When exploring patients during exercise makes sense?

This editorial refers to ‘Clinical characteristics and determinants of exercise-induced pulmonary hypertension in patients with preserved left ventricular ejection fraction’, by A. Young Lim et al. on page 276. Dealing with exertional dyspnoea or unexplained shortness of breath is a common problem in clinical practice. However, the exploration of such symptoms is difficult and does not always lead to definite positive diagnosis and thus appropriate treatment. Moreover, the perception of dyspnoea is subjective and relies on determinants that are often unclear. In these patients, exploring pulmonary pressures and diastolic function during exercise appears to be an interesting way to assess the potential causes triggering their symptoms. In this issue of European Heart Journal - Cardiovascular Imaging, Lim et al.1 present a remarkable study exploring the value of exercise-induced pulmonary hypertension (EIPH) in patients with preserved left ventricular ejection fraction and complaining about unexplained dyspnoea. This exhaustive work included a large number of patients (1383 were analysed) and enabled a comprehensive description of the clinical aspects and features of EIPH in this population. To date, this population has not been well characterized, so the data published in this issue allow interesting insights in this not-so-well-known clinical entity. EIPH has been explored and demonstrated as clinically interesting in the field of heart valve diseases and in the prognostic assessment of patients diagnosed for a heart failure with preserved ejection fraction.2–4 Notably, larger studies confirming those first results are mandatory to justify a more generalized use of exercise stress echocardiography in our routine clinical practice. The first surprising fact in the study by Lim et al. appears to be the population with EIPH. Indeed, these patients were young (mean age 61.6 years) with significant male predominance (55.3%) and few co-morbidities such as chronic obstructive pulmonary disease or chronic kidney disease. Those characteristics were highly different from the patients included in heart failure with preserved ejection fraction (HFpEF) studies.2 Indeed, we reported in one of our study that HFpEF was associated with higher age, female predominance, and significant burden of co-morbidities.2,5 Moreover, a significant proportion of these patients had a history of atrial fibrillation, which is known to promote diastolic dysfunction and symptoms in such condition. Notably, patients presenting atrial fibrillation were excluded from the study of Lim et al. Hence, the phenotype of the patients presented by Lim et al. does not appear to correspond to the classical HFpEF populations. Further studies would be interesting to assess whether those patients have nevertheless, some kind of ‘early-stage’ HFpEF (with impaired e’ values) or a different clinical entity? The second point we would like to underscore concerns the methodology of this work. Stress echocardiography was not obtained during but immediately after the exercise, when preload decreases. We know from previous published studies that, rather than the absolute level of the pulmonary pressures, the kinetics of the elevation are essential to consider. Indeed abrupt and marked elevation, the pulmonary pressures have been well characterized in HFpEF populations2 and are probably more significant than their absolute level at exercise. Pulmonary pressures are known to rapidly return to normal ranges after exercise, so their measurement may not reflect the true level of systolic pulmonary arterial pressure. Indeed, in the study from Argiento et al.,6,7 mean pulmonary arterial pressure decreased from 30 mmHg at exercise to 19 mmHg after 5 min of recovery. It should be noted that data are limited concerning the potential value of the pulmonary pressure during recovery since it depends on various factors such as blood pressure, cardiac output, and the operator experience more particularly regarding the delay to acquire the tricuspid regurgitation flow. We therefore suggest that in patients with unexplained dyspnoea, the pulmonary pressures should be measured during exercise. Moreover, an arbitrary value of 10 mmHg has been assumed for right atrial pressure in this study, which might lead to errors in the estimation of the systolic pulmonary arterial pressure. It would be more accurate to estimate the right atrial pressure by assessing dimension and collapsibility of the inferior vena cava but validation studies are limited.8 Exercise-induced increase in systolic pulmonary arterial pressure (PAP) in patients with asymptomatic aortic stenosis (AS), mitral regurgitation (MR), and their healthy control (Ctrl) subjects.2,3,9 Another point we would like to discuss is why the patients did undergo chest discomfort or exercise intolerance. To perform aerobic exercise, optimal oxygen delivery to the muscles is compulsory. This process requires oxygenation of the blood, oxygen carrying, and extraction, adequate cardiac output to match the demand. This oxygen consumption can be increased in normal subjects by increasing either (i) cardiac output with faster heart rate or increased stroke volume or (ii) oxygen extraction. The measurement of VO2 during exercise would have been meaningful in this population because it enables to objectively assess the reason and level of functional limitation and carries out important information on prognosis. It has been described that in HFpEF, reduction of VO2 was the consequence of an inadequate increase in cardiac output attributable to lower stroke volume or heart rate.11 Some of the patients with HFpEF have poor exercise tolerance due to the diversion of the blood flow from the locomotor muscles to perfuse the diaphragm and accessory respiratory muscles. This diversion is responsible for insufficient oxygen extraction explaining the insufficient decrease of the CvO2 at exercise. Hence, further studies exploring those patients with unexplained chest discomfort should include a cardiopulmonary exercise to precisely assess the determinants of the functional limitation. Also, it would be meaningful to know whether the diagnosis of EIPH in symptomatic patients with preserved ejection fraction impacts prognosis. In this study, patients with EIPH were older with more co-morbidities such as hypertension and dyslipidemia and had worse echocardiographic features such as left atrial enlargement or higher E/e’ ratio. Hence, it remains to demonstrate whether EIPH is a risk factor for adverse outcomes or simply a marker of advanced stage of any kind of disease. Further studies assessing prognosis should give us new insights into this clinical entity. It would also be meaningful to evaluate what potential treatments could improve the functional status (perhaps prognosis?) of those patients. However, we know it is a hard task because in HFpEF patients, prognosis has been found to be comparable to those with reduced ejection fraction but the potential treatments remain, to date scarce and inconclusive.12 In other words, this study gives us remarkable perspectives about the exploration of chest discomfort in our patients although the potential prognostic value and therapeutic management of EIPH have still to be established. Thanks to Julien Magne for his help.