- Academic Editors
†These authors contributed equally.
The optimal management of heart valve disease (HVD) is still debated and many studies are underway to identify the best time to refer patients for the most appropriate treatment strategy (either conservative, surgical or transcatheter interventions). Exercise pulmonary hypertension (PH) can be detected during exercise stress echocardiography (ESE) and has been demonstrated to have an important prognostic role in HVD, by predicting symptoms and mortality. This review article aims to provide an overview on the prognostic role of exercise PH in valvulopathies, and its possible role in the diagnostic-therapeutic algorithm for the management of HVD.
Heart valve diseases (HVD) is a common etiology of heart failure, which is a prominent driver of hospitalization and mortality in cardiovascular disease (Fig. 1, Ref. [1]). Echocardiography is the gold standard technique for the diagnosis of HVD, assessing mechanisms and severity of valve disease and guiding the clinician to select the most appropriate treatment strategy. Clinical presentation and symptomatic status are pivotal to plan treatment strategy, but prognosis and therapeutic management are mainly influenced by echocardiographic features, such as left ventricular ejection fraction (LVEF), left ventricular filling pressures, right ventricular function (RVF) and estimation of pulmonary hypertension (PH). PH is commonly associated with HVD, being present either at rest or detected after exertion with stress testing (Fig. 1).
Prevalence and global burden of left heart valve diseases (adapted from Coffey S et al. [1], “Global epidemiology of valve heart disease”).
The pathophysiological mechanisms underlying the development of PH in left HVD are summarized in Fig. 2: in mitral regurgitation (MR), left atrium (LA) volume overload and left ventricle (LV) volume overload occurs; in mitral stenosis (MS) mainly an increase in LA pressures and LV filling pressures takes place; again, aortic regurgitation (AR) leads to LV volume and pressure overload, while aortic stenosis (AS) causes an increase in LV pressures (Stage 1). As a consequence, LV remodeling and diastolic dysfunction occurs, resulting in increased filling pressures and LA dilatation and dysfunction (Stage 2). The retrograde transmission of LA pressure to the pulmonary circulation unit leads to a progressive right ventricle (RV) pressure overload (Stage 3), which, finally, results in the development of PH and subsequent RV remodeling and dysfunction (Stage 4).
Key patho-mechanisms of pulmonary hypertension and right ventricular failure in heart valve disease. LA, left atrium; LV, left ventricle; TAPSE/sPAP, tricuspid annular plain systolic excursion/systolic pulmonary arterial pressure; mPAP/CO, mean pulmonary arterial pressure/cardiac output; RV, right ventricle.
According to European Society of Cardiology (ESC) PH guidelines [2], PH due to left HVD belongs to group 2, which includes all forms caused by underlying left-sided heart disease. In addition to right heart catheterization, resting echocardiography may also help in assessing the probability of PH: a tricuspid regurgitation velocity (TRV) greater than 3.4 m/s is highly suspicious for PH (class I, level of evidence B) [2]. Additional signs of right heart overload such as right heart enlargement, reduced TAPSE/sPAP (tricuspid annular plain systolic excursion/systolic pulmonary arterial pressure) ratio or a “D-shaped” left ventricle may help make the diagnosis of PH in patients with a TRV between 2.7 and 3.4. PH is indicative of the severity of the underlying valvular disease. PH complicates severe and symptomatic mitral valve disease in 60–70% of patients [3]. Almost half of symptomatic patients with aortic stenosis may present with PH [4]. Detection of exercise-induced PH during a stress-test is critical, since it is indicative of decreased survival, regardless of the presence of symptoms at rest.
Exercise stress echocardiography (ESE) is not only specifically indicated in
HVD. However, it could be helpful to assess the origin of stress-related dyspnea
during exertion in patients with HVD who are asymptomatic at rest. Therefore, ESE
is indicated in those cases with an apparent mismatch between resting
echocardiography and patient-reported exercise symptoms [5]. During exercise,
haemodynamic changes include increasing of stroke volume and heart rate, with a
reduction of systemic vascular resistance resulting in increased systolic
pulmonary arterial pressure (sPAP). On exertion, healthy individuals will
increase pulmonary artery pressures proportional to the increase in cardiac
output; a slope of the relationship mean PAP/cardiac output
Either direct (mitral regurgitation/stenosis) as well as indirect (aortic regurgitation/stenosis) exposure of the LA to pressure overload may trigger remodeling characterized by LA dilatation, interstitial fibrosis and systolic/diastolic failure [7]. Once the LA has lost its compliance and reservoir function, there is an increase in LV filling pressure [8, 9] which becomes more evident during exercise. The development of PH in the context of HVD is not only attributed to a mere retrograde transmission of hemodynamic pressures to the right-heart circulation unit. Superimposed mechanisms of pulmonary vascular remodeling due to capillary damage with alveolar edema may lead to collagen deposition and fibrosis, more so in the pulmonary veins, with lesions similar to those observed in pulmonary veno-occlusive disease [6].
A cut-off of sPAP
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
Rest PH (sPAP |
Exercise PH (sPAP | ||||
Clinical Status | Prevalence | Prognosis | Prevalence | Prognosis | |
Aortic Stenosis | Symptomatic | 15–30% | - In 14,980 patients, risk of long-term mortality progressively rose as resting sPAP level increased (HR 1.14–2.94, p |
- | - |
Asymptomatic | 6% | - In 2588 patients, residual PH after TAVR identify patients at increased mortality [16]. | 55% | - In 69 patients, exercise PH was independently associated with ≈ 2-fold increased risk of cardiac event at almost 2 years follow-up [11]. | |
Aortic Regurgitation | Long-standing Asymptomatic | 16–24% | - In 8392 patients, long-term mortality rose as eRVSP increased (aHR 3.32, 95% CI 2.85 to 3.86 in severe PH, p |
- | - |
Mitral Stenosis | Long-standing Asymptomatic | 14–33% | ≈3-fold increased risk of death at 10 y (HR 2.98, 95% CI, 1.55–5.75, p = 0.001) [14]. | - In 130 patients, sPAP achieved at peak exercise was an important predictor of adverse outcome (aHR 1.025; 95% CI, 1.010–1.040, p = 0.001) [15]. | |
Primary Mitral Regurgitation | Symptomatic | 20–30% | - | - | |
Asymptomatic | 6–30% | - Between 382 patients with asymptomatic severe degenerative MR undergoing MV repair, those with PH displayed a doubled-risk of late mortality compared with the remaining patients (HR 2.54; 95% CI, 1.17–4.80, p = 0.018) [7]. | ≈ 50% | - In 78 patients, exercise PH (but not resting PH) was independently associated with the occurrence of symptoms (HR = 3.4, p = 0.002) [10]. | |
Secondary Mitral Regurgitation | Symptomatic for most | 37–62% | - In 873 patients, operative mortality was correlated with the degree of preoperative PH (2%, 3%, 8%, and 12% for none, mild, moderate, and severe PH, respectively, p |
40% | - In 159 patients, incidence of cardiac events during follow-up was significantly higher in patients with exercise PH compared with those without exercise PH (4 years: 40 |
Adapted from Filippetti L et al. [14], “The Right Heart Pulmonary
Circulation Unit and Left Heart Valve Disease”.
PH, pulmonary hypertension; sPAP, systolic pulmonary arterial hypertension; CI,
confidence interval; eRVSP, estimated right ventricle systolic pressure; HR,
hazard ratio; aHR, adjusted hazard ratio; TAVR, transcatheter aortic valve
replacement; MR, mitral regurgitation; MV, mitral valve.
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
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
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.
Recommendations in 2021 ESC Guidelines (Ref. [20]) | Recommendations in 2017 ESC Guidelines (Ref. [21]) | |||||
RV dilatation and/or dysfunction | Resting PH | Exercise-PH | RV dilatation and/or dysfunction | Resting PH | Exercise- PH | |
Mitral Regurgitation | - | Pulmonary hypertension (sPAP at rest |
- | - | “Pulmonary hypertension (sPAP at rest |
- |
Mitral Stenosis | - | - asymptomatic patients with severe MS: pulmonary hypertension (systolic pulmonary pressure |
- | - | - asymptomatic patients: pulmonary hypertension (systolic pulmonary pressure |
- |
- symptomatic patients: pulmonary hypertension is one of the unfavourable clinical characteristics for PMC | - symptomatic patients: pulmonary hypertension as one of the unfavourable clinical characteristics for PMC | |||||
Aortic Regurgitation | - | - | - | - | - | - |
Aortic Stenosis | - | - | - | - | “Severe pulmonary hypertension (systolic pulmonary artery pressure at rest |
- |
RV, right ventricle; PH, pulmonary hypertension; ESC, European Society of Cardiology; HVD, heart valve disease; LV, left ventricle; MR, mitral regurgitation; MS, mitral stenosis; PMC, percutaneous mitral commissurotomy; SAVR, surgical aortic valve replacement; AS, aortic stenosis; EF, ejection fraction; sPAP, systolic pulmonary arterial pressure.
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
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
Exercise PH is likely to occur in
Stress echocardiography is a helpful tool in patients with MS with a valve area
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].
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
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
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
Table 1 summarizes key studies reporting data dealing with the assessment of right ventricular-pulmonary circulation functional unit in HVD, at rest and during exercise. According to available literature there is a pivotal prognostic role of exercise PH in HVD. One of the limitations of exercise echocardiography is the lack of a widely accepted standardization.
The RIGHT-NET Investigators [41, 42] have recently proposed a shared ESE protocol focused on the assessment of right heart and pulmonary circulation (Fig. 6, Ref. [42]). The RIGHT Heart International NETwork (RIGHT-NET) is an international multicenter initiative investigating exercise Doppler echocardiography, focusing on right heart pulmonary circulation, in a wide array of populations including healthy subjects, elite athletes, individuals at risk of or with overt PH [43, 44]. Two studies from the RIGHT-NET cohort have been performed so far, aiming to assess reproducibility [42] and feasibility of exercise echocardiography [45]. Both studies reported a good reproducibility and feasibility with this methodology. A recently published work from the RIGHT-NET investigators reported a strong prognostic value of right ventricular performance under exercise in healthy subjects and in several cardiorespiratory condition [46].
The RIGHT Heart International NETwork (RIGHT-NET) exercise echocardiography protocol (reproduced from Ferrara F et al. [42], with license to reuse n. 5627190387). Proposed standardized methodology for exercise stress echocardiography and key echo-Doppler parameters. 2D, 2-Dimensional; TDI, tissue Doppler imaging; TRV, tricuspid regurgitant velocity; E, mitral inflow E velocity as measured by pulse wave Doppler; e’, early diastolic velocity of the lateral and septal (average) mitral annulus as measured by TDI; LVOT, left ventricular outflow tract; RVOT, right ventricular outflow tract; VTI, velocity time integral; ECG, electrocardiography.
ESE has been conducted with cycloergometer and there are additional protocols using different physical stressors in order to detect exercise PH and RV function. Such protocols may include treadmill [47], handgrip [48] and two-step protocols [49]. Unfortunately, ESE, when specifically focused on right heart-pulmonary circulation unit under stressors, is not included in current guidelines’ recommendations on management of HVD, as shown in Table 2. According to the evidence reported is this review, consideration should be given to the estimation of exercise pulmonary pressures in the diagnostic algorithm of HVD, leading to a better pre-operative risk stratification and providing guidance to achieve the optimal therapeutic strategy. Notwithstanding that the gold-standard for the assessment of pulmonary pressures is still right heart catheterization, ESE represents an affordable, non-invasive diagnostic tool, that is also associated with low complication rates and therefore easily translatable to every day clinical practice as part of a reliable decision-making algorithm.
New evidence from large studies that better analyze this phenomenon is urgently needed.
HVD are often complicated by both resting as well as exercise PH. While resting PH is considered among factors addressing optimal timing for surgical referral, exercise PH is still underrated in the decision-making process. Through pressure/volume overload, HVD lead to increased LV filling pressure, LA remodeling and dysfunction which are mechanisms resulting in increased pressure to the pulmonary circulation. The ability to adapt to such increases of pulmonary pressure, especially during exercise, is likely to determine the recurrence of symptoms and outcomes following therapeutic interventions. Exercise echocardiography is a reliable non-invasive tool to assess exercise PH. Therefore, there is an urgent need for worldwide standardization and acceptance of this technique.
HVD, heart valve diseases; PH, pulmonary hypertension; ESE, exercise stress echocardiography; TRV, tricuspid regurgitation velocity; TAPSE, tricuspid annular plane systolic excursion; sPAP, systolic pulmonary artery hypertension; LV, left ventricle; LVEF, left ventricle ejection fraction; RV, right ventricle; LA, left atrium; MR, mitral regurgitation; MS, mitral stenosis, AS, aortic stenosis; AR, aortic regurgitation; TEER, transcatheter edge-to-edge repair; AVR, aortic valve replacement.
AS and MB have been involved in drafting the manuscript and provided substantial contributions to the conception of the work. AM and FC made substantial contributions to acquisition of data and echocardiogram images. ACar and SR made substantial contributions with tables, other figures and interpretation of data for the work. ACit, RC and RS have been involved in interpreting of data for the work. EB and AMM made substantial contributions to conception and design of the manuscript. All authors contributed to editorial changes in the manuscript. All authors have given final approval of the version to be published. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
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This research received no external funding.
The authors declare no conflict of interest.
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