The current study demonstrates lower levels of BrachD in subjects who are male, overweight, have a higher BP, HR and increased fasting glucose or insulin concentrations even after controlling for PP. Analysis by BMI-Insulin group revealed that BrachD was lower in obese subjects. A trend was seen for decrease in BrachD with the addition of hyper-insulinemia to either BMI category. The magnitude of decrease in BrachD with adiposity was greater than the difference between normal and high insulin levels within the same BMI category. These data suggest that overweight may have a greater effect on vascular function than hyperinsulinemia and that the combination of excess adiposity and hyperinsulinemia will produce the greatest decline. In addition, regression models with PP as a covariate demonstrated that gender was also an important determinate of BrachD with fasting glucose retaining significance for subjects with a normal insulin level. HR was important for the overweight group. Thus, this cross-sectional study demonstrates that gender, obesity, BP, glucose level and hyperinsulinemia may provide individual contributions towards lower levels of vascular function in healthy adolescents and young adults.
Recently, Whincup et al reported a strong, graded, inverse relationship between brachial distensibility and DBP, adiposity, and fasting insulin in adolescents in the United Kingdom.[18
] Similar to the present study, an inverse relationship between BrachD and DBP was found in both genders. In contrast to the present study, Whincup did not find a relationship between BrachD and adiposity or fasting insulin when the group was stratified by gender. In addition, no relationship was seen between BrachD and SBP or fasting plasma glucose. There are a number of differences between the present study and Whincup’s report aside from the different methods employed, that may account for these discrepancies. We present data from a broader sampling of a healthy population versus contrasts between cohorts at low or high risk for adult CV disease. Our higher number of participants (969 vs. 383) offers greater power and use of only morning studies to control for circadian variation also support the validity of our observations while adding to the previously published results [18
Many investigations in adults have documented differences in vascular stiffness by gender. Male gender was found to be an independent determinant of pulse wave velocity, a measure of central arterial compliance[23
] and Young’s elastic pressure modulus, a measure of carotid stiffness.[24
] Studies of the muscular brachial artery in adults whether using the wall-tracker method[25
] or own technique,[5
] also demonstrate reduced distensibility of this artery in men. Estrogen may play a role in these gender differences since hormone replacement therapy in post-menopausal women improves arterial stiffness (reduced pulse wave velocity) independently of change in BP.[26
] Furthermore, in the limited data relating gender to arterial stiffness in pediatric subjects, girls were found to have greater distensibility of large arteries than boys but only after puberty had occurred.[27
] Our data extend these observations on gender differences in brachial artery properties by providing the largest number of measurements in adolescents to date. Furthermore, our method accounts for baseline brachial diameter in the calculation of distensibility thus decreasing the likelihood that the decline in BrachD seen in males is due to gender difference in arterial size.
Large studies in adults demonstrate increased carotid and aortic stiffness related to obesity even after adjustment for mean arterial pressure.[11
] Although few data are available in children, adiposity has been related to decreased brachial distensibility [18
] and lower carotid compliance in small studies of adolescents.[15
] Our findings on a larger population of youth confirm the adverse effects of obesity while emphasizing the greater effect of overweight as compared to hyperinsulinemia on the vascular properties of the brachial artery in the young.
The relationship between blood pressure and vascular stiffness is complex. Although decreased arterial compliance is associated with hypertension,[29
] whether the increased stiffness is the cause or the effect of the arterial pressure elevation is debated.[30
] Data supporting the role of arterial stiffness in the pathophysiology of hypertension include the observation that normotensive adults at genetic risk for hypertension have reduced brachial artery distensibility when measured via the same technique as employed in the current study.[31
] Furthermore, decreased arterial compliance at baseline was associated with increased SBP later in adulthood in a study that employed radial artery tonometry.[32
] Few data are available in children concerning the effect of blood pressure on vascular function. Brachio-radial pulse wave velocity was independently correlated with mean arterial pressure healthy children[33
] while carotid artery elasticity was reduced in children with hypertension.[34
] Our data provide additional observations demonstrating that reduction in brachial artery distensibility, a vascular territory less well studied in children, is associated with higher blood pressure levels at a young age independent of baseline PP and may indicate an increased risk for future development of clinical hypertension.
Insulin is known to affect autonomic tone.[35
] Therefore, it is not surprising that higher HR was found in our hyperinsulinemic group. However, an earlier study in adults using the same measurement device as used in the current study did not find HR to be a significant determinate of BrachD in multivariate modeling.[5
] Although studies using other techniques have demonstrated a relationship between HR and arterial stiffness in central and leg arteries,[36
], no relationship was found between sympathetic tone measured with heart rate variability and brachial distensibility in hypertensive adults[37
] or subjects with type 1 diabetes.[38
] One investigator suggested that sympathetic tone only impacted the brachial artery in the distal muscular rather than proximal elastic portion.[39
] Another explanation for this discrepancy may involve the wider distribution of normal HR values found in children. It is possible the effect of insulin on the more narrow range of adult HR is insufficient to change BrachD as our results suggest that insulin-mediated sympathetic stimulation of HR as found in obesity may indeed affect brachial artery stiffness in younger individuals.
Adults with glucose-intolerance demonstrate increased arterial stiffness with abnormalities in vascular function predicting adverse CV outcomes.[40
] Even “high normal” levels of fasting glucose are independently related to carotid stiffness[41
] and brachial distensibility.[5
] Furthermore, decreased aortic compliance has been found in non-diabetic adults with a family history of diabetes.[42
] Children with type 1 diabetes also demonstrate increased aortic augmentation index, a measure of large artery stiffness.[43
] However, the relationship between glucose levels and distensibility of the brachial artery in healthy youth and those with Type 2 diabetes or hyperinsulinemia has not been studied systematically. Similar to our findings, Whincup’s study of adolescents[18
] found decreased brachial distensibility with increasing insulin resistance, but no relationship with fasting glucose. However, our analyses went on to stratify subjects by insulin status. With this approach, we found our normo-insulinemic subjects had reduced brachial distensibility associated with higher fasting glucose levels even though they remained within the normal range. This suggests that glucose metabolism exerts a greater influence on distensibility in non-hyperinsulinemic, healthy youth.
In conclusion, gender, BMI, BP, HR, fasting plasma glucose concentration, and hyperinsulinemia have individual adverse effects on brachial artery distensibility in healthy adolescents and young adults. Defining the individual contributions and mechanisms by which each of these factors contributes to vascular dysfunction is required in order to develop targeted, effective strategies to prevent, reverse, or limit the development and progression of cardiovascular disease.