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. 2023 Oct;16(10):e010555.
doi: 10.1161/CIRCHEARTFAILURE.123.010555. Epub 2023 Sep 4.

Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension

Franz P Rischard  1 , Roberto J Bernardo  2 , Rebecca R Vanderpool  3 , Deborah H Kwon  4 , Tushar Acharya  5 , Margaret M Park  4 , Austin Katrynuik  6 , Michael Insel  1 , Saad Kubba  5 , Roberto Badagliacca  7 , A Brett Larive  8 , Robert Naeije  9 , Joe G N Garcia  6 , Gerald J Beck  8 , Serpil C Erzurum  10 , Robert P Frantz  11 , Paul M Hassoun  12 , Anna R Hemnes  13 , Nicholas S Hill  14 , Evelyn M Horn  15 , Jane A Leopold  16 , Erika B Rosenzweig  17 , W H Wilson Tang  4 , Jennifer D Wilcox  18
Affiliations

Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension

Franz P Rischard et al. Circ Heart Fail. 2023 Oct.

Abstract

Background: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition.

Methods: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO2peak)>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance.

Results: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P=0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P=0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P=0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise.

Conclusions: RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise.

Keywords: catheterization; exercise; hypertension, pulmonary; magnetic resonance imaging; oxygen consumption.

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Conflict of interest statement

Disclosures Dr Rischard has consulting relationships with Bayer and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Merck, and Janssen. Dr Naeije reports relationships including consultancies, speakers fees, and membership of advisory boards with AOP Orphan Pharmaceuticals, Johnson & Johnson, Lung Biotechnology Corporation, and United Therapeutics. Dr Garcia is Chief Executive Officer and founder of Aqualung Therapeutics Corporation. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Hassoun has served as consultant for Merck. Dr Hemnes has consulting relationships with Janssen, Merck, Gossamer, Bio, United Therapeutics, Bayer, Tenax. She owns stock in Tenax therapeutics and she has received research support from National Heart, Lung, and Blood Institute and Cardiovascular Medical Research and Education Fund. Dr Hill is the chair for an Aerovate steering committee. He is a consultant for Bellerophon and Liquidia and Merck. Dr Horn has consulting relationships with Biotronik and AADI biosciences. She serves on the DSMB for SoniVie and V-waves Ltd. She receives research support from Merck and Cereno. Dr Leopold Abbott has served as a consultant for Aria. She has research support from Astellas Pharma and United Therapeutics. Dr Rosenzweig has received consulting fees from Acceleron for a scientific advisory board meeting; and her institution receives grant support from Bayer, United Therapeutics, Janssen, and SonVie. Dr Tang served as consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, WhiteSwell, Kiniksa, Boston Scientific, and CardiaTec Biosciences and has received honorarium from Springer Nature and American Board of Internal Medicine. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.. Defining right ventricular functional recovery.
A change in RV end-diastolic volume (RVEDV) (A) and RV ejection fraction (RVEF) (B) from baseline to follow-up both correlated with peak oxygen consumption, VO2peak, at follow-up. However, a change in RVEDV better discriminated high exercise capacity (VO2peak >15mL/kg/min) than did a change in RV ejection fraction (RVEF). Vertical solid lines indicate best Youden index of 0.72 at an RVEDV of −15mL or 0.51 for RVEF at +4%. Based on these cutoffs, the number of true positives (TP) and true (TN) and false (FN) negatives were similar in RVEDV and RVEF. However, the number of false positives (FP) was higher for RVEF. C) Receiver operating characteristic (ROC) analysis predicting VO2peak>15 mL/kg/min shows a change in RVEDV of −15mL is more predictive than RVEF +4mL as well. D) Kaplan-Meier plot of RVFnRec and no RVFnRec by clinical worsening shows higher freedom from clinical worsening in the RVFnRec group.
Figure 2.
Figure 2.. Near normalization of right ventricular volume in functional recovery.
A) The treatment related change in RV end-diastolic volume (RVEDV) relative to RVEDV index at follow-up in the functional recovery (RVFnRec) and no RVFnRec patients. Only RVFnRec patients achieve a therapeutic change in RVEDV that nears normalization at follow-up. B) RVEF and RVEDVI at follow-up in the RVFnRec, no RVFnRec, and healthy controls. Solid vertical line indicates the upper 95% CI and the dark horizontal line the lower 95% CI for RVEDV and RVEF in the control cohort, respectively. C) Treatment related changes in short (first column) and long (second column) axis cardiac MRI images at Baseline and Follow-up. Substantial, improvements in RV volume and ejection fraction are seen in the RVFnRec group. However, relative wall thickness (mass/volume) remained almost twice the healthy control value in both the RVFnRec and no RVFnRec groups.
Figure 3.
Figure 3.. Afterload changes predicting right ventricular functional recovery.
(A) non-linear relationship between pulmonary vascular resistance (PVR) and compliance (Ca) at baseline and follow-up. Most RVFnRec patients had moved to the steep portion of the curve by follow-up. Solid line indicates an upper normal PVR of <3 WU. (B) receiver operating curve analysis of longitudinal changes between baseline and follow-up in mean pulmonary artery pressure (mPAP), PVR, Ca, and effective pulmonary elastance (Ea). Changes in Ca were the most closely related afterload parameter to changes in RV end-diastolic volume (RVEDV) (C-E). Vertical line indicates the highest (“best”) Youdin index cutoff for each afterload parameter.
Figure 4.
Figure 4.. The physiological significance of right ventricular functional recovery through exercise at follow-up.
Peak predicted oxygen consumption was higher in RVFnRec than no RVFnRec but both were well below normal matched controls (A). The linear pressure-flow relationship of RVFnRec patients and no RVFnRec patients was similar (B). The arrowheads represent peak and the tails resting mPAP/cardiac output. The thick arrow represents the median vector in each group. Despite similar mPAP/cardiac output, the cardiac output at peak was higher (B) and the change in stroke volume index (SVI) (C) was higher in RVFnRec than that of no RVFnRec patients. Pulmonary vascular α distensibility was similar between groups (D). Taken together (B-D) these findings indicate similar RV afterload at exercise but improved RV output reserve in the RVFnRec cohort.
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