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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

How should we assess right ventricular function in 2008?

J.G. Coghlan1,* and J. Davar2

1 FRCP Department of Cardiology, Royal Free Hospital
2 MRCP Department of Cardiology, Royal Free Hospital

* Corresponding author. E-mail address: Gerry.Coghlan{at}royalfree.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Assessment of patients with...
 Tools for assessing right...
 Conclusion
 References
 
The right ventricle is neglected in clinical practice, both because it is difficult to assess and because there is a lack of awareness of the pivotal role it plays in cardiac and pulmonary vascular diseases. Substantial progress is now being made and methods of assessing right ventricular function are beginning to be standardised and evaluated systematically in clinical studies. Clinicians need simple reproducible tests of right ventricular function to improve their management of pulmonary hypertension, carcinoid heart disease, congenital heart disease and left heart failure. Academics require robust methods of analysing the contribution of right ventricular myocardial failure to the clinical syndrome of cor-pulmonale and heart failure, so that the pathobiological processes can be resolved and optimal therapeutic approaches identified to support and improve right ventricular function in these conditions.

While awaiting such developments we must recognise that current measures in clinical usage (right atrial area, right ventricular diameters, change in fractional area and right ventricular ejection times) give helpful if incomplete information, and should form part of standard echocardiographic assessment. Clinicians should also be aware of the progress in the fields of wall stress and strain rate imaging as these may well be validated in the near future. MRI is already well recognised as the imaging technique of choice for right ventricular dysplasia and will certainly deliver to the clinician accurate assessment of right ventricular ejection fraction, mass and identification of areas of localised myocardial damage before long.

Key Words: End systolic elastance • Right ventricular wall stress • Mean normalised systolic ejection rate (MNSER) • Magnetic resonance imaging (MRI) • Combinable magnetic resonance (CMR) • Brain natriuetic peptide (BNP)


   Introduction
Top
 Abstract
 Introduction
Assessment of patients with...
 Tools for assessing right...
 Conclusion
 References
 
Right ventricular (RV) function is the primary determinant of prognosis and effort tolerance in many groups of patients. Clinicians require measures that are widely available, easily obtained, highly reproducible, and provide clear information on prognosis, likely response to therapy or provide feedback on the success of therapeutic interventions. However, RV function is notoriously difficult to evaluate, given its geometry, inter-relationship with the left ventricle, and sensitivity to alterations in pulmonary pressure.

In patients with left ventricular (LV) failure, myocardial infarction, congenital heart disease, and pulmonary hypertension, RV function is an important predictor of mortality and quality of life.1 In the setting of myocardial infarction, echocardiographic assessment of RV function is sufficient to provide useful information on prognosis.2 While it is generally held that impaired RV function contributes significantly to the morbidity and mortality, for example, in congenital heart disease, providing unequivocal supportive data are difficult.3 Thus, in many congenital heart disease patients, the state of the right ventricle is almost certain to be the pre-eminent determinant of quality of life; however, the development of therapies to address their problems is hampered by lack of information on RV function.4

Were we able to assess RV function readily, we could determine whether compensatory mechanisms are being utilized to maintain cardiac output, whether such mechanisms have been exhausted, and investigate therapeutic regimes that support RV function despite an increased workload. We could predict prognosis more accurately, refine transplant waiting lists, and avoid surgery in patients likely to be harmed by the procedure. In addition, we could tailor medical therapy for patients with pulmonary arterial hypertension (PAH), hypoxic lung disease, and left heart failure. Thus, it is easily demonstrable that it would be helpful to know the state of the right ventricle in quite a sizable population of patients, and if we had a simple method of providing this information, clinicians would rapidly incorporate such techniques to inform their discussions on prognosis, and to guide their treatment choice.

Measures such as ejection fraction (EF) or end-systolic volumes are easily understood by clinicians, and we have pre-conceived ideas of how we should interpret such data. End-systolic elastance has been a foreign language to most clinicians; fortunately, the need to improve our understanding of the left ventricle to support the biventricular pacing industry has moved the argument forward, and thus, for many clinicians, ventricular dyschrony and strain rate5 are comfortable concepts, providing a rational basis for moving towards more meaningful measures of RV function.

In this paper, we shall describe the measures that relate directly or indirectly to RV function that currently deserve a place in routine practice, on the basis of widespread availability, agreed standards for performance, interpretation (where possible), and evidence for correlation with outcome. Then, we shall consider tools that have the potential to play a significant role in RV assessment in the near future.


   Assessment of patients with right ventricular impairment
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 Abstract
 Introduction
 Assessment of patients with...
Tools for assessing right...
 Conclusion
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We assess right atrial pressure, RV end-diastolic pressure, cardiac index, pulmonary pressure, and mixed venous oxygen consumption haemodynamically. Using exercise, we assess the 6 min walking distance (6MWD) and cardiopulmonary exercise tests, and we assess tricuspid gradient, pericardial effusions, LV eccentricity index (EI), RV ejection time, the Tei index, right atrial area, tricuspid regurgitant volume/area, RV diameters, change in fractional area, and estimated cardiac output echocardiographically. Many other measures have been proposed and given variable results. Magnetic resonance imaging (MRI) gives us EF and volumes, as well as stroke volumes and cardiac output, but not presently in clinically available packages. Finally, more recently neurohormonal markers of ventricular dysfunction have given practical, if non-specific, measures of the degree of RV stretch or cellular damage.

None of the measures in current clinical practice provide uncontaminated information on either systolic or diastolic function. Their use is justified on the basis of the predictive information provided. Pulmonary artery pressure is uniformly measured in patients with PAH, although we know that there is an inconsistent relationship between pressures, effort tolerance, and prognosis. In patients with Eisenmenger’s syndrome, we find a favourable prognosis despite higher pressures than idiopathic PAH,6 whereas in patients with systemic sclerosis7 and sickle cell anaemia8 we find a more adverse prognosis at lower pressures. Another drawback of using pulmonary artery pressure as a guide to management is that the impact of drug therapy on effort tolerance and prognosis is disproportionate to the impact on pulmonary pressures.9,10 Pulmonary artery pressure remains pivotal, because one cannot get away from the simple observation that the primary cause of death in PAH patients is RV failure caused directly and indirectly by the elevated pulmonary pressures.11 Any therapeutic manoeuvre that reduces pulmonary pressure close to normal while maintaining cardiac output and blood oxygenation will ultimately permit reasonable RV recovery, as seen in lung transplantation,12 pulmonary endarterectomy,13 and the small proportion of patients who normalize pressures on drug therapy.11 Although the improvement in exercise capacity in patients treated with epoprostanol has not been shown to relate to resting mean pulmonary artery pressure, it is related to a reduced rate of rise of pulmonary pressure with exercise, facilitating an increase in pulmonary blood flow with exercise.14 Yet, despite its pivotal role, pulmonary artery pressure gives us little more information on RV function than systemic pressure tells us about LV function.

Validated correlates of survival in PAH are invasively determined right atrial pressure, mixed venous oxygen saturation and cardiac index,15 6MWD at baseline and absolute level at 3 months,16 VO2max,17 the presence of pericardial effusion, LV EI, right atrial area on echocardiography18 and serum brain natriuretic peptide (BNP) or N-terminal prohormone brain natriuretic peptide (NTproBNP) levels at baseline, and direction and magnitude of change on during follow up.19,20 None of these measure RV function, but all depend on the RV function in these patient population and this is the common factor that explains their predictive value. It is probable that the prognostic accuracy of any of these measures depends on the degree to which changes are dependent only on variations in RV function, and how much is noise, e.g. changes in cardiac output with anxiety during catheterization. Further, those measures that are performed at rest relate very poorly to effort limitation, which is the dominant issue in terms of quality of life from the patient’s perspective.

In contrast, measures that do not depend on RV function, such as pulmonary artery pressure and pulmonary vascular resistance, are poor predictors of survival, even though afterload is the dominant cause of RV failure. It appears that there is a threshold level of afterload beyond which RV response becomes the main determinant of survival and quality of life.

Other proposed measures of RV systolic and diastolic functions that have been explored, but not yet in routine clinical use, include right ventricular ejection fraction (RVEF) and RV wall stress,21 Tei index,22 tricuspid annular plane systolic excursion (TAPSE; a measurement of systolic elevation of tricuspid annular plane),23 tricuspid deceleration duration, E/E' ratio, and tricuspid annular velocity. In some of these cases, the amount of work done to date is small and one cannot make any conclusion on their potential value in the future. In others, studies have given conflicting results, suggesting that either for technical or more fundamental reasons, these measures are unlikely to contribute to our measures in the near future. The latter group would include the Tei index and TAPSE; the former is difficult to perform in many patients24 and does not reliably correlate with clinical improvement,25 the latter gives conflicting results despite an ability to perform the assessment in most patients suggesting that improvements in technology will not resolve the confounding issues.26


   Tools for assessing right ventricular function
Top
 Abstract
 Introduction
 Assessment of patients with...
 Tools for assessing right...
Conclusion
 References
 
Methods proposed for assessing RV function include echocardiography, MRI, intermittent haemodynamic monitoring, implantable haemodynamic monitors, nuclear medicine, natriuretic peptide levels, as well as indirect measures such as cardiopulmonary exercise testing.

Echocardiography
The presence and size of pericardial effusion has long been recognized as an adverse prognostic finding in PAH,18,27,28 this is an end-stage finding, occurring when the right heart has failed. The degree of septal shift in diastole29 and its correlate, EI,24 has also been found to correlate with outcome and to improve with effective therapy. This has not, however, been a consistent finding.18,27 Recently, septal deformation has been shown to simply reflect the presence of a ≥5 mmHg elevation of RV pressure over LV pressure, and thus is a marker of advanced disease where RV pressure is substantially raised. The maximal septal deformation occurs during the isovolumic relaxation period, in patients with markedly elevated RV systolic pressures (~70 mmHg) and delayed RV relaxation.30

The majority of the proposed methods of echocardiographic assessment of RV function are based on volumetric approximations of the RV. Such approaches have inherent limitations, first as volume-related measures such as EF are load dependent, second because of the complex geometry of the RV.31

The issue of RV geometry is usually overcome using geometry-independent parameters such as tricuspid annular velocity and the Tei index. Tricuspid annulus velocity assessed by Doppler has been shown to correlate closely with radionuclide ventriculography-assessed RVEF, with systolic annular velocity of <11.5 cm/s having sensitivity of 90% and specificity of 85% for predicting RVEF of <45%.32 TAPSE is a simple and easily obtained measurement with reasonable correlation with radionuclide EF33 and MRI-derived volumes.34 Although simple to perform, assessments that depend on tricuspid annular excursion have inherent limitations as independent measures of RV systolic function.26

Another useful geometry-independent method is the RV myocardial performance index (RV MPI) calculated using Doppler as the ratio of the isovolumic contraction and relaxation times to the ejection time. The clinical value of this technique has been demonstrated in 77 patients with advanced heart failure selected for cardiac resychronization therapy. Patients in the highest tercile had 3.3-fold increased risk of an adverse outcome (95% CI, 1.3–8.5). In the same study, each 0.1 unit increase in RV MPI was associated with a 16% increase in risk (95% CI, 8–26) of adverse events.35 However, calculation of the parameter is not always feasible.24

The development of 3D echocardiography promises reliable assessment of volumetric parameters even of such an complex chamber as RV. However, both short-axis summation method and, recently, longitudinal axial plane method have also been shown to be accurate for the assessment of RV volume.34 Furthermore, in a recent study, real-time 3D echo estimates of RV volume and RVEF showed only moderate correlation with MRI measures of these parameters, and the correlation was not improved by contrast-enhanced 3D echocardiography using Sonovue.36

While utilizing the above methods in evaluating ventricular performance (left or right), it is essential to take into account loading conditions so as to distinguish between contractile function and pump function.37 In the left ventricle, the relationship between rate-corrected mean velocity of circumferential fibre shortening and systolic wall stress has been shown to be independent of heart rate, preload, and afterload.38

Joyce et al.39 used the same concept to evaluate the relationship between peak systolic wall stress in RV and mean normalized systolic ejection rate (MNSER) in patients with isolated ASD II (volume overload), pulmonic stenosis (pressure overload), and normal subjects. Over a wide range of loading conditions, it was shown that increases in peak systolic wall stress cause an incremental slowing of MNSER corrected for heart rate. If further studies confirm that this is an independent measure of RV contractility, then it may represent the first clinically useful measure of this parameter.

Another promising tool for RV assessment is strain rate assessment but, at present, data are scarce and variability of the results are too high to rely on this method.40

Magnetic resonance imaging
Magnetic resonance imaging yields high-quality images of the right ventricle and pulmonary arteries, 3D reconstruction of this complex system is achievable, and flow velocities are readily assessed. However, even with this ostensibly ‘perfect’ technique, interpretation of RV parameters should be—age, gender, and BSA—normalized in order to determine normality or severity of abnormality.41 Estimates of pulmonary pressure can be derived from pulmonary artery distensibility, but the inability to measure pressure directly and limitations in respect of lung parenchymal imaging mean that this will never be a stand-alone imaging technique.

Magnetic resonance imaging is already the imaging technique of choice for the evaluation of arrhythmogenic RV dysplasia. This is of special relevance to those caring for patient with pulmonary hypertension, as this condition is associated with impaired contraction of and dilation of the right ventricle in the absence of increased pulmonary pressure.42

In the setting of pulmonary hypertension, combinable magnetic resonance (CMR) shows increased RV mass43 and volume indices,44 as well as reduced LVEF/RVEF,44 compared with healthy volunteers. Following these preliminary studies, Saba et al.45 found that a ventricular mass index of >0.6 (RV mass divided by LV mass) had a sensitivity of 84% and specificity of 74% for the detection of pulmonary hypertension, albeit in a relatively small study of 26 patients. Despite these encouraging findings, MR still has no role in establishing the diagnosis of pulmonary hypertension, as exemplified by the findings of Roeleveld et al.46 In 44 patients with proven pulmonary hypertension, none of the currently proposed methods for assessing pulmonary pressures perform well compared with direct pressure measurement (pulse wave velocity, cross-sectional area of the pulmonary artery, acceleration time, acceleration time/ejection time, and ventricular mass index).

While diagnosis may be beyond the scope of MRI at present, there is much greater potential for this technique, in terms of monitoring the impact of therapy. A recent study in 25 patients with chronic obstructive pulmonary disease suggests that RV mass increases before baseline pulmonary pressure increases or RVEF decreases.47 However, the association reported was not an increase in mass in absolute terms but rather mass divided by RV diastolic volume. Further work is required to confirm these findings. Wilkins et al.48 have recently used MR scanning in patients treated with sildenafil in addition to conventional therapy. They demonstrated a modest reduction in RV mass (–8.8 g; 95% CI, –2 to –16). Greater changes were observed in BNP and 6MWD, thus MRI in this study was less sensitive to the short-term therapeutic response than other available measures. Long-term studies will be required to see whether the MR changes correlate better with outcome, however, in 13 matched patients treated with bosentan, despite similar haemodynamic and 6MWD response no such reduction in RV mass was demonstrated. The long-term follow-up data available to date do not suggest that sildenafil is associated with a superior prognostic impact compared with bosentan,49,50 hence, at present, it is unclear whether the observed difference in MRI responses to the two agents has any clinical significance.

In contrast to the limited scope for MRI in the clinical management of pulmonary hypertension to date, this technique has already contributed significantly to our understanding of the adaptive changes observed in patients with pulmonary hypertension.

Patients with pulmonary fibrosis in the setting of collagen vascular disease have been shown to have impaired RV diastolic dysfunction, but preserved LV diastolic function using CMR.51 Kuehne et al.52 have combined CMR and invasive pressure measurement techniques to derive RV pressure volume loops. In a study of six patients without severe symptoms, because of pulmonary hypertension, they were found to have increased RV contractility, but reduced RV and LV stroke volumes. Delayed contrast hyper-enhancement of the RV insertion points to the septum and extending into the septum as septal bowing appears53 has also been described in patients with increasing severity of pulmonary hypertension.

Taken together, these findings suggest that abnormalities of RV function appear early in the setting of pressure overload. Diastolic dysfunction occurs first followed by increased contractility and hypertrophy followed by muscle damage and possibly fibrotic change.

Serum markers
Many small trials have now been published demonstrating the usefulness of BNP or NTproBNP in monitoring the response to therapy of PAH,54–58 CTEPH,59,60 acute pulmonary embolic disease,61 and even hypoxic ling disease.62 The potential of natriuretic peptides in assessing and monitoring the impact of therapies on RV stretch is not surprising as they are released in response to pressure and volume overload of the right ventricle.63 Most trials, to date, are observational, but they consistently demonstrate that falling levels during treatment or follow-up are associated with improved haemodynamics55,57,59,60 and survival55,56,62 while the converse is found with increasing levels. The threshold determined for the diagnosis of RV strain varies with the population and from study to study56,61,62, but is generally lower than the levels recommended for the diagnosis of left heart failure if one is aiming for high sensitivity, and higher than the recommended if the aim is specificity. In addition, the level associated with a poor outcome at diagnosis or after initial treatment varies among studies.55–57 To date, no large prospective trial had been completed evaluating the role of BNP or NTproBNP specifically addressing either of these questions in a homogenous population.

From the trials published to date, there is sufficient data to recommend that all patients with PAH should have regular monitoring of BNP or NTproBNP, and that one of the aims of therapy should be to achieve near normal levels where possible. Further, the reduction in natriuretic peptide levels should be included as a secondary end point in future drug trials. What we do not yet know are the precise prognostic implications of failing to achieve low natriuretic peptide levels, and whether one should augment therapy on the basis of this finding alone.

Troponin is released from damaged myocytes, and is now the cardiac enzyme of choice for diagnosing myocardial infarction.64 Troponin is also released in acute cardiac failure65 and pulmonary embolism.66 It is hardly surprising that the release in patients with advanced pulmonary hypertension has been associated with a particularly adverse prognosis,58 unfortunately, to date, only one study has assessed the importance of this marker. Intriguingly, in this trial, norepinephrine and epinephrine levels fared rather poorly as markers of haemodynamic deterioration or death.

Exercise assessment of the right ventricle
Ideally, one would assess RV function during exercise, as the preservation of contractile reserve cannot be measured at rest. As with LV systolic dysfunction, improvement during exercise confers a better prognosis and effort tolerance. Three-dimensional assessment of RV contractile function is difficult enough at rest, similarly complex measures such as the Tei index are not possible in most patients during exercise. In every day practice, the only available measure during exercise is the tricuspid gradient67 and the change in pressure during exercise has not yet been correlated with clinical outcome.

Cardiopulmonary exercise testing provides many measures, the VO2max in particular correlates well with prognosis and quality of life. In expert hands, this is a reproducible technique but differences between centres, mean that in studies such as the STRIDE 1 inter-observer variability gave inconsistent results.68 Until there is improved standardization, this technique gives information unique to the unit performing the test.

The 6MWD correlates roughly (r=0.6) with the VO2max even in the best hands only when age and body mass is taken into account.69 Thus, it is probably not a measure of the anaerobic threshold but rather a measure of the best sustainable aerobic performance.70 In advanced pulmonary hypertension, RV contractile reserve is the dominant determinant of maximal cardiac output during exercise. Thus, for any individual, all other factors being equal (arthritis, leg ulceration, and training effects), the direction and magnitude of change of 6MWD should correlate with changes in RV contractile reserve. In this context, it is difficult to understand why changes in 6MWD in response to therapy do not correlate with survival.16 One possible explanation is that contractile reserve underpins the effort tolerance and other factors in determining myocyte survival.

Finally, the response of BNP levels to exercise in patients with RV dysfunction has not been published. However, BNP release with exercise behaves inconsistently in patients with left heart failure,71 so it is not clear whether this is a avenue worth pursuing.


   Conclusion
Top
 Abstract
 Introduction
 Assessment of patients with...
 Tools for assessing right...
 Conclusion
References
 
Accurate evaluation of RV function is essential for developing logical patient-centred strategies in pulmonary hypertension and other conditions such as tricuspid valve surgery for carcinoid. Six-minute walk distance, 2D and Doppler echocardiography, and invasive haemodynamics, despite their obvious limitations, remain the cornerstone of RV assessment at present. The role of MRI and CMR is increasing rapidly, but standardization of measures and normal values require further work. Natriuretic peptides have been adopted, despite the absence of adequately designed prospective studies because of the consistency of the results published to date and their relative ease of use. Considerable efforts to make progress in this important field are required over the next few years. The contributors to this supplement show the way forward in each area, and outline how the various tools at our disposal will develop to meet this challenge.

Conflict of interest: JG Coghlan does consultancy work for Actelion, Encysive, and has received educational grants and support for staff from both. He undertakes lectures for Actelion, Encysive, Pfizer, and GSK.

J Davar Provides consultancy services for TomTec and Acuson.


   References
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L. P. Badano, C. Ginghina, J. Easaw, D. Muraru, M. T. Grillo, P. Lancellotti, B. Pinamonti, G. Coghlan, M. P. Marra, B. A. Popescu, et al.
Right ventricle in pulmonary arterial hypertension: haemodynamics, structural changes, imaging, and proposal of a study protocol aimed to assess remodelling and treatment effects
Eur J Echocardiogr, October 7, 2009; (2009) jep152v1.
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