Hypertension and target organ damage in children and adolescents

Sustained elevation of blood pressure (BP) impacts not only the vascular wall, but also other structures, such as the heart, kidney and central nervous system, producing so-called hypertension-induced target organ damage. The capacity of hypertension to produce a greater or lesser degree of organ damage depends on closely-linked factors, which include both hemodynamic and nonhemodynamic ones. The severity of elevated BP values, duration of hypertension, individual susceptibility, family predisposition and ethnicity are among the most important factors. Due to the relatively short period of hypertension, the presence of organ damage in children and adolescents is usually the consequence of very high BP values, which promptly lead to clinical manifestations such as congestive heart failure, renal insufficiency or acute encephalopathy [1,2]. In other cases, organ damage, mainly in the kidney, is the origin of hypertension and the resultant high BP further accelerates the damage [3]. In both, very high values of BP and secondary hypertension are present. During the last few years, there has been a renewed interest in measuring BP in children and adolescents after the recognition that essential hypertension [4,5] is common in adolescents with a substantial long-term health risk for hypertensives. Furthermore, the recognition of essential hypertension in children and adolescents introduces new elements in the scenario of elevated BP in this age group. First, levels of elevated BP are always mild with a predominance of isolated systolic hypertension. This creates uncertainty about whether pharmacological treatment should be introduced, or not, accompanying life style changes, dietary advice and weight reduction if being overweight or obesity exist. Therefore, the more precise the BP values, the better the success rate. In this regard, ambulatory BP measurement is now increasingly recognized as being useful in the diagnosis and management of hypertension [6], and has contributed significantly to our understanding of hypertension by revealing or ‘unmasking’ blood pressure phenomena that are not readily apparent using traditional techniques of measurement in clinical practice. These have included the dipping and nondipping patterns of nocturnal BP [7] and white-coat hypertension [8] to which masked hypertension must now be added [9]. The latter is a condition in which subjects classified as normotensive by conventional office or clinic measurement are hypertensive with ambulatory BP monitoring or self-measurement. Second, there is the necessity to assess subtle alterations in the target organs, which in turn are modified by the physiological changes corresponding to growth and maturation. This leads to the use of percentile distributions for many of the most frequent measurements of organ damage, including left ventricular mass (LVM) [10] and carotid wall thickness [11]. The relationship between early markers and BP values in children and adolescents has been the focus of several studies. The abnormal increase of LVM and/or geometry has been recognized as one of the most important markers of risk for hypertension-induced cardiovascular morbidity and mortality in adults. The last Task Force for BP in Children [12] has recommended performing echocardiography, as the only marker of organ damage, in all hypertensive children and in those prehypertensives in the presence of diabetes or kidney disease. The relationship between hypertension and LVM, however, is more difficult to recognize because children and adolescents grow rapidly and their BP increases with age. Cross-sectional studies have shown that the major determinants of left ventricular growth are body size and sex, with a smaller contribution made by BP [13,14]. The important contribution of somatic growth and the recognition that lean body mass contributes somewhat more to cardiac growth than fat mass were neatly demonstrated in the Bogalusa Heart Study [15]. Recently, the potential role of adiposity in the increment of LVM has been highlighted. Adiposity and LVM are related in childhood, and this association tracks and becomes stronger in young adulthood [16]. Studies of normal and hypertensive children have found that systolic BP and LVM index (LVMI) are positively associated across a wide range of BP values, with no clear threshold to predict a pathologically increased LVMI. Although epidemiological studies do not help to establish the difference between appropriate and excessive increases in LVM, operational thresholds have been established. Both the allometric definition of excessive mass (> 51 g/m2) as well as the percentile distribution of mass and geometry have been recommended [10]. The relationship between LVMI and systolic BP is more evident when BP is measured using 24-h ambulatory BP monitoring (ABPM). Consequently, the hemodynamic load appears to play a more important role in the growth of LVM than was previously recognized using office BP. Accordingly, LVM tends to be greater in those groups with a higher ambulatory BP. In one cross-sectional study, both subjects with sustained hypertension as well as masked hypertensives had a significantly higher LVMI than confirmed normotensives [17]. Moreover, in a group of adolescents who had sustained masked hypertension, LVMI was significantly higher than that observed in normotensive adolescents [18]. Assessment of vascular damage, however, received little attention prior to the advent of the advanced ultrasound technology which permits the non-invasive study of vascular walls and lumen. Intima–media thickness measurement at the carotid artery is the most common of the methods to assess structural abnormalities. Because age and sex influence the values of intima–media thickness [11], measured values should be related to percentiles or expressed as standard deviation scores. In the few pediatric studies available, hypertensive children and adolescents tend to have an increase of intima–media thickness compared to those of normotensive controls [19,20], although one study did not observe differences among normotensives, white-coat, masked or sustained hypertensives [17]. Moreover, a relationship between intima–media thickness and endothelial function has been established in the Cardiovascular Risk in Young Finns Study [21]. The measurement of increment in urinary albumin excretion (UAE) is a powerful method to identify those adults who are at risk for multiple cardiovascular risk factor intervention. Changes in UAE appear to run in parallel to cardiovascular risk, and prompt intervention to avoid the progressive increment of UAE may result in better protection against hypertension-induced morbility and mortality [22]. The role of microalbuminuria assessment in pediatrics, however, is limited to diabetic children and adolescents. A close relationship between UAE and nocturnal BP has been observed in normotensive type 1 diabetics. Not only is there a strong correlation between UAE and nocturnal BP [23], but also there is a nondipping pattern that heralds the development of persistent microalbuminuria [24]. The significance of microalbuminuria in pediatric essential hypertension, however, has yet to be established and a routine urinary albumin assessment is therefore not yet recommended. Future studies using UAE in quantitative terms instead of in qualitative ones, and recognizing the significance of ‘normal’ values in the high range of normality as potential markers of risk, can contribute to the introduction of UAE assessment in pediatrics [25]. In this issue of the journal, Stabouli [26] reviews the information available regarding ambulatory BP and organ damage. The author concludes that, using both refined BP values obtained out of the clinic, as well as evidence of early organ damage, a better success of reducing cardiovascular and renal risk can be obtained even when other evidence is not yet available. To date, the close relationship between ambulatory BP values and organ damage supports the utility of ABPM in this age group in the absence of data concerning the prediction of the outcome. Furthermore, the relationship between ambulatory BP and organ damage can also help to define ‘reference values’ for ambulatory BP. Functional, rather than distribution-based definitions of ambulatory hypertension, must be developed further. Functional definitions may be validated by correlating intermediate signs of target organ involvement, such as LVM [27], with the BP levels obtained by conventional and automated measurements or by studying the relationship of these BP levels with pediatric risk factors that predict the development of hypertension in adulthood [28,29]. The prompt recognition of early organ damage can help in making decisions about the convenience of starting pharmacological treatment aiming to reduce hypertension-induced consequences later in life. Moreover, monitoring changes in organ damage during antihypertensive treatment can offer valuable information about the success of the treatment itself. Better BP assessment, using ABPM when indicated, may contribute to a more refined approach to reduce cardiovascular and renal risk, although caution is desirable when inferring future potential benefits from cross-sectional studies. Ambulatory BP monitoring has come of age in pediatrics. Future research can offer stronger normative data and important information to help delineate more precise guidelines for whom and with respect to when ambulatory BP monitoring would be advantageous among children and adolescents. Acknowledgements This study was funded by the Instituto de Salud Carlos III, Ministry of Health, Madrid, Spain (Ciber CB 06/03/0039). There are no conflicts of interest.