Our data demonstrate that significant abnormalities in cardiac and vascular measures can be identified in youth with pre-hypertension (increased LVM, carotid thickness, arterial stiffness and decreased diastolic function). Although a deteriorating risk factor profile was seen across the BP distribution, the adverse cardiac and vascular changes are largely independent of other traditional CV risk factors. This is evident from the observation that classification as PreHT was an independent predictor of many measures of TOD (LVMI, E/Ea, Avg lat-sept Ea/Aa, internal cIMT, PEM, YEM, AIx, BrachD, PWV) even after adjusting for CV risk factors including BMI and presence of T2DM. This suggests that even mild elevation in BP is an important etiology for TOD.
In hypertensive adults, elevated LVM is a well described independent risk factor for adverse CV events30
and is associated with development of depressed LV systolic function, a precursor of heart failure.31
Concentric hypertrophy, the geometric pattern most frequently seen in sustained hypertension, is also associated with a poor prognosis.32
However, cardiac abnormalities can be found in pre-hypertensive adults. Recent studies found depressed diastolic function in pre-hypertensives33, 34
and two large studies found higher LVM in these patients even after adjustment for other CV risk factors.35, 36
Prehypertension may also lead to more ageing-related increase of LVM10
Furthermore, progression from pre- to sustained hypertension in the Strong Heart was predicted by both baseline systolic BP and also by baseline LVM37
with the probability of developing incident hypertension increasing 36% for each standard deviation of LVMI.38
The finding that development of mild LV thickening may accelerate progression to higher BP levels suggests that pre-hypertension is not a benign condition.
LVH can also be identified in youth with hypertension.39, 40
Using the adult cut-point of 51 g/m2.7
, Daniels, et al, found the prevalence for hypertension-related LVH to be 8% in a clinic population11
while a multi-center study found the prevalence to be as high as 15.5%.41
If the pediatric definition of ≥95th
percentile of LVM is used, the prevalence may be as high as 30 to 40%.41–43
Important epidemiologic studies of CV risk factors in youth also confirm a strong association between BP levels and LV thickness in non-hypertensive subjects. The Muscatine Heart Study demonstrated that resting SBP exerted an independent influence on LVM in children44
while the Bogalusa Heart Study found the cumulative burden of SBP from childhood to adulthood was a significant predictor of LVMI in young adults.45
Other cross-sectional studies of normal children confirm the independent relationship between BP and LVM.46, 47
Therefore, it is not surprising that youth diagnosed with pre-hypertension may also exhibit LVH12, 48
with odds for having elevated LVMI increasing by 54% for each incremental increase in the standard deviation score for 24-hour ambulatory systolic BP.49
Higher ambulatory BP is also significantly associated with a higher prevalence of abnormal LV geometry in children and adolescents50
and BP also relates to LA diameter51
and decreased diastolic function in youth.52, 53
Our data confirm the adverse effect of pre-hypertensive BP levels on LV structure and function in a larger cohort of adolescents and young adults.
As with LVM, carotid structure is also adversely affected by hypertension. Among all the metabolic syndrome components, hypertension carried the greatest odds ratio (1.43, CI 1.27–1.60) for presence of carotid plaque, a risk factor for stroke, in a large study of Japanese subjects age 19 to 88 years.54
However, hypertension is also linked to early carotid changes. Carotid IMT increased across BP categories in all race and gender groups in the Atherosclerosis Risk in Communities (ARIC) Study,55
a finding replicated in other large population-based studies.56, 57
Presence of hypertension also predicts progression of cIMT,58, 59
so it is not surprising that greater carotid thickness can be found in adults with pre-hypertension35, 60
and normal adults with multiple CV risk factors,61
with a 0.058 mm increase in cIMT seen per 1 SD (21 mmHg) increase in BP in a multi-ethnic study by Psaty et al.62
The adverse changes in carotid structure seen in hypertensive adults are accompanied by parallel deterioration in carotid function. The ARIC study found increased carotid stiffness predicted development of hypertension3
and hypertension was associated with increased carotid stiffness.63
However, as in earlier studies,64
the increase in stiffness was dependent upon baseline distending pressure. In contrast, other investigators have found the hypertensive-related increase in carotid stiffness to be independent of baseline pressure but only in younger hypertensives.65
Hypertension may have a stronger effect on arterial stiffness in younger individuals while age and other CV risk factors may be more important at older ages. Data demonstrating that pre-hypertensive men, if young, have lower carotid distensibility than controls66
support this hypothesis. It is possible that other age-related risk factors have a more powerful effect on carotid stiffness than BP, at older ages.
Recent studies have demonstrated a relationship between BP and carotid structure and function in youth. Children referred to a hypertension clinic were found to have thicker common carotid artery cIMT compared to controls. In two studies, the relationship was not independent of BMI.67, 68
However, other investigators have found the relationship between BP and cIMT to be significant even when adolescents are matched by BMI,69
or statistical adjustment for adiposity is performed.70
In a large recent study from our group, we found the obesity-independent relationship between BP and cIMT also existed for the carotid bulb and internal carotid artery segments.71
A few studies have related increased carotid stiffness to hypertension in youth.72
However, one investigator found the relationship only when lean controls, rather than obese controls, were compared to the hypertensive youth.68
Two other studies, found the relationship to be obesity-independent.71, 73
Our current paper extends these observations by providing data on all 3 carotid artery segments and examining the effect of both hypertension and pre-hypertension on carotid artery thickness and stiffness.
The majority of studies relating BP to arterial stiffness measure PWV. PWV is a robust measure which not only predicts CV events,74, 75
but also CV mortality.76
Indeed, increased arterial stiffness, including faster PWV,77
has been found with greater CV risk such as in hypertension. There are also some limited data relating hypertension in adults to higher AIx78, 79
and lower BrachD.80
Unfortunately, treatment of hypertension in adulthood may not normalize PWV81
and annual rates of progression of PWV are higher in hypertensives compared to controls even if BP is well controlled.82
Underlying abnormalities in arterial stiffness may be contributing to development of hypertension83
which then causes further deterioration in arterial elasticity. Higher PWV84
have also been documented in pre-hypertensive adults. PWV gradually increased as a function of BP classification from normal to pre- to stage II hypertension in one study.86
Furthermore, studies of normotensive young adults with a positive family history of hypertension have demonstrated lower BrachD,80
higher PWV87, 88
suggesting an underlying genetic tendency for vascular dysfunction that may impact risk for developing hypertension. Therefore, to prevent development of sustained hypertension, it may be useful to assess arterial stiffness in high risk individuals.
Arterial stiffness assessment is being performed in increasing numbers of pediatric studies. As in adults, most pediatric studies focus on PWV although normative data remain spars. A recent study by Reusz, et al, provided PWV results on 1008 healthy subjects (6 to 20 years) obtained with a similar method as employed in our study.90
They found a strong correlation between BP and PWV although no multivariable analyses correcting for other CV risk factors were performed.90
Our previous data on 670 adolescents and young adults demonstrated that mean arterial pressure remained a predictor of PWV (and AIx and BrachD) even after correcting for adiposity, metabolic abnormalities (glucose, insulin, type 191
or type 226
diabetes) and inflammation. A few studies have specifically evaluated the relationship between BP classification and PWV including one that found higher PWV in pre-hypertensive adolescents compared to controls, but only in Caucasians.92
Our data found higher PWV in pre-hypertensive non-Caucasians, however, we measured the standard carotid-femoral PWV and in the Zhu, et al, paper, carotid to dorsalis pedis was measured,92
and it is known that PWV is higher in smaller leg vessels compared to the central aorta.26
A study examining younger children, mean age 11.4 years, demonstrated higher PWV in subjects with SBP ≥ 90th
percentile, the cut-point for pre-hypertension, compared to normotensives.93
However, the investigators did not determine if differences existed between pre- and true-hypertensives. Our findings confirm the graded increase in PWV from normo- to pre- to hypertensive youth, We also provide BP level stratified data for AIx and BrachD, techniques previously employed to investigate other CV risk factors in youth such as diabetes94
and metabolic syndrome,95
but not to date used for pediatric hypertension research.
Our finding of a graded increase in the prevalence of TOD across the BP strata, although cross-sectional, suggests that progression to higher levels of BP increases CV risk at a young age. However, our cross-sectional findings need to be confirmed in longitudinal studies. Furthermore, due to our study design, our population had a high prevalence of obesity and T2DM. However, BP classification remained an independent predictor of all the TOD measures even in multivariable models where BMI and presence of diabetes were entered as covariates. Furthermore, the prevalence of both obesity and T2DM are increasing around the globe. Therefore, our data point to the importance of modifying CV risk factors in high risk youth even if only at borderline levels.
Some studies have suggested that the relationship between BP and arterial stiffness merely reflects the effect of increased distending pressure on the vessel.63
Investigations of brachial arterial compliance under isobaric conditions demonstrating impaired vascular function in hypertensives refute this assertion.96, 97
Furthermore, our model controlled for MAP and still found an effect of BP group on BrachD, suggesting the effect was independent of baseline pressure.
There is much controversy on the appropriate method to index LVM to correct for differences in body size. Some studies have shown that fat-free body mass is more closely related to LVM than other anthropometric measures.46, 98, 99
We chose to index LVM to ht2.7
because measurement of fat-free mass requires specialized equipment not readily available to many physicians and because the de Simone method of indexing LVM 20
has produced a gender-independent partition value of 51 g/m2.7
that has proven better at predicting incident CV events4, 99
compared to other allometric adjustments including indexing to ht1.7
suggested by 4, 100
Chirinos, et al,101
which was only superior at predicting all-cause mortality.
Our data provide additional support for the argument that BP is having an important effect on the CV system in adolescents and young adults even with only modest elevation in BP (above the 90th
%). This supports the concept that pediatricians should be prospectively identifying children and adolescents with BP above the 90th
percentile and should begin lifestyle intervention earlier to prevent cardiac and vascular consequences. This also suggests that it may be necessary to consider implementation of pharmacologic intervention earlier and at a lower BP to prevent progression to sustained hypertension as documented in the adult TROPHY study.102
This is especially important as these target organ changes may well be part of a vicious cycle that leads to further increases in BP and greater target organ disease. Longitudinal trials addressing the issue of earlier treatment based on intermediate non-invasive CV endpoints rather than using arbitrary cut-points are needed.