Coronary Artery Disease in Youth: Present Markers, Future Hope?
Article Outline
BMI, Body mass index, CIMT, Carotid intima media thickness, T1DM, Type 1 diabetes mellitus, VCAM-1, Vascular cell adhesion molecule-1
Atherosclerosis begins in childhood. Pediatric autopsy studies of children who died from accidents, suicide, or homicide demonstrated that atherosclerosis begins early, with raised fibrous plaques present in children as young as 8 years old.1 The extent of these lesions was related to high body mass index (BMI), high blood pressure, high low-density lipoprotein cholesterol concentrations, and low high-density lipoprotein cholesterol concentrations. However, children with a high relative risk for adult cardiovascular disease have a low absolute risk for detectable cardiovascular events (ie, myocardial infarction or stroke) during childhood. Additionally, the relative infrequency of cardiac events in children greatly increases the level of difficulty for clinicians and researchers trying to identify high-risk pediatric populations.
Surrogate markers must be used to assess cardiovascular disease risk in children and young adults. Measures of vascular function and arterial atherosclerotic load such as brachial reactivity, augmentation index, and carotid intima media thickness (CIMT) have already demonstrated that children with T1DM and obesity have decreased vascular distensibility, increased arterial stiffness, and increased carotid intima medial thickening.2, 3, 4, 5 Although not without problems, brachial reactivity, augmentation index, and CIMT remain the best available methods for assessing vascular function and atherosclerotic load. Surrogate markers using alternative modalities are needed. The study of endothelial function at the cellular level may provide such an alternative route for predicting cardiovascular disease. Endothelial function is maintained by a carefully modulated interaction between endothelial cells located in the vessel walls and those circulating in the blood stream. Although abnormalities in endothelial function occur early in the course of cardiovascular disease, we don't know how early these changes are present and what factors influence them.
DiMeglio et al6 used polychromatic flow cytometry to measure circulating endothelial cells in youth with T1DM and compared values with those of healthy control subjects. Adolescents with T1DM had decreased levels of circulating endothelial progenitor cells (CD34+CD133+CD31). These cells promote endothelial integrity and may be important in vascular repair. Furthermore, endothelial progenitors are inversely related to cardiovascular risk in adults. Conversely, circulating angiogenic macrophages (CD34+CD45-) correlate with the presence of coronary artery disease and were observed in higher number in adolescents with T1DM. Angiogenic macrophages promote new vessel growth and may indicate ongoing vessel injury. Vascular reactivity, as expected, was decreased in adolescents with T1DM and correlated with CD34+CD133+CD31 levels, indicating there may be functional significance to these cells that deserves further study. Further assessment of these cell lines could potentially provide a non-invasive means of assessing cardiovascular risk in clinic settings and serve as a marker of efficacy of treatments for cardiovascular disease prevention.
Similarly, cells that have detached from the vascular walls and circulating in the blood stream are thought to represent structural damage or injury to the vascular endothelium. Focusing on the number of circulating endothelial cells seen in children of varying weights, Kelly et al found a significant association with number of circulating endothelial cells and waist circumference, systolic and diastolic blood pressure, and triglyceride levels.7 The number of activated endothelial cells, determined by quantifying the surface expression of the endothelial biomarker vascular cell adhesion molecule-1 (VCAM-1) on circulating endothelial cells, were lowest in children who were of normal weight and increased over the range of weight categories (overweight, BMI 85%-94%; obese, BMI 95%-98%; and severely obese, BMI ≥99%). In addition, the numbers of activated circulating endothelial cells were directly related to systolic blood pressure, independent of BMI, and were inversely related to high-density lipoprotein cholesterol concentrations.
These studies may provide a means toward the direct evaluation of the biology of injured endothelium in youth. The association of circulating endothelial cells with multiple cardiovascular risk factors and the finding that the number of endothelial cells present predicts cardiovascular events, regardless of lipid levels and blood pressure, make this an attractive means of assessing cardiovascular risk in children. Still, because of the numbers of patients in each of the studies was small and the age range wide in the second study, these results should be seen as preliminary with further research needed to confirm the findings.
That said, the assessment of risk is of no value unless there are means to ameliorate the vascular abnormality. The third report, by Trigona et al, evaluated children with T1DM and control subjects to determine the effects of varying degrees of exercise on endothelial function by measurement of brachial artery reactivity and arterial response to nitroglycerine.8 In addition, vessel wall thickness as determined by CIMT was measured with ultrasound scanning. As expected, children with diabetes mellitus had lower vascular reactivity, higher blood pressure, and greater CIMT than control subjects. However, when divided by degree of daily exercise, children with T1DM who participated in ≥60 minutes of moderate to vigorous exercise daily had better vascular reactivity than children who were sedentary (<60 minutes of moderate/strenuous exercise daily). There was no difference in flow-mediated dilatation between the active children with diabetes mellitus and sedentary healthy children. Children recruited were 6 to 17 years of age, and these changes were present even in the pre-pubertal children and before the onset of other clinically evident cardiovascular risk factors, such as dyslipidemia. These data emphasize both the deleterious effects of diabetes mellitus on cardiovascular risk and the beneficial effects of exercise on vascular function.
Early cardiovascular disease is the major cause of death in adults with childhood-onset T1DM and metabolic syndrome. The increasing evidence that vascular change occurs early in children with diabetes mellitus highlights the need for early intervention.
Many risk factors cannot be changed (ie, diabetes mellitus diagnosis, family history of obesity, and/or early cardiovascular disease). Clinicians must focus on risk factors that can be altered to affect cardiovascular outcomes. Although exercise has clearly been demonstrated to improve vascular reactivity, Trigona et al demonstrated that children with diabetes mellitus were less active than healthy control subjects. The beneficial effects of exercise on vascular distensibility make daily moderate to vigorous activity an important component of diabetes care, and we would argue that children with diabetes mellitus should be encouraged to be active and given written prescriptions for at least 60 minutes of exercise per day during their initial diabetes education.
Attention to the identification and treatment of dyslipidemia, hypertension, and maintenance of near normal glycemia in patients with diabetes mellitus is critical to decreasing morbidity and mortality. Cardiovascular disease begins in childhood, and primary prevention must be a priority for pediatricians. To deal with the issue, an improved understanding of the basic mechanisms of disease is needed. Use of surrogate markers, such as those discussed and those yet to be discovered, will help elucidate the pathophysiology of the endothelial abnormalities that precede overt cardiovascular disease and help to identify therapies and interventions to prevent cardiovascular disease in our high-risk pediatric populations.
References
- Berenson GS, Sathanur R, Srinivasan, Bao W, Newman WP, Tracy RE, et al for The Bogalusa Heart Study. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med ;338:1650–1656.
- . Impaired flow-mediated vasodilation, carotid artery intima-media thickening, and elevated endothelial plasma markers in obese children: the impact of cardiovascular risk factors. Pediatrics. 2006;117:1560–1567
- Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet. 2001;358:1400–1404
- Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation. 2004;109:1750–1755
- Radial artery tonometry demonstrates arterial stiffness in children with type 1 diabetes. Diabetes Care. 2004;27:2911–2917
- Endothelial abnormalities in adolescents with type 1 diabetes: a biomarker for vascular sequelae?. J Pediatr. 2010;157:540–546
- Circulating activated endothelial cells in pediatric obesity. J Pediatr. 2010;157:547–551
- Pre-clinical non-invasive markers of atherosclerosis in children and adolescents with type 1 diabetes are influenced by physical activity. J Pediatr. 2010;157:533–539
PII: S0022-3476(10)00588-3
doi:10.1016/j.jpeds.2010.07.010
© 2010 Mosby, Inc. All rights reserved.
Refers to article:
- Preclinical Noninvasive Markers of Atherosclerosis in Children and Adolescents with Type 1 Diabetes Are Influenced by Physical Activity , 18 June 2010
- Endothelial Abnormalities in Adolescents with Type 1 Diabetes: A Biomarker for Vascular Sequelae? , 14 June 2010
- Circulating Activated Endothelial Cells in Pediatric Obesity , 14 June 2010
