Children from families with premature coronary heart disease. Biochemical risk markers beyond traditional risk factors

 The concept of primary prevention is more complicated because the risk status of subjects without CHD can vary greatly. Indeed, effective primary prevention is dependent on reliable, sensitive and cost-effective methods of screening that will allow to identify high risk groups- i.e. subjects that will benefit most from the lowering of the CHD risk. Early identification of a high risk status is important because as atherosclerosis becomes clinically symptomatic, the global risk for further coronary events increases greatly, beyond the global risk factor clustering in comparison to asymptomatic subjects [1].
According to the National Cholesterol Education Program (NCEP) and to the European Atherosclerosis Society, the positive history of premature CAD is defined as an incidence of CHD, stroke, sudden coronary death, the presence of angiographically evidenced coronary atherosclerosis or revascularisation procedures (PTCA or CABG) performed in one or two parents before the age of 65 years (mother) or 55 years (father) [1].
The Framingham Heart Study investigators showed that familial history of premature CHD in a subject significantly increases his or her global risk independently from his or her basal risk factor status and is considered a predisposing risk factor of CHD. The extent to which familial predisposition enhances the global CHD risk is however poorly defined. The history of premature CHD in first-degree relatives was shown to be a more predictive CHD risk factor than hypertension, cigarette smoking and hypercholesterolemia. The reported frequency of CHD risk factors among children in this study was between 6,7% (boys aged 7-14 years) and 26,6% (boys aged 15-19 years).
One of the most extensively investigated CHD risk factors is hypercholesterolemia. Children and adolescents with elevated cholesterol levels are prone to having hypercholesterolemia in adulthood and can easily be identified and adequately treated. However, there is the large group of children with normal lipid levels that have a high risk status because of the familial history of premature CHD. However, in groups of children without lipid disorders and other major CHD risk factors, it is important to find other biochemical correlates of CHD risk. No study so far exists to prove that the reduction of one non-traditional factor is independently associated with the reduction of the risk of CHD events. According to the recommendations published in Circulation, the levels of such risk factors (even more firmly established CRP) should not be used for monitoring the clinical benefit of the therapy [2-3].

None of the so-called non-traditional risk markers that have so far been proved to be of incremental prognostic value and independent of traditional risk markers in population of high risk children (ie. from families with history of premature CHD). Within these non-traditional risk markers, there isn’t yet one set of markers (endothelial damage markers, elastin-derived peptides, antioxidant enzymes) that seem to have stronger prognostic value than the others.

It has been shown that the endothelium’s vasomotor function can be adversely influenced by early life factors such as low birth weight [4]. Therefore, it is likely that markers of the early atherosclerotic process are vasoactive and might be endothelium-associated substances. There are numerous biochemical correlates of atherosclerosis which are included into the conditional risk factors category - associated with the increased risk of CHD - however the magnitude of the causal link has yet to be documented [1-5]. The data on biochemical risk factors in children with familial history of CHD is sparse. The markers that allow insight into the endothelial function in vivo are presently widely investigated because they would facilitate the assessment of the global risk factor burden, including poorly defined factors.

In children with a high risk of CHD, the concentration of soluble endothelial adhesion molecule (ICAM-1) and von Willebrand factor were shown to be significantly higher in comparison to children without the familial history of premature CHD [6]. This might reflect the increased recruitment of inflammatory cells into the subendothelial layer and reflect the extent of endothelial injury in atherosclerosis. Numerous large studies showed that the concentration of C-reactive protein (CRP) is a predictor of cardiovascular events in apparently healthy subjects. In healthy children, increased serum CRP levels are associated with a decreased endothelial vasodilatory function and an increased carotid artery intima-media thickness (IMT) which is a reliable surrogate for atherosclerosis. It seems that IMT is the currently most reliable noninvasive marker of preclinical atherosclerosis in high risk children with hypercholesterolemia and diabetes [7, 8]. The CRP levels are associated with body mass index in teenagers, so diet and lifestyle modification should reduce the CRP levels, but it's not sure if the risk reduction will be associated with the lowering of CRP or reduction of other metabolic abnormalities associated with obesity (eg. insulin resistance).
The metabolism of the arterial connective tissue protein elastin seems to be different in high risk children – the turnover of elastin is increased, leading to an elevated concentration of proatherogenic elastin degradation products and to the presence of anti-elastin antibodies in the blood. The levels of antithrombotic prostacyclin (PGI2) and its metabolite 6 ketoPGF1_a in children of parents who had acute myocardial infarction before the age of 45 years are significantly lower whereas the levels of prothrombotic and vasoconstrictive thromboxane A2 are higher than in healthy children [9]. The activation of the immune system, evidenced by the presence of antibodies against heat shock protein (HSP60) reflecting a chronic inflammatory process may also play a role in the development of atherosclerosis in young individuals [10]. Moreover, activity of antioxidant enzymes (catalase and glutathione peroxidase), selenium concentration and the total antioxidant status are significantly decreased in the blood of high risk children than in children without the familial history of premature CAD suggesting impaired scavenging of noxious free radicals [11].
Few predominantly retrospective studies demonstrated altered concentrations of the above described biochemical soluble markers in high risk children in comparison to children without a history of premature CAD, yet they suggested that they might be useful in screening for the increased risk of CHD in children. This screening approach nevertheless needs validation.
First, it must be confirmed that in large population-based prospective studies altered concentrations of such biochemical markers are indeed associated with an increased risk of coronary events in high-risk children - normal values in various age-groups has yet to be established and essays standardised anyway. Second, it should be proved that pharmacological or non-pharmacological prevention both normalises the levels of biochemical markers and reduces the risk of future CHD events to comparable levels of those of children from families without a history of premature CAD. Finally, the association of these non-traditional risk markers weaken in the presence of established risk factors, hence their prognostic value is probably limited to a population of children from high-risk families without traditional risk factors – it is important that the prognostic value of these factors be independent from and incremental to traditional risk factors.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Conclusion:

To conclude, although the familial history of premature CAD is associated with biochemical and functional abnormalities of the endothelium in children, it seems that the widespread use of non-traditional markers for clinical purposes is premature and according to a Statement for Healthcare Professionals from the Centers for Disease Control and Prevention and the American Heart Association, there are no indications for routine measurements of CRP and other inflammatory markers for the assessement of CHD risk, at least in the adult population. Nonetheless, cardiologists treating adult patients with an early manifestation of coronary atherosclerosis should remember about the increased CHD risk of their children [12].
Familial history which is a very strong risk factor is associated with metabolic and functional abnormalities of the endothelium and some markers of endothelial injury exist and are significantly altered in high risk children, but so far no clinical data exist to justify their use in general clinical practice. This may however change, since this field is being intensively investigated.