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Exercise pulmonary haemodynamics predict outcome in patients with systemic sclerosis

Stamm A, Saxer S, Lichtblau M, Hasler ED, Jordan S, et al. Eur Respir J 2016;48:1549-1552

Background: Patients with systemic sclerosis (SSc, AKA scleroderma) commonly develop pulmonary arterial hypertension (PAH), which is associated with worse survival. Whether SSc patients with normal resting right heart catheterization (RHC) hemodynamics but an abnormal increase in mean pulmonary artery pressure (mPAP) during exercise represent an intermediate phenotype between patients with no PAH and resting PAH is unknown. This single-center retrospective review aimed to define outcomes of SSc patients with exercise-induced PAH.

Methods: All SSc patients undergoing diagnostic RHC both at rest and with exercise due to a clinical suspicion of PAH from 2005-2016 were examined retrospectively. Patients were excluded if they were clinically unstable or had musculoskeletal issues precluding exercise, had significant interstitial lung disease, or had post-capillary pulmonary hypertension at rest (pulmonary artery wedge pressure [PAWP]>15mmHg) or with exercise (PAWP > 20 mmHg). Standard RHC parameters were measured at rest and then during supine symptom-limited, stepwise incremental cycle ergometry exercise, which started at 10 Watts of power followed by an increase of 10 Watts every 3 minutes. Patients were divided into 3 groups: 1) resting PAH (mPAP ≥ 25 mmHg and PAWP ≤ 15 mmHg, “PHrest”), 2) exercise-induced PAH (mPAP<25 at rest but >30mmHg at maximal exercise with a mPAP/cardiac output (CO) slope of >3 and PAWP<20, “PHexercise”), and 3) no PAH at rest or with exercise. Follow-up data was extracted from the charts every 3-6 months after the RHC. An event was defined as death or lung transplantation.

Results: Out of 84 patients undergoing exercise-RHC, 72 were included in this analysis. At baseline, patients with PHrest and PHexercise were significantly older than those with no PH. Patients with PHrest had worse WHO functional class, higher NT-proBNP, lower 6-minute walk distance, larger right atrial area and higher tricuspid jet velocity on echocardiogram. Patients with PHexercise and those without PH were indistinguishable based on these parameters. All patients with PHrest were treated with PH-specific medications, as were 57% of those with PHexercise. At 3 and 12 months, there was no significant improvement in functional class, 6-minute walk distance, or NT-proBNP in the PHexercise patients treated with PH-specific medications, although there is no untreated control group for comparison.

Patients with PHrest tended to have mild PH with a median mPAP of 30 mmHg, PAWP of 12 mmHg, and pulmonary vascular resistance (PVR) of 3.6 Wood units (WU). During exercise, mPAP rose to a median of 50 mmHg and CO to 6.2 L/min, with a ΔmPAP/ΔCO slope of 24. Patients with PHexercise had a median resting mPAP of 20 mmHg and PVR of 1.6 WU, with increases during exercise to a mPAP of 33 mmHg and ΔmPAP/ΔCO slope of 14. Interestingly, although the patients without PH did not reach the exercise-induced mPAP definition, they did tend to have an abnormal ΔmPAP/ΔCO slope (median 3.7).

Ten patients died during follow-up (18% of those with PHrest, 18% PHexercise, and 7% without PH). Death was related to progressive right heart failure in all the PHrest patients who died and 80% of the PHexercise patients who died. Transplant-free survival was significantly worse in the PHrest and PHexercise groups compared to the patients without PH. Mean transplant-free survival was 4.4 years in the PHrest group, 5.2 years in the PHexercise group, and 9.5 years in the no PH group. Importantly, there was no significant difference in transplant-free survival between the PHrest and PHexercise patients. Resting hemodynamics did not predict survival, but mPAP increase during exercise did accurately prognosticate.

Conclusions: In SSc patients felt to be at risk for PAH who underwent RHC, those with PAH only with exercise represent an intermediate hemodynamic phenotype between those with no PAH and those with resting pulmonary hypertension. Despite having more mild hemodynamic derangements, those with exercise-induced PAH had similar survival compared to patients with PAH evident at rest. The clinical utility of treating SSc patients with PAH manifested only during exercise continues to be unknown and deserves further prospective, controlled study.

Commentary: The current study by Stamm and colleagues1 supports the idea that an abnormal pulmonary vascular response to exercise – or exercise-induced pulmonary hypertension (EiPH) – represents a true intermediate disease state between resting PAH and normal pulmonary vasculature. The previous definition of EiPH (mPAP > 30) was justifiably removed from societal guidelines in 2009 after new studies exposed significant knowledge gaps in what constitutes an abnormal pulmonary vascular response to exercise. There was also uncertainty regarding the type, posture, and intensity of exercise as well as concerns about proper measurement methodologies (including the influence of exercise-induced intrathoracic pressure swings on waveform analysis2 and cardiac output measurement techniques3). Recently, considerable progress has been made in defining the boundary between normal and pathologic exercise hemodynamics. Two new potential diagnostic criteria have emerged, both focusing on pressure/flow relationships: Naeije, Lewis, and colleagues4 have proposed a mPAP/CO slope ≥ 3 mmHg/L/min during exercise is abnormal, while Herve and colleagues5 have suggested mPAP ≥ 30 mmHg with total pulmonary resistance (mPAP/CO) > 3 WU at peak exercise is pathologic. In the current study, the authors found that SSc patients with EiPH as defined by the Herve definition exhibited worsened survival compared to subjects free of any PAH.1 The current study builds upon one by Kovacs and Oslchewski,6 who found borderline PAH (mPAP 20-24 mmHg) in SSc to be associated with an abnormal PV response to exercise, increased risk of development of resting PAH, and worse prognosis. However, the current study is the first to suggest worsened survival in the EiPH population regardless of resting pressure (IQR resting mPAP was 17-21 mmHg). In fact, subjects with and without EiPH were hemodynamically indistinguishable at rest, though measures of pulmonary vascular compliance (which may be more sensitive to subtle changes in resistance) were not reported. Interestingly, EiPH was not associated with worse baseline functional capacity, which contrasts prior work by Tolle and colleauges.7

Why SSc patients with only EiPH may do worse than those free of any pulmonary vascular disease remains unclear. Development of PAH in SSc portends a relatively poor prognosis compared with other forms of PAH, and recent evidence points toward intrinsic right ventricular (RV) myocardial disease as an important driver. SSc-PAH subjects demonstrate markedly worsened RV-pulmonary arterial coupling at rest8 as well as impaired RV reserve9 compared with idiopathic PAH counterparts. However, it remains unclear if EiPH or borderline PAH is enough to directly impact RV function, particularly in this population with ‘susceptible’ RVs, or if development of full-blown resting PAH is required. Given the retrospective nature of the current study and lack of consistent hemodynamic re-evaluations, it is not clear how many EiPH subjects went on to develop resting PAH. However, echo-estimated pulmonary pressures on follow up would suggest this was the likely case (at least in the EiPH patients that died). Whether we as clinicians can impact the development of resting PAH or if treatment of EiPH has long term benefits also remains unknown. Small, single center studies have shown hemodynamic improvements with PAH specific therapy in EiPH.10 In the current study, 57% of subjects with EiPH were treated with PAH specific therapies in a non-randomized and non-placebo controlled fashion. Although not adequately powered to detect significant differences, there were no changes in functional class or 6 minute walk distance over 1 year of follow up, and there was possible progression of disease as evidenced by increasing pro-BNP during this time. Without randomization or a placebo group, however, it is impossible to know if clinicians tended to treat sicker SSc patients, or if clinical worsening would occur more rapidly without treatment.

Overall, the manuscript by Stamm and colleagues represents an important step towards cementing the clinical relevance of a diagnosis of EiPH. It provides new insight into the prognostic implications of exercise hemodynamics in systemic sclerosis and reinforces the need for placebo-controlled clinical trials of PAH specific therapies in the EiPH population. In the interim, and in the context of a properly performed exercise hemodynamic evaluation, those SSc patients meeting criteria for EiPH require vigilant monitoring for worsening clinical and hemodynamic disease.


  1. Stamm A, Saxer S, Lichtblau M, Hasler ED, Jordan S, Huber LC, Bloch KE, Distler O, Ulrich S. Eur Respir J. 2016;48:1549-1552

  2. Boerrigter BG, Waxman AB, Westerhof N, Vonk-Noordegraaf A, Systrom DM. Measuring central pulmonary pressures during exercise in COPD: how to cope with respiratory effects. Eur Respir J. 2014;43(5):1316–1325.

  3. Hsu S, Brusca SB, Rhodes PS, Kolb TM, Mathai SC, Tedford RJ. Use of Thermodilution Cardiac Output Overestimates Diagnoses of Exercise-induced Pulmonary Hypertension. Pulmonary Circulation 2016, In Press.

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  9. Hsu S, Houston BA, Tampakakis E, Bacher AC, Rhodes PS, Mathai SC, Damico RL, Kolb TM, Hummers LK, Shah AA, McMahan Z, Corona-Villalobos CP, Zimmerman, SL, Wigley FM, Hassoun PM, Kass DA, Tedford RJ. Right ventricular functional reserve in pulmonary arterial hypertension. Circulation. 2016;133:2413–2422.

  10. Saggar R, Khanna D, Shapiro S, Furst DE, Maranian P, Clements P, Abtin F, Dua S, Belperio J, Saggar R. Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single- center, open-label pilot study. Arthritis Rheum. 2012 Dec;64(12):4072-7

Article summary by: Matthew Lammi MD, MSCR; Assistant Professor of Medicine, Louisiana State University Health Sciences Center, Comprehensive Pulmonary Hypertension Center-University Medical Center

Expert commentary by: Samuel B Brusca, MD, Steven Hsu, MD, and Ryan J. Tedford, MD; Associate Professor of Medicine; Division of Cardiology, Johns Hopkins School of Medicine