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Submaximal Exercise Testing (SET) in Idiopathic Pulmonary Arterial Hypertension (IPAH)

Divya Padmanabhan Menon

Jordan Ray

Charles Burger


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Conference: 2017 PH Professional Network Symposium

Release Date: 06.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1055

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.


Despite multiple advancements in IPAH pharmacotherapy, mortality at the one year mark remains high at 15%. Assessment of disease progression and response to therapy remains an area of concern - 6-minute walk distances (6MWD) have limited sensitivity / specificity while cardiopulmonary exercise tests (CPETs) conversely, are too complex and expensive for routine follow up. Submaximal exercise testing (SET) potentially provides a compromise with simplistic, non-invasive testing but enhanced physiological data to assess the severity of the PAH. Particularly, SET provides end-tidal exhaled carbon dioxide (CO2) levels (PETCO2) that has been demonstrated to decrease with worsening disease. It also measures breathing efficiency [minute ventilation to exhaled CO2 (VE/VCO2) ratio] that increases with disease progression. Both parameters have demonstrated correlations with right heart catheterization (RHC) metrics and prognostic risk scores in IPAH patients. We aim to address gaps in knowledge regarding SET parameter patterns with varying medication regimens in this cohort, particularly in the face of changing treatment paradigms favoring upfront combination therapy.


We conducted a retrospective study utilizing longitudinal data from approximately 80 IPAH patients followed at PH clinic at Mayo Clinic, Florida from 2000-2017. Exclusion criteria included recurrent PH post-transplant and NYHA-IV patients in right heart failure. An online database including demographics, vitals and BMI, diagnoses, group of PH, New York Heart Association or WHO Funtional Class (FC), 6MWD, Brain Natriuretic Peptide (BNP), current medication regimen, echocardiographic and RHC data (if obtained peri-SET date) and SET data (VE/VCO2, PETCO2) was utilized. Statistical analysis included use of Wilcoxon-Mann-Whitney / Kruskal-Wallis Tests for analysis of non-parametric data and correlation analyses. SET device Shape-HF™ (Shape Medical Systems, Inc.) was used for the study and the protocol involved continuous evaluation of vitals while obtaining data on breathing efficiency (VE/VCO2 slope) and PETCO2. Standard SET testing (6 minutes total – 2 minutes of rest followed by 3 minutes step exercise and a minute of rest) was performed. Goal respiratory exchange ratio (RER) of <0.9 was considered the primary indicator of submaximal testing.


• In WHO functional class 1 and 2 patients (Figure 1), overall, there was no significant difference in ventilatory assessments between patients on monotherapy (Endothelin Receptor Antagonists - ERA, Phosphodiesterase-5 inhibitors - PDE5I, Prostacyclins - PCs) or dual therapy (combinations of ERA, PDE5I or PCs) independent of FC. Nonetheless, a comparison of monotherapy with ERAs against ERA + PDE5I combination in FC I-II revealed higher PETCO2s and lower breathing efficiency ratios in the combination cohort for FC II, with a trend for difference in PETCO2 for FC I patients. This suggests that combination therapy may result in reduced physiologic dead space fractions. • We additionally evaluated changes in SET metrics immediately after addition of a medication class to treatment regimen and its correlations with standard lab/echocardiographic parameters, Functional class and 6MWD. Correlations of these with SET changes at the final SHAPE testing data point while on that regimen before a further medication up-titration was made, was also evaluated. Different patterns of statistically significant correlations were noted in both cases as detailed in Table 1. • Of note, 6MWD showed no correlation with both PETCO2 and Ve/VCO2 early after an up-titration, but showed statistically significant correlations at later time points with consistent therapy on each regimen. This strongly suggests that 6MWD could lag as an indicator of clinical response to therapy when compared with SET.


Overall, SET presents a non-invasive, low risk testing method for serial longitudinal follow up of IPAH patients. Multiple studies have demonstrated SETs utility in IPAH severity stratification and prognostication given its correlation with established disease severity scores. We present novel data evaluating its ability in assessing response to therapy via pulmonary vascular perfusion and dead space fractions in IPAH. Our preliminary results suggest that SET may have increased sensitivity in identifying subclinical disease progression compared to the more conventional assessments including 6MWD. In addition, within cohorts that have achieved a “favorable” functional class (WHO I-II), SET may have in role in identifying suboptimal responders, especially with patients on monotherapy, with potential applicability in tailoring individualized clinical decision making.


Figure 1: SET parameters in patients in Functional class I, II


Early and late changes in SET metrics after addition of a medication class and its correlation with markers of disease severity