Primary hypertension is generally believed to have its origins in early life. It may affect target organs in youth, leading to cardiovascular morbidity and mortality much later in life. 1,2 The mechanisms through which hypertension develops are only partly understood. Increasing evidence suggests that stiffness of the cardiovascular system plays a role. High blood pressure and pulse pressure are associated with parameters of stiffness of the arterial wall. 3 Arterial wall stiffness is itself associated with atherosclerosis 4 and is a risk factor for manifest cardiovascular disease. 5 Arterial wall stiffness and blood pressure levels at least partly interact through arterial wall connective tissue metabolism. 6,7 Some studies indicate that the origins of increased arterial wall stiffness trace back to very early life. 8 Thus, both the level of blood pressure and arterial wall stiffness may be partly determined in early life and depend on arterial wall connective tissue metabolism.
Research on the relation between blood pressure and tissue stiffness is largely confined to the cardiovascular system. However, if part of the arterial wall stiffness is set in early life through mechanisms controlling connective tissue metabolism, this might also be true for other body tissues. Tissue stiffness may partly be controlled locally, enabling the body to adapt to local changes. However, some of the control may be inborn and thus detectable in various body tissues and organ systems. Such constitutional tissue stiffness might partially explain interindividual differences in blood pressure levels or arterial wall stiffness. To our knowledge, this possibility has not been explored in a healthy population. Joint mobility and skin extensibility, which can be measured noninvasively, may represent phenotypic stiffness of various body parts. We assessed whether these markers are associated with blood pressure in healthy schoolchildren.
The Montessori school (303 students) and Jenaplanschool Het Spoor (311 students) are primary schools in the city of Zeist, The Netherlands, for students ranging in age from 4 years (first grade) to 12 years (8th grade). All 173 healthy pupils (48% boys) from both schools in the age range between 8 and 10 years were invited to participate. Of these, 117 students (response rate 68%) agreed to participate and were examined during special sessions at school over a total period of 3 weeks in November 2000. Because race is a known correlate of joint mobility, 9 we restricted this analysis to 95 white children.
Body height was measured to the nearest centimeter and weight to the nearest 100 g without shoes and heavy clothing. The dominant hand and foot were registered for each child.
Blood pressure was measured at the start and at the end of the examination, each after 5 minutes rest. The Omron R3 (CEMEX medical technics, Nieuwegein, The Netherlands) has been validated against intra-arterial systolic (deviation = +2.2 mmHg ± 3.9) and diastolic blood pressure (deviation = −0.2 mmHg ± 2.7). 10,11 It was used at the wrist with the student in a sitting position while keeping the device at the level of the heart. The mean of the two measurements was used for analysis. The pulse pressure was taken to be an indicator for vascular stiffness. Pulse pressure was calculated as systolic minus diastolic pressure.
As a measure of capsule and ligament stiffness, the ranges of joint motion of the shoulder (anteflexion), elbow (flexion and extension), wrist (palmar and dorsal flexion), hip (flexion and extension), knee (flexion and extension) and ankle (plantar and dorsal extension) were measured bilaterally to the nearest 5° with a standard 2-legged 360° goniometer, using the “anatomical landmark” method. 12 Children were asked to actively stretch or bend the joint maximally without interference by the investigator, and subjects were not allowed to help the ipsilateral muscles by use of contralateral limbs. Before the present study, a small reliability study was performed concerning joint mobility. Sixteen healthy children in this age range were independently measured by two raters (R.H.H.E. and R.E). The correlation between the raters’ measurements was 0.69 with respect to the mean individual Z-scores of joint mobility as specified in “Data Analysis.”
As a measure of skin stiffness, skin extensibility was measured at the ventral part of the forearm and the medial part of the upper leg using a vacuum tissue compliance meter. The skin displacement was indicated in millimeters using a standard negative pressure of 15 kiloPascal (kPa). 13
Muscle strength was measured to provide an indicator of stiffness of the muscular system, but also because it might partly explain maximal joint motion. The strength of the proximal and distal muscles in lower and upper extremities was measured with a hand-held myometer in Newtons (N). 14 Inter-rater variability of a single muscle-strength measurement was reported to have a standard error of the difference of 17% and intra-observer reproducibility over a 3-month period expressed as a coefficient of variation ranging between 6% (elbow flexors) and 16% (hip flexors). 14 Measurements were sequentially performed three times, and the highest value was used for analysis. In the upper extremity, shoulder abductors and grip strength were measured, whereas in the lower extremity, hip flexors and dorsal extensors of the foot were measured.
A short parental questionnaire provided information about the child’s locomotor health status and physical activity level.
This study was approved by the Medical Ethics Committee of the Wilhelmina Children’s Hospital (University Medical Center Utrecht) and informed consent was obtained from all parents.
To account for large differences in distributions and amplitudes between various measurement locations, Z-scores of measurements at each location were first calculated separately for joint motion and skin extensibility. Subsequently, tissue-specific mean Z-scores were calculated for each child. We were interested in effects of two tissue parameters on both systolic and diastolic blood pressure, which were strongly correlated (Pearson’s r = 0.67). To deal with the correlated nature of these dependent variables, we used a multivariate generalized linear model with both systolic and diastolic blood pressure simultaneously included as dependent variables and indicators of joint mobility and skin extensibility as independent variables. Because pulse pressure is a direct derivative of systolic and diastolic blood pressures, we did not include this in the multivariate model but analyzed it separately as a dependent variable in a univariate generalized linear model. All analyses were adjusted for age, sex, body weight and body height because these are reported determinants of blood pressure, joint mobility and skin extensibility. 1,15,16 Analyses were also adjusted for muscle strength. Model fitting was evaluated by analysis of residuals. All associations are expressed as regression coefficients from generalized linear models with 95% confidence intervals (CI).
Table 1 gives general characteristics of the study population for boys and girls separately. Because the sex subgroups were too small for meaningful statistical analysis, all further analyses were performed for the total group.
Table 2 shows relations between blood pressure and stiffness parameters. Higher joint mobility was associated with both lower systolic and diastolic blood pressure levels (Table 2, model 1). There was no clear relation with pulse pressure. Higher skin extensibility was associated with lower pulse pressure (Table 2, model 2). When including both joint mobility and skin extensibility in the model (Table 2, model 3), there was a 4.5 mmHg lower diastolic blood pressure with every standard deviation (SD) increase in joint mobility. The association with systolic blood pressure was in the same direction but of smaller magnitude. This suggested that joint mobility was somehow related more to levels of blood pressure than to pulse pressure. Therefore, we added an analysis with the mean arterial pressure (MAP), calculated as (2*diastolic blood pressure + systolic blood pressure)/3, as the dependent variable. The association between MAP and joint mobility was −3.7 mmHg/SD joint mobility (CI = −7.0 to −0.3), with simultaneous adjustment for age, sex, body height, body weight and muscle strength. For every SD higher skin extensibility, there was a 2.0 mmHg higher diastolic blood pressure and a 3.2 mmHg lower pulse pressure, apparently through lower systolic and higher diastolic blood pressure levels. This inverse association between pulse pressure and skin extensibility is graphically shown in Figure 1. There was no relation between MAP and skin extensibility (0.4 mmHg/SD skin extensibility; CI = −1.5 to 2.4). In all analyses, adjustment for body mass index instead of body weight and height did not make any material difference, nor did further adjustments for reported musculoskeletal problems and physical activity levels (hours of sports per week) (data not shown).
Spearman correlations between systolic and diastolic blood pressure were 0.70, between systolic and pulse pressure 0.71 and between diastolic blood pressure and pulse pressure 0.07. Total joint mobility was positively associated with total skin extensibility (0.2 SD joint motion per 1 SD change in skin extensibility; CI = 0.04–0.3). Joint mobility showed a somewhat smaller variability (SD = 0.45) than skin extensibility (SD = 0.77).
The results of our study indicate that healthy children with stiffer joints and skin have higher average blood pressure and pulse pressure levels, independent of several confounders.
The study was intended as a quick scan of our hypothesis of constitutional stiffness underlying cardiovascular risk. It was relatively small and possibly underpowered for some of the relations addressed. The cross-sectional design limits causal interpretations. Organ systems of children at this age undergo rapid growth related changes. The dynamics of associations between the organ systems studied are not fully understood. In our analyses, there may still be residual confounding, or other unknown confounders may play a role. For example, body weight and body height were consistently adjusted for, but it may be specific fat distributions that have the strongest confounding effects. Because our measurements were performed during classes, we were not able to use elaborate measuring procedures, and we do have to accept the possibility of residual confounding. Furthermore, some misclassification may be present. If misclassification was nondifferential, our results may be an underestimate; if differential, the reading of skin extensibility, for example, would somehow depend on blood pressure. One explanation for the latter would be that the observer might erroneously read lower skin extensibility given knowledge of the subject’s higher blood pressure. One of our observers was indeed aware of the hypothesis, but the other observer was not. Among the 54 children measured by the second observer, we found, for example, a very similar relation between diastolic blood pressure and skin extensibility (−2.9 mmHg/15 kPa; CI = −5.8 to −0.08), as for the total group (−3.0 mmHg/15 kPa; CI = −5.0 to −1.1). This seems to rule out observation bias as a source of differential misclassification. We cannot rule out other sources of differential misclassification, although we feel that such misclassification would not seem very likely. We consider selection bias with regard to specific associations such as blood pressure and joint mobility to be unlikely, particularly because little, if anything, is known about such associations. Stiffness parameters were measured without knowledge of children’s blood pressure levels. Blood pressure was measured using an automated device with standardized procedures to avoid measurement bias.
Although previous research on this subject is limited, differences among individuals in connective tissue seem to be a plausible explanation of our findings. Connective tissue may be altered in various tissues by pathological metabolic changes or may vary genetically. A known example of metabolic origin is diabetes mellitus. Limited joint mobility is considered one complication of diabetes and has been attributed to microvascular disease. 17 However, the stiffness of the cardiovascular system in diabetics is related to increased collagen crosslinking and advanced glycation end products. 18 Furthermore, pharmacological collagen crosslink breakers reduced arterial wall stiffness in both diabetic and nondiabetic animals. 19 Thus, disturbances in glucose metabolism may lead to changes in connective tissue, which may be reflected in stiffening of the cardiovascular system but possibly also limited joint mobility. Genetic collagen diseases such as Ehlers-Danlos syndrome may also provide (extreme) models for our findings. Low blood pressure or orthostatic hypotension is associated with Ehlers-Danlos syndrome, and Ehlers-Danlos type symptoms of hypermobility might even partly cause the orthostatic hypotension such as commonly encountered in chronic fatigue syndrome. 20 Collagen abnormalities in various tissues have also been related to cardiovascular disease. Spontaneous cervical artery dissections have been associated with ultrastructural abnormalities in the skin such as found in Ehlers-Danlos type syndromes. 21
The above examples suggest that changes in connective tissue, both in genetic and metabolic disease, have detectable consequences in various tissues. It is unknown whether such changes play a role only in specific diseases or whether they also contribute to cardiovascular risk among the healthy. Larkin et al. 22 reported that restricted joint mobility was found not only among those with diabetes mellitus but also among hypertensives. Blood pressure and particularly pulse pressure are related to arterial wall stiffness. The stiffness of animal and human vessel walls is partly determined by connective tissue structure (crosslinking), 6,7 and animal experiments have shown that changes in blood pressure may induce changes in the connective tissue components of the aortic wall. 23 Although the connective tissue composition varies considerably across tissues, collagens type I and III dominate in ligaments, tendons and capsules, as they do in arterial walls. 24 Similarities in connective tissue composition of different tissues may explain our findings with respect to joint mobility, skin extensibility and blood pressure.
We suggest that relations between blood pressure and the flexibility of tissues such as joint capsules and skin are not only present in patients with overt connective tissue disease of either genetic or metabolic origin. Among healthy children, we found that those who have more flexible joints and skin have lower blood pressure levels and lower pulse pressures as indicators of less elastic arterial walls. There is the question to what extent the association between diastolic blood pressure and joint mobility is consistent with our hypothesis. Primarily on the basis of observations in the elderly, stiff arteries are thought to produce lower diastolic blood pressure. In our young group of children, we observed higher joint mobility with lower diastolic blood pressure. We believe that our data might be compatible with both lower diastolic and systolic blood pressure because higher joint mobility was significantly associated with lower MAP. It is not clear to us why this would hold for joint mobility whereas higher skin extensibility would be primarily associated with lower pulse pressure and not MAP. Connective tissue structure, such as the degree of collagen crosslinking, is regulated by genetic mechanisms and tissue specific localized enzymatic processes. 25,26 Phenotypic indicators such as trunk flexibility were shown to run in families. 27 We suggest that interindividual differences in the stiffness of various tissues partly indicate a constitutional trait.
Our data suggest that the associations are of considerable magnitude because a range of 2 SD in joint mobility would be equivalent to more than 7 mmHg diastolic blood pressure. Likewise, a range of 2 SD in skin extensibility would be associated with 6 mmHg of pulse pressure. These findings may contribute to a better understanding of the etiology of high blood pressure and interindividual differences in arterial wall characteristics.
We gratefully acknowledge Rian Eijsermans and Martine van Riessen for their support in the conduct of the study. We also acknowledge the children of the primary schools Het Spoor and Montessori in Zeist and their parents for their kind co-operation.
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Keywords:© 2003 Lippincott Williams & Wilkins, Inc.
blood pressure; pulse pressure; tissue stiffness