The prognosis and management of pediatric PH primarily depend on assessment of vasoreactivity.4,8
Conventionally, vasoreactivity has been measured by PVR, and recent work has shown the use of PVR with clinical challenge to predict outcomes in children with idiopathic PH.9
Although PVR provides valuable information, there are several important limitations to its exclusive use. First, PVR requires the use of invasive methods. We have recently introduced a novel noninvasive method of estimating PVR using ultrasound CMM flow propagation measurements,5
and so have made progress with this issue. Secondly, PVR is a steady-state parameter that measures opposition to continuous flow, thereby neglecting the dynamic and pulsatile nature of the pulmonary circulation.6,7
The dynamic nature of cardiac pumping requires a coordinated effort between ventricular work during systole and arterial work during diastole to most efficiently move blood into the peripheral vasculature over the cardiac cycle. Diastolic work by the proximal arteries depends strongly on proximal artery compliance. Neglecting this through the sole measurement of PVR produces an incomplete picture of right heart loading and efficiency of the pulmonary vasculature. When evaluating efficacy of treatments for primary PH or when determining reactivity of the pulmonary vasculature for presurgical planning in secondary PH, the addition of compliance evaluation should provide the most comprehensive means of quantifying right ventricular afterload and pulmonary vascular efficiency. Such an evaluation may be especially useful when coupled with currently used protocols for challenging the pulmonary vasculature using vasodilators because changes in proximal PA compliance with challenge would indicate that any potential stiffness of the artery under baseline conditions may be caused by the strain–stiffening effect that manifests at higher PA pressures than as a result of structural changes in wall properties (ie, true structural remodeling). Strain–stiffening of the artery may be relieved purely by decreasing mean PA pressure through a pulmonary vasodilator; conversely, structural remodeling of the wall will not reverse because of acutely lowered pressures. This may provide an additional means of sorting through the vagaries of hemodynamic response in these complex cases. We have recently reported on a novel parameter, reactivity in compliance, which should provide just such an assessment of strain–stiffening versus structural remodeling in the proximal pulmonary vasculature.1
However, the invasive nature of this method precludes it from being used for routine follow-up or evaluation of novel therapies. The current study extends this prior work to the noninvasive area, which we believe is an important advance. The potential to evaluate compliance and reactivity noninvasively promises the possibility of bedside evaluation of such patients, remote-site examination, and potentially decreased risks.
Noninvasive measures of arterial stiffness have been reported previously.10–15
These have focused on measures of changes in arterial area (pulsatility) or diameter (distensibility), or extraction of circumferential strain from such changes. We have shown use in CMM DTI for assessing PA pulsatility as well.16
The primary limitation of these methods is that they provide a measure of arterial deformation only without indication of the level of deforming force (pressure). In this regard, use of compliance, which includes pressure, should provide the best representation of the mechanical response of the arterial wall in the clinical situation. Deformation-only measures may be useful in situations where changes in function are to be determined, such as in reactivity testing, when an adequate TR jet may not be available.
The use of CMM DTI produces certain advantages when measuring diameter. Because CMM DTI has much better temporal resolution than conventional 2-dimensional imaging, it can track time-dependent changes in arterial motion to the same degree as conventional M-mode imaging. However, unlike conventional M-mode imaging, which only provides structural information, CMM DTI is most sensitive to arterial motion. By measuring wall velocity and then integrating to obtain local wall position, the method produces smoother diameter versus time traces than conventional M-mode, primarily because some sort of edge-detection method is needed to obtain instantaneous diameter using conventional M-mode. Such edge-detection methods are notorious in producing “jagged” edges, which require smoothing during postprocessing. Secondly, because wall velocity is instantaneous obtained, it can be used by itself for estimating the degree of arterial stiffening between PH and normotensive conditions, and thereby provides a quick method for assessing PA stiffness. These studies show peak wall velocities of approximately 4 cm/s for healthy control subjects; this decreases to 2.9 cm/s for patients with PH. Lastly, the capability of obtaining instantaneous diameter versus time data allows additional types of analyses, especially in the catheterization laboratory where associated pressure data can also be digitized simultaneously into the ultrasound scanner. For example, displays preliminary data showing diameter–pressure curves of the PA for a control subject and a patients with PH, obtained using a combination of the CMM DTI method and simultaneously digitized pressure data. Such types of analysis may be used when access to invasive data is available, as when studies are performed in the catheterization laboratory, and may provide an increased level of accuracy because the entire diameter–pressure curve can be used for analysis. However, it must be understood that CMM DTI poses several limitations as well, which we discuss briefly below.
Figure 8 Preliminary data showing diameter–pressure plots obtained using color M-mode Doppler tissue imaging (CMM DTI) and invasively measured pressure digitized simultaneously into ultrasound scanner for control subject and patient with pulmonary hypertension (more ...)
The use of the TR jet to obtain Cdyn is a necessary requirement, which should be applicable to the large majority of pediatric patients with PH, but that also produces limitations in the method. The most obvious limitation is the relatively small number of individuals with normal pulmonary hemodynamics who have an easily identifiable and measurable TR Doppler jet envelope. In our studies, 30 control subjects were initially selected; however, only 10 of these had a measurable TR Doppler envelope. In contrast, 27 of 30 patients with PH had measurable TR Doppler envelopes. The second limitation is that use of the TR jet velocity provides peak Ps only; ideally, both diastolic pressure and Ps are needed to capture true mechanical compliance. This may produce problems when using this method for patients with high peak pulmonary pressures but normal compliance, such as those with moderate to severe pulmonary regurgitation, where potentially higher TR jet velocities would cause a false decrease in Cdyn values and so indicate decreased compliance. Conversely, pulmonary regurgitation may also impose additional wall-motion changes; studying the true accuracy of this method in patients with PH would be warranted. The agreement between Cdyn measured invasively and that measured noninvasively was most likely increased by the large variability we see in Cdyn, especially for normal pulmonary dynamics. However, this issue is of less importance because the proposed approach for using Cdyn involves examination of changes (ie, reactivity) from a baseline value for a particular patient. Nevertheless, a wider study documenting variability in Cdyn for a spectrum of pressure and flow conditions (eg, high pressure, high flow; high pressure, low flow) is warranted.
The wide range of compliance values seen for the control subjects indicates the high degree of mechanical flexibility inherent in the upstream PAs. We have documented such variability in animal models of normotensive and hypertensive PAs using biomechanical testing coupled with sophisticated finite element analysis techniques,17
and believe the compliance capacity of these arteries is an essential feature of the normal pulmonary vasculature. Understanding the relationships between compliance and associate physiologic parameters such as age and body surface area would be of interest for future studies. Nevertheless, our study provides some guidance for clinical use of this method. When control subjects and patients with hypertension were grouped together, a threshold of 40% change/100 mm Hg for Cdyn
could be set as the change from normal compliance (values > 40) and stiff vessels (values < 40). Baseline evaluation of a patient can, thus, provide initial indication of whether the PAs have stiffened. Subsequent evaluation using vaso-dilator challenge would then indicate whether structural remodeling has taken place (nonreactive in compliance), or whether the artery is undergoing strain–stiffening (reactive in compliance). Based on our studies, the use of 40% change/100 mm Hg could be recommended as a threshold; cases where Cdyn
increases beyond 15% to 20% of the baseline value with vasodilator challenge would, thus, be classified as reactive in compliance. Note that the 40% value should be considered an initial proposal, and further studies to more extensively document the range of normal and hypertensive values for Cdyn
over a range of causes are needed to better guide ultimate clinical application.
Besides the limitations imposed by the TR jet measurement technique, there are other limitations that should be mentioned. We used the RPA for PA diameter measurements in place of the main PA. Several reasons underlie this choice. First, because both are functionally elastic arteries, they would be expected to have similar wall architecture, characterized predominantly by elastin lamellar layers in the medial layer and collagen reinforcement in the adventitia and, thus, similar mechanical response. Second, the RPA is well visualized by the suprasternal view (short or long axis) and this window has been used for evaluation of PA size and distensibility18
; it is far more difficult to obtain a view where the main PA runs perpendicular to the ultrasound beam line, a necessary requirement to ensure minimal angulation errors in the CMM DTI data. Third, the suprasternal view allows M-mode imaging to be performed, which has superior resolution to 2-dimensional echocardiography. Fourth, RPA diameter measurements have been used in prior angiographic studies evaluating PA distensibility and we wished to maintain continuity with prior work.19
Because of the study design, changes in arterial wall compliance could not be correlated with histologic changes such as those seen with IVUS; this requires further investigation. Of particular interest would be the time course of changes in PA compliance and wall histology after correction of cardiac defects associated with increased PA pressure, which may lead to a better understanding of the pathogenesis of pulmonary vascular disease. CMM DTI, being a spectral estimation technique similar to conventional color Doppler imaging, also has decreased spatial resolution when compared with conventional Doppler or traditional pulse echocardiographic amplitude imaging modalities. For example, the spectral estimation technique used in CMM DTI to obtain velocity is time-limited to allow rapid imaging, which may cause increased uncertainty in measuring wall velocity. Although the 5-millisecond temporal resolution of the method should be sufficient to track most wall-motion phenomena, it may still be incapable of tracking very rapid changes in wall motion. Likewise, the color Doppler method for measuring local velocity, which requires relatively larger pulse lengths and multiple pulses, decreases spatial resolution; still, the resultant spatial resolution obtained in our study (1.6–1.9 mm) should be sufficient to capture motion of the PA wall. Lastly, certain anesthetic agents may alter vascular tone during the catheterization. However, in these studies, the majority of the patients undergoing catheterization received a combination of sevoflurane, isoflurane, propofol, and remifentanyl. Patients received inhaled sevoflurane and isoflurane for induction and were maintained on intravenous propofol and remifentanyl during the procedure. The remaining patients received conscious sedation in the form of intravenous fentanyl. None of these agents should alter vascular tone.
We conclude the CMM DTI appears to be a promising noninvasive means of assessing pulmonary vascular compliance in patients with PH and should prove useful in examining reactivity in compliance as a subsequent parameter to PVR in evaluating and sorting these patients.