Determinants of exercise-induced pulmonary arterial hypertension in systemic sclerosis

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Abstract

Background

Exercise-induced pulmonary arterial hypertension (EIPH) in systemic sclerosis (SSc) has already been observed but its determinants remain unclear. The aim of this study was to determine the incidence and the determinants of EIPH in SSc.

Methods and results

We prospectively enrolled 63 patients with SSc (age 54 ± 3 years, 76% female) followed in CHU Sart-Tilman in Liège. All patients underwent graded semi-supine exercise echocardiography. Systolic pulmonary arterial pressure (sPAP) was derived from the peak velocity of the tricuspid regurgitation jet and adding the estimation of right atrial pressure, both at rest and during exercise. Resting pulmonary arterial hypertension (PH) was defined as sPAP > 35 mm Hg and EIPH as sPAP > 50 mm Hg during exercise. The following formulas were used: mean PAP (mPAP) = 0.61 × sPAP + 2, left atrial pressure (LAP) = 1.9 + 1.24 × left ventricular (LV) E/e′ and pulmonary vascular resistance (PVR) = (mPAP–LAP) / LV cardiac output (CO) and slope of mPAP–LVCO relationship = changes in mPAP / changes in LVCO. Resting PH was present in 3 patients (7%) and 21 patients developed EIPH (47%). Patients with EIPH had higher resting LAP (10.3 ± 2.2 versus 8.8 ± 2.3 mm Hg; p = 0.03), resting PVR (2.6 ± 0.8 vs. 1.4 ± 1.1 Woods units; p = 0.004), exercise LAP (13.3 ± 2.3 vs. 9 ± 1.7 mm Hg; p < 0.0001), exercise PVR (3.6 ± 0.7 vs. 2.1 ± 0.9 Woods units; p = 0.02) and slope of mPAP–LVCO (5.8 ± 2.4 vs. 2.9 ± 2.1 mm Hg/L/min; p < 0.0001). After adjustment for age and gender, exercise LAP (β = 3.1 ± 0.8; p = 0.001) and exercise PVR (β = 7.9 ± 1.7; p = 0.0001) were independent determinants of exercise sPAP.

Conclusion

EIPH is frequent in SSc patients and is mainly related to both increased exercise LV filling pressure and exercise PVR.

Introduction

Systemic sclerosis (SSc) is a rare and complex disease, characterized by an extensive vasculopathy associated with auto-antibodies and fibrosis, with a multifactorial etiology [1]. Pulmonary arterial hypertension (PH), resulting from a pre-capillary mechanism, may be frequent in SSc with an approximated incidence of 8% to 13%, leading to an increased morbidity and mortality [2]. Echocardiography is an accurate non-invasive tool for the daily-life screening of patients at risk of PH [3]. Exercise echocardiography assessment of the pulmonary circulatory system has evolved over these last few years [4], [5], [6] and exercise-induced PH (EIPH) has recently been suggested as a potential useful tool for the early identification of patients with SSc at risk of developing resting PH [7], [8]. It seems however, that the incidence of EIPH may overestimate the percentage of onset of resting PH during follow-up [9]. Some recent studies have underlined that the origin of EIPH in SSc could be secondary, not only to pulmonary vasculopathy, but also to myocardial [10] and/or pulmonary impairment [11], [12]. Therefore, a post-capillary involvement in EIPH has been hypothesized in the literature [13], [14]. Hitherto, the echocardiographic determinants of EIPH in SSc remain unclear. The present study sought to evaluate the incidence of EIPH and its determinants in patients with SSc.

Section snippets

Methods

We prospectively studied 68 consecutive patients from January 2008 to November 2012 with a diagnosis of SSc, followed in the rheumatology center of CHU Sart-Tilman in Liège. Five patients refused the study protocol. Exclusion criteria were: (1) inability to provide informed consent, (2) previous ischemic heart or valvular heart diseases and (3) inability to perform an exercise test. Eighteen patients were excluded, 15 due to poor echogenicity and unquantifiable sPAP secondary to severe thinness

Population characteristics

Fifteen patients were excluded due to unquantifiable sPAP, 1 for moderate mitral regurgitation and 2 for known coronary artery diseases. Among the remaining 45 patients, 47% developed EIPH (n = 21). The sPAP increased significantly during exercise (from 25 ± 7 to 46 ± 14 mm Hg; p < 0.0001). Patients with EIPH had higher resting sPAP (29 ± 6 vs. 21 ± 5 mm Hg; p < 0.001), resting mPAP (20 ± 4 vs. 14 ± 3 mm Hg; p < 0.0001), exercise sPAP (58 ± 9 vs. 36 ± 8 mm Hg; p < 0.0001, Fig. 1), exercise mPAP (37 ± 6 vs. 24 ± 5 mm Hg; p < 0.0001) and

Discussion

The present study shows that (1) EIPH is common in patients with SSc (47%), (2) main mechanisms explaining EIPH are increased estimated exercise LV filling pressure and increased PVR and (3) taking into account the main factors generally considered as influencing sPAP (e.g. age, CO or pulmonary disease), the relationship between estimated exercise LV filling pressure, exercise PVR and exercise sPAP remains significant.

Conclusion

EIPH is frequent in patients with SSc (47%) and may be detected using exercise echocardiography. In patients with EIPH, our results suggest the potential role of increased exercise LV filling pressure and increased PVR. Exercise echocardiography could be useful for the screening and the understanding of the pathophysiological mechanisms leading to PH in patients with SSc. Further studies are needed to confirm these results and their impact on the outcome.

Source of funding

Damien Voilliot is supported by a research grant of the European Association of Cardiovascular Imaging.

Acknowledgments

We specially thank Carmine Celentano for his precious help and support for investigations in this study.

References (44)

  • G. Lefèvre et al.

    Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis

    Arthritis Rheum

    (2013)
  • J.P. Schwaiger et al.

    Screening patients with scleroderma for pulmonary arterial hypertension and implications for other at-risk populations

    Eur Respir Rev Off J Eur Respir Soc

    (2013)
  • R. Naeije et al.

    Exercise-induced pulmonary hypertension: physiological basis and methodological concerns

    Am J Respir Crit Care Med

    (2013)
  • G.D. Lewis et al.

    Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases

    Circulation

    (2013)
  • R. Saggar et al.

    Hemodynamics in pulmonary arterial hypertension: current and future perspectives

    Am J Cardiol

    (2012)
  • V. Codullo et al.

    Stress Doppler echocardiography in systemic sclerosis: evidence for a role in the prediction of pulmonary hypertension

    Arthritis Rheum

    (2013)
  • N. Collins et al.

    Abnormal pulmonary vascular responses in patients registered with a systemic autoimmunity database: Pulmonary Hypertension Assessment and Screening Evaluation using stress echocardiography (PHASE-I)

    Eur J Echocardiogr J Work Group Echocardiogr Eur Soc Cardiol

    (2006)
  • A.U. Wells et al.

    Fibrosing alveolitis in systemic sclerosis. Bronchoalveolar lavage findings in relation to computed tomographic appearance

    Am J Respir Crit Care Med

    (1994)
  • V.D. Steen et al.

    Severe organ involvement in systemic sclerosis with diffuse scleroderma

    Arthritis Rheum

    (2000)
  • W.D. Hager et al.

    Exercise during cardiac catheterization distinguishes between pulmonary and left ventricular causes of dyspnea in systemic sclerosis patients

    Clin Respir J

    (2013)
  • M. Ciurzyński et al.

    Exaggerated increase of exercise-induced pulmonary artery pressure in systemic sclerosis patients predominantly results from left ventricular diastolic dysfunction

    Clin Res Cardiol Off J Ger Card Soc

    (2013)
  • D. Mukerjee et al.

    Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach

    Ann Rheum Dis

    (2003)
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