Article

Adjusting Therapy in Pulmonary Arterial Hypertension - The Role of Novel Echocardiographic Techniques

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Abstract

In theory, echocardiography allows an accurate measurement of pulmonary artery pressure, approximate right atrial pressure, cardiac output, right ventricular diastolic function and non-volumetric assessment of systolic function, as well as some insight into the structural alterations of right ventricular architecture. Unfortunately, the vast array of possible measures complicates distillation of the few parameters that provide reproducible prognostically important information. The modest reductions in afterload achieved with current therapies (<5mmHg on average) and the unpredictability of right ventricular response, coupled with the complexity of the populations treated, means that only large-scale survival studies should be considered when determining which parameters inform patient management. Of currently widely used measures, only tricuspid annular plane systolic excursion (TAPSE) and pericardial effusion are recommended when adjusting therapy. Increased use of contrast echo, strain rate imaging, vector velocity imaging and 3D echocardiography appear to hold most hope for the future; however, none as yet has the database to support inclusion into standard clinical practice.

Keywords

Contrast echocardiography, speckled tracking, strain rate imaging, vector velocity imaging, right ventricle,

Disclosure:The authors have no conflicts of interest to declare.

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DOI:https://doi.org/10.15420/ecr.2010.8.2.26

Correspondence Details:John G Coghlan, Department of Cardiology, Royal Free Hospital, Pond Street, London, NW3 2QG, UK. E: Gerry.Coghlan@royalfree.nhs.uk

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Goals in Pulmonary Arterial Hypertension Treatment

Pulmonary arterial hypertension (PAH) arises from pathological thickening, obstruction and constriction of the pulmonary arterioles.1 This leads to progressive elevation of pulmonary pressures initially on exertion, then at rest.2 Symptoms present late, often only when the pressures can rise little further and the cardiac output (CO) falls due to right ventricular (RV) overload.3 As the condition progresses towards the end stage, the right heart dilates and exhibits reduced function, resulting in clinical evidence of heart failure. With rare exceptions, current therapies yield modest reductions in pulmonary pressures, but by reducing pulmonary vascular resistance lead to significant increases in CO. The function and size of the right heart improves slightly and the clinical benefit is modest. As the gains in terms of RV function and pulmonary pressures are modest, techniques that focus on these aspects of cardiac function are relatively insensitive to the changes that are achieved with treatment.

The objectives of treatment have been outlined in the recent European Society of Cardiology and European Respiratory Society (ESC/ERS) guidelines. The domains identified are clinical (functional class 1 or 2, no blackouts, with no evidence of heart failure), exercise (six-minute maximum walking distance [6MWD] >500m, O2 consumption on exercise >15ml/kg/minute) and objective (normal N-terminal portion of proBNP [NTproBNP], tricuspid annular plane systolic elevation [TAPSE] >20mm, absence of pericardial effusion, right atrial pressure [RAP] <8mmHG, cardiac index >2.5l/minute). Failure to achieve these objectives is an indication to increase treatment.3 Therefore, at a simplistic level we already have echocardiographic criteria for adjusting PAH therapy. In reality, most patients do not achieve these goals, and there have been no randomised trials to demonstrate that goal-directed therapy improves survival or quality of life.

Ultimately, we require therapies that will reverse the haemodynamic process and normalise pulmonary artery pressure (PAP). Therefore, the ability to accurately measure PAP remains a pivotal goal for non-invasive tests. In addition, improving right ventricular function is an important secondary goal, thus reproducible and accurate assessment of RV systolic and diastolic function will eventually help to guide therapy.

Recent Echocardiographic Imaging Techniques
Contrast Echocardiography

Contrast echocardiography may be performed with agitated saline solution to improve the signal quality of Doppler flow recordings.4,5 Contrast echocardiography may also improve endocardial border detection and assessment of cavity sizes and function.6

Myocardial Doppler Velocity and Myocardial Isovolumic Acceleration

Myocardial motion is characterised by relatively low-velocity and high-amplitude signals. 2D images have good spatial resolution, whereas spectral Doppler and M-mode have the best temporal resolution.7,8 Myocardial velocities quantify global and regional left ventricular (LV) function independently of endocardial border delineation. Tissue Doppler echocardiography is an angle-dependent Doppler technique. Tethering by adjacent segments and in particular of the mitral valve annulus (annular calcification or prosthetic valves) may cause errors in assessment. These limitations also apply to tissue tracking. Complex fibre architecture, translation and rotation of the heart in the chest are common limitations to all cardiac imaging modalities. Deformation imaging can be obtained with Doppler and non-Doppler techniques.

The shape of a structure deforms during motion when different elements of the structure move with different velocities. Myocardial strain is the percentage of shortening or lengthening of a myocardial segment. Strain rate is the rate at which the myocardium shortens or lengthens.9 These modalities partially compensate for tethering of abnormal myocardial segments by adjacent normal segments and passive motion of the heart within the chest. Doppler strain is calculated as the spatial gradient between two velocities separated by a short distance (sample distance) within the myocardial wall. Systolic strain rate correlates more closely with invasive parameters, including peak elastance, than systolic tissue velocity in experiments.10 Doppler systolic strain rate and isovolumic myocardial acceleration are indices of global LV systolic performance that are less dependent on loading conditions. Myocardial acceleration during isovolumic contraction has been validated as a sensitive, non-invasive method of assessing left and RV performance.

The main limitations of Doppler strain and strain rate relate to reproducibility. Increasing region of interest (ROI) size, changing sample distance and very high frame rate >200 per second do not totally solve these problems. In theory, peak systolic strain rate is the best available parameter for measuring segmental function. However, Doppler strain rate curves are noisy. Doppler strain is obtained through integration of the strain rate signal; therefore, noisy strain rate signals may co-exist with a less noisy strain signal of questionable value. Doppler strain and strain rate are angle-dependent Doppler techniques and loading variations and myocardial stiffness are important determinants of myocardial deformation.

Speckle Tracking and Vector Velocity Imaging

Non-Doppler deformation imaging includes speckle tracking and vector velocity imaging. Speckle-tracking echocardiography (STE) enables an objective assessment of three myocardial deformation components: longitudinal, radial and circumferential, or torsion.11 Speckles are unique natural acoustic markers generated by the reflected ultrasound beam. The speckle pattern is unique for each myocardial region and is relatively stable throughout the cardiac cycle. The geometric position of speckles changes from frame to frame, and represents local tissue movement. These markers are tracked by calculating frame-to-frame changes using a sum of absolute difference algorithm. The displacement between speckles represents myocardial deformation (strain). Tracking a defined region of speckles allows the calculation of displacement velocity, strain and strain rate. An image frame rate recorded in conventional 2D mode may not be adequate for strain-rate calculations. Longitudinal parameters are obtained in apical views, while radial and circumferential parameters and torsion are obtained in short-axis views. Radial-strain measurements did not correlate well with sonomicrometry, demonstrated larger variability and have not been as extensively studied.11–13

STE is an angle-independent technique, as the movement of speckles can be followed in any direction.11,12 STE has better lateral resolution due to a higher density of scan lines on conventional echocardiography. STE also has better reproducibility as it does not require using an ROI. Limitations include poor image quality, which induces poor wall tracking, and the technique may not be reliable when the frame rate is <40 per second. Tracking problems at rapid heart rates (HRs) >120 per minute have been described.14 Other limitations include out-of-plane motion of speckles, drop-outs and insufficient temporal resolution. Although speckle-derived strain has been validated in various circumstances, this recent technique requires further supporting data. 3D speckle tracking is a step forward to achieve this goal.

Vector velocity imaging combines speckle tracking with border and annulus tracking while correcting for changes in RR periodicity. It could overcome some of the limitations associated with speckle tracking by utilising other features to maintain focus on the ROI. While some reduction in global function has been shown using this technique in one study of children with pulmonary hypertension, its true potential remains unexplored.15

3D Echocardiography

3D echocardiography includes full-volume, realtime 3D and 3D zoom. Acquisition is usually carried out over four to six cardiac cycles. Despite technical improvements, this technique remains mainly useful in patients with good images, which might explain why 3D echocardiography has not been widely used in clinical practice.16,17 LV ejection fraction (LVEF) and volume magnetic resonance imaging (MRI) data increase with 3D.18 Although these imaging modalities have been widely available for more than 10 years, they are not routinely used in many echo laboratories due to cumbersome image acquisition and to the expertise required for post-processing analysis and interpretation.

The Right Ventricle

The right ventricle is a difficult chamber to functionally assess because of its complex shape, thin walls, trabeculations, extreme load dependency and variable position within the chest during respiration and changes in body position and in response to dilation. The importance of the right ventricle is increasingly recognised, although our tools for assessing RV function remain crude. In patients with LV dysfunction, the presence of associated RV dysfunction is an independent predictor of mortality.19 In pulmonary hypertension, mortality is due to RV failure, and those in whom the right ventricle is well adapted to pressure work (Eisenmenger’s) survive much longer with similar or higher pressures than those with a normal right ventricle (idiopathic PAH [iPAH]), who in turn have a significantly better prognosis at higher pressures than those with RV replacement fibrosis (scleroderma).20 We appear to have reached the limit of current medical therapies in our ability to selectively reduce pulmonary pressures; however, we have evidence that not all therapies are equal in terms of the impact on RV function. Sildenafil appears to improve RV function, despite a similar impact on PAPs compared with bosentan.21

Assessing the RV contractile function and response over time requires not just the ability to measure volumes and rate of contraction, but also the ability to resolve the changing environment of the right ventricle. Concerns such as accurate determination of pre-load and afterload, including not just pulmonary vascular resistance but also pulmonary artery compliance relating to dynamic work required to distend proximal pulmonary arteries, and impedance (inertia of stored blood and vessel tone) arise. Given that 30–50% of RV work load is pulsatile, any technique that omits one of these components may fail to correctly determine the implications of changes observed in other parameters. Optimal evaluation of the RV therefore requires instantaneous assessment of RAP, systolic and diastolic PAPs, pulmonary artery distensibility, blood flow acceleration and volumetric changes (absolute volumes and rate of change of volume) through systole and diastole during the same beat.

Current Knowledge of Right Ventricular Changes in Response to Pulmonary Arterial Hypertension

The functional abnormalities of PAH are global RV hypokinesia, paradoxical movement of the interventricular septum associated with the leftward deviation of the interatrial septum, RV dysfunction (increased end-diastolic volume, increased end-systolic volume, increased mass, reduced ejection fraction [EF], reduced cardiac index, reduced stroke volume), pulmonary and tricuspid insufficiency, reduced flow velocity in the pulmonary artery and decreased systolic right coronary artery blood flow.

Despite the large number of observable changes on echocardiography, only Tei index,22 TAPSE, pericardial effusion23,24 and RA23 area have been shown to be independent predictors of outcome.

Assessing Right Ventricular Systolic Function

Realtime 3D echocardiography has the potential to provide correct volumetric analysis and prevent exclusion of the contribution of the RV outflow tract (RVOT), and, if combined with strain rate imaging, could provide a comprehensive assessment of RV volume, contraction and relaxation (see Figure 1). A good correlation between 3D echo and CMR for RV end-systolic and end-diastolic volumes and for RVEF has been shown.25 However, this technique is likely to suffer from the same limitations as MRI scanning. Trabeculation of the right ventricle prevents accurate assessment of end-systolic volumes in particular.26 Furthermore, the reduction in frame rate may render the thin RV free wall relatively difficult to clearly define, especially in patients with substantial wall movement associated with increased HR or CO. TAPSE is obtained by performing M-mode interrogation of the lateral tricuspid annulus as contraction in the longitudinal plane represents the dominant contribution to RV function. The impact of volume off-loading (tricuspid regurgitation [TR]) is not fully understood.27 TAPSE has been validated against MRI-assessed RVEF26 and in a single study and was able to predict prognosis in PAH;28 therefore, it has been included as a prognostic parameter in the ESC/ERS guidelines.

The S-wave of the lateral tricuspid annular velocity profile provides another method of assessing longitudinal free-wall movement.29 In a study from Meluzin et al.,29 30 control patients had much higher S-waves (15.5+2.6cm/second) compared with patients with impaired RV function on radionuclide scanning (10.3+2.6cm/second), but the correlation of this parameter with RVEF was less than optimal. An EF of 25% was associated with S-waves ranging from 5.5 to 11.7cm/second.

The Myocardial Performance Index (MPI) was developed by Tei, and relies on the idea that as function deteriorates, the proportion of systole occupied by isometric contraction and relaxation increases.30 In healthy people this is <0.3, and as function deteriorates the index rises. While an association between MPI and prognosis has been shown in patients with pulmonary hypertension to date, these have only been based on initial findings at diagnosis. MPI can be measured in only a proportion of patients.23 Tissue Doppler-based assessments are more readily interpreted31 and could lead to increased utility of this measurement. Doppler strain and strain rate are more sensitive than tissue Doppler imaging and conventional echo. It has been suggested that apical contraction is compromised early using strain-rate imaging in patients with PAH. Strain-rate imaging overcomes peristaltic contraction, which may influence global assessments.15,32,33 Limitations include direction dependency and the need for frame-by-frame quality assurance; therefore, this technique remains a research tool in patients with pulmonary hypertension.

Speckle Tracking and Vector Velocity Imaging

Global peak systolic strain may help detect RV dysfunction when conventional echo is normal.32 The thin wall of the right ventricle may render post-processing important as adjacent extracardiac stationary speckles may also be tracked (see Figure 2). The analysis of vector velocity data in each region could provide detailed information on regional changes in RV function early in the development of pulmonary hypertension (see Figure 3). Only one study in PAH using vector velocity imaging has been published to date.15

Assessing Right Ventricular Diastolic Function

The tricuspid free-wall isovolumetric relaxation time (IVRT), tricuspid lateral annular early diastolic velocity (E’) and tricuspid lateral annular IVRT differed significantly between the overweight and control children.34 As with the current controversy over the prevalence of diastolic heart failure, it would be essential to document the accuracy of abnormal findings against invasively determined diastolic dysfunction, or to show that observed changes were predictive of an adverse prognosis.

Assessing Loading Conditions

From the early 1980s, it has been possible to echocardiographically estimate pulmonary artery pressure using Doppler assessment of tricuspid velocity.35 Initial studies suggested that this was a highly accurate measure of pulmonary systolic pressure; however, these were unblinded studies.36,37 Attempts to define filling pressures using the jugular venous pressure or inferior vena cava collapse do not reliably improve the accuracy of estimation.

Subsequent studies have shown that in practice echocardiographic estimation correlates poorly with pulmonary pressures.38,39 Performing echocardiography within one hour of catheterisation, Fisher et al.39 found that the 95% confidence interval for patients with a mean systolic pressure of 62mmHg was ±38mmHg, and that a significant portion of this inaccuracy was due to attempts to estimate RA pressure using the IVC diameter variation. Intriguingly, they observed that pressures were generally overestimated where tracing quality was scored as good, and underestimated when the envelope was poorly defined.

In one study, as a result of the use of contrast echocardiography, an additional 15 of 38 patients were designated as having elevated pulmonary artery systolic pressure during stress echocardiography.40 However, while some of these results were assessed against invasive evaluation, it is evident from Fisher et al. that increased signal quality is not always associated with increased accuracy.39 The result is that while very abnormal velocity readings (>3.4m/second) have a high predictive value for pulmonary hypertension, the reproducibility is poor and velocity alone cannot be used to identify those who have responded to therapy even where this includes a significant reduction in pressures versus those whose pressures remain very elevated.41

Pulmonary regurgitant flow is used to estimate diastolic and mean PAP. Estimation of PAP diastolic pressure with TR flow has been described.42 Estimation of mean PAP with RVOT flow acceleration time has also been described and is dependent on CO, and is valid when HR is between 60 and 100bpm and when there are no intracardiac shunts.

Full haemodynamic assessment always includes CO and cardiac index calculations. In a similar way to invasive assessment, the average of five measurements must be obtained. Unfortunately, as with estimates of pulmonary systolic pressure, there are few data to suggest that echocardiographic estimates of CO are currently sufficiently reproducible to meet clinical need in the management of patients with PAH.39 Therefore, the problem in essence is that echocardiography can provide data on so many aspects of ventricular function and the haemodynamic loading to which the ventricle is exposed; however, clarifying which of these adds incremental information both at baseline and during therapy is difficult. Small studies with inadequate patient follow-up cannot inform the debate. As with pharmaceutical studies, it is time to move to adequately ‘blinded’ and powered studies of pre-defined parameters with survival as the agreed end-point.

Conclusion

No other technique has the capacity of echocardiography to measure as many of the relevant parameters required to describe the RV–pulmonary artery interaction. Nevertheless, even if all possible measures were accurate and reproducible, together they would not fully describe this interaction.

The real strengths of echocardiography lie in providing ongoing monitoring of RV structural and functional responses to the loads faced. Since the RV tolerance of the afterload demand is the main determinant of outcome in PAH, if we can define a limited number of parameters that change with changing prognosis, therapy of PAH can be adjusted using clinical assessment and echocardiography.

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