall in cardiovascular complications.
Measurement of blood pressure in childhood is important, as levels from as early as the first year of life track into adulthood. Essential, or idiopathic, hypertension is rare in childhood. It should only be diagnosed when secondary causes have been excluded. In these cases, it is usual to find a strong family history of hypertension. The commonest cause of secondary childhood hypertension is renal disease, but other aetiologies include coarctation of the aorta, endocrine disease, such as pheochromocytoma or hyperthyroidism, and adverse consequences of therapeutic regimes, such as oral contraceptives, sympathomimetics, and so on. 32 Recent reports have shown an association between blood pressure and the index of body mass (see below). 32,33
According to recommendations made by the National High Blood Pressure Education Program, children older than 3 years should have their blood pressure measured when visiting the doctor. The risk for hypertension, however, cannot be estimated by a single measurement. 34 Blood pressure varies during the day and is influenced by factors of measurement, including the size of cuff, as well as by other less well-controlled factors, such as anxiety and stress. Accurate measurement in childhood requires use of a cuff that is appropriate to the size of the child’s right upper arm, with an inflatable bladder having a width that is equal or greater than two-fifths of the circumference of the arm at a point midway between the olecranon and the acromion. The length of the bladder within the cuff should be sufficient to cover at least four-fifths of the circumference of the arm. An oversized cuff can underestimate pressure, whereas an undersized cuff can overestimate the measurement. Before labelling a child as hypertensive, serial measurements should be performed and evaluated according to age, sex, and height-specific percentile plots. 32,34
The management of childhood hypertension is directed at identifying a cause and any predisposing factors. Changes in lifestyle, and pharmacologic interventions, are recommended based on criterions established according to the age of the child, the degree of hypertension, and the response to treatment. In children whose serial measurements lie between 90th and 95th percentiles, modifications of lifestyle are advocated to achieve decreased caloric intake and increased activity. 34 A reduction in the intake of salt, and increased intake of potassium and calcium, consumption of fresh fruits and vegetables and low-fat dairy products, as well as regular physical exercise and loss of weight, may assist in lowering the blood pressure in children. In adolescents, diets high in polyunsaturated fatty acids are reported to lower both systolic and diastolic measurements. For those found to have measurements lying between the 95th and 99th percentiles plus 5 mm Hg, re-evaluation should occur within 1 or 2 weeks. If this finding is confirmed, pharmacological therapy should be initiated. 34 Antihypertensive medication should also be initiated if there is evidence of damage to end-organs. 34 A number of classes of drugs can be used to lower blood pressure in the young. Blockers of the renin-angiotensin system have been used, particularly in children with co-existing pathology such as diabetes or proteinuria, while β-adrenergic and calcium channel blockers have been successfully administered in children with migraines. 34
Cigarette Smoking
Cigarette smoking is the most important preventable cause of premature death in Western societies. A strong epidemiological link between cigarette smoking and atherosclerosis has been confirmed in many studies. In young individuals who would otherwise be at very low risk of developing cardiovascular disease, 35 cigarette smoking may cause as many as three-quarters of the events related to atherosclerosis. The longer a person smokes, the higher the risk for coronary arterial disease. In most European countries, 3% of 11-year-olds, 10% of 13-year-olds, and up to one-third of 15-year-olds, are daily smokers, according to the British Medical Association Tobacco Control Resource Centre. There is also evidence that those who begin smoking before the age of 20 years have the highest incidence, and earliest onset, of coronary arterial disease and hypertension.
Tobacco smoke contains hundreds of potential toxic compounds that may accelerate atherogenesis and increase the risk of complications. Endothelial dysfunction occurs early in both active and passive smokers, with a decrease in the bioavailability of nitric oxide. 36 Cigarette smoking also increases pro-inflammatory cytokines and adhesion molecules, and disturbs the coagulation system. 37 Smoking is also associated with other abnormal risk factors, including blood pressure and lipid profile. Cigarette smoking has recently been targeted by many countries, with legislation introduced to ban smoking in public places. Early evidence has shown an impressive rapid reduction in acute coronary arterial events. 38 A major initiative in the young, which includes education in schools on smoking, is a further prerequisite for a successful strategy for reduction of smoking in the population.
Genetics/Family History
The important contribution of genetic make-up in the atherosclerotic process has long been recognised. 39 Identification of single gene disorders, such as familial hypercholesterolaemia, has been important in establishing causal relations between risk factors and disease, and has enormously increased our understanding of atherogenesis. 40 In the absence of overt conventional risk factors, a clear association between family history of premature coronary arterial disease and endothelial dysfunction has been reported, further supporting the importance of the genetic background. 41,42 There has been an explosion of new information from genome-wide association studies, linking a range of genetic polymorphisms to cardiovascular risk in adults. 43,44 This has led to identification of new locuses, which will stimulate research into novel pathways contributing to vascular disease. Large studies of children will be required to determine whether the genetic variations associated with risk in adults operate from an early age to promote atherogenesis or, alternatively, are involved in destabilising established lesions to produce clinical complications.
NOVEL RISK FACTORS
A number of classical risk factors have clearly been linked to the evolution of the preclinical phase of atherosclerosis from childhood. High levels of these individual risk factors, such as cholesterol or hypertension, nonetheless, are uncommon in the absence of specific genetic conditions, such as familial hypercholesterolaemia and other diseases. It is likely, therefore, that a number of previously unrecognised factors, which are more prevalent in the population, may also contribute to initiation and progression of atherosclerosis.
Infection and Inflammation
Atherosclerosis has long been recognised as an inflammatory disorder, and the pathways involved in disturbed vascular biology have been described. 45 Recently, it has become clear that extrinsic inflammatory stimuluses may be involved in vascular inflammation and atherosclerosis. Infection is the commonest inflammatory condition in the young. The first evidence for a causal link with vascular disease came from animal studies in chickens with herpesvirus. 46 Data from human cross sectional epidemiological studies have subsequently implicated a number of viral and bacterial infections. This has led to the concept of the total pathogen burden influencing atherosclerosis, rather than isolated specific agents. 47 Several mechanisms have been proposed. The first is a direct effect of pathogens in the arterial wall, with systemic inflammatory activation leading to secondary arterial mural changes. 48 Most of the clinical studies, including numerous trials using antibiotics, have been performed in adults. They have produced conflicting results and are mostly disappointing. 49 This may be the result of confounding by the burden of other risk factors or, alternatively, because the role of infection may be greatest earlier in the evolution of arterial disease. The latter concept is supported by both animal studies and recent work using surrogate markers of early arterial disease in children and young adults. For example, a reversible effect of even mild infection of the upper respiratory tract on endothelium-dependent flow-mediated dilation has been shown in prepubertal children, 50 and young men who are seropositive for Chlamydia pneumoniae have increased thickness of the carotid intimal and medial layers. 51 In addition, other chronic infections, including the human immunodeficiency virus, have been linked with functional and structural arterial abnormalities from childhood and adverse cardiovascular outcome. 52,53 The vascular consequences of childhood infection are likely to depend on a number of factors, including the burden, frequency, and chronicity of infection, the susceptibility of the host, and the presence of other coexisting risk factors for atherosclerosis. Currently, there is no evidence to support a therapeutic strategy against infection for prevention of vascular events in the young, except perhaps in situations of high risk. After transplantation of the heart in children, cytomegalovirus, in particular, has been linked to systemic coronary endothelial dysfunction, and recently to progression of coronary arteriopathy. 54 It may, therefore, become an interesting target for specific treatment in these patients.
Children with chronic inflammatory conditions, such as systemic lupus erythematosus and rheumatoid arthritis, have evidence for abnormalities for arterial structure and function, including reduced flow-mediated dilation and increased thickness of the carotid intimal and medial layers, which are likely to represent accelerated atherosclerosis. 55 Similar abnormalities in the same measures have been associated with increased cardiovascular morbidity and mortality in adults. Childhood vasculitis, including Kawasaki disease, may result in both acute and sustained arterial mural abnormalities, even in the absence of acute coronary arterial complications. 56 Long-term and careful follow-up of these children is important to determine the potential interaction with later acquired risk factors, and the indications for more active preclinical treatment.
Recently, evidence has emerged that chronic periodontal inflammation, which is prevalent in both children and adults, may have adverse effects on the arterial wall. In a randomised controlled trial, reduction in this inflammatory stimulus by periodontal treatment led to recovery of endothelial function, providing evidence for a causal link and a potential new opportunity for population-based reduction of cardiovascular risk. 57
Early Life Programming
For more than a century, it has been recognised that critical windows in early development may affect permanently later outcome and disease. It was the impact of early nutrition in animal studies that promoted the use of the term programming to describe the potential impact of early influences on later outcome. 58 An association between birth weight and weight at 1 year, and later cardiovascular risk, led to the development of the hypothesis of fetal origins for cardiovascular disease ( Fig. 59-3 ). 59–61 This concept proposed that low birth weight was a surrogate for adverse events that had occurred in intra-uterine life. Blood pressure is the most commonly reported end point in large epidemiological studies examining the developmental origins of cardiovascular disease, since it can be measured easily and non-invasively in different age groups. More than 50 studies have shown an inverse association between birth weight and blood pressure in adulthood, at the rate of 1 to 2 mm Hg per kilogram. 62 This association is seen in both males and females, and for both systolic and diastolic levels of blood pressure. The causal relationship, however, between adverse fetal environment, intra-uterine retardation of growth, and later cardiovascular disease, has been controversial. As a result of a series of randomised controlled trials, it has been suggested that the postnatal acceleration of growth is the important adverse influence, rather than events occurring antenatally. This has been termed the catch up growth hypothesis. 63,64 The critical postnatal window which affects long-term development may vary from a few weeks to few months (see Fig. 59-3 ). 59–61 Despite strong evidence for early life programming, both antenatally and postnatally, the mechanisms by which later arterial phenotype and cardiovascular outcome are influenced remain speculative. They may include effects on the growth and development of organs such as the liver or kidney, neurohormonal homeostasis, and levels of cardiovascular risk factors, as well as direct effects on the arterial wall. Evidence for programming has been demonstrated for blood pressure, cholesterol, and insulin resistance, as well as for endothelial function and arterial distensibility. 63,65
