Background

The development of pulmonary hypertension at rest in patients with heart failure, chronic obstructive pulmonary disease, interstitial lung disease, thrombo-embolic disease, connective tissue disease, sleep apnoea disorders or cardiac valve disease often signals progression of the disease and poor outcome . According to Ohm’s law, pulmonary arterial blood flow (cardiac output), PCWP and PVR primarily determine the PAP _mean . A PAP _mean ≥ 25 mmHg currently defines pulmonary hypertension; coexisting PCWP (or left atrial pressure or left ventricular end diastolic pressure) ≤ 15 mmHg indicates pulmonary arterial hypertension (PAH), whereas elevated PCWP indicates at least some degree of PVH. RHC remains the gold standard for pulmonary hypertension diagnosis. It also enables the evaluation of pulmonary vasoreactivity and oxygen saturation measurements. Because of its noninvasive nature, Doppler echocardiography is the screening tool of choice in patients who are suspected of having pulmonary hypertension. By adding the estimated right atrial pressure, the PAP _syst may be estimated from the tricuspid regurgitant jet. In the absence of tricuspid regurgitation, pulmonary regurgitation may be used to derive PAP. In patients with healthy and diseased pulmonary circulations, PAP _syst closely correlates with PAP _mean at rest and in different states of activity . A PAP _syst threshold of 36 mmHg is currently retained for the screening of pulmonary hypertension. Agreement between catheter and Doppler assessment of PAP highly depends on accurate recording of the tricuspid regurgitant jet and operator skill.

Pulmonary pressures are intrinsically dynamic with exercise, sleep, load conditions, high altitude, right ventricular performance or therapeutic interventions. Despite normal or near-normal PAP _syst at rest, dynamic exercise may unmask a large rise in PAP _syst that may be considered as a latent stage of pulmonary hypertension. Early therapeutic interventions at this stage might result in a more favourable outcome. Although challenging, ESE allows the noninvasive assessment of PAP _syst during exercise but head-to-head comparisons between Doppler derived PAP _syst and catheter measurements have seldom been performed . Besides the difficulty in analysing tricuspid regurgitant velocity signals during ESE, the right atrial pressure based on inferior vena cava imaging has never been validated during exercise, when venous compliance is known to decrease . It is worth noting that owing to the rapid return of PAP to baseline, Doppler measurements during recovery appear unreliable .

Healthy individuals

Physiologically, during dynamic exercise the high vascular compliance of the pulmonary circulation is such that a several-fold increase in pulmonary blood flow may be accommodated with small rise in PAP and fall in PVR . Moreover, the relationships between PAP _syst and cardiac output or workload are highly linear using ESE. When log PAP _mean is plotted as a function of log cardiac output, both takeoff and plateau patterns may be identified in healthy subjects . In healthy individuals of various ages, Mahjoub et al. demonstrated that PAP _syst does not increase above 60 mmHg at low-level exercise . Unlike resting PAP _syst , the rise in PAP _syst is largely influenced by age, and 50% of patients aged > 70 years have a PAP _syst ≥ 60 mmHg at maximal workload. Both age-related vascular stiffening and reduced compliance of left ventricular (LV) filling, which is reflected back on the pulmonary vascular bed, are likely to account for the pulmonary pressure response during exercise . Thus, whereas a large exercise-induced rise in PAP _syst in a young patient should be considered as an abnormal response, interpretation of an increase in PAP _syst ≥ 60 mmHg at peak exercise in elderly patients with exertional dyspnoea or fatigue requires caution. It is noteworthy that well-trained athletes may experience a large increase in PAP _syst at high workload (tricuspid regurgitant maximal velocity ranging from 3.10 to 3.72 m/s in athletes vs 1.95 to 2.58 m/s in non-athletes) . A large increase in blood flow probably influences the exercise PAP response in athletes . Finally, using either RHC or ESE, age and workload achieved are key determinants of exercise PAP _syst , making it difficult to define normal PAP values during exercise .

Cardiac valvular disease

The usefulness of ESE in the management of cardiac valvular disease has been recently reviewed . In patients with asymptomatic organic mitral regurgitation, Magne et al. found that peak PAP _syst > 60 mmHg is frequent (46%) during ESE and is mainly related to an exercise-induced increase in mitral regurgitation severity . Importantly, exercise pulmonary hypertension (with a threshold of 56 mmHg) was a stronger predictor of 2-year symptom-free survival than resting PAP _syst , which is close to the 60 mmHg recommended by the American College of Cardiology/American Heart Association guidelines . Despite the lack of prospective prognostic data, a threshold of 60 mmHg during exercise is also recommended by current guidelines in mitral stenosis; decreased mitral valve compliance during exercise correlates with exercise-induced pulmonary hypertension in this setting . The significance of exercise-induced pulmonary hypertension in patients with asymptomatic aortic stenosis or regurgitation has not been specifically addressed. Last, owing to abnormal left ventricular function or residual pathology of the pulmonary vascular bed, exercise pulmonary hypertension should be considered when there is no significant relief of symptoms after valve replacement .

Systolic heart failure

Pulmonary hypertension is a frequent complication of both systolic and diastolic left ventricular dysfunction. In patients with heart failure and reduced LVEF, PAP _mean often increases sharply during exercise, associated with a blunted increase in cardiac output and a close correlation between PCWP and PAP _mean at each level of exercise . Interestingly, some patients with heart failure and reduced LVEF may experience a decrease in PAP _mean during exercise . Multiple intricate factors, including larger rise in functional mitral regurgitation volume during exercise, myocardial dyssynchrony or absence of left ventricular contractile reserve bolster exercise-induced pulmonary hypertension, while right ventricular failure hinders exercise-induced pulmonary hypertension . A positive relationship between exercise pulmonary hypertension and adverse outcome has been found in patients with left ventricular systolic dysfunction and coronary artery disease , whereas a decrease in PAP _syst during exercise might identify a subset of heart failure patients with worse prognosis . A multivariable approach, including assessment of right ventricular functional performance, is needed for a comprehensive interpretation of exercise PAP alteration in heart failure patients.

Heart failure with preserved ejection fraction

In clinical practice, significant exercise-induced PVH may be observed in the case of inducible ischaemia in patients with preserved LVEF at rest and exertional dyspnoea. In a large, heterogeneous population of patients with preserved LVEF referred for ‘diastolic’ ESE, exercise-induced pulmonary hypertension (PAP _syst > 50 mmHg at 50 W) has been associated with increased left ventricular filling pressure at rest, older age, female sex, increased systolic blood pressure at rest, shorter exercise duration and lower exercise oxygen saturation. These latter clinical characteristics are, in effect, similar to those of patients with HFpEF . In patients with HFpEF, exercise intolerance is associated with a significant rise in PAP _syst during dynamic exercise and concomitantly with a fall in left ventricular systolic performance and eventually with the development or worsening of functional mitral regurgitation . Using RHC, Borlaug et al. found that despite normal resting haemodynamic variables, a substantial number of dyspnoeic patients (65 ± 13 years) experienced a large exercise increase in PCWP, while controls (47 ± 17 years) did not . Exercise PAP _syst did correlate tightly with exercise PCWP and ≥ 45 mmHg accurately predicted a haemodynamic-based HFpEF diagnosis . Whether exercise PCWP rise is the sole mechanism of increased lung water and stiffness in patients with overt HFpEF remains uncertain. In addition, a precapillary component of pulmonary hypertension (vascular stiffness) is likely to further exacerbate exercise pulmonary hypertension in patients with HFpEF .