Right Ventricular Imaging for Predicting Risk in Pulmonary Arterial Hypertension: The Elephant in the Room

FOR RELATED ARTICLE, SEE PAGE 1232Pulmonary arterial hypertension (PAH) remains a fatal disease. In a recent analysis from the Pulmonary Hypertension Association registry, the 1-, 2-, and 3-year mortality in patients with PAH was 8%, 16%, and 21%, respectively.1Chang K.Y. Duval S. Badesch D.B. et al.Mortality in pulmonary arterial hypertension in the modern era: early insights from the Pulmonary Hypertension Association Registry.J Am Heart Assoc. 2022; 11e024969Crossref Scopus (22) Google Scholar Patients in the intermediate- and high-risk categories have a significantly higher mortality compared with patients in the low-risk category.1Chang K.Y. Duval S. Badesch D.B. et al.Mortality in pulmonary arterial hypertension in the modern era: early insights from the Pulmonary Hypertension Association Registry.J Am Heart Assoc. 2022; 11e024969Crossref Scopus (22) Google Scholar Current guidelines recommend risk stratification every 3 to 6 months and aggressive up-titration of PAH-specific medical therapy as needed to achieve a low-risk status.2Humbert M. Kovacs G. Hoeper M.M. et al.2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2022; 43: 3618-3731Crossref PubMed Scopus (237) Google Scholar Thus, risk stratification has taken center stage in the management of PAH. FOR RELATED ARTICLE, SEE PAGE 1232 Several multiparametric scores are available for assessing risk in patients with PAH.3Hoeper M.M. Kramer T. Pan Z. et al.Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model.Eur Respir J. 2017; 50Crossref Scopus (400) Google Scholar, 4Benza R.L. Gomberg-Maitland M. Elliott C.G. et al.Predicting survival in patients with pulmonary arterial hypertension: the REVEAL Risk Score Calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies.Chest. 2019; 156: 323-337Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 5Boucly A. Weatherald J. Savale L. et al.Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension.Eur Respir J. 2017; 501700889Crossref Scopus (431) Google Scholar All these risk scores, directly or indirectly, evaluate the status of right ventricular function, which is the major determinant of survival in patients with PAH.6van de Veerdonk M.C. Kind T. Marcus J.T. et al.Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.J Am Coll Cardiol. 2011; 58: 2511-2519Crossref PubMed Scopus (614) Google Scholar To achieve this, the risk scores rely predominantly on invasive hemodynamic markers of right heart function, including cardiac output, mixed venous oxygen saturation, and right atrial pressures.3Hoeper M.M. Kramer T. Pan Z. et al.Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model.Eur Respir J. 2017; 50Crossref Scopus (400) Google Scholar, 4Benza R.L. Gomberg-Maitland M. Elliott C.G. et al.Predicting survival in patients with pulmonary arterial hypertension: the REVEAL Risk Score Calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies.Chest. 2019; 156: 323-337Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 5Boucly A. Weatherald J. Savale L. et al.Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension.Eur Respir J. 2017; 501700889Crossref Scopus (431) Google Scholar They also include indirect noninvasive surrogates of right ventricular function such as functional class, exercise capacity, and serum N-terminal pro brain natriuretic peptide level.3Hoeper M.M. Kramer T. Pan Z. et al.Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model.Eur Respir J. 2017; 50Crossref Scopus (400) Google Scholar, 4Benza R.L. Gomberg-Maitland M. Elliott C.G. et al.Predicting survival in patients with pulmonary arterial hypertension: the REVEAL Risk Score Calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies.Chest. 2019; 156: 323-337Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 5Boucly A. Weatherald J. Savale L. et al.Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension.Eur Respir J. 2017; 501700889Crossref Scopus (431) Google Scholar Risk scores based only on noninvasive surrogate measures of right ventricular function have been proposed and validated.7Boucly A. Weatherald J. Savale L. et al.External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry.Eur Respir J. 2022; 592102419Crossref Scopus (23) Google Scholar, 8Hoeper M.M. Pausch C. Olsson K.M. et al.COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension.Eur Respir J. 2022; 602102311Crossref Scopus (44) Google Scholar, 9Benza R.L. Kanwar M.K. Raina A. et al.Development and validation of an abridged version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for use in patients with pulmonary arterial hypertension.Chest. 2021; 159: 337-346Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar The elephant in the room in risk stratifying PAH patients, is the direct assessment of the structure and function of the right ventricle, using echocardiography or cardiac MRI. Echocardiographic assessment of the right ventricle is routinely obtained in every patient with PAH at the time of diagnosis and during follow-up,2Humbert M. Kovacs G. Hoeper M.M. et al.2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2022; 43: 3618-3731Crossref PubMed Scopus (237) Google Scholar and right ventricular function is strongly associated with mortality.10Forfia P.R. Fisher M.R. Mathai S.C. et al.Tricuspid annular displacement predicts survival in pulmonary hypertension.Am J Respir Crit Care Med. 2006; 174: 1034-1041Crossref PubMed Scopus (812) Google Scholar,11Tello K. Wan J. Dalmer A. et al.Validation of the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio for the assessment of right ventricular-arterial coupling in severe pulmonary hypertension.Circ Cardiovasc Imaging. 2019; 12e009047Crossref Scopus (167) Google Scholar Patients have better outcomes when the right ventricle is able to compensate for a given degree of afterload in the pulmonary circulation.12Hsu S. Simpson C.E. Houston B.A. et al.Multi-beat right ventricular-arterial coupling predicts clinical worsening in pulmonary arterial hypertension.J Am Heart Assoc. 2020; 9e016031Crossref Scopus (30) Google Scholar Ironically, despite its availability and prognostic importance, echocardiographic assessment of the right ventricle is not included in any of the currently available risk prediction models.3Hoeper M.M. Kramer T. Pan Z. et al.Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model.Eur Respir J. 2017; 50Crossref Scopus (400) Google Scholar, 4Benza R.L. Gomberg-Maitland M. Elliott C.G. et al.Predicting survival in patients with pulmonary arterial hypertension: the REVEAL Risk Score Calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies.Chest. 2019; 156: 323-337Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 5Boucly A. Weatherald J. Savale L. et al.Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension.Eur Respir J. 2017; 501700889Crossref Scopus (431) Google Scholar,8Hoeper M.M. Pausch C. Olsson K.M. et al.COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension.Eur Respir J. 2022; 602102311Crossref Scopus (44) Google Scholar,9Benza R.L. Kanwar M.K. Raina A. et al.Development and validation of an abridged version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for use in patients with pulmonary arterial hypertension.Chest. 2021; 159: 337-346Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar A risk score that includes direct, noninvasive assessment of the right ventricular structure and function will be a useful prognostic tool. To address this knowledge gap, in this issue of CHEST, El-Kersh and colleagues13El-Kersh K. Zhao C. Elliott G. et al.Derivation of a risk score (REVEAL-ECHO) based on echocardiographic parameters of patients with pulmonary arterial hypertension.Chest. 2023; 163: 1232-1244Abstract Full Text Full Text PDF Scopus (1) Google Scholar report a risk score based on common echocardiographic variables to risk stratify PAH patients. They studied 2,400 patients enrolled in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL). Using Cox proportional hazards models, they identified four echocardiographic parameters that predict mortality independently: qualitative severity of right ventricular enlargement, qualitative assessment of right ventricular function, tricuspid regurgitation velocity, and presence of pericardial effusion. Using these four echocardiographic variables and PAH etiology, they developed the REVEAL-Echo score. Higher REVEAL-Echo score is associated with worse 1-year survival. A score of less than 2 is associated with less than 5% 1-year mortality (low risk), a score between 2 and 3 is associated with 5% to 10% 1-year mortality (intermediate risk), and a score of 4 or higher is associated with greater than 10% 1-year mortality (high risk). REVEAL-Echo score correlates with other known prognostic markers of PAH. More importantly, REVEAL-Echo score identified a subgroup of patients with relatively increased risk of mortality despite their low- and intermediate-risk status based on REVEAL 2.0 lite score.9Benza R.L. Kanwar M.K. Raina A. et al.Development and validation of an abridged version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for use in patients with pulmonary arterial hypertension.Chest. 2021; 159: 337-346Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar In harmony with the recent European guidelines,2Humbert M. Kovacs G. Hoeper M.M. et al.2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2022; 43: 3618-3731Crossref PubMed Scopus (237) Google Scholar using the REVEAL 2.0 lite and REVEAL-Echo scores together allows PAH patients to be categorized into four risk strata (low risk, intermediate-low risk, intermediate-high risk, and high risk). El-Kersh and colleagues13El-Kersh K. Zhao C. Elliott G. et al.Derivation of a risk score (REVEAL-ECHO) based on echocardiographic parameters of patients with pulmonary arterial hypertension.Chest. 2023; 163: 1232-1244Abstract Full Text Full Text PDF Scopus (1) Google Scholar have to be applauded because the REVEAL-Echo score is the first PAH risk tool that integrates detailed echocardiographic assessment of the structure and function of the right ventricle. Although current noninvasive PAH risk scores are good in predicting mortality, this study demonstrates that incorporating right ventricular size and function further refines their predictive ability. Patients with a low- or intermediate-risk score based on REVEAL 2.0 lite but with a higher REVEAL-Echo score have a higher mortality than expected based on the REVEAL 2.0 lite score alone. Similarly, in a single-center analysis, PAH patients with a high REVEAL 2.0 risk score and right ventricular dilatation had a much higher mortality than those with a high REVEAL 2.0 score and normal right ventricular size.14Pi H. Carlson S.D. Barros L.M. et al.Risk prediction and right ventricular dilation in a single-institution pulmonary arterial hypertension cohort.J Am Heart Assoc. 2022; 11e025521Crossref Scopus (2) Google Scholar This dichotomy has important clinical implications. If a PAH patient has a low-risk REVEAL 2.0 lite score but has moderate or severe right ventricular enlargement or dysfunction on echocardiography, this patient’s clinical treatment goal is not achieved, and treatment should be escalated. This is especially true in relatively younger PAH patients, who usually have higher functional capacity. As a corollary, if a PAH patient has an intermediate or higher REVEAL 2.0 lite risk score but has a normal right ventricular size and function, an alternative explanation for their symptoms, other than PAH, should be considered. PAH-specific therapies should not be escalated in such a patient. Thus, this study reminds us again that the ultimate goal in the management of PAH is to normalize the right ventricular function if possible or at least to couple the right ventricle to the increased afterload. Although El-Kersh and colleagues13El-Kersh K. Zhao C. Elliott G. et al.Derivation of a risk score (REVEAL-ECHO) based on echocardiographic parameters of patients with pulmonary arterial hypertension.Chest. 2023; 163: 1232-1244Abstract Full Text Full Text PDF Scopus (1) Google Scholar have moved the needle forward in PAH risk prediction, there is more to achieve. REVEAL-Echo score is based on qualitative echocardiographic assessment of right ventricular size and function, which is subjective. Including quantitative measures of right ventricular function such as tricuspid annular plane systolic excursion, tissue Doppler velocity of the lateral tricuspid annulus, right ventricular fractional area change, or right ventricular ejection fraction will likely provide a more refined risk stratification. The ratio of estimated systolic pulmonary artery pressure over tricuspid annular plane systolic excursion has been validated as a noninvasive surrogate of right ventricular-pulmonary artery coupling,11Tello K. Wan J. Dalmer A. et al.Validation of the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio for the assessment of right ventricular-arterial coupling in severe pulmonary hypertension.Circ Cardiovasc Imaging. 2019; 12e009047Crossref Scopus (167) Google Scholar and it may be of value. In fact, the 2022 European Respiratory and Cardiology society PAH guidelines have this ratio in their risk stratification.2Humbert M. Kovacs G. Hoeper M.M. et al.2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2022; 43: 3618-3731Crossref PubMed Scopus (237) Google Scholar The REVEAL-Echo score also includes PAH etiology. This weighting seems to skew the risk category assignment; for example, if a patient with portopulmonary or heritable PAH has a completely normal echocardiography, they are still assigned an intermediate-risk score. This suggests that PAH etiology drives the risk assignment as much as or more than the echocardiographic variables. The REVEAL Registry enrolled patients from more than a decade ago.15Benza R.L. Miller D.P. Gomberg-Maitland M. et al.Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).Circulation. 2010; 122: 164-172Crossref PubMed Scopus (1213) Google Scholar Since then, there have been several changes in the management of PAH, including upfront combination therapy.2Humbert M. Kovacs G. Hoeper M.M. et al.2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2022; 43: 3618-3731Crossref PubMed Scopus (237) Google Scholar In fact, modern registries have revealed improved survival in PAH.1Chang K.Y. Duval S. Badesch D.B. et al.Mortality in pulmonary arterial hypertension in the modern era: early insights from the Pulmonary Hypertension Association Registry.J Am Heart Assoc. 2022; 11e024969Crossref Scopus (22) Google Scholar,7Boucly A. Weatherald J. Savale L. et al.External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry.Eur Respir J. 2022; 592102419Crossref Scopus (23) Google Scholar,8Hoeper M.M. Pausch C. Olsson K.M. et al.COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension.Eur Respir J. 2022; 602102311Crossref Scopus (44) Google Scholar Thus, the REVEAL-Echo score needs external validation in contemporary PAH patients before it can be widely accepted. The REVEAL-Echo score has to be used in conjunction with the REVEAL 2.0 lite score, which can be cumbersome. Integrating REVEAL 2.0 lite and REVEAL-Echo scores into one score will make it more functional. Finally, an important unanswered question is whether a noninvasive risk model including echocardiographic parameters of right ventricular size and function is as good as, or better than, the current risk prediction models, which rely heavily on invasive hemodynamics. If so, this can obviate the need for routine follow-up right heart catheterization in the management of PAH patients. The authors have reported to CHEST the following: T. T. has served as consultant to United Therapeutics, J&J, Merck, Aria CV, and Altvant Science. None declared (E. L. B.). Derivation of a Risk Score (REVEAL-ECHO) Based on Echocardiographic Parameters of Patients With Pulmonary Arterial HypertensionCHESTVol. 163Issue 5PreviewA REVEAL-ECHO risk score, derived using four echocardiographic parameters, may discriminate risk further when used as an adjunct to current risk assessment scores. Further validation is required. Full-Text PDF