Abstract
Although atherosclerosis has long been regarded as an inevitable degenerative disorder associated with ageing, there is now considerable evidence that the underlying pathological process is highly modifiable and may be prevented by appropriate management. The vascular damage is known to begin in childhood and develops silently for decades before clinical events such as myocardial infraction or stroke occur. This has been shown in numerous autopsy studies and is being confirmed in the modern era, using intravascular ultrasound [1, 2]. The initiation and progression of arterial disease from childhood is influenced by many classical risk factors. Longitudinal studies have shown that risk factor levels measured in childhood are predictive of risk factor level and cardiovascular disease in later life [3, 4]. In a recent analysis of the Framingham study, the risk factor analysis at 50 years was highly predictive of future cardiovascular events [5]. This growing body of evidence supports the hypothesis that the cardiovascular system responds to cumulative rather than acute exposure to adverse influences. Thus, effective ‘lifetime’ reduction in cardiovascular events may be best achieved by earlier risk factor management than is currently advocated. In the AREX study, a genetic variant that unexpectedly resulted in modest low-density lipoprotein (LDL) cholesterol lowering from childhood was associated with a very substantial reduction in later clinical events indicating the ‘investment’ opportunity for early risk management [6]. The scientific community, healthcare providers and even politicians have become increasingly interested in the concept of prevention as it becomes clear that the impact of arterial disease on life expectancy in the population cannot be managed solely by better clinical treatment of the disease and its complications. In this review, we will consider how to detect and treat preclinical disease from childhood, new insights into genetic and environmental factors that might influence its development and possible treatment strategies.
Detection of early vascular disease
Preclinical disease cannot be investigated simply by managing levels of risk factors in childhood and their effect on the usual endpoints of cardiovascular outcome because of the very long time course that this would require. As a result, a number of ‘surrogate’ endpoints of vascular structure and function have been developed, which seem to be on the casual pathway of future atherosclerosis and clinical events. Endothelial function can be studied noninvasively using high-resolution ultrasound to quantify brachial artery flow-mediated dilatation and early structural changes can be evaluated by pulse wave velocity and carotid intima media thickness measurement. These various tests are simple, accurate, repeatable and reproducible and have been used in large studies of children and adolescents including the Bogalusa Heart study, the MUSCATINE study, the cardiovascular risk in Young Finn's study and the ALSPAC study [7–9]. In serial measurements, these have characterized the impact of a range of early risk factors on later changes in vascular structure and function [7, 10]. Recently, measurement of endothelial function in middle-aged asymptomatic patients has also been shown to predict the rate of evolution of carotid intima media thickness [11]. This approach to early disease has opened up a new field of ‘vascular epidemiology’ in which early life influences can be studied on objective measures of arterial disease and the effects of treatments determined.
Cardiovascular risk factors in childhood
Many of the classical risk factors that effect cardiovascular outcome in adults have been shown to initiate and progress arterial disease from childhood [12]. These include hypercholesterolemia, cigarette smoking, hypertension, type 1 and type 2 diabetes and a family history of premature cardiovascular disease. Definitions of healthy levels of each risk factor in the young are difficult as children and adolescents are growing and developing, and a single range value for all stages of childhood is inappropriate. The Project Heart Beat study showed different trends in cardiovascular risk factors with age between ethnic groups and between boys and girls, which were dependent by the onset of puberty [13]. The adoption of percentiles has enabled estimation of age, ethnicity and sex-related normal ranges and these have been adopted by the National High Blood Pressure Education Program and the American Academy of Paediatrics [14, 15]. This approach will need further refinement and, in particular, normal values will need to reflect changes in population profiles, particularly in the modern era of the obesity epidemic. This has developed at different rates in different ethnic groups. INHANE, another population study in the United States from 1963 to 2002, has showed much greater detrimental changes in obesity and blood pressure in non-Hispanic Blacks and Mexican Americans than in White children [16].
The vascular biology of atherosclerosis involves an early shift from a quiescent nitric oxide-dominated environment to a proinflammatory prooxidant state [17]. The impact of inflammation on vascular phenotype has been shown in both experimental and clinical studies [18]. In a large cohort of prepubertal children, common upper respiratory tract infections were shown to induce endothelial dysfunction and inflammatory disease have been associated with evidence of abnormal vascular structure and function [19]. This has altered the understanding of pathophysiology and has provided new opportunities for treatment. For example, in a randomized clinical trial of older patients' treatment of periodontal disease, a common chronic infection/inflammation resulted in progressive improvement in endothelial function over a 6-month period [20].
The genetic contribution to the atherosclerotic process and its complications has long been recognized. This may occur by a number of mechanisms including an influence on circulating cardiovascular risk factors and an effect on the vascular response involved in atherogenesis. In addition, genetic factors may contribute to plaque stability and risk of clinical events in later disease. Monogenic disorders, such as familial hypercholesterolemia, have contributed greatly to the understanding of causal relationships between risk factors and disease [21]. Recently, Genome wide Association Analysis has identified several chromosomal loci, which affect cardiovascular outcome [22]. This will highlight new potentially important causal pathways, which might be targets for intervention. Studies of large, well characterized populations of children using a range of continuous ‘intermediate’ phenotypes will be informative for defining genetic influences on early disease. For example, do the loci linked to adverse cardiovascular outcomes operate by promoting atherogenesis or by destabilizing established lesions? They should also aid in prioritizing new biomarker targets for follow-up and interventional trial.
Identification of high cardiovascular risk in children
A stepwise approach to the definition of cardiovascular risk in children has been suggested by the American Heart Association [23]. This involves identification of a predisposition to the development of cardiovascular disease from a range of diseases in childhood including chronic kidney disease, diabetes, Kawasaki disease, as well as levels of common circulating cardiovascular risk factors. This approach, in the future, will need to take into account young individuals with a genetically determined high risk, which will influence targets for modifiable cardiovascular risk factors. Further understanding of genetic influences on responses to treatment will refine a ‘personalized approach’ to cardiovascular risk reduction in childhood.
Treatment from childhood: time for action
Strategies to target cardiovascular risk from an early stage of life are crucial if the population burden of atherosclerosis is to be reduced. The risk factor burden in the childhood population is increasing as a result of detrimental changes in lifestyle. These involve less physical exercise, increased caloric intake and poor nutrition and this leads to an epidemic of childhood obesity around the world [24]. The effects are already being shown by an increased prevalence of metabolic syndrome and type II diabetes in the young [25]. Guidelines for the prevention of cardiovascular disease in children and adolescents have generally used two major approaches. The first is a population-based strategy directed at improving lifestyle factors such as diet and physical activity. The second approach has involved the identification of children at high risk and institution of more aggressive therapy for those children. Both are valid [23].
Population-based treatments for children emphasize lifestyle changes including increase in exercise, reduced caloric intake and improved nutrition. Clinical trials have shown rapid benefits of these types of lifestyle improvements on objective evidence of vascular dysfunction in children who are unfit and overweight [26]. A recent statement of the American Heart Association emphasizes the implementation of nutritional guidelines and gives specific suggestions on possible ways to achieve this goal [27]. The focus on nutrition has been driven not only by the emergence of childhood obesity, but also by the concerns of the consequences on child health of the recent economic downturn. Less favourable childhood socioeconomic circumstances have long been known to be associated with a higher prevalence of cardiovascular risk factors and a higher risk of cardiovascular disease [28, 29]. The problems of obesity and adverse economics could interact with unfavourable consequences [30]. The proposed channelling of large economic stimulus packages towards childhood cardiovascular risk prevention could provide a potent short-term economic and health benefit and modify favourably a major threat to the future health of the population.
In children at higher cardiovascular risk or those in whom lifestyle has failed to produce significant sustained improvement in risk profile, early initiation of pharmacotherapy is recommended. For example, in children with familial hypercholesterolemia, statins have been shown to reduce not only LDL cholesterol but also to result in regression of carotid intima media thickness, even before puberty [31]. A recent analysis in a US insurance-based population of children revealed a 15–20.2% increase in the prevalence of antidiabetic, dyslipidemic and antihypertensive medication use from 2004 to 2007 [32]. The long-term use of drugs such as statins in children remains controversial. A storm of discussions followed the recently revised, more liberal recommendations of the American Academy of Paediatrics. This was based largely on the lack of long-term safety data for the use of drugs in children.
In conclusion, reduction of cardiovascular events in the population requires not only a particular attention to individuals with clinical manifestations but also a much more extensive prevention approach. This should begin in childhood as evidence is accumulating on the benefits of early intervention for future cardiovascular gain. This is analogous to compound interest for financial models. Lifestyle models must be emphasized from an early age, supplemented by effective medications to target multiple cardiovascular risk factors in high-risk children. This approach to risk management will require full engagement from paediatricians, cardiologists, healthcare providers and governments and represents perhaps the most important issues in atherosclerosis research and management today.