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Hypertension is associated with increased left ventricular mass (LVM) and carotid intima-media thickness (cIMT), which predict cardiovascular (CV) events in adults. Whether target organ damage is found in pre-hypertensive youth is not known. The authors measured body mass index, blood pressure, fasting glucose, insulin, lipids and C-reactive protein, LVM/height2.7 (LVM index), diastolic function, cIMT, carotid stiffness, augmentation index, brachial artery distensibility, and pulse wave velocity (PWV) in 723 patients aged 10 to 23 years (29% with type 2 diabetes mellitus). Patients were stratified by blood pressure level (normotensive: 531, pre-hypertensive: 65, hypertensive: 127). Adiposity and CV risk factors worsened across blood pressure group. There was a graded increase in cIMT, arterial stiffness, and LVM index and decrease in diastolic function from normotension to pre-hypertension to hypertension. In multivariable models adjusted for CV risk factors, status as pre-hypertension or hypertension remained an independent determinant of target organ damage for LVM, diastolic function, internal cIMT, and carotid and arterial stiffness. Pre-hypertension is associated with cardiovascular target organ damage in adolescents and young adults.
J Clin Hypertens (Greenwich). 2011;13:332–342. ©2011 Wiley Periodicals, Inc.
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Patient characteristics are displayed in Table I. NT participants were slightly younger than pre-HTN and HTN patients. There were no differences in race but there were fewer men in the HTN group. The prevalence of T2DM and measures of adiposity and BP worsened from NT to pre-HTN to HTN. NT patients tended to have a better lipid profile, metabolic control, and level of inflammation than the other groups. HTN had the lowest activity levels (all P≤.05 for comparisons listed above).
Table I. Patient Characteristics by Blood Pressure Category
|Variable||NT (n=531)||Pre-HTN (n=65)||HTN (n=127)|
|Race, % non-Caucasian||58.0||58.5||70.9|
|Sex, % maleb||37.9||37.7||23.6|
|Presence of T2DM, %c||21.9||40.0||55.9|
|SBP, mm Hgd||111.3||9.9||119.3||10.6||128.8||13.1|
|DBP, mm Hgd||61.5||11.7||67.9||11.1||72.9||14.6|
|MAP, mm Hgd||80.8||7.8||85.9||8.2||91.0||10.9|
|Heart rate, beats per mina||66.1||10.6||70.1||10.0||71.5||11.9|
|CPM, counts/non 0 minf||684||255||610||240||560||169|
LVMI increased across the BP groups (Table II and Figure 1). HTN patients demonstrated a higher prevalence of abnormal geometry, 23.6% (for all abnormal patterns combined) compared with 7.7% for NT and pre-HTN (P≤.05). There were no group differences in systolic function (shortening fraction, velocity of circumferential fiber shortening, or wall stress [data not shown]). NT patients had better diastolic function than HTN patients for all measures. Values for NT patients were also better than those for pre-HTN patients for mitral E/A ratio, TDI Ea/Aa septal ratio, average septal/lateral Ea/Aa ratios, and E/average Ea/Aa TDI lateral and septal ratios (all P≤.05).
Table II. Cardiac Structure and Function by Blood Pressure Category
|Variable||Normal (n=531)||Pre-HTN (n=65)||HTN (n=127)|
|LVMI, g/m2.7a|| 32.8||8.9||35.9||9.8||40.7||11.2|
|Relative wall thicknessb||0.30||0.06||0.31||0.05||0.33||0.07|
|Geometry, No. (%)c|
| Normal||490 (92.3)||60 (92.3)||97 (76.4)|
| Concentric hypertrophy|| 19 (3.4)|| 2 (3.1)|| 6 (4.7)|
| Eccentric hypertrophy|| 18 (3.4)|| 3 (4.6)||17 (13.4)|
| Concentric remodeling|| 4 (0.8)|| 0 (0)|| 7 (5.5)|
|Mitral Doppler E/A ratiod||2.02||0.55||1.86||0.51||1.82||0.46|
|Mitral Doppler E wave/TDI Ea lateral ratiob||5.71||1.44||6.01||1.65||6.70||1.51|
|Mitral Doppler E wave/TDI Ea septal ratioe||7.33||1.68||7.84||2.04||8.30||1.61|
|Mitral TDI lateral velocity Ea/Aa ratiof||2.74||0.87||2.56||0.77||2.36||0.69|
|Mitral TDI septal velocity Ea/Aa ratiod||2.07||0.62||1.82||0.49||1.68||0.52|
|Average Ea/Aa TDI lateral and septal ratiosg||15.0||2.2||14.3||2.5||13.4||2.5|
|Mitral Doppler E wave/average Ea/lateral and Ea/septal tissue Doppler lateral and septal ratiosh||6.36||1.37||6.74||1.64||7.33||1.36|
Figure 1. Cardiac structure and function by blood pressure group. LVMI indicates left ventricular mass index. P<.05 for *normotension (NT)<pre-hypertension (pre-HTN)<HTN; †NT<pre-HTN and HTN; §NT and pre-HTN<HTN; ‡‡NT>pre-HTN; §§NT>pre-HTN and HTN.
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NT patients had significantly lower IMT than the other BP groups for the bulb and internal carotid artery segments and they had more flexible common carotid arteries as measured by PEM and YEM (Table III, Figure 2, and Figure 3, all P≤.05). There was a graded increase in AIx and femoral PWV with a similar decrease in BrachD among the BP groups (Table III), indicating progressively stiffer vessels across the BP strata.
Table III. Arterial Structure and Function by Blood Pressure Category
|Variable||NT (n=531)||Pre-HTN (n=65)||HTN (n=127)|
|Common cIMT, mma||0.50||0.09||0.51||0.10||0.53||0.10|
|Bulb cIMT, mmb||0.49||0.10||0.50||0.13||0.54||0.10|
|Internal cIMT, mmb||0.40||0.09||0.44||0.10||0.44||0.10|
|Peterson, mm Hgb||184.4||55.3||202.3||57.8||221.8||81.5|
|YEM, mm Hg/mmb||268.5||128.2||304.9||115.5||308.5||132.7|
|BrachD, mm Hg, % changed||6.16||1.31||5.75||1.21||5.32||1.11|
Figure 2. Carotid intima-media thickness (cIMT) by blood pressure group. P<.05 for ‡‡normotension (NT)<hypertension (HTN); *NT<pre-HTN and HTN.
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Figure 3. Arterial stiffness by blood pressure group. YEM indicates Young’s elastic modulus; AIx, augmentation index; BrachD, brachial artery distensibility; PWV, pulse wave velocity. P<.05 for mean differences by analysis of variance. *Normotension (NT)<pre-hypertension (pre-HTN) and HTN; ‡NT<pre-HTN<HTN; §§HT<pre-HTN<HTN.
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Multivariable models demonstrated that BP group remained a significant predictor of LVMI, E/Ea lateral ratio and average septal/lateral Ea/As, and E/average Ea/Aa TDI lateral and septal ratios (Table IV). BP group was also an independent predictor of (Table V) vascular damage for the internal cIMT, common carotid stiffness (PEM, YEM), AIx, BrachD, and PWV even after adjusting for CV risk factors and distending pressure (MAP). Plotting the age by BP group interaction for BrachD revealed a steeper decline in BrachD across BP groups for adolescents than young adults (data not shown).
Table IV. Multivariable Models Indicating Independent Determinants of Cardiac Structure and Function
|Variable||LVMI||RWT||E/A Ratio||E/Ea Lateral Ratio||E/Ea Septal Ratio||Ea/Aa Lateral Ratio||Ea/Aa Septal Ratio||Average Lateral and Septal Ea/Aa Ratios||E/Average Ea Lateral and Septal|
| NT||−0.06|| || ||−0.45|| || || ||−0.46|| |
| Pre-HTN||−0.063|| || ||−0.38|| || || ||−0.29|| |
| HTNa||0|| || ||0|| || || ||0|| |
|Age||0.0047|| || || || ||−0.026||−0.044|| || |
|Female||−0.1||−0.010|| || || || || || || |
|Non-white race|| || || || || || || ||−0.58||0.27|
|T2DM|| || ||−0.16||0.44||0.64|| || ||−0.68||0.52|
|BMI z score ||0.075|| ||0.13|| ||0.50||−1.61||−0.11|| ||0.37|
|Waist/height ratio||0.88||0.12||−1.08||2.95|| || || ||−1.81|| |
|MAP|| || ||−0.54|| || ||−1.25||−0.81||−4.27|| |
|Heart rate||−0.0033|| ||−0.010|| || ||−0.017||−0.011|| || |
|LDL-C|| || || || || || || ||−0.008|| |
|HDL-C|| || || || || || || ||0.016|| |
|TG|| ||0.010|| || || || || || || |
|Fasting glucose|| || || || || || || || || |
|Fasting insulin|| || || || || || ||−0.108|| || |
|CRP|| || || || || ||0.08|| || || |
Table V. Multivariable Models Indicating Independent Determinants of Arterial Structure and Function
| NT|| || ||−0.045||−0.086||−0.12||−3.61||0.29||−0.061|
| Pre-HTN|| || ||0.022||−0.046||−0.014||−3.76||−0.03||−0.036|
| HTNa|| || ||0||0||0||0||0||0|
|Age * BP category|
| NT|| || || || || || ||−0.013|| |
| Pre-HTN|| || || || || || ||0.003|| |
| HTNa|| || || || || || || || |
|Age ||0.011||0.0093||0.016||0.022|| || ||0.0064||0.014|
|Female ||−0.097||−0.051||−0.12||−0.087|| || ||0.015|| |
|Non-white race ||0.059|| ||0.052|| ||−0.12|| || ||0.070|
|T2DM ||0.066||0.055|| || || || || || |
|Height || || || || || ||−0.32|| || |
|BMI z score || || ||0.020||0.036|| || ||−0.088|| |
|Waist/height ratio || || || || ||1.10|| || ||0.50|
|MAP || ||0.29|| || ||0.43||27.89||−0.0025||0.37|
|Heart rate || ||−0.0020|| || || || || || |
|LDL-C|| ||0.00065||0.001|| || || || || |
|TG || || || || || ||1.97|| || |
|Fasting glucose || || ||0.055|| ||−0.25|| || ||0.065|
|Fasting Insulin || || || ||0.051||−0.091|| ||−0.0025|| |
|Counts/non 0 min|| || || || || ||−6.42|| || |
|R2 ||0.16||0.11||0.20||0.16||0.17|| 0.25||0.43||0.60|
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Our data demonstrate that significant abnormalities in cardiac and vascular measures can be identified in youth with pre-HTN (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 pre-HTN was an independent predictor of many measures of TOD (LVMI, E/Ea, average lateral-septal 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 left ventricular (LV) systolic function, a precursor of heart failure.31 Concentric hypertrophy, the geometric pattern most frequently seen in sustained HTN, 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 Pre-HTN may also lead to more age-related increases in LVM.10 Furthermore, progression from pre-HTN to sustained HTN in the Strong Heart Study was predicted by both baseline systolic BP and also by baseline LVM,37 with the probability of developing incident HTN increasing 36% for each standard deviation (SD) of LVMI.38 The finding that development of mild LV thickening may accelerate progression to higher BP levels suggests that pre-HTN is not a benign condition.
LVH can also be identified in youth with HTN.39,40 Using the adult cutpoint of 51 g/m2.7, Daniels and colleagues found the prevalence for HTN-related LVH to be 8% in a clinic population,11 while a multicenter 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 patients. The Muscatine Heart Study demonstrated that resting systolic BP exerted an independent influence on LVM in children,44 while the Bogalusa Heart Study found that the cumulative burden of systolic BP from childhood to adulthood was a significant predictor of LVMI in young adults.45 Other cross-sectional studies of healthy children confirm the independent relationship between BP and LVM.46,47 Therefore, it is not surprising that youth diagnosed with pre-HTN may also exhibit LVH,12,48 with odds for having elevated LVMI increasing by 54% for each incremental increase in the SD 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 adolescents,50 and BP also relates to left atrial 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 HTN. Among all the metabolic syndrome components, HTN carried the greatest odds ratio (1.43; confidence interval, 1.27–1.60) for presence of carotid plaque, a risk factor for stroke, in a large study of Japanese patients aged 19 to 88 years.54 However, HTN is also linked to early carotid changes. cIMT increased across BP categories in all race and sex groups in the Atherosclerosis Risk in Communities (ARIC) study,55 a finding replicated in other large population-based studies.56,57 Presence of HTN also predicts progression of cIMT,58,59 so it is not surprising that greater carotid thickness can be found in adults with pre-HTN35,60 and normal adults with multiple CV risk factors,61 with a 0.058-mm increase in cIMT seen per 1-SD (21-mm Hg) increase in BP in a multi-ethnic study by Psaty and colleagues.62
The adverse changes in carotid structure seen in hypertensive adults are accompanied by parallel deterioration in carotid function. The ARIC study found that increased carotid stiffness predicted development of HTN3 and that HTN was associated with increased carotid stiffness.63 However, as in earlier studies,64 the increase in stiffness was dependent on 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 HTN 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 an HTN clinic were found to have thicker common carotid artery cIMT compared with 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 BMI69 or when statistical adjustment for adiposity is performed.70 In a large recent study from our group, we found that 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 HTN in youth.72 However, one investigator found the relationship only when lean controls, rather than obese controls, were compared with 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 HTN and pre-HTN on carotid artery thickness and stiffness.
The majority of studies relating BP to arterial stiffness measure PWV. PWV is a robust measure that 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 HTN. There are also some limited data relating HTN in adults to higher AIx78,79 and lower BrachD values.80 Unfortunately, treatment of HTN in adulthood may not normalize PWV,81 and annual rates of progression of PWV are higher in hypertensives compared with controls even if BP is well-controlled.82 Underlying abnormalities in arterial stiffness may be contributing to development of HTN,83 which then causes further deterioration in arterial elasticity. Higher PWV84 and AIx85 values have also been documented in pre-hypertensive adults. PWV gradually increased as a function of BP classification from normal HTN to pre-HTN to stage II HTN in one study.86 Furthermore, studies of normotensive young adults with a positive family history of HTN have demonstrated lower BrachD80 and higher PWV87,88 and AIx89 values, suggesting an underlying genetic tendency for vascular dysfunction that may impact risk for developing HTN. Therefore, to prevent development of sustained HTN, 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 sparse. A recent study by Reusz and colleagues provided PWV results on 1008 healthy patients (6–20 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 with controls, but only in Caucasians.92 Our data found higher PWV in pre-hypertensive non-Caucasians; however, we measured the standard carotid-femoral PWV. In the Zhu and colleagues paper,92 carotid to dorsalis pedis was measured, and it is known that PWV is higher in smaller leg vessels compared with the central aorta.26 A study examining younger children, mean age of 11.4 years, demonstrated higher PWV in patients with systolic BP ≥90th percentile, the cutpoint for pre-HTN, compared with normotensives.93 However, the investigators did not determine whether differences existed between pre-HTN and true HTN. Our findings confirm the graded increase in PWV from normo-HTN to pre-HTN to HTN in 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 used for pediatric HTN research to date.
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 that 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 height2.7 because measurement of fat-free mass requires specialized equipment not readily available to many physicians and because the de Simone method of indexing LVM20 has produced a sex-independent partition value of 51 g/m2.7 that has proven better at predicting incident CV events4,99 compared with other allometric adjustments, including indexing to height1.7 suggested by4,100Chirinos and colleagues,101 which was only superior in predicting all-cause mortality.