Introduction
In the 1940s, Irvin Page developed his mosaic theory of the pathogenesis of primary hypertension (PH). The basis of this concept relied on the recognition of many interconnected factors, including all known mechanisms playing a role in the elevation of blood pressure (BP) [
1]. The so-called “Page’s Mosaic” described an interplay between anatomic, genetic, metabolic, nervous, hemodynamic, and environmental factors. The elevation of BP and the eventual development of PH were the end result of the interplay of all these factors, indicating that the pathogenesis of PH is multifactorial. Despite the fact that many new mechanisms and factors influencing BP control have been discovered since then, the mosaic theory is still valid [
2].
Another theory was described over 40 years ago by Arthur Guyton. His model of BP regulation is based on the relationship between volume and peripheral vascular resistance. It explains the main mechanisms in regulating peripheral blood flow, along with adaptations of other neural, hormonal, and autacoid systems concerning the changes in resistance–volume relations. Moreover, it describes not only physiological regulations of BP and peripheral flow but also explains the pathogenesis of most of the secondary forms of arterial hypertension. The main mechanisms of BP control described by Guyton also work for PH, however both models fail to explain the inciting events in PH. Recent findings from experimental and clinical studies have suggested that metabolic abnormalities, sympathetic nervous system (SNS) alterations, immune activation, early arterial changes and their interrelationships may in fact represent inciting events in the development of sustained PH.
Children with PH in the early stages of hypertensive disease are usually not affected by other confounding factors typically present in adulthood; issues such as diabetes mellitus, nicotinism, and atherosclerosis. Thus, data from pediatric studies may shed more light on the pathogenesis of early stages of PH.
Treatment of PH in childhood and adolescence: is rejuvenation of the arterial system possible?
Due to the fact that all main alterations in PH resemble those found in premature aging, one may say that the treatment should focus on rejuvenation of the vascular system. It was found that immunosuppressive treatment directed against T-lymphocytes, or applying mycophenolate mofetil, were both effective in animal models of hypertension [
72]. It was also found that patients with rheumatoid arthritis treated with mycophenolate mofetil, had a lower prevalence of arterial hypertension when compared to other patients [
73]. However, due to important severe side effects, immunosuppressive treatment in the form of immunosuppressive drugs does not seem to be a practical solution for the treatment of PH. There were several attempts to use antioxidants as a solitary or supplementary therapy in adults with PH, but the results of those trials have remained disappointing [
74]. Thus, there remain two main forms of antihypertensive treatment; non-pharmacological and pharmacological therapy.
Non-pharmacological treatment is based on daily physical activity and diet. According to the guidelines, it is recommended to start pharmacological treatment in all cases of life-threatening and secondary hypertension. In cases of PH in children, pharmacological treatment should commence with TOD and/or with stage 2 hypertension or when non-pharmacological treatment is ineffective. Most children and adolescents with PH present with stage 1 hypertension with only subtle TOD and should therefore begin non-pharmacological therapy. The efficiency of non-pharmacological treatment based on vigorous physical exercise and diet depends on the motivation and conscious decisions made by the patient in reference to make a change to his/her lifestyle. The effects are quite small in adults but quite encouraging in children and adolescents. The treatment should be focused towards decreasing visceral fat and increasing fitness level; physical exercise exerts significant positive effects, which act at a molecular level on the main disturbances found in PH [
75]. Preventive and therapeutic effects of structured exercise training during adulthood, is well documented [
76]. Importantly, physical fitness exerts a strong modifying effect on BP trajectories over the life span of an adult male. Results from the Aerobics Centre Longitudinal Study, including 13,953 men between 20 and 90 years of age without hypertension, cardiovascular disease or cancer, who completed 3 to 28 (mean of 3.8) follow-up medical examinations between 1970 and 2006, showed that subjects with higher fitness levels experienced an SBP increase later than those with low fitness levels [
77]. Interventional studies in children showed that physical activity is associated with the lowering of BP in 11–12-year-old obese and hypertensive children. It was also found that volume is more important than intensity when referring to physical activity [
78]. In one of the first reports on the effects of non-pharmacological therapies on obese children, it was found that both exercise and diet caused significant hypotensive effects and increased post-ischemic dilation of the forearm vessels. However, the effects of exercise programs were significantly greater in terms of BP reduction, improvement in cardiovascular fitness and endothelial function when compared to diet alone [
79]. Similarly, Woo et al. documented that diet plus exercise caused greater positive effects on endothelial function in 9–12-year-old obese children when compared to diet alone. Significant improvement of flow-mediated dilation in the brachial artery was evident after only 6 weeks, with sustained improvement being observed in those who exercised regularly for 1 year [
80].
When deciding on pharmacological treatment, one may choose from eight different groups of antihypertensive medications. However, some of these medications may also cause more harm than benefit when used in adolescents with PH; this is not considered BP lowering, but rather a decrease in cardiovascular risk.
Thiazides are the most commonly prescribed antihypertensive drugs worldwide; however, their use poses the risk of DM and worsening of metabolic abnormalities [
81]. A recent meta-analysis of 22 clinical trials with 143,153 non-DM patients revealed that antihypertensive treatment, with a combination of diuretics, was associated with an increased risk of new-onset DM when compared to other antihypertensive agents or placebo [
82]. Also, the ALLHAT study showed that chlorthalidone produced a greater increase in the fasting glucose level and a significantly higher risk of DM than that of amlodipine or lisinopril [
83]. Therefore, thiazides and other diuretics should not be used as the first or even second-line drug of choice, regarding the treatment of PH in children and adolescents.
Although beta-blockers slow down the heart rate and decrease BP, their primary use is associated with the development of obesity and IR [
84]. Weight gain during beta-blocker therapy is mainly related to reduced energy expenditure. Sharma et al. showed that beta-blockers in obese hypertensive patients reduced the basal metabolic rate by 12 % when compared with other antihypertensive therapies [
85]. Furthermore, beta-blockers decreased insulin secretion from pancreatic β-cells along with blood flow in the skeletal muscles, which led to the impairment of glucose metabolism and IR. A large meta-analysis of hypertensive patients treated with beta-blockers revealed an increased risk of new-onset DM compared to other non-diuretic antihypertensive agents [
86]. However, it seems that there are significant differences throughout the spectrum of adverse metabolic effects caused by non-selective and selective beta-blockers. It was found that a long-acting form of metoprolol, which is a selective beta1-blocker, did not aggravate insulin resistance [
87,
88]. Nevertheless, the direct comparison of nebivolol and metoprolol indicated that nebivolol had a better metabolic profile as it did not increase IR or SOX [
89,
90]. In view of these potentially severe adverse effects, beta-blockade should not be used as first-line therapy in children and adolescents. However, new beta-blockers such as nebivolol, are devoid of the negative effects of old beta-blockers and may be an alternative for adolescent girls with PH, in whom the use of blockers of the RAS system can be problematic due to the adverse effects of RAS blockers in pregnancy.
From a pathophysiological point of view, the best choices in pharmacological therapy of PH are drugs which exert not only hypotensive effects, but also positive metabolic effects. The best choices are dihydropyridine calcium channel blockers (CCBs) which are metabolically neutral and blockers of the renin–angiotensin system – ACE inhibitors (ACEi) and AT2 receptor blockers (ARBs).
CCBs are generally considered as having a low potential to impair the metabolic profile. Indeed, a meta-analysis of ten randomized clinical trials evaluated the effects of antihypertensive drugs on glucose metabolism. It was found that the risk of new-onset DM among subjects taking CCBs was not significantly greater compared to patients treated with beta-blockers or diuretics. However, CCBs were associated with a higher incidence of DM than ACEi [
91]. On the other hand, a recent re-analysis of data from the NAVIGATOR trial showed that CCBs were not associated with a higher risk of new-onset DM [
92].
The majority of clinical trials evaluating the effects of ACEi and ARBs on glucose homeostasis have revealed that inhibition of the RAS system was associated with increased insulin sensitivity, better glucose uptake by the skeletal muscles and a lower incidence of new-onset DM in hypertensive subjects. The HOPE study demonstrated a favorable influence of ramipril on cardiovascular incidents in high-risk patients and a reduction of new-onset DM by 34 % when compared to placebo [
93]. The ALLHAT trial, which evaluated the influence of CCBs, ACEi and diuretics on cardiovascular events, revealed that lisinopril reduced the relative risk of developing DM by 30 % when compared to chlorthalidone and by 17 % when compared to amlodipine therapy [
83]. In addition, the LIFE study, which enrolled 9,193 patients treated with atenolol or losartan, showed a significantly reduced new-onset DM in the losartan group compared to the atenolol group [
94]. Similar results have also been presented in other studies [
95,
96]. Some findings have indicated that weight loss in obese individuals was associated with the inhibition of RAS [
97]. This may be partly due to reduced SNS activity, resulting in decreased renin release and change in adipocyte function. The inhibition of RAS may result in a shift in adipocyte distribution from visceral to subcutaneous depots. Furthermore, there is a correlation between 24-h BP and the expression of genes related to RAS in adipocytes [
98,
99]. Moreover, it has been suggested that AT2 increases SOX in human pre-adipocytes and can be inhibited by ARB. Telmisartan was more effective in this field than other ARBs. It was found that telmisartan improved adiponectin secretion in pre-adipocytes and had beneficial metabolic effects via selective peroxisome proliferator-activated receptor-γ modulation [
100]. In addition, patients treated with ACEi or ARBs showed a significant reduction in visceral fat, compared to other antihypertensive drugs. In a study involving 54 Japanese patients with MS and abdominal obesity, telmisartan was associated with a significant reduction in the plasma glucose/insulin levels and visceral fat tissue, whereas amlodipine had no effect [
101].