Mitral regurgitation is one of the most common HVD linked with PH at rest. The prevalence of PH depends on the presence of symptoms, the grade of MR severity and the LV systolic function. In primary MR, the prevalence of PH varies from 20–30% in symptomatic patients and from 6 to 30% in asymptomatic patients. The presence of resting PH $>$50 mmHg correlates with poor prognosis in patients undergoing mitral valve (MV) surgery (as summarized in Table 1, Ref. [6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18]), increasing the likelihood of continued post-operative symptoms by $>$2 fold. However, early surgery still provides the best opportunity for patients to improve their quality of life in those patients with PH at rest. Ghoreishi M et al. [19] found that pre-operative sPAP are able to predict both early as well as late survival after surgery. They stress that the optimal timing for surgery should precede the onset of resting PH, defined as a sPAP of 40 mmHg or higher. Patients with severe chronic primary MR with concomitant PH at rest have a worse prognosis after MV repair (especially those 65 years old) with a higher risk of mitral re-operation [10]. According to international recommendations [20, 21], a sPAP value $>$50 mmHg should be considered as a red-flag to consider mitral valve repair in patients with severe degenerative MR without overt LV dysfunction or dilation (class IIa).

In cases of secondary MR, which are usually symptomatic, the prevalence of resting PH ranges from 37 to 62% of patients and is a known independent predictive factor for chronic heart failure or death from any cause. According to this report, mortality increases as PH rises, further supporting the role of PH in predicting poor outcomes [22].

In asymptomatic patients with severe primary MR, exercise PH is more commonly found than resting PH, with a prevalence of about 50% of patients (see Table 1). Exercise-PH correlates with a $>$3-fold increased risk of recurrent symptoms and predicts the recurrence of symptoms better than resting PH [23]. Moreover, exercise-PH is associated with significantly lower 2-year symptom-free survival. When stress PH is greater than 60 mmHg, patients should be considered for surgery [14]. In a cohort of 97 patients with moderate-severe primary MR, PH at peak-exercise was a predictor of the recurrence of symptoms within 2 years [24]. Exercise-PH was estimated to be present in 40% [14] of patients with functional MR regardless of LV function. The independent determinants of exercise-PH are the occurrence of resting PH, MR severity with exercise, alongside with left ventricular diastolic dysfunction [13]. Exercise PH is associated with poor outcomes, regardless of the degree of the severity of secondary MR, and results in a 5.3-fold increase risk for cardiac death due to cardiovascular causes [13].

ESE may be useful when a mismatch between symptoms and the severity of regurgitation is present at rest [20]. Stress-echo may also help when a mild to moderate resting MR is associated with changes in mitral regurgitant volume and increased sPAP at peak exercise [25] (Fig. 3). Furthermore, ESE may help to assess myocardial reserve contractility [5]. The occurrence of shortness of breath during exercise with a concomitant increase in MR and sPAP identifies a cluster of patients who will benefit take from a tailored therapeutic approach. Current HVD guidelines [20] recommend surgery in asymptomatic patients at rest when severe degenerative MR coexists with preserved LVEF and when exercise PH $>$60 mmHg is present (Class IIa). This recommendation was already present in the previous edition of the ESC Guidelines [21] (see Table 2, Ref. [20, 21]). In patients with degenerative MR, ESE may be helpful to detect a rise in pulmonary arterial wedge pressure at peak of exercise, which is associated with adverse outcomes [15]. Normally, wedge pressure at rest is strongly dependent on preload and is sometimes underestimated at rest. Therefore, ESE is likely to be a powerful technique to unmask PH in MR before it becomes clinically manifest. When exercise PH and exercise limitations are unmasked by ESE, early surgery should be considered [26].

Fig. 3.

Mitral regurgitation. Stress echocardiography in a patient affected by moderate resting mitral regurgitation, showing a dynamic rise in functional mitral regurgitation severity and systolic pulmonary artery pressure at peak of exercise. At rest, PISA-radius is 0.7 cm (panel a) and systolic trans-tricuspid gradient is 30 mmHg (panel b). During exercise, PISA-radius increased up to 1.2 cm (panel c) and trans-tricuspid gradient to 50 mmHg (panel d). PISA-r, Proximal Isovelocity Surface Area-radius; TTG, trans-tricuspid gradient.

In chronic secondary MR, ESE is particularly useful to determine that MR is the etiology of the patient’s dyspnea (class of recommendation 1 for American College of Cardiology/American Heart Association (ACC/AHA) guidelines 2020 [26]), to determine the etiology of the MR etiology, and to determine myocardial viability [5]. The detection of exercise pulmonary hypertension and the appearance of B-lines on chest-X-ray is indicative of pulmonary congestion (estimated by echocardiogram or right heart catheterization) is a contraindication and both findings are associated with increased mortality. ESC Guidelines [20] recommend surgery in cases of moderate to severe chronic MR, in patients with symptoms despite optimal medical therapy and in those patients with indications for coronary artery bypass graft (CABG surgery). When surgery is not indicated, MV transcatheter edge-to-edge repair (TEER) represents an alternative option especially when COAPT criteria are fulfilled [27]. Time for intervention referral is suggested by sPAP value $>$50 mmHg [20], while a PH at rest $>$70 mmHg for TEER. In patients with secondary MR, in 200 consecutive patients, exercise PH was found to play a key role in identifying those most likely to benefit from TEER as opposed to conservative medical management [28].

Prevalence of resting PH in MS is related to symptomatic status and MS severity varying from 14 to 33% in moderate PH and ranges from 5 to 9.6% in severe PH [14] (see Table 1). MS is likely to be asymptomatic until PH develops and is associated with recurrence of symptoms. In a recent study, Yang B et al. [29] reported that resting PH results in a 3-fold increased risk of death at 10 year follow-up [29]. The authors also reported that moderate to severe PH significative impaired post-operative survival after MV surgery [29]. They concluded that since 10 year post-operative survival is inversely associated with pre-operative sPAP, early referral to surgery should be considered to achieve a better prognosis in MS patients [29].

As summarized in Table 2, in patients with significant MS (i.e., valve area 1.5 cm${}^2$) but without symptoms, the detection of sPAP $>$50 mmHg at rest can be considered as an indication to perform percutaneous mitral commissurotomy (PMC) (class IIa Recommendation) [20]. Conversely, in symptomatic patients with significant MS, severe PH favors MV surgery over PMC [20].

Exercise PH is likely to occur in $>$30% of patients presenting with significant MS [14] and is considered to be a marker of severity in MS patients. Its presence is influenced by several hemodynamic features such as atrio-ventricular mean pressure gradient, left atrial volume, and right ventricular function. Recently [30], sPAP at peak of exercise has been reported to be a predictor of poor outcomes in patients with MS. Compared to other left HVD, mitral stenosis is characterized by the strongest correlation between increased left atrial pressure, exercise post-capillary pulmonary pressure, and the onset of symptoms.

Stress echocardiography is a helpful tool in patients with MS with a valve area $>$1.5 cm${}^2$ and concomitant symptoms. An abnormal response to exercise correlates with either a mean trans-mitral gradient $>$15 mmHg, or estimated exercise sPAP $>$60 mmHg [31] (Fig. 4). In these patients, referral for mitral valve commissurotomy should be considered (class II b) [15, 26, 32].

Fig. 4.

Mitral stenosis. Physical stress echocardiography of a 76-year old patient affected by moderate MS at rest. Panel-a and panel-b show a thickened mitral valve with reduced diastolic opening, in 2D long axis parasternal view (a) and in short axis view (b). Panel-c and panel-d show a mean trans-mitral gradient of 6 mmHg and a systolic trans-tricuspid gradient equal to 30 mmHg at rest, respectively. At peak of exercise, mean trans-mitral gradient reaches 15 mmHg (panel-e) and systolic trans-tricuspid gradient increases up to 61 mmHg (panel-f), consistent with significant exercise-PH. MG, mean gradient; TTG, trans-tricuspid gradient.

AS is the most common HVD in western countries [20]. PH detected by echocardiography in symptomatic patients is found between 15–30% of patients [14, 33]. This value has also been confirmed by studies with right heart catheterization performed before transcatheter aortic valve replacement (TAVI) [16, 34]. In contrast, the prevalence of PH in asymptomatic AS is lower, about 6% as reported in several studies [14, 35] (see also Table 1).

The significance of PH complicating AS remains poorly characterized. A large retrospective study involving 14,980 patients with at least moderate AS, demonstrated that PH negatively affected prognosis even at mildly increased pulmonary pressures with a significant increase in mortality when PH becomes more severe [17].

PH impacts outcomes in symptomatic AS, both in conservative (medical) treatment and after intervention (whether surgical or transcatheter) [16, 34]. A recent metanalysis [36] showed how much baseline PH predicts mortality in patients with severe AS after TAVI. PH is associated with increased long-term cardiac mortality and all-cause mortality, using a resting sPAP cut-off of 60 mmHg or higher. In a recent study performed on 617 consecutive patients with severe AS undergoing TAVI, 46% of the study population experienced a reduction of sPAP after intervention, whereas residual PH resulted in a higher risk of all-cause mortality after 30 days [37].

Less data are available for asymptomatic forms of AS and limited data are also available regarding prognosis and survival. Likewise, little is known about the role played by PH in low-flow, low-gradient AS. This population is unquestionably the most difficult to treat and the timing for intervention is still a very challenging issue.

In a study performed by Lancellotti P et al. [35], exercise PH (with aPAP cut-off of 60 mmHg) was more common than resting PH (55% vs 6%) in asymptomatic AS patients. The authors also reported an independent association between exercise PH and a 2-fold increase in the risk of cardiac events after a 3-year follow-up (as summarized in Table 1), supporting the importance of exercise PH as an additional prognostic tool over other echocardiographic parameters, to improve risk-stratification in these patients. Thus, the presence of exercise-induced PH may identify a group of patients with a worse prognosis, in which consideration should be given for earlier intervention (Fig. 5). However, this consideration is not discussed in the current guidelines [20].

Fig. 5.

Aortic stenosis. Stress-echocardiography in a patient affected by moderate aortic stenosis (AS) at rest. Panel-a and panel-b show a calcific aortic valve with reduced systolic opening in a 2D long axis parasternal view (a) and a short axis view (b). At rest, aortic valve peak velocity is 3.5 m/sec resulting in a mean gradient of 32 mmHg (panel-c), systolic trans-tricuspid gradient of 31 mmHg (panel-d). At peak of exercise, aortic valve peak velocity increases up to 4.4 m/sec with a mean gradient of 50 mmHg (panel-e) and systolic trans-tricuspid gradient reaches 58 mmHg (panel-f), consistent with a significant exercise-PH. AV-Vmax, aortic valve peak velocity; MG, mean gradient; TTG, trans-tricuspid gradient; PH, pulmonary hypertension.

ESE should be performed in asymptomatic patients with severe AS. Current 2021 ESC guidelines on HVD [20] suggest low-dose dobutamine (up to 20 mcg, without atropine) for evaluating low-flow, low-gradient aortic stenosis to discriminate “true” from “pseudo-severe” AS. However, the detection of the presence and/or possible worsening of exercise PH is not always a part in discussion regarding therapeutic decision-making for these patients. The previous version of the 2017 ESC Guidelines [21] mentioned sPAP $>$60 mmHg at rest (confirmed with invasive measurement), as one of the findings in favor of aortic valve replacement (AVR) in asymptomatic severe AS with normal LVEF (class IIa). Furthermore, given that pulmonary congestion continues to be present after stress testing, the evaluation of pulmonary B-lines during the recovery stage of ESE can add further prognostic information, as stated in the comprehensive ABCDEG stress-echo approach [38].

PH develops in the most advanced stages during the course of AR, because the LV has been exposed to chronic volume and pressure overload. The prevalence of severe PH $>$60 mmHg in severe AR patients is less documented and estimated to be about 16–24% [14]. There is limited data regarding the correlation between PH and AR. A recent study [18] investigated moderate to severe AR patients focusing on the association between PH and mortality. This study found that the presence of PH at rest was related to adverse outcomes, even at mildly elevated levels.

Data regarding the correlation between exercise PH and AR is limited. Further studies are necessary to investigate whether stress induced-PH could play a potential role in prognostic stratification that could be useful for planning interventions, and providing more prognostic information on follow-up compared to data obtained during an echocardiogram exam.

The role of exercise echocardiography in severe AR patients is still under-investigated. Patients with severe AR and low LVEF were examined in a recent study [39]. The results showed that the increase in LVEF of $\ge$6% during low-dose dobutamine stress-echo was associated with a significant recovery of post-operative LVEF, without any significant association with reduced cardiovascular events. Another recent study [40] evaluated patients with asymptomatic severe AR with preserved ejection fraction (EF) aiming to find a predictive value for stress echocardiography. The study found that the absence of contractility reserve was associated with post-operative deterioration of LV contractility and the occurrence of symptoms [40]. These observations suggest a possible role of stress echo in AR risk stratification to plan the correct timing for surgery, but further studies are needed. ESE might have a role in asymptomatic AR patients when a mismatch between severity of AR and LV size is present (i.e., moderate AR and disproportionately markedly dilated LV especially with early systolic impairment) or with unexpected involvement of right heart chambers.