The Value of Hemodynamic Measurements or Cardiac MRI in the Follow-up of Patients With Idiopathic Pulmonary Arterial Hypertension

Abstract

BackgroundTreatment of patients with pulmonary arterial hypertension (PAH) is conventionally based on functional plus invasive measurements obtained during right heart catheterization (RHC). Whether risk assessment during repeated measurements could also be performed on the basis of imaging parameters is unclear, as a direct comparison of strategies is lacking.Research QuestionHow does the predictive value of noninvasive parameters compare with that of invasive hemodynamic measurements 1 year after the diagnosis of idiopathic PAH?Study Design and MethodsOne hundred and eighteen patients with idiopathic PAH who underwent RHC and cardiac MRI (CMR) were included in this study (median time between baseline evaluation and first parameter measures, 1.0 [0.8-1.2] years). Forty-four patients died or underwent lung transplantation. Forward Cox regression analyses were done to determine the best predictive functional, hemodynamic, and/or imaging model. Patients were classified as high risk if the event occurred < 5 years after diagnosis (n = 24), whereas patients without event were classified as low risk.ResultsA prognostic model based on age, sex, and absolute values at follow-up of functional parameters (6-min walk distance) performed well (Akaike information criterion [AIC], 279; concordance, 0.67). Predictive models with only hemodynamic (right atrial pressure, mixed venous oxygen saturation; AIC, 322; concordance, 0.66) or imaging parameters (right ventricular ejection fraction; AIC, 331; concordance, 0.63) at 1 year of follow-up performed similarly. The predictive value improved when functional data were combined with either hemodynamic data (AIC, 268; concordance, 0.69) or imaging data (AIC, 273; concordance, 0.70). A model composed of functional, hemodynamic, and imaging data performed only marginally better (AIC, 266; concordance, 0.69). Finally, changes between baseline and 1-year follow-up were observed for multiple hemodynamic and CMR parameters; only a change in CMR parameters was of prognostic predictive value.InterpretationAt 1 year of follow-up, risk assessment based on CMR is at least equal to risk assessment based on RHC. In this study, only changes in CMR, but not hemodynamic parameters, were of prognostic predictive value during the first year of follow-up. Treatment of patients with pulmonary arterial hypertension (PAH) is conventionally based on functional plus invasive measurements obtained during right heart catheterization (RHC). Whether risk assessment during repeated measurements could also be performed on the basis of imaging parameters is unclear, as a direct comparison of strategies is lacking. How does the predictive value of noninvasive parameters compare with that of invasive hemodynamic measurements 1 year after the diagnosis of idiopathic PAH? One hundred and eighteen patients with idiopathic PAH who underwent RHC and cardiac MRI (CMR) were included in this study (median time between baseline evaluation and first parameter measures, 1.0 [0.8-1.2] years). Forty-four patients died or underwent lung transplantation. Forward Cox regression analyses were done to determine the best predictive functional, hemodynamic, and/or imaging model. Patients were classified as high risk if the event occurred < 5 years after diagnosis (n = 24), whereas patients without event were classified as low risk. A prognostic model based on age, sex, and absolute values at follow-up of functional parameters (6-min walk distance) performed well (Akaike information criterion [AIC], 279; concordance, 0.67). Predictive models with only hemodynamic (right atrial pressure, mixed venous oxygen saturation; AIC, 322; concordance, 0.66) or imaging parameters (right ventricular ejection fraction; AIC, 331; concordance, 0.63) at 1 year of follow-up performed similarly. The predictive value improved when functional data were combined with either hemodynamic data (AIC, 268; concordance, 0.69) or imaging data (AIC, 273; concordance, 0.70). A model composed of functional, hemodynamic, and imaging data performed only marginally better (AIC, 266; concordance, 0.69). Finally, changes between baseline and 1-year follow-up were observed for multiple hemodynamic and CMR parameters; only a change in CMR parameters was of prognostic predictive value. At 1 year of follow-up, risk assessment based on CMR is at least equal to risk assessment based on RHC. In this study, only changes in CMR, but not hemodynamic parameters, were of prognostic predictive value during the first year of follow-up. Pulmonary arterial hypertension (PAH) is a progressive condition, characterized by extensive pulmonary vascular remodeling, resulting in an ongoing rise in right ventricular (RV) pressure overload.1Vonk Noordegraaf A. Westerhof B.E. Westerhof N. The relationship between the right ventricle and its load in pulmonary hypertension.J Am Coll Cardiol. 2017; 69: 236-243Crossref PubMed Scopus (249) Google Scholar To secure RV systolic function and thus oxygen supply to all organs, the right ventricle adapts via several compensatory mechanisms. However, ultimately these are insufficient and progression to RV dysfunction and failure remains inevitable, with a grim prognosis as a result.2van der Bruggen C.E.E. Tedford R.J. Handoko M.L. van der Velden J. de Man F.S. RV pressure overload: from hypertrophy to failure.Cardiovasc Res. 2017; 113: 1423-1432Crossref PubMed Scopus (36) Google Scholar According to guidelines, right heart catheterization (RHC) is recommended to support the diagnosis of PAH. In addition, RHC should be considered to guide treatment decisions including adjustments in treatment regimen and/or referral to a transplantation center (class IIa recommendation).3Galiè N. Humbert M. Vachiery J.L. et al.ESC Scientific Document Group2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Heart J. 2016; 37: 67-119Crossref PubMed Scopus (2980) Google Scholar However, whether hemodynamic assessment during follow-up is preferred above noninvasive monitoring is currently unclear. A risk stratification algorithm has been published in the European Respiratory Society/European Society of Cardiology (ERS/ESC) guidelines and has been validated by several groups.4Boucly A. Weatherald J. Savale L. et al.Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension.Eur Respir J. 2017; 50: 1700889Crossref PubMed Scopus (263) Google Scholar, 5Hoeper 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; 50: 1700740Crossref PubMed Scopus (243) Google Scholar, 6Kylhammar D. Kjellström B. Hjalmarsson C. et al.A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension.Eur Heart J. 2018; 39: 4175-4181Crossref PubMed Scopus (196) Google Scholar In addition, studies by Weatherald et al7Weatherald J. Boucly A. Chemla D. et al.Prognostic value of follow-up hemodynamic variables after initial management in pulmonary arterial hypertension.Circulation. 2018; 137: 693-704Crossref PubMed Scopus (82) Google Scholar and Chin et al8Chin K.M. Rubin L.J. Channick R. et al.Association of N-terminal pro brain natriuretic peptide and long-term outcome in patients with pulmonary arterial hypertension.Circulation. 2019; 139: 2440-2450Crossref PubMed Scopus (21) Google Scholar have demonstrated that after 4 months of follow-up, right atrial pressure (RAP), stroke volume index (RHC-SVi), and serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are independently associated with death or lung transplantation and are therefore important parameters to determine treatment response in patients with PAH. Notwithstanding the unquestionable predictive value of invasive hemodynamic assessment, several studies have shown that noninvasive imaging by cardiac MRI (CMR) also has great predictive value at baseline.7Weatherald J. Boucly A. Chemla D. et al.Prognostic value of follow-up hemodynamic variables after initial management in pulmonary arterial hypertension.Circulation. 2018; 137: 693-704Crossref PubMed Scopus (82) Google Scholar,9D’Alonzo G.E. Barst R.J. Ayres S.M. et al.Survival in patients with primary pulmonary hypertension: results from a national prospective registry.Ann Intern Med. 1991; 115: 343-349Crossref PubMed Scopus (2818) Google Scholar, 10van Wolferen S.A. Marcus J.T. Boonstra A. et al.Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension.Eur Heart J. 2007; 28: 1250-1257Crossref PubMed Scopus (550) Google Scholar, 11Swift A.J. Capener D. Johns C. et al.Magnetic resonance imaging in the prognostic evaluation of patients with pulmonary arterial hypertension.Am J Respir Crit Care Med. 2017; 196: 228-239Crossref PubMed Scopus (73) Google Scholar, 12Courand P.Y. Pina Jomir G. Khouatra C. et al.Prognostic value of right ventricular ejection fraction in pulmonary arterial hypertension.Eur Respir J. 2015; 45: 139-149Crossref PubMed Scopus (28) Google Scholar, 13Swift A.J. Rajaram S. Campbell M.J. et al.Prognostic value of cardiovascular magnetic resonance imaging measurements corrected for age and sex in idiopathic pulmonary arterial hypertension.Circ Cardiovasc Imaging. 2014; 7: 100-106Crossref PubMed Scopus (64) Google Scholar The noninvasive character of CMR may enable easier routine follow-up of patients with PAH, as it is more patient-friendly and carries minimal patient risks. As in our institute functional, hemodynamic, and imaging assessments are routinely combined during follow-up, we have a unique cohort to compare the predictive value of these various modalities of monitoring patients with idiopathic PAH. Therefore, the aim of this study was to compare the predictive value of CMR parameters with that of invasive hemodynamic measurements at 1-year follow-up. We retrospectively evaluated all patients with idiopathic PAH (iPAH) or hereditary PAH seen between March 2000 and September 2018 at the Amsterdam University Medical Center (location, VU University Medical Center, The Netherlands, a tertiary referral center for PAH). A diagnosis of idiopathic or hereditary PAH was made by a multidisciplinary pulmonary hypertension team after extensive clinical evaluation according to the ERS/ESC guidelines in the relevant time period.3Galiè N. Humbert M. Vachiery J.L. et al.ESC Scientific Document Group2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Heart J. 2016; 37: 67-119Crossref PubMed Scopus (2980) Google Scholar Because the repeated functional, hemodynamic, and imaging measurements were performed for clinical purposes, this study did not fall within the scope of the Medical Research Involving Human Subjects Act (confirmed by the Medical Ethics Review Committee of the VU University Medical Center, 2012.288). Functional assessment of the patients was performed by 6-min walk distance (6MWD), New York Heart Association (NYHA) classification, and NT-proBNP level. RHC was performed with a balloon-tipped, flow-directed, 7.5F triple-lumen Swan-Ganz catheter (Edwards Lifesciences LLC). Cardiac output (CO) was measured by either the Fick method or thermodilution (23% direct Fick, 4% indirect Fick, and 73% thermodilution). Pulmonary vascular resistance (PVR) was calculated as follows: PVR = (mPAP – PAWP)/CO, where mPAP is mean pulmonary arterial pressure and PAWP is pulmonary arterial wedge pressure. CMR was performed on a 1.5T Avanto or Sonata scanner equipped with a six-element phased array coil (Siemens Medical Solutions). Image acquisition and postprocessing were performed as described previously.14van der Bruggen C.E. Happé C.M. Dorfmüller P. et al.Bone morphogenetic protein receptor type 2 mutation in pulmonary arterial hypertension: a view on the right ventricle.Circulation. 2016; 133: 1747-1760Crossref PubMed Scopus (54) Google Scholar,15van 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 (502) Google Scholar The RV ejection fraction (RVEF) was calculated according to the following formula: RVEF = (RVEDV – RVESV)/RVEDV × 100%, where RVESV is RV end-systolic volume and RVEDV is RV end-diastolic volume. In line with Mauritz et al,16Mauritz G.J. Marcus J.T. Boonstra A. Westerhof N. A. stroke volume assessment in patients with pulmonary arterial hypertension: data Cardiovasc PubMed Scopus Google Scholar stroke volume was calculated on the basis of ventricular ventricular end-diastolic volume ventricular end-systolic volume are as mean or on variables are as absolute and analyses were on the data was and values of of patients at baseline were calculated with J. for Scholar baseline and follow-up were with A. for Scholar between baseline and follow-up were by for variables and by for with the for multiple The predictive value of functional, hemodynamic, and imaging parameters was by and Cox regression T. for Scholar Forward Cox regression was to determine the best predictive functional, hemodynamic, or imaging < as to be included in the model. To compare the predictive value of the various the and information criterion are The information criterion a of the of the model and the information by the of parameters in the models and the of the predictive value. A low information and could be as a better model. 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RHC is recommended in the ERS/ESC guidelines at the time of In addition, is a IIa to RHC to treatment response and in of clinical N. Humbert M. Vachiery J.L. et al.ESC Scientific Document Group2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Heart J. 2016; 37: 67-119Crossref PubMed Scopus (2980) Google Scholar However, as is from multiple not all PAH routine hemodynamic assessment at follow-up. be that an invasive follow-up is not to a noninvasive as a direct comparison is currently lacking. In this unique study we were to compare follow-up with and functional with and with The best predictive model was obtained by functional assessment with imaging and hemodynamic However, the between the models functional assessment with imaging or were that routine follow-up of patients with may be performed with in cardiovascular imaging may to multiple clinical modalities and CMR in the A.J. J. et al.A cardiac magnetic resonance to and pulmonary arterial hypertension Heart J Cardiovasc Imaging. PubMed Scopus Google Scholar prospective cohort studies should whether an is and should be in the treatment algorithm of PAH. imaging was performed by CMR, studies have shown that CMR is more in changes in RV function time is M.C. et assessment of right ventricular systolic function in patients with pulmonary hypertension a comparison with cardiac magnetic resonance Cardiol. 2017; 69: PubMed Scopus Google Scholar 1 year of follow-up, change in and was whereas only patients with a low risk of at high in and In in hemodynamic parameters was observed in and patients < 5 years). that patients be at high risk for hemodynamic parameters The results of this study the of RV on prognosis of patients with predictive are to RV to RV der Bruggen C.E.E. Tedford R.J. Handoko M.L. van der Velden J. de Man F.S. RV pressure overload: from hypertrophy to failure.Cardiovasc Res. 2017; 113: 1423-1432Crossref PubMed Scopus (36) Google Scholar strategies are not to RV 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 (502) Google Scholar is in our study, in in RV volume or could be observed after 1 year of studies have that when PVR is by of the right ventricle may de Veerdonk M.C. In Marcus J.T. et right ventricular in pulmonary arterial hypertension.Eur Respir J. 2017; PubMed Scopus (28) Google R. R. B. et al.Prognostic of right heart in idiopathic pulmonary arterial hypertension.J Heart Lung 2018; 37: Scopus Google Scholar treatment strategies with or Savale L. et in pulmonary arterial hypertension: a Respir J. 2014; PubMed Scopus Google S. a in pulmonary arterial hypertension.Eur Respir 2016; PubMed Scopus Google Scholar may to early of the right ventricle and ultimately may the prognosis of patients with this to the prognosis of patients with PAH is to to the right However, it is to treatment when is only in right heart failure or from models with important in RV when with T. et Society on Pulmonary of right ventricular function in the and an Society J Respir Crit Care Med. 2018; PubMed Scopus Google Scholar The of this study is in comparison with to the the to regression analyses including prognostic of PAH. 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Pan Z. et al.Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model.Eur Respir J. 2017; 50: 1700740Crossref PubMed Scopus (243) Google Scholar The age between the studies be by the high of patients with hereditary PAH included in this study who are on at an age patients with B. B. et of pulmonary arterial hypertension in of J Respir Crit Care Med. 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