Vascular phenotype
It is increasingly recognised that differences in the pattern of hypertension is associated with differential mortality risk [
17]. Systolic and diastolic hypertension in young adults, which is associated with an elevated systemic vascular resistance, have been shown to be associated with the highest risk when compared to other patterns of hypertension such as isolated systolic hypertension [
17]. Thus, the pattern of hypertension is closely related to the vascular phenotype and may provide valuable prognostic information [
18].
In this study, the blood pressure phenotype in the three hypertension groups was slightly different, despite having similar systolic blood pressure. Specifically, the renal patients had higher diastolic blood pressure and mean blood pressure, while the essential hypertension group had greater pulse pressure. These findings are in keeping with previous large studies of blood pressure in these populations [
5,
19] and suggest differing vascular abnormalities. However, it is not possible to definitively characterize vascular phenotype using this information because of the important role of cardiac output in determining blood pressure. Therefore, we combined blood pressure measurements with cardiac MRI to assess cardiac output and calculate systemic vascular resistance and total arterial compliance. This allowed full characterization of vascular phenotype and ruled out the possibility that blood pressure differences were simply due to differences in cardiac output.
We demonstrated that hypertensive renal disease was associated with increased systemic vascular resistance, whilst essential hypertension was characterized by decreased total arterial compliance and ascending aortic compliance. Children with renovascular hypertension fell somewhere in between these two groups. These findings are in keeping with the blood pressure phenotypes of elevated pulse pressure in the essential hypertension patients and elevated mean blood pressure in the renal disease patients. However, it should be noted that this is a treated population and untreated children may have different or more marked vascular abnormalities. Consequently, extrapolating these findings may be premature, and further studies are required. Nevertheless, our findings suggest that treated children cannot be considered to have normal vascular phenotype.
Raised systemic vascular resistance is known to occur in renal parenchymal disease [
20] and possible causes include persistent abnormal renin-angiotensin stimulation [
21], sympathetic overdrive [
22] and reduced endothelial nitric oxide bioavailability [
23]. Conversely, reduced total arterial compliance and increased pulse pressure are recognised to be central to the development of essential hypertension [
24‐
26]. Our data further suggest that even after treatment, the essential hypertension children continue to have increased vessel stiffness.
Renal artery stenosis results in renal ischaemia, which in turn leads to wide-ranging maladaptive neurohumoral and vascular responses. Vasoconstriction is primarily mediated through renin-angiotensin-aldosterone axis activation and increased sympathetic activity in renovascular hypertension [
27,
28]. Thus, renovascular children would be expected to have significantly elevated systemic vascular resistance before invasive treatment [
27,
28].
Our results indicate that this does not completely normalize after therapy. Furthermore, the increased arterial stiffness in renovascular cases suggests that any abnormal vascular remodelling that may be the result of high pre-treatment blood pressure appears to persist despite successful therapy.
The fact that these treated patients continue to have raised blood pressure is important as even mildly elevated blood pressure confers additional cardiovascular risk, particularly in those burdened from a young age [
17]. Thus, further treatment escalation may be appropriate and better understanding of the underlying pathophysiology might help determine success. For instance, children with renal disease may benefit from more aggressive vasodilation with more use of calcium channel blockers. Conversely, essential hypertension patients may be better treated with newer therapies such as neprilysin inhibitors (e.g., Sacubitril/Valsartan) that target aortic stiffness [
18].
Cardiac phenotype
One of the major benefits of using MRI to assess these children is the ability to comprehensively evaluate the myocardial response to elevated blood pressure. In this study, conventional metrics of left ventricular systolic and diastolic function were normal. Furthermore, the left ventricular mass was not increased in the hypertension groups. The lack of significant changes in the left ventricular structure and global function is probably related to the fact that this was a treated population. However, we did find abnormal myocardial velocities with both radial peak systolic and early diastolic velocities being different amongst the groups. We also showed that radial peak systolic and early diastolic velocities correlated with measures of afterload, particularly systemic vascular resistance (peak systolic and early diastolic velocities) and diastolic blood pressure (early diastolic velocities). This is in keeping with the well-recognized association between afterload and both systolic and diastolic function [
29]. Interestingly, there were no group differences in radial peak systolic or early diastolic velocities in models adjusted for systemic vascular resistance (for peak systolic velocity) or diastolic blood pressure (for early diastolic velocity). This suggests that differences in myocardial velocities in the different groups of pediatric hypertension are at least partly explained by differences in vascular phenotype. However, our findings do not preclude direct myocardial disease in some of these patients (particularly the renal children) due to the small patient population.
There is also evidence from our study that radial early diastolic velocity correlates with radial peak systolic velocity. This is in keeping with the known association between systolic and diastolic function [
30], but did not explain group differences in radial early diastolic velocities. A surprising finding of this study was that patients with essential hypertension appeared to have higher longitudinal early diastolic velocities. We think this is due to the higher bulk motion of the heart in essential hypertension patients, rather than better myocardial relaxation. Although it is possible to correct for radial bulk motion using short axis tissue phase mapping, it is not possible to correct for longitudinal bulk motion. This is a limitation of this technique and in the future, four-chamber or long axis approaches should be considered.
Limitations
The main limitation of this study is the small number of patients in each group. The main reason for the small numbers was the difficulty in recruiting renal artery stenosis patients. Renal artery stenosis is a relatively rare condition and may be associated with other comorbidities. As other conditions such as significant midaortic syndrome may have potential confounding effects, it was important that only a “pure” population of renal artery stenosis was included in the study. Hence, it was not possible to recruit a larger number of renal artery stenosis children from a single-centre study. However, in spite of that, we were able to demonstrate significant differences in cardiovascular structure and function among the groups using MRI. Nevertheless, larger multicentre studies are required to properly confirm our results. The relatively small study numbers also precluded the inclusion of additional potential confounding factors into the ANOVA models such as differences in hypertensive treatment and the length of treatment among the groups. Variation in current medication therapy may contribute to differences in vascular phenotype among the groups. Future studies will need to consider multicentre recruitment to increase the power of the study population to adjust for the potential effects of different hypertensive treatment.
Another important limitation was that the majority of patients were being actively treated with anti-hypertensive medication. This was because of difficulties in recruiting patients before they began therapy. In particular, most patients were referred to our center having already been diagnosed with hypertension and started on therapy. This also made it difficult to ascertain the length of diagnosis and therapy. Thus, we cannot make firm conclusions about the differences in cardiac and vascular phenotype in treatment-naïve patients or the response to treatment in the different groups. In particular, we are not powered to investigate the effect of length of treatment on vascular or cardiac phenotype. Nonetheless, we were able to demonstrate persistent vascular changes associated with renal disease and hypertension despite optimal clinical treatment in this population. Future studies should consider a prospective evaluation of the effects of anti-hypertensive therapy in treatment-naïve children, including investigation of the time course of any improvements.
A final limitation is that the supine resting position may also be associated with elevated systemic vascular resistance [
31]. However, as the method for systemic vascular resistance assessment was applied identically across the entire study cohort, the intergroup differences demonstrated in the study are likely to be significant.