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

Background Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated 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 PAH by right heart catheterization and cardiac MRI (CMR) at diagnosis and CMR and invasive cardiopulmonary exercise (CPET) following treatment (∼11 months). Sex, age, race/ethnicity matched healthy control subjects (n=62) with one-time CMR and non-invasive CPET were recruited from the PVDOMICS project. We examined therapeutic CMR changes relative to the evidence-based peak oxygen consumption (VO2peak)>15mL/kg/min to define RVFnRec by receiver operating curve analysis. Afterload was measured in the as mean pulmonary artery pressure, resistance, compliance, and elastance. Results A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (AUC 0.87, P=0.0001) and neared upper 95% CI RVEDV of controls. 22/63 (35%) of subjects met this cutoff which was reinforced by freedom from clinical worsening, RVFnRec 1/21 (5%) versus no RVFnRec 17/42, 40%, (log rank P=0.006). A therapy-associated increase of 0.8 mL/mmHg in compliance had the best predictive value of RVFnRec (AUC 0.76, CI 0.64-0.88, P=0.001). RVFnRec subjects had greater increases in stroke volume, and cardiac output at exercise. Conclusions RVFnRec defined by RVEDV therapeutic decrease of -15mL 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. What is new? Right ventricular functional recovery (RVFnRec) represents a novel endpoint of therapeutic success in PAH. We define RVFnRec as treatment associated normative RV changes related to function (peak oxygen consumption). Normative RV imaging changes are compared to a well phenotyped age, sex, and race/ethnicity matched healthy control cohort from the PVDOMICS project. Previous studies have focused on RV ejection fraction improvements. However, we show that changes in RVEDV are perhaps more important in that improvements in LV function also occur. Lastly, RVFnRec is best predicted by improvements in pulmonary artery compliance versus pulmonary vascular resistance, a more often cited metric of RV afterload. What are the clinical implications? RVFnRec represents a potential non-invasive assessment of clinical improvement and therapeutic response. Clinicians with access to cardiac MRI can obtain a limited scan (i.e., ventricular volumes) before and after treatment. Future study should examine echocardiographic correlates of RVFnRec. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Sources of funding: The PVDOMICS study received grants U01 HL125218 (PI: E.B. Rosenzweig), U01 HL125205 (PI: R.P. Frantz), U01 HL125212 (PI: A.R. Hemnes), U01 HL125208 (PI: F.P. Rischard), U01 HL125175 (PI: P.M.Hassoun), U01 HL125215 (PI: J.A. Leopold), and U01 HL125177 (PI: G.J. Beck) and the Pulmonary Hypertension Association. The PAH cohort is a continuously enrolling (since 1/21) cohort at UA of treatment naive patients. This registry/biorepository is funded directly by the UA. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional review board at the University of Arizona gave ethical approval of this work (IRB #1100000621). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data is available upon reasonable request from the contact author. * ANOVA : analysis of variance BNP : brain natriuretic peptide Ca : pulmonary vascular compliance CI : confidence interval CMR : cardiac MRI CTEPH : chronic thromboembolic pulmonary hypertension EDV : end-diastolic volume EF : ejection fraction ERS/ESC : European Respiratory Society/European Society of Cardiology ESV : end-systolic volume Ea : effective pulmonary arterial elastance LV : Left ventricle PA : pulmonary artery PAH : pulmonary arterial hypertension PAP : pulmonary artery pressure PCWP : pulmonary capillary wedge pressure PVR : pulmonary vascular resistance RAP : right atrial pressure REVEAL : United States Registry to Evaluate Early and Long-Term PAH Disease Management RV : right ventricle RVFnRec : RV functional recovery sRVP : systolic RV pressure SV : stroke volume PTE : thromboendarterectomy WSPH : World Symposium of Pulmonary Hypertension VO2peak : peak oxygen consumption