European Heart Journal Supplements (2007) 9 (Supplement H), H48–H53 doi:10.1093/eurheartj/sum022

Exercise echocardiography in pulmonary hypertension ´ry* and Adriana Pavelescu Jean-Luc Vachie ´partement de Cardiologie, Ho ˆpital Erasme, Universite ´ Libre de Bruxelles, De 808 Route de Lennik, 1070 Brussels, Belgium

KEYWORDS Doppler echocardiography; Exercise testing; Exercise echocardiography; Right ventricular function; Pulmonary hypertension

Exercise testing and echocardiography: key players in pulmonary arterial hypertension management The physical activity of patients suffering from pulmonary arterial hypertension (PAH) is severely limited, because of an abnormal cardiovascular adaptation to exercise. As a result, exertional dyspnea is the most typical symptom leading to diagnosis of the condition.1 In normal individuals, the physiological adaptation to exercise includes an increase in stroke volume and heart rate (HR) with minimal increase in mean

* Corresponding author. Tel: þ32 2 5554866; fax: þ32 2 5556567. E-mail address: [email protected]

pulmonary artery pressure (PAP) despite a more than three-fold increase in cardiac output (CO).2 Therefore, a slight decrease in pulmonary vascular resistance (PVR) is observed at peak exercise, as a consequence of passive distension of compliant small vessels and/or recruitment of additional vessels in the upper portion of normal lungs.3 In PAH, exercise capacity is markedly impaired compared with healthy subjects, with a reduced work rate, peak VO2, maximal HR and oxygen pulse.4 This is resulting from a limited cardiac reserve as a result of RV inadaptation further aggravated by a rapid increase in PAP,5 although other factors may be involved.6 In PAH, exercise intolerance, whether assessed by the 6 min walking distance or cardiopulmonary exercise

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Doppler echocardiography plays a key role in the detection of pulmonary hypertension, the leading cause of right ventricular (RV) dysfunction. Reliable estimates of pulmonary pressures and cardiac output (CO) can be obtained at rest, allowing for screening and diagnosis of pulmonary arterial hypertension (PAH), a group of diseases characterized by increased pulmonary vascular resistance progressing to RV failure and death. However, these resting indices poorly correlate with symptoms, exercise response, and have modest prognosis significance. This is partially explained by the limited information obtained from pressure measurements on the severity of RV dysfunction, the major determinant of exercise response and prognosis in PAH. Exercise echocardiography (Ex-echo) may provide significant additional information in the understanding and the management of the disease. In asymptomatic subjects at risk of PAH, it may uncover abnormal increases in pulmonary pressure and CO during exercise, which may be reflecting early stage disease. In addition, the technique may be useful to better understand the physiology of exercise limitation, a typical manifestation of PAH. Several limitations need to be considered when using Ex-echo in the management of PAH, including the absence of a clear consistent definition of normal values, an unknown threshold for abnormal response and the limited quantitative information on RV function provided by simple pressure analysis. Newer echocardiographic techniques such as Tissue-Doppler imaging, and strain and strain rate analysis may provide further insights in the understanding of RV dysfunction. However, technical limitations currently prevent their application to Ex-echo. Clinical studies are underway to better explore the potential role of Ex-echo in the management of PAH.

Exercise echocardiography in PH

testing, is responsible for a poor quality of life, has an influence on clinical outcome, and is closely related with survival.7,8 In contrast, resting haemodynamic measurements poorly correlate with symptoms and do not predict the degree of exercise limitation.7,8 Interestingly, a better haemodynamic adaptation to exercise may explain the clinical benefit of prostacyclin therapy in idiopathic PAH (iPAH), in the presence of a modest decrease in resting PVR.5 There is no doubt that echocardiography plays a central role in the management of PAH. Several echoDoppler indices have been validated to detect abnormal increases in pulmonary pressures, to assess the severity of RV dysfunction, and to guide the diagnosis of pulmonary hypertension. In addition, direct and indirect indices of RV dysfunction have significant prognostic value.9 Therefore, echocardiography should be an excellent noninvasive tool to assess the adaptation of the pulmonary circulation and the right heart to exercise in normal and diseased states.

How to perform exercise echocardiography?

Figure 1 Echocardiographic determination of systolic pulmonary artery pressure at rest and peak exercise. Systolic pulmonary artery pressure at rest and peak exercise in patients (dotted lines) with chronic obstructive pulmonary disease, atrial septal defect, and high altitude pulmonary edema-susceptible, compared with corresponding healthy controls (lines). All patients had higher resting systolic pulmonary artery pressure with a steeper increase in pressure during exercise. High altitude pulmonary edema-susceptible subjects had similar resting values, but an increase in slope that is comparable with patients, suggesting an abnormal response of the pulmonary circulation to stress12,19,23 (see Table 1 for abbreviations).

Clinical application of exercise echocardiography in pulmonary hypertension Exercise echocardiography has been used to detect abnormal increases in pulmonary pressure in patients with various cardiac and pulmonary conditions (Table 1), including chronic obstructive pulmonary disease (COPD),12 heart transplantation,15 susceptibility to high altitude pulmonary edema (HAPE),16,17 and congenital heart diseases.18,19 It has also been used as a screening tool for exerciseinduced pulmonary hypertension in scleroderma20,21 and in relatives of patients with PAH.22,23 In addition, Ex-echo has been used in cases chronic thrombo-embolic pulmonary hypertension.24

Case-controlled studies in pulmonary hypertension The response to exercise in patients with COPD,12 atrial septal defect (ASD),19 or HAPE23 was compared with matched controls (Table 1). Changes in systolic PAP observed in these three studies are presented in Figure 1. In a subgroup of patients with COPD, invasive haemodynamic measurements were obtained during exercise, showing that even patients with normal resting values may present exercise-induced pulmonary hypertension.12 In this study, RV size poorly correlated with resting values of systolic PAP. Compared with healthy volunteers, asymptomatic adults with ASD were found to have higher level of resting systolic PAP (17 + 8 vs. 31 + 8 mmHg), which increased significantly during exercise (changed from

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Stress echocardiography is defined by an echocardiography examination performed during exercise, hypoxia, or pharmacological testing in order to guide diagnosis of cardiovascular diseases.10 In the setting of pulmonary hypertension, exercise appears superior to other stresses because it may provide a better understanding of the symptoms related to daily physical activity. Bicycle testing presents significant advantages compared with treadmill, including the ability to repeat measurements throughout exercise and a better standardization of position and loading conditions.10 In addition, new tilting tables allow subjects to pedal in semi-recumbent position while the position can easily be adapted to improve echocardiographic windows. In contrast to mitral valve or ischaemic heart diseases, exercise echocardiography (Ex-echo) for pulmonary hypertension does not focus on ventricular function or the degree of valvular regurgitation. Measurements include the calculation of CO from the left ventricular (LV) outflow tract and right ventricular (RV) systolic pressure from the maximal velocity of the tricuspid regurgitant (TR) jet,11 a reliable, reproducible and useful estimate of systolic PAP. Contrast-enhanced signals by agitated saline infusion may improve the rate of measurable TR jet velocity at rest from 56 to 92% and at exercise from 39 to 89%.12,13 It is also part of the clinical setting of exercise testing to monitor HR, systemic blood pressure, and oxygen saturation. Normal values of Doppler-derived systolic PAP during exercise have consistently been reported to be ,40–45 mmHg (Figure 1) in healthy individuals and control groups,12,14–18 although highly trained individuals may reach higher levels of pressure.14

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Scleroderma (n ¼ 65) No Scleroderma (n ¼ 51) No Relatives of iPAH cases (n ¼ 52) No Alkotob et al.20 Collins et al.21 Grunig et al.22

Treadmill Treadmill Supine bicycle 25 W/2 in.

Supine bicycle 25 W/2 in. Yes (n ¼ 11) HAPE-S (n ¼ 9) Grunig et al.23

Upright bicycle Yes (n ¼ 10) Asymptomatic ASD (n ¼ 10) Oelberg et al.19

CTRL, controls; IVC, inferior vena cava inspiratory collapse; PAPs, systolic pulmonary artery pressure; ASD, atrial septal defect; HAPE-S, high-altitude pulmonary edema susceptible; NR, normal response to exercise; AR, abnormal response to exercise; ULN, upper limit of the normal.

46 + 20 (COPD) 22+4 (CTRL) Estimated from IVC Not reported 31+8 (ASD) 17+8 (CTRL) Fixed value (5 mmHg) Not reported 28+4 (HAPE-S) 27+4 (CTRL) Fixed value (5 mmHg) 40 mmHg 25 + 8 Fixed value (10 mmHg) .35 mmHg 24 + 8 Fixed value (5 mmHg) .40 mmHg 24+4 (NR) 23+3 (AR) .45 mmHg Supine bicycle 10 or 25 W/in. Estimated from IVC Yes (n ¼ 12) Himelman et al.12 COPD (n ¼ 36)

PAPs ULN RAP estimate Control group Exercise protocol Population Author

baseline 2 mmHg in controls vs. 20 mmHg in ASD) in association with a reduced exercise performance.19 However, pulmonary and systemic flows during exercise were not reported, which makes the results difficult to interpret. Hypoxia-induced excessive rise in systolic PAP is a key determinant of HAPE, a common disorder among mountaineers. Such abnormal increase in pressure can be detected during an acute hypoxic challenge performed at sea level.23,25 Subjects susceptible to HAPE (HAPE-S) were found to present increased PAP response to both hypoxia and exercise.23 Interestingly, no overlap was found between controls and HAPE-S subjects who all presented with increases in systolic PAP .45 mmHg at peak exercise (Figure 2). Exercise testing performed in hypoxic condition further increases systolic PAP, but does not result in a better discrimination between controls and HAPE-S subjects.17 Ex-echo may therefore be a convenient and reliable way to assess susceptibility to HAPE at low altitude. However, further studies are needed to establish this technique as standard practice.

Screening in pulmonary arterial hypertension Pulmonary arterial hypertension is a rapidly progressive disorder for which appropriate therapy should be initiated once diagnosis is established. Unfortunately, the non-specific nature of the symptoms (dyspnea and fatigue) and the subtlety of the clinical signs explain why patients are usually diagnosed late (on average 2 years after the first manifestations) in advanced stage of disease.1 Therefore, an early marker of disease would be desirable, especially in groups at risk. Two studies sought to determine the incidence of stress-induced pulmonary hypertension in patients referred with a diagnosis of scleroderma20 or a wide range of autoimmune disorders.21 Although the authors reported an abnormal increase in systolic PAP at peak exercise, a low threshold for upper limit of normal21 and the absence of confirmation of pulmonary hypertension by invasive haemodynamics do not help understanding what is the true prevalence of abnormal response to exercise in these populations. The identification of genetic mutations associated with familial or iPAH led to question whether or not asymptomatic gene carriers could be identified by a systematic noninvasive assessment of PAP at rest and during exercise. To answer this question, Grunig et al.22 performed Ex-echo and linkage analysis on 52 members of four index patients from two German iPAH families. Cut-off for the upper limit of normal for systolic PAP was 40 mmHg, and patient’s relatives were separated into two groups according to the cut-off value in abnormal responders (ARs, n ¼ 14) and normal responders (NRs, n ¼ 27). At peak exercise, AR reached significantly higher pressure compared with NR during supine bicycle exercise at all stages from 25 to 100 W (Figure 3). Both groups had similar increases in CO, suggesting that an abnormal response of the pulmonary circulation under stress could account for the differences in systolic PAP in the AR group (Figure 3). All 14 AR but only two NR members shared the risk haplotype with the iPAH patients, which may suggest that Ex-echo can be helpful

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Table 1 Summary of clinical studies using exercise echocardiography in the setting of pulmonary hypertension

83 + 30 (COPD) 31+7 (CTRL) 51 + 10 (ASD) 19+8 (CTRL) 55 + 11 (HAPE-S) 36+3 (CTRL) 39 + 8 38 + 12 37+3 (NR) 56 + 11 (AR)

J.-L. Vanchie ´ry and A. Pavelescu

Baseline PAPs (mmHg) Peak PAPs (mmHg)

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Exercise echocardiography in PH

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in the detection of genetic abnormalities in asymptomatic individuals. Similar results were reported by the same group in a larger cohort of 75 family members of index patients (five adults and five children), compared with 56 control subjects.23 Whether or not this pathological rise of PASP in asymptomatic family members could be an early sign of iPAH remains to be demonstrated. A European multicentric case-controlled study is currently ongoing to further explore this hypothesis.

Pitfall of exercise echocardiography Exercise echocardiography in pulmonary hypertension carries some important limitations. The first one is inherent to the definition of pulmonary hypertension, based on a measure of mean PAP, while Doppler provides calculated estimates of systolic PAP, although both systolic and mean PAP are closely related.26 The second one is the somehow inconsistent definition of normal values at rest and during exercise for systolic PAP. At rest, Doppler-derived measurement of systolic PAP is highly influenced by age, gender, body mass index (BMI), and ventricular function. In a large series of .15 000 echocardiographic examinations, the estimated 95% upper limit of normal systolic PAP was at 37 mmHg.27 A resting value of systolic PAP (.40 mmHg), considered to be the upper limit of normal in most studies (Table 1), was found in 6% of

patients after the age of 50 years and in 5% of patients with BMI .30 kg/m2. This is likely to have an influence on the normal values at exercise, although the extent of this influence remains unknown. In addition, physical fitness is also a determinant of systolic PAP measured at peak exercise.14 This is at least in part explained by the linear relationship between flow and pressure: a higher increase in flow will passively induce a more pronounced increase in pressure without active changes of the pulmonary circulation.3 Therefore, Ex-echo should always combined pressure and flow measurements to allow for appropriate interpretation. Furthermore, clinical studies should include control groups matched for age and gender. In addition, Doppler echocardiography does not provide reliable estimates of LV filling pressure. Impaired LV filling can lead to a passive increase in systolic PAP that would not be captured by Ex-echo.22 Finally, although its role in the disease management is indisputable, no Doppler-echocardiographic indices of RV function have been validated during exercise.

Current role of exercise echocardiography in pulmonary arterial hypertension and future directions Despite an increasing interest, no recommendations currently exist on the role of Ex-echo in the management of

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Figure 2 Systolic pulmonary artery pressure response to exercise in controls and high altitude pulmonary edema susceptible. Discrimination between controls (n ¼ 11) and high altitude pulmonary edema susceptible (n ¼ 9) subjects by their systolic pulmonary artery pressure response to exercise estimated by Doppler echocardiography. No significant differences at rest between both groups (P ¼ 0.28). Asterisks denotes mean maximal systolic pulmonary artery pressure in controls (36þ3 mmHg) vs. high altitude pulmonary edema susceptible (55 þ 11 mmHg) subjects23 (P , 0.002).

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PAH. However, this technique may be useful to uncover an abnormal response of the pulmonary circulation in patients with symptoms and clinical presentation compatible with the diagnosis of PAH. In any case, patients with a high suspicion of PAH should always undergo a right heart catheterisation, which remains the gold standard to establish the final diagnosis. Further investigations are definitely needed to establish the role of this exciting technique as a tool for screening for PAH in groups at risk, which may lead to early identification and appropriate management. In addition, it may help to better understand the natural course of the disease and the significance of exerciseinduced pulmonary hypertension. Combination with other Doppler-derived variables (CO and indices of RV function) may also provide a unique opportunity to explore the physiology of exercise in PAH further. Finally, Ex-echo may provide an elegant way to assess the effectiveness of PAH therapies. Conflict of interest: none declared.

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Figure 3 Exercise echocardiography in relatives of patients with pulmonary arterial hypertension (adapted from Grunig et al.22; with kind permission from Lippincott Williams and Wilkins). All family members with exercise-induced pulmonary hypertension (abnormal response group, n ¼ 14) were carriers of the haplotype associated with idiopathic pulmonary arterial hypertension, in contrast with only two of the 27 members with normal systolic pulmonary artery pressure response to exercise (normal response group). Resting values were normal in both groups (mean systolic pulmonary artery pressure, 23+4 vs. 24+4 mmHg in abnormal response vs. normal response members, respectively, P , 0.57). Doppler-derived estimate of systolic pulmonary artery pressure was significantly different between abnormal response and normal response members.

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H53 exercise by saline-enhanced Doppler echocardiography. Am Heart J 1990;119:685–688. 25. Vachie ´ry JL, McDonagh T, Moraine JJ, Berre ´ J, Naeije R, Dargie H, Peacock AJ. Doppler assessment of hypoxic pulmonary vasoconstriction and susceptibility to high altitude pulmonary oedema. Thorax 1995;50:22–27. 26. Chemla D, Castelain V, Herve P, Lecarpentier Y, Brimioulle S. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest 2004;126:1313–1317. 27. McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation 2001;104:2797–2802.

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