Curr Hypertens Rep (2014) 16:426 DOI 10.1007/s11906-014-0426-z

PEDIATRIC HYPERTENSION (JT FLYNN, SECTION EDITOR)

Autonomic Nervous System Dysregulation in Pediatric Hypertension Janusz Feber & Marcel Ruzicka & Pavel Geier & Mieczyslaw Litwin

Published online: 16 March 2014 # Springer Science+Business Media New York 2014

Abstract Historically, primary hypertension (HTN) has been prevalent typically in adults. Recent data however, suggests an increasing number of children diagnosed with primary HTN, mainly in the setting of obesity. One of the factors considered in the etiology of HTN is the autonomous nervous system, namely its dysregulation. In the past, the sympathetic nervous system (SNS) was regarded as a system engaged mostly in buffering major acute changes in blood pressure (BP), in response to physical and emotional stressors. Recent evidence suggests that the SNS plays a much broader role in the regulation of BP, including the development and maintenance of sustained HTN by a chronically elevated central sympathetic tone in adults and children with central/visceral obesity. Consequently, attempts have been made to reduce the SNS hyperactivity, in order to intervene early in the course of the disease and prevent HTN-related complications later in life.

This article is part of the Topical Collection on Pediatric Hypertension J. Feber (*) : P. Geier Division of Nephrology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, 401 Smyth Road, Ottawa, Ontario K1H 8 L1, Canada e-mail: [email protected] P. Geier e-mail: [email protected] M. Ruzicka Division of Nephrology, The Ottawa Hospital, University of Ottawa, 1967 Riverside Dr. Suite 5-21, Ottawa, Ontario K1H 7 W9, Canada e-mail: [email protected] M. Litwin Department of Nephrology and Hypertension, Children’s Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland e-mail: [email protected]

Keywords Arterial hypertension . Autonomous nervous system . Sympathetic nervous system . Children

Introduction Pediatric hypertension seems to be changing, mainly because of the childhood obesity epidemic [1]. In the past, the diagnosis of hypertension (HTN) was quite rare in childhood, and most hypertensive children suffered from secondary HTN [2]. Recent reports indicate however, that up to 91 % of children evaluated for HTN have no underlying cause identified [3], which suggests that the prevalence of primary HTN (PH) is increasing. This epidemiologic shift revives the discussion and research on etiology and pathogenesis of HTN. Whilst secondary HTN has clearly defined pathologic entities, if identified, the etiology of primary HTN is still not completely understood. There are multiple factors which may cause or contribute to arterial HTN in children, including obesity, poor sleep quality, smoking, insulin resistance, sympathetic nervous system (SNS) activation, alteration in sodium homeostasis, changes in renin-angiotensin system (RAS), changes in endothelial function, hyperuricemia, genetic background, low birth weight and prematurity [4]. This suggests that primary HTN is a polyfactorial disease with a complex interplay between various pathogenetic mechanisms. In this article, we will focus on reviewing the dysregulation of SNS as a potential cause and/or contributor to sustained HTN, mainly in children with obesity.

The role of SNS in Hypertension Over the last several decades, the conceptual role of the SNS has changed significantly. In the past, the SNS was viewed as

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an important system for short lasting, but powerful effects on blood pressure (BP) in order to avoid large and potentially dangerous fluctuations in BP. Implementation of new methods of assessment of central sympathetic outflow, such as microneurography and the radiotracer method of assessment of norepinephrine spillover rate, provided evidence supporting the concept of the SNS as a system playing a significant role in the development and maintenance of sustained HTN, through its long lasting effect on baseline central sympathetic tone [5]. Several mechanisms leading to and maintaining central sympathetic hyperactivity in HTN have been identified. An impaired vagal heart rate control exerted by arterial baroreflex, impaired volume-sensitive cardiopulmonary reflex, arterial chemoreceptors as well as humoral factors such as angiotensin II, aldosterone or leptin with direct central sympathoexcitatory effects have all been shown to play at least partial roles in HTN related increases in central sympathetic activity [6, 7]. In adults with HTN, the central sympathetic outflow increases in parallel with the severity of HTN [8]. Furthermore, in adults with HTN, central sympathetic outflow is markedly more elevated in those with an impaired circadian rhythm of BP, namely in patients with an absent nocturnal drop in BP or even an increase in BP during sleep [8]. Patients with masked and white coat HTN also have an increased central sympathetic outflow [9, 10] . In children, the studies on SNS activity in childhood HTN date back to 1998 when Urbina et al., assessed the sympathetic to parasympathetic activity balance by the HR variability using the ratio of low to high frequency (LF/HF) power measured by fast Fourier analysis [11]. The study was performed in a small group of healthy adolescents and showed a trend towards sympathetic predominance in children with higher BP levels [11]. Sorof et al., found increased HR and BP variability in obese children with isolated systolic hypertension [12]; in this study the HR and BP variability was assessed by office HR/BP measurement and ambulatory blood pressure monitoring (ABPM). Interestingly, obese hypertensive patients had the highest HR, obese normotensive and non-obese hypertensive patients had intermediate HR, and nonobese normotensive patients had the lowest HR, suggesting that both obesity and HTN can be associated with SNS activation. These initial findings of SNS hyperactivity in hypertensive children, measured by indirect methods, were later confirmed by direct measurement of sympathetic activity using microneurography in children with primary HTN [13]. More recent studies with indirect markers of SNS activity showed an increased BP variability on ABPM in untreated hypertensive children [14]. Genovesi et al., performed a more detailed analysis of the sympathovagal function, by using markers of oscillatory (low frequency, high frequency) and nonlinear modulation of the sinoatrial mode and baroreflex slope [15]. The authors observed that hypertensive children

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had significant baroreflex impairment as compared to control subjects [15]. Altered vagal and sympathetic activity in hypertensive children was recently confirmed by Zhou et al. 2012 [16]. The authors analyzed HR variability from 24 h Holter monitorings in 180 children and noted that systolic BP correlated negatively with markers of autonomic nervous system activity such as standard deviation of normal to normal RR intervals, the root mean square of successive differences, low-frequency and high-frequency [16]. These recent studies confirm that hypertensive children indeed suffer from an imbalance in their autonomic nervous system activity, with a shift towards sympathethic hyperactivity. In addition to sustained forms of hypertension, increased sympathetic activity is also present in patients with white coat hypertension (WCH) [13, 17, 18]. Patients with WCH have an elevated BP in the office but have otherwise normal BP in an out of office setting or on 24 h BP monitoring; they may therefore be considered at risk of developing hypertension and/or target organ damage later in life [19•]. Smith et al., performed microneurography in three groups of 12 matched children with WCH, primary HTN and normotension, and found that central sympathetic hyperactivity exists in children with WCH; albeit to a lesser degree than in children with primary HTN [13]. We analyzed BP and HR rhythms (Fourier analysis of ABPM recordings) as indirect markers of the sympathetic activity in normotensive, WCH and primary hypertensive (PH) children [19•]. We noted a higher prevalence of shorter 12 h ultradian rhythms in PH and WCH children; both groups had reduced BP amplitudes and delayed BP acrophases compared to normotensive children [19•]. This abnormal cardiovascular rhythmicity may serve as indirect proof of sympathetic hyperactivity in children with sustained PH and WCH. A significant baroreflex impairment, i.e., decreased parasympathetic activity, was also present in children with prehypertension [15]. This would suggest that ANS dysregulation is already present in early stages of hypertension as was recently documented by Fitzgibbon et al. [20]. The authors used beat-to-beat BP and R-R intervals of ECG recordings to calculate baroreflex sensitivity (BRS) and heart rate variability (HRV); they found that BRS and HRV were significantly decreased in children with a higher BP as compared to children with a lower BP. The authors concluded that children with elevated, yet not clinically hypertensive BP, displayed altered autonomic regulation [20]. The ANS dysregulation may even be induced by perinatal stress as suggested by Johansson et al., who found that children born preterm or at term but small for gestational age (SGA) excreted higher levels of urinary catecholamines and had a higher HR when compared with children born at term with normal birth weight; blood pressure did not differ between the groups [21]. This association between early prenatal stress and sympathetic overactivity suggests that preterm birth

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and fetal growth restriction may pre-program these children for ANS dysregulation with the possibility of having a higher risk of developing HTN in adulthood [21]. More recent studies showed an altered circadian and ultradian cardiovascular rhythmicity (as indirect markers of ANS dysregulation) in SGA children, independent of blood pressure level [22•]. This suggests a developmental programming of the sympathetic activity, which is already manifesting in children before they develop hypertension later on in life. The fetal programming of BP regulation was recently confirmed by Chen et al., on a huge patient population enrolled in the Bogalusa Heart Study [23•]. Low birth weight was significantly associated with an increased blood pressure variability, even after adjustments for the BP levels were undertaken [23•]. In addition to the inborn/perinatal factors described above, the activity of the ANS seems to be influenced by ethnicity. The HR and the double product of HR and mean arterial pressure were greater in Caucasian boys than in AfricanAmerican boys [24]. Urbina et al., also noted an increased sympathetic tone in Caucasian adolescents compared with that of African American youth [11]. However, the sympathetic tone seems to change over time (crossover pattern) as indicated by a higher sympathetic tone in African Americans reaching adulthood [25]. Recent data suggest that the signaling of ANS can be also modulated by the immune system and vice versa (reciprocal communication), which may contribute to the development and maintenance of hypertension [26, 27].

SNS in Obesity and Hypertension In adults with central, but not peripheral obesity, the central sympathetic outflow as assessed by microneurography is elevated [28–30]. In obese patients without HTN, renal norepinephrine spillover is significantly increased, but cardiac sympathetic spillover is markedly reduced [31–34]. In contrast, obese hypertensive patients were found to have elevated renal sympathetic activity to a similar extent, but no reduction in cardiac sympathetic activity [31–36]. This suggests that the renal sympathetic hyperactivity is an important and necessary component but not sufficient cause for the development of HTN in obese adults. It remains unclear why some obese patients develop HTN whereas others do not. A genetic predisposition to development of HTN in response to weight gain may provide a partial explanation as suggested by results of the longitudinal study by Masuo et al., [37]. In children, SNS activation (measured by an increased HR) is also associated with the visceral obesity and metabolic abnormalities typical of metabolic syndrome [38]. According to Landsberg’s hypothesis [39], further modified by Grassi [40], SNS activation in obesity is a metabolic reflex, which causes dissipation of energy excess; clinical markers of this

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reflex are increased HR and elevated BP. According to this hypothesis, chronic activation of the SNS decreases thermogenesis but leads to HTN [39]. One of the first studies on SNS activation in children showed that, in a general pediatric population (Bogalusa study), an increased HR correlated with higher BP and skinfold thickness as a marker of adiposity [24]. Furthermore, the “double product” of HRxBP was found to be significantly elevated in obese children [24], which would indicate that obese children suffer from greater adrenergic stimulation. An elevated HR and pulse pressure resulting in a hyperdynamic circulation were shown to be associated with increased insulin levels and triglycerides concentrations [41]; this suggests that there is link between SNS activity and obesity. In the study by Gillardini et al., obese and hypertensive children had a significantly higher HR, urinary epinephrine and norepinephrine excretion, waist circumference and BMI-SDS, in comparison with obese and normotensive children [42]. Moreover, the urinary epinephrine and norepinephrine excretion correlated with waist circumference. It seems however that there is a threshold value of adiposity, above which BP and SNS activity increases. Data from Tu et al., who analyzed a cohort of 1,111 school children, indicates that until BMI was below the 85th percentile, the effect of body mass on BP was minimal. However, when BMI surpassed the threshold of the 85th percentile, the effect of adiposity on BP increased by 4-fold. Moreover, the rise in BMI above the 85th percentile was accompanied by an increased HR and serum leptin concentrations [43•]. Noticeably, the sharp rise in serum levels of leptin in children with BMI above the 85th percentile correlated with an increased prevalence of prehypertension and hypertension. Not all obese subjects develop hypertension and not all obese people present SNS activation. There is convincing evidence that intact leptin action and intact central nervous system pathways, transmitting signals from adipose tissue, are necessary for SNS activation in obesity. The leptin mutation itself does not lead to hypertension and SNS activation in obese children and adults [44, 45]. The activation of SNS by leptin is due to the release of melanocortin (α-MSH), which acts on the melanocortin 4 receptor (MC4R) and causes SNS activation. Patients with the most common monogenic form of obesity, caused by loss-of-function mutation in MC4R, have lower BP and urinary norepinephrine excretion levels in comparison with obese patients without the MC4R mutation [46]. This proves that activation of SNS in obesity depends on an intact leptin-melanocortin pathway. Figure 1 illustrates possible mechanisms of sympathetic hyperactivity in obese hypertensive patients. In a recent study including several obese adolescents, it was found that patients with the dysfunctional MC4R mutation had lower muscle sympathetic nerve activity measured by MSNA after 30 seconds of apnea when compared to non-carriers [47••]. In an analysis of adolescents of

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Central nervous system Intact POMC – MCR pathway

SNS activity ↑

SNS activity ↑ SNS activity ↑

Visceral fat

IR ROS leptin

BP ↑

Immune activity

Fig. 1 Evolving mechanisms of sympathetic hyperactivity in children with obesity and hypertension. Abbreviations: SNS – sympathetic nervous system; BP – blood pressure; IR – insulin resistance; MCR – melanocortin receptor; POMC – proopiomelanocrtin; ROS – reactive oxygen species

French Canadian origin, it was found that a risk variant of the fat mass and obesity-associated (FTO) gene encoding enzymes, involved in the control of appetite in the brain was associated not only with greater BP (on average 4.4 mm Hg for SBP), but also with insulin resistance, greater increase in SBP during mental stress, intrabdominal and subcutaneous fat and greater adrenergic drive, as assessed by the power spectral analysis of diastolic BP [48]. Interestingly, the relations between FTO variants, BP and sympathetic drive seemed to be independent of associations between FTO variants and anthropometrical parameters. There is an increasing amount of data indicating that it is not obesity but rather fat tissue distribution and visceral obesity that determine the risk of incipient hypertension, metabolic abnormalities and target organ damage in hypertensive children [49]. Studies of obese adults have shown that MSNA correlates with waist circumference [28]. Syme et al., reported that in a cohort of 324 adolescents of French Canadian origin, visceral fat deposition correlated both with BP elevation and increased SNS drive, but only in boys [50]. It seems therefore that the deposition of visceral fat depends, among others, on androgen action. Interestingly, this gender difference in the relation between visceral fat and sympathetic activity has not yet been described in adults. There are no data directly comparing sympathetic activity between adolescent girls and boys, but the physiological rise in BP is observed only in boys during a pubertal growth spurt [51] and ratio of boys to girls among adolescents with primary HTN is 2-3:1 [49, 52–54]. This would again suggest a gender difference in SNS activity

and deserves further research. In a recent study, Pausova et al., analyzed associations between functional polymorphisms of androgen receptors, BP and sympathetic activity in a cohort of French Canadian adolescents. They found that greater activity of androgen receptors was associated not only with a greater BP (the difference between high activity receptor carriers and intermediate and low activity carriers was 1.8 up to 8 mm Hg) but also with an increased BP during mathematical stress [55]. Moreover, boys with a high activity receptor form had a greater amount of visceral fat and greater activity of sympathetic tone as assessed by the power spectral analysis of diastolic BP. These associations have not been found in girls. We were able to confirm the relation between visceral fat and sympathetic activity in boys by analyzing changes in cardiovascular rhythmicity during 12 months of antihypertensive treatment in 50 boys with primary hypertension [56•]. The decrease of waist circumference correlated with the changes in BP amplitude and the decrease of visceral fat correlated with the decrease of the 24 h mean arterial pressure and HR acrophases. This suggests that the visceral fat indeed plays an important role in the sympathetic activity of adolescent boys with hypertension [56•]. Although the strict relationship between obesity and SNS activation has been established, there is still an uncertainty as to the primary disturbance. Data from the Tecumseh Blood Pressure study indicates that accelerated HR not only correlates with adiposity and elevated BP but also precedes obesity and hypertension [57]. It was found that children, who had faster HR (but normal BP) at the age of seven years of age, had a greater BP and greater subscapular skinfold thickness at the age of 20 [57]. This would suggest that the sympathetic hyperactivity is a primary disturbance preceding obesity and hypertension. In our study, the abnormal BP and HR rhythmicity, as indirect markers of sympathetic hyperactivity, persisted despite effective 1-year antihypertensive therapy; this indicates again that it may indeed be the primary abnormality in children with primary hypertension [56•, 58].

Relevance of the Sympathetic Hyperactivity for Target Organ Involvement Besides well-documented hemodynamic effects of SNS, trophic adrenergic mechanisms appear to play a significant role in the development of left ventricular hypertrophy (LVH) and vascular structural and functional alterations [59, 60]. The central sympathetic activation (measured by microneurography) was found to be associated with the development of LVH (measured by cardiac MRI) in hypertensive adults [61]. Interestingly, this association was observed across a wide range of BP levels suggesting that sympathetic hyperactivity may have an independent effect on left ventricular mass [61]. More recently, Lambert et al., observed that the

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left ventricular mass correlated with the central sympathetic outflow (assessed by microneurography) independently of the BP level [62]. Data on the relationship between ANS/SNS dysfunction and target organ involvement in children with PH are based on surrogate/indirect markers of ANS/SNS activity. Litwin et al., analyzed the prevalence of LVH and increased intima media thickness (IMT) in 72 children with untreated PH in comparison with a control group of healthy children. Interestingly, from all ABPM results, only HR was a significant determinant of LVH in a step-wise regression analysis [52]. These findings suggest that the SNS hyperactivity may, indeed contribute to the development of TOD in hypertensive children. This could be especially important in obese children, who may develop TOD even with absent or mild hypertension. In fact, our previous studies indicated that both LVH and carotid artery intima-media thickness (cIMT) were predicted by metabolic abnormalities and visceral obesity [49, 52–54], rather than by hypertension. We speculated that these relationships between TOD and visceral obesity may have been, at least partly, due to the increased sympathetic activity. In our recent study, we therefore focused on BP and HR rhythmicity as surrogate markers of sympathetic activity in correlation with the development of LVH during 1-year of antihypertensive therapy in 50 adolescent boys [56•]. Surprisingly, there was no correlation between BP/HR rhythmicity and LVH at baseline (before therapy), yet the changes in cardiovascular rhythmicity and the regression of LVH after one year of antihypertensive therapy significantly correlated with the decrease of visceral obesity [56•]. Moreover, the abnormal BP/HR rhythmicity, i.e., abnormal sympathetic activity persisted despite successful antihypertensive therapy; this has led to the reduction of the BP and regression of LVH, but did not induce normalization of BP/HR rhythmicity [56•]. It seems therefore, that the sympathetic hyperactivity (induced by visceral tissue) plays a significant role in the development of target organ involvement in children.

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hypertension, these medications may actually lead to weight gain because of their antithermogenic effect (as observed in large clinical trials using beta-blockers) [63]. However, several classes of BP lowering drugs may have an adjuvant central sympathoinhibitory effect, without causing a loss of modulation of central sympathetic outflow. This applies namely to the blockers of the renin-angiotensinaldosterone system which were shown to decrease central sympathetic outflow in patients with primary hypertension [64, 65] and several forms of secondary hypertension such as renovascular hypertension and primary hyperaldosteronism, patients with chronic kidney disease and patients with chronic heart failure [66]. Finally, new approaches targeting SNS in hypertension, namely baroreceptor activation therapy and endovascular catheter based renal sympathetic denervation have been recently shown to decrease BP in patients with resistant hypertension. Baroreflex activation therapy is based on the concept of enhancement of the central sympathoinhibitory effect of baroreflex on static sympathetic tone. In contrast, sympathetic renal denervation decreases both central sympathoexcitatory effects by renal afferents and decreases the total as well as renal sympathetic outflow [67]. The experience with these interventions is limited solely to adults [68], but even in adults, the data on efficacy and safety are mostly derived from prospective observational studies; they are further awaiting confirmation by prospective randomized controlled trials such as Simplicity HTN 3 [69]. As a matter of fact, based on a press release by the Medtronics Inc. (around the time this manuscript went to publication), the Simplicity HTN-3 trial met safety endpoints, but failed to meet efficacy primary endpoints. More detailed data are expected at the American College of Cardiology meeting in late March 2014. Certainly, one could not endorse renal denervation for treatment of resistant HTN beyond research protocols at this point. Due to the invasive nature of these surgical procedures, they will likely remain reserved for the treatment of the most severe resistant hypertension.

Treatment of ANS Dysregulation Conclusion In view of the recent findings on sympathetic stimulation induced by visceral obesity, it seems logical that in obese patients non-pharmacological interventions including weight loss and exercise (which specifically decreases renal sympathetic activity) should be the first line therapy [58]. These measures are, however, difficult to implement and are frequently not successful in both adults and children. BP lowering drugs with direct central sympatholytic effect used in the treatment of HTN may decrease central sympathetic outflow, but their use is limited by their side effects and the loss of modulation of SNS (e.g., libido, erectile dysfunction, orthostatic hypotension, etc). In patients with obesity

Recent evidence suggests that the increase in central sympathetic outflow plays a significant role in the maintenance of HTN in children and namely in those with obesity HTN. There is no known unifying mechanism for obesity HTN and central sympathetic hyperactivity in children, but several factors such as perinatal stress and low birth weight, the degree of visceral obesity, genetic polymorphisms of proteins (involved in the regulation of central sympathetic outflow), hormonal abnormalities and intact leptin-melanocortin pathway, appear to play a role. As an increase in organ specific central sympathetic outflow may be detrimental for the

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development of the HTN-related TOD, beyond the level of BP per se, treatments directed to lowering BP and decreasing central sympathetic hyperactivity may prevent obesity HTNrelated TOD and adverse vascular outcomes.

Curr Hypertens Rep (2014) 16:426 12.

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14. Acknowledgments We wish to thank Mrs. Brandy Brookings, the administrative assistant in the Division of Nephrology, Children’s Hospital of Eastern Ontario, for her revision of the English language.

15.

Compliance with Ethics Guidelines 16. Conflict of Interest Janusz Feber, Marcel Ruzicka, Pavel Geier, and Mieczyslaw Litwin, declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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