In adults, initial stages of hypertension are associated with elevated sympathetic drive and significant alterations in indirect autonomic markers. There is growing evidence that children in the highest-pressure percentiles will be more likely to develop hypertension in adulthood, although mechanisms are not understood. We assessed whether computer analysis of RR interval and arterial blood pressure variability could detect early autonomic alterations in childhood hypertension, as assessed by noninvasive time and frequency domain measures of baroreflex regulation. We studied 75 children, subdivided in 3 subgroups of similar age (9.7±0.2 years): control subjects, prehypertensive children (ie, children with arterial pressure values >90th and <95th percentile for age, gender, and height), and children in the hypertensive range (ie, >95th percentile; systolic arterial pressure: 97±3/57±2, 121±5/70±1, and 128±2/80±2 mm Hg, respectively). We observed that hypertensive children demonstrate a significant impairment of the baroreflex as compared with control subjects (index α: 20±2 and 40±4 ms/mm Hg; spontaneous baroreflex slope: 20±2 and 37±5; ms/mm Hg; P<0.05 in both cases) and reduced RR variance. A similar baroreflex impairment is also observed in children whose arterial pressure falls short of this limit, ie, in the prehypertensive range. In conclusion, hypertensive children display a marked baroreflex impairment. A similar baroreflex impairment is also observed in the prehypertensive state. Baroreflex assessment could furnish additional information in the clinical assessment of pediatric hypertension.
Cardiovascular diseases represent the major cause of death and disability in the global world, involving not only the Western affluent societies but also the emerging low-middle–income countries.1,2 Accordingly, the scientific community is expressing a growing effort to find new strategies capable of implementing successful primary prevention.3 In this context, recent epidemiological studies compellingly indicate that early application of lifestyle changes should be preferable to drug only–based prevention.4,5 This approach may be particularly appropriate in hypertension because of the well-recognized continuum of increased risk, even if pressure values are within the reference range.6,7 Hypertension, in addition, interacts with overweight and obesity to produce a supra-additive rise of risk, which can be attenuated, if not normalized, by diet and exercise.5,8–10
The idea that early prevention,11 rather than treatment, should form the basis of a medical approach to chronic illnesses, calls for attention to childhood antecedents of cardiovascular conditions.12 In this context, childhood hypertension13 might represent an interesting area of exploration because of the growing evidence that children in the highest-pressure percentiles will be more likely to develop hypertension in adulthood, as dictated by the tracking hypothesis.14 In adults, initial stages of hypertension are associated with elevated sympathetic drive,15 and, as a corollary, with significant alterations in indirect autonomic markers, such as a reduced baroreflex gain and an altered profile of RR interval variability, evident already in subjects with high-normal (or prehypertensive) pressure values.16 Autonomic dysregulation is also observed in adult obesity,17 particularly if accompanied by hypertension.18 The aim of this study was to assess whether noninvasive analysis of the RR interval and arterial blood pressure variability in time and frequency domains could detect early autonomic alterations in children with arterial pressure values in the highest percentile range, as compared with a control population of similar age.
Methods
As part of an epidemiological study19 considering primary school children, we enrolled 38 children with arterial pressure (AP) values >95th percentile for age, gender, and height (defined as hypertensive subjects [Ht]). In addition, we studied 16 children with AP between the 95th and 90th percentile (prehypertensive subjects [Pre-Ht]) and 21 children with AP <90th percentile (control subjects [C]). Pre-Hts and Hts were also subjected to blood drawing for chemistry and metabolic analysis. All of the children were also studied by echocardiography (Aloka ProSound SSD 5000). After clinical examination, children were finally subjected to ECG and noninvasive continuous AP assessment (Task Force Monitor, CNSystems) for 10 minutes of rest followed by 10 minutes of unaided standing to subsequently evaluate autonomic regulation. A software tool (HeartScope20), based on a sympathovagal model,21,22 furnishes markers of oscillatory (low frequency [LF] and high frequency [HF])23 and nonlinear24 modulation (Ro index) of the sino atrial node. HeartScope also computes baroreflex slope (BRS) by sequence analysis25 and index alpha26 by spectral analysis. The study was approved by the institutional review committee, and all of the children’s parents gave their informed consent. All of the statistical computations were performed with a commercial statistical package (SPSS 13) setting significance at P<0.05.
Results
Baseline Population Values
By design in the 3 considered groups, age distribution was similar, whereas AP was progressively and significantly greater from Cs to Pre-Hts and to Hts; body mass index (BMI) was also greater in the Pre-Ht and Ht groups (see Table 1).
Table 1. Descriptive Statistics of the Study Population
Variables
Total (n=75: 33 Boys/42 Girls), Mean±SEM
Cs (n=21: 10 Boys/11 Girls), Mean±SEM
Pre-Hts (n=16: 9 Boys/7 Girls), Mean±SEM
Hts (n=38: 14 Boys/24 Girls), Mean±SEM
HR indicates heart rate; DAP, diastolic arterial pressure, by sphygmomanometry; IVS, intraventricular septum; PW, posterior wall; LVMI, height normalized left ventricular mass index; HDL, high-density lipoprotein; HOMA, homeostatic model assessment; TSH, thyroid-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; NA, not applicable. Metabolic variables were, for ethical reasons, obtained only in Hts and Pre-Hts.
Significant differences (corrected for BMI):
(*P<0.05) Pre-Hts vs Cs,
(†P<0.05) Hts vs Cs,
(‡P<0.05) Hts vs Pre-Hts.
Significant differences (not corrected for BMI):
(§P<0.05) Pre-Hts vs Cs,
(∥P<0.05) Hts vs Cs,
(¶P<0.05) Hts vs Pre-Hts.
#Significant linearity is indicated.
Age, y
9.72±0.22
9.31±0.51
9.97±0.30
9.84±0.31
HR, bpm
84.7±1.4
75.4±2.1
86.8±2.8*§
89.0±1.9†∥#
SAP, mm Hg
118.1±2.3
97.1±2.7
121.3±5.2*§
128.4±1.9†∥#
DAP, mm Hg
71.5±1.5
57.3±2.0
69.7±1.5*§
80.1±1.6†‡∥¶#
BMI, kg/m2
21.61±0.52
17.21±0.62
21.85±1.03§
23.89±0.59∥#
IVS, cm
0.76±0.02
0.65±0.03
0.79±0.03*§
0.80±0.02∥#
PW, cm
0.72±0.01
0.63±0.02
0.75±0.02*§
0.77±0.01∥#
LVMI, g/m2
36.75±0.65
33.53±1.37
37.15±1.24
38.32±1.00∥#
Total cholesterol, mmol/L
NA
NA
3.92±0.17
4.08±0.13
HDL cholesterol, mmol/L
NA
NA
1.52±0.08
1.48±0.06
Triglycerides, mmol/L
NA
NA
0.79±0.1
0.79±0.12
Fasting plasma glucose, mmol/L
NA
NA
4.5±1.0
4.7±1.0
Insulin, μU/L
NA
NA
11.14±1.49
12.77±1.21
HOMA index
NA
NA
2.26±0.29
2.71±0.26
Creatinine, μmol/L
NA
NA
45.1±1.8
44.2±0.9
Uric acid, mmol/L
NA
NA
0.25±0.01
0.27±0.01
TSH, mU/L
NA
NA
2.08±0.13
2.33±0.15
FT3, pmol/L
NA
NA
6.64±0.20
6.87±0.14
FT4, pmol/L
NA
NA
16.59±0.49
15.69±0.37
Echocardiographic evaluation showed slight increase in intraventricular septum and posterior wall thickness in the Ht and Pre-Ht groups as compared with Cs. Left ventricular mass indexed by height was also slightly increased in Hts and Pre-Hts as compared with Cs. Metabolic assessment (performed only in Ht and Pre-Ht groups) showed nonsignificant group differences in examined variables (all in reference range).
Autonomic Evaluation
Regarding differences between groups at rest (Table 2 and Figure 1), significant differences were observed in monovariate time and frequency domain measures, being RR interval, total variance, and absolute values of LFRR and HFRR components slightly and gradually decreased from C to Pre-Ht and to Ht. Insignificant changes were observed in normalized oscillatory markers, whereas a gradual significant increase in the nonlinear Ro index was noticed (Table 2 and Figure 1).
Table 2. Descriptive Statistics of Resting Values of RR Interval, SAP Variability, and Spontaneous Baroreflex Indices
Variables
RR, Mean±SEM, ms
VARRR, Mean±SEM, ms2
LF, Mean±SEM
HF, Mean±SEM
LF/HF, Mean±SEM
mHz
ms2
nu
mHz
ms2
nu
Children are subdivided in 3 groups according to blood pressure levels. VAR indicates variance; Ro, regularity index; SYS, systolic arterial pressure by Finapres; nu, normalized units.
Significant differences (corrected for BMI):
(*P<0.05) Pre-Hts vs Cs,
(†P<0.05) Hts vs Cs,
(‡P<0.05) Hts vs Pre-Hts.
Significant differences (not corrected for BMI):
(§P<0.05) Pre-Hts vs Cs,
(∥P<0.05) Hts vs Cs,
(¶P<0.05) Hts vs Pre-Hts.
#Significant linearity is indicated.
Cs
808.0±21.8
7587±1363
0.12±0.01
2709±658
47.74±2.97
0.31±0.01
2562±471
43.91±3.19
1.41±0.27
Pre-Hts
703.0±24.4*§
4013±93§
0.13±0.01
1749±733
55.74±3.91
0.31±0.01
778±174§
32.88±3.78§
2.80±0.80
Hts
686.2±14.9†∥#
3719±714∥#
0.13±.0.00
1325±239∥#
54.41±2.68
0.32±0.01
1096±417∥#
36.26±2.66
2.70±0.59
(Continued)
Table 2. Continued
SYS, Mean±SEM, mm Hg
α Index, Mean±SEM, ms/mm Hg
BRS, Mean±SE, ms/mm Hg
Ro, Mean±SEM
94.7±3.2
40.1±4.4
37.5±5.0
0.206±0.015
111.8±2.4§
22.7±3.3*§
26.1±2.7*§
0.271±0.017*§
127.4±2.3†‡∥#
19.8±2.1†∥#
20.4±2.1†∥#
0.266±0.012†∥#
Figure 1. Average values (and SEMs) of systolic and diastolic (top) arterial pressure values, of heart rate (middle left), of RR variance (middle right), of α index (bottom left), and of BRS (bottom right) in Cs (open bars), Pre-Hts (Ph; lined bars), and Hts (Ht; crossed bars).
Bivariate indices of spontaneous baroreflex demonstrated a consistent gradual reduction in sensitivity from C to Pre-Ht and Ht both in the case of BRS and of the index α. These changes remained significant after BMI correction (Table 2 and Figure 1). It should also be noted that the index α and BRS provided quite similar results, as demonstrated by the Bland-Altman plot, with essentially no bias (bias: −0.01±0.04 ms/mm Hg; graphics not shown for simplicity).
Regarding effects of active orthostatism (Table 3), active orthostatism, as compared with resting condition, induced in all 3 of the considered groups a significant reduction of RR interval and of RR interval variance (and as a corollary a reduction of its absolute spectral components). Standing induced a significant increase of LFRR in normalized units and, conversely, a reduction of HFRR normalized units. Both indices of spontaneous baroreflex sensitivity (α index and BRS) were significantly reduced by active orthostatism, being the reduction of α index significantly greater in the C group as compared with Pre-Ht and Ht groups. Small changes in systolic AP (SAP) were noted: some increase in C contrasted with some decrease in Ht.
Table 3. Stand-Induced Changes: Descriptive Statistic of Major RR Interval and SAP Variability Indices and of Baroreflex Gain in Children, Subdivided in 3 Groups According to Blood Pressure Levels
Significant group differences (corrected for BMI):
(*P<0.05) Pre-Hts vs Cs,
(†P<0.05) Hts vs Cs.
Significant group differences (not corrected for BMI):
(‡P<0.05) Pre-Hts vs Cs,
(§P<0.05) Hts vs Cs.
Difference (∥P<0.01) vs rest condition.
Cs
−129.27±14.90∥
−3972±1441∥
−1492±742∥
23.41±3.25∥
−1892±430∥
−22.80±3.62∥
5.02±1.49∥
0.136±0.018∥
Pre−Hts
−84.87±11.65*‡∥
−1243±514∥
−368±636∥
22.78±4.51∥
−533±147∥
−19.19±3.54∥
5.10±2.09∥
0.095±0.021∥
Hts
−97.0±18.16†§∥
−1756±598∥
−397±164∥
20.82±3.09∥
−865±4051∥
−18.14±2.68∥
6.22±1.39∥
0.130±0.012∥
(Continued)
Table 3. Continued
Δ SYS, mm Hg
Δ α Index, ms/mm Hg
Δ BRS, ms/mm Hg
4.50±2.89∥
−20.12±4.97∥
−13.34±5.71∥
0.91±3.44∥
−7.28±2.09*‡∥
−10.50±2.59∥
−3.93±2.90†
−7.67±1.56†§∥
−7.06±1.68∥
Correlations
The α index correlated significantly with cardiovascular (heart rate, SAP, and diastolic AP), echocardiographic (intraventricular septum but not posterior wall nor left ventricular mass indexed by height), and autonomic variables (Table 4 and Figure 2). The general profile also remained after BMI correction, with the exception of echocardiographic indices. BRS values demonstrated a similar link with hemodynamic and autonomic variables, albeit of lesser magnitude. Multiple stepwise regression analysis suggested that the α index could be predicted by the combination RR variance, systogram, Ro, and heart rate, whereas BRS could be predicted only by RR variance and systogram.
Table 4. Simple Correlations Among Time, Frequency Domain, and Causal Indices of Baroreflex Gain and Hemodynamic, Echocardiographic, and Cardiac Autonomic Parameters
Variables
α Index
BRS
No BMI Correction
BMI Correction
No BMI Correction
BMI Correction
r
P<
r
P<
r
P<
r
P<
Correlations are presented without correction for BMI (left) and with correction (right). HR indicates heart rate; DAP, diastolic arterial pressure by sphygmomanometry; SYS, SAP by Finapres; IVS, intraventricular septum; PW, posterior wall; Ro index, regularity index; nu, normalized units.
*Significant values.
HR
−0.610*
0.000*
−0.599*
0.000*
−0.523*
0.000*
−0.450*
0.000*
SAP
−0.495*
0.000*
−0.283*
0.016*
−0.419*
0.000*
−0.214*
0.071*
DAP
−0.503*
0.000*
−0.325*
0.005*
−0.441*
0.000*
−0.273*
0.020*
SYS
−0.443*
0.000*
−0.321*
0.006*
−0.445*
0.000*
−0.344*
0.003*
IVS
−0.318*
0.006*
−0.217*
0.067*
−0.176*
0.136*
−0.141*
0.239*
PW
−0.180
0.129
−0.111
0.355
−0.121
0.308
0.0794
0.511
RR variance
0.656*
0.000*
0.760*
0.000*
0.606*
0.000*
0.629*
0.000*
LF absolute
0.561*
0.000*
0.704*
0.000*
0.598*
0.000*
0.559*
0.000*
LF nu
−0.280*
0.015*
−0.210*
0.076
−0.100
0.393
−0.088
0.461
HF absolute
0.721*
0.000*
0.672*
0.000*
0.536*
0.000*
0.608*
0.000*
HF nu
0.249*
0.031*
0.188
0.113
0.025
0.830
0.063
0.601
LF/HF
−0.258*
0.025*
−0.154
0.197
−0.054
0.647
0.029
0.809
Ro index
−0.571*
0.000*
−0.540*
0.000*
−0.445*
0.000*
−0.402*
0.000*
Figure 2. Simple correlations between spontaneous baroreflex sensitivity indices (α index, top; BRS, bottom) and heart rate (left), SAP (middle), and BMI (right). Note the individual scatter of data points. r indicates regression coefficient; p, significance level.
Discussion
In this investigation, we report that children with AP values above the 95th percentile for age, gender, and height, ie, in the hypertensive range, demonstrate a significant impairment of the spontaneous baroreflex and a reduction in RR variability, suggesting defective vagal regulation of the SA node. Similar impairment is observed also in children whose AP falls short of this limit, ie, in the prehypertensive range.
It is well recognized that essential hypertension, in adults, is characterized by complex disturbances of cardiovascular regulation. In this context, circumstantial and direct evidence suggest a mechanistic involvement of the autonomic nervous system and, in particular, a shift of the sympathovagal balance,15,16 more evident in the early stages, and accompanied by an impairment of stimulated and spontaneous baroreflex.27,28 Computer analysis of RR and AP variabilities showed alterations in time and frequency domain markers of autonomic regulation, inclusive of a lesser increase with stand of the normalized powers of the LF and HF components, observed not only in patients with hypertension but also in subjects with AP in the high reference range.16
Considering the slowly progressive nature of essential hypertension, it is conceivable that early assessment of related (mal) adaptive changes (eg, altered cardiovascular regulation) in hypertensive children might represent a unique clinical model to delve into the influence of various mechanisms underlying the progression of the disease since its inception.
Data presented in this study suggest that selective early autonomic alterations, notably, baroreflex impairment, could precede the development of hypertension and not the opposite, possibly by way of obesity-linked carotid artery thickening.29 Accordingly, we might argue that the likely attendant reduction of carotid artery distensibility, by impairing the functional properties of this major reflexogenic area,30 would reset the reflex autonomic balance to a slightly less vagal tone and the hemodynamic equilibrium to a slightly higher AP. This hypothesis, although supported by the observed strong inverse correlation between baroreflex sensitivity and AP (Figure 2), cannot be taken to imply causality.
The thesis of a key role of baroreflex impairment in childhood hypertension is conversely corroborated by concordant findings of the various techniques used to explore spontaneous (dys)regulation of the baroreflex.25,26 However, a significant role of the heart, suggested by the link between baroreflex measures and indices of cardiac performance (either heart rate or echocardiographic parameters), cannot be simply dismissed.
The spontaneous baroreflex can be assessed by a variety of models,31 but essentially 2 approaches are of more common use in clinical studies: one based on time domain measures, ie, the so called BRS25 by the sequence method, and a second one, based on bivariate spectral analysis techniques, usually named the α index.26
As reported previously in adults,31 and also shown in this study in the case of children, BRS and α index provide quite similar results, with no evident bias when examined with a Bland-Altman approach. A recognized limitation of the BRS-α index approach is that the underlying model implicitly assumes that changes in RR are fully explained by changes in SAP variability,32 without explicit allowance for the difference between feed-back and feed-forward pathways or for the effects of other inputs or noise, such as chemoreflexes or metaboreflexes.
Overall, both methodologies used in this study clearly indicate that baroreflex gain is relatively reduced both in Ht and Pre-Ht children. Our study, however, did not address a possible molecular or genetic underpinning of this observation.
We report that baroreflex gain, as assessed by the α index, is significantly correlated to hemodynamic values, such as heart rate and SAP, as well as to autonomic indices, particularly nonlinear ones, and to BMI. Similar correlations are observed also in the case of BRS. The α-index is also correlated with some echocardiographic measures of the left ventricle, suggesting a possible initial inhomogeneous cardiac involvement. This link is, however, lost when correcting for BMI, corroborating the well-known interaction between obesity and hypertension on cardiac mass,33 also in childhood. Stepwise regression analysis confirmed the tight link between measures of spontaneous baroreflex and either RR variance or AP.
Data also clearly show, as a corollary, that pressure group values are strongly affected by BMI13 and, thus, focus on the potentially unitary pathophysiologic mechanisms of autonomic and metabolic disturbances. However, this side of the problem could not be fully analyzed, insofar as C children, for ethical reasons, were not subjected to metabolic assessment, and we did not examine children with diabetes.
Regarding indices of autonomic regulation of the SA node, spectral analysis revealed small but not significant differences between pressure groups, that, as in adults,16 were characterized by a slight prevalence of LF oscillations in the Ht group. Conversely nonlinear methods, such as the regularity index (Ro), appeared significantly different in the 3 groups. Given the strong correlation between Ro and baroreflex gain, we could, thus, hypothesize that baroreflex mechanisms play a key role in determining nonlinear properties of short-term RR variability in children.
As for the stand-induced changes in autonomic parameters, a clear response to the orthostatic stimulus was apparent in all of the groups, at variance with what occurs in adult hypertensive patients16 who display a markedly diminished responsiveness, again suggesting that we were, indeed, exploring autonomic dysfunction in the making, well before full development of hypertensive autonomic dysregulation. Globally considered, the hypertensive phenotype, thus, appears in children associated to reduced baroreflex gain and initial signs of accentuated cardiac function.34
In this context, autonomic evaluation might provide a valuable surrogate end point for behavioral preventive strategies, based on tailored lifestyle changes,35 such as healthy eating habits and regular aerobic exercise.36 Indeed, several years ago we showed26 that moderate aerobic exercise was capable, in mildly hypertensive adults, not only to reduce AP values but also to increase baroreflex gain, as assessed by the α index.
In children, the definition of hypertension is based on a probabilistic13 (subjects with AP values above a determined percentile are considered hypertensive) and not an epidemiological (subjects with AP values shown to be associated with an increased cardiovascular risk) criteria as in adults. Our data showing that autonomic alterations are present even in children with AP values not permanently above the 95th percentile corroborate the concept that criteria to define hypertension in children should avoid predetermined generalized thresholds37 and could be complemented by ancillary measures, such as autonomic evaluation.
Perspectives
The findings of this observational study, in spite of its limitations, show the presence in hypertensive and in prehypertensive children of an autonomic dysfunction, characterized by reduced RR variance and marked baroreflex impairment. These findings should be viewed in the context of an attendant progressive cardiac and metabolic involvement, suggestive of an early impairment of vagal regulation of the SA node, that could guide personalized hypertensive therapy38 and prevention by way of autonomic and baroreflex assessment. Because in these children, Ht and Pre-Ht groups spent more time being inactive (studying and/or watching television) and less time in sport activity (please see Table S1, available online at http://hyper.ahajournals.org), we believe that an ideal intervention might start by considering increasing the structured time dedicated to exercise and sport.
Acknowledgments
Sources of Funding
This work was supported by Fondo Investimenti per la Ricerca Scientifica e Tecnologica (FIRST), Agenzia Spaziale Italiana (ASI) contratto 7048 Disturbi del Controllo Motorio e Cardiorespiratorio (DCMC), and Rotary Club of Monza-East.
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On the cover: Structure-based identification of an ACE2 activator. (A) Free (open) and inhibitor bound (closed) ACE2 structures (PDBID: 1R42 and 1R4L, respectively). Secondary structure is shown in red for helices, gray for loops, and gold for strands. (B) Sphere clusters targeting 3 sites on ACE2. Spheres are in yellow, and secondary structure is shown as in A. B shows the structure of the inhibitor-bound conformation of ACE2 (inhibitor not shown). The cluster for site 1 was generated based on the structure of the open form of the enzyme, but it is shown superposed on the closed form to show its relative position to the other clusters. The view of the structure rotated 90° around the horizontal axis. (See page 1312.)
From the Clinica Nefrologica, S. Gerardo Hospital (S.G., F.P., V.T., A.S.), and Dipartimento di Medicina Clinica e Prevenzione (S.G., F.P., A.S.), University of Milano Bicocca, Milan, Italy; Federazione Italiana Medici Pediatri (M.G.), Milan, Italy; Department of Technologies for Health, Galeazzi Orthopaedic Institute (A.P.), and Department of Clinical Sciences “L. Sacco” (M.P., D.L.), University of Milano, Milan, Italy.
From the Clinica Nefrologica, S. Gerardo Hospital (S.G., F.P., V.T., A.S.), and Dipartimento di Medicina Clinica e Prevenzione (S.G., F.P., A.S.), University of Milano Bicocca, Milan, Italy; Federazione Italiana Medici Pediatri (M.G.), Milan, Italy; Department of Technologies for Health, Galeazzi Orthopaedic Institute (A.P.), and Department of Clinical Sciences “L. Sacco” (M.P., D.L.), University of Milano, Milan, Italy.
From the Clinica Nefrologica, S. Gerardo Hospital (S.G., F.P., V.T., A.S.), and Dipartimento di Medicina Clinica e Prevenzione (S.G., F.P., A.S.), University of Milano Bicocca, Milan, Italy; Federazione Italiana Medici Pediatri (M.G.), Milan, Italy; Department of Technologies for Health, Galeazzi Orthopaedic Institute (A.P.), and Department of Clinical Sciences “L. Sacco” (M.P., D.L.), University of Milano, Milan, Italy.
From the Clinica Nefrologica, S. Gerardo Hospital (S.G., F.P., V.T., A.S.), and Dipartimento di Medicina Clinica e Prevenzione (S.G., F.P., A.S.), University of Milano Bicocca, Milan, Italy; Federazione Italiana Medici Pediatri (M.G.), Milan, Italy; Department of Technologies for Health, Galeazzi Orthopaedic Institute (A.P.), and Department of Clinical Sciences “L. Sacco” (M.P., D.L.), University of Milano, Milan, Italy.
From the Clinica Nefrologica, S. Gerardo Hospital (S.G., F.P., V.T., A.S.), and Dipartimento di Medicina Clinica e Prevenzione (S.G., F.P., A.S.), University of Milano Bicocca, Milan, Italy; Federazione Italiana Medici Pediatri (M.G.), Milan, Italy; Department of Technologies for Health, Galeazzi Orthopaedic Institute (A.P.), and Department of Clinical Sciences “L. Sacco” (M.P., D.L.), University of Milano, Milan, Italy.
From the Clinica Nefrologica, S. Gerardo Hospital (S.G., F.P., V.T., A.S.), and Dipartimento di Medicina Clinica e Prevenzione (S.G., F.P., A.S.), University of Milano Bicocca, Milan, Italy; Federazione Italiana Medici Pediatri (M.G.), Milan, Italy; Department of Technologies for Health, Galeazzi Orthopaedic Institute (A.P.), and Department of Clinical Sciences “L. Sacco” (M.P., D.L.), University of Milano, Milan, Italy.
From the Clinica Nefrologica, S. Gerardo Hospital (S.G., F.P., V.T., A.S.), and Dipartimento di Medicina Clinica e Prevenzione (S.G., F.P., A.S.), University of Milano Bicocca, Milan, Italy; Federazione Italiana Medici Pediatri (M.G.), Milan, Italy; Department of Technologies for Health, Galeazzi Orthopaedic Institute (A.P.), and Department of Clinical Sciences “L. Sacco” (M.P., D.L.), University of Milano, Milan, Italy.
From the Clinica Nefrologica, S. Gerardo Hospital (S.G., F.P., V.T., A.S.), and Dipartimento di Medicina Clinica e Prevenzione (S.G., F.P., A.S.), University of Milano Bicocca, Milan, Italy; Federazione Italiana Medici Pediatri (M.G.), Milan, Italy; Department of Technologies for Health, Galeazzi Orthopaedic Institute (A.P.), and Department of Clinical Sciences “L. Sacco” (M.P., D.L.), University of Milano, Milan, Italy.
Correspondence to Daniela Lucini, Centro Terapia Neurovegetativa, Università di Milano, Ospedale “L. Sacco” Via G.B. Grassi, 74, 20157 Milan, Italy. E-mail [email protected]
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Daniela Lucini,
Luca Giovanelli,
Mara Malacarne,
Giuseppina Bernardelli,
Alessandro Ardigò,
Wolfgang Gatzemeier,
Nadia Solaro,
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Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.