Statistics from Altmetric.com
- aortic stenosis
- aortic regurgitation
- cardiac computer tomographic (ct) imaging
- valve disease surgery
To be aware of the prevalence, pathophysiology and outcomes of mixed aortic valve disease (MAVD), which refers to combined aortic stenosis and aortic regurgitation.
To assess the haemodynamic and clinical severity of MAVD using an echocardiographic multiparameter approach and, when necessary, other imaging modalities (dobutamine stress testing, multidetector computed tomography and cardiac magnetic resonance).
To identify the triggers and optimal timing for aortic valve intervention in MAVD.
Mixed aortic valve disease (MAVD) refers to the coexistence of aortic stenosis (AS) and aortic regurgitation (AR). Despite the relatively high prevalence of MAVD, there are very few data on the outcome and management of this entity.1–6 Nonetheless, a few recent studies have reported that the prognosis of patients with combined moderate AS and moderate AR is similar or worse than those with isolated severe AS or AR.2 3 The therapeutic management of MAVD is complex and is currently based on the guideline recommendations for the predominant lesion, AS or AR.1 7 The objective of this Education in Heart article is to provide an overview of the prevalence, pathophysiology, outcomes, diagnosis, severity grading and strategies for the therapeutic management of MAVD.
Prevalence, pathophysiology and outcomes of MAVD
Prevalence of MAVD
In a nationwide epidemiology study conducted in Sweden,8 the overall incidence rate of multiple valve disease was 6.4 per 100 000 person-years. This rate increased markedly with age and was higher in men (8.5 per 100 000 person-years) than in women (5.8 per 100 000 person-years).8 MAVD was the most frequent multiple valve disease and 17.9% of patients with AR were diagnosed with concomitant AS.
Pathophysiology of MAVD
The pathophysiology and clinical impact of MAVD are complex and relate to the severity and chronicity of each aortic valve lesion and to the repercussions of these lesions on the remodelling and function of the left ventricle (LV) and other upstream cardiac chambers.5 In patients with MAVD, AS indeed imposes a pressure overload that aggravates LV concentric hypertrophy, resulting in decreased LV compliance and thus in a disproportionate rise in LV diastolic pressure per unit of volume increase during diastole. The combination of modest LV dilation and marked LV wall thickening results in patients with MAVD having larger indexed LV mass than patients with either isolated AR or isolated AS.3 6 Furthermore, the vast majority of patients with MAVD develop symptoms well before their LV end-systolic dimension reaches the cut-point value of 50 mm, that is, one of the triggers for intervention recommended in the guidelines1 7 for patients with severe AR. These findings suggest that the LV hypertrophy resulting from AS may not allow the LV to dilate as a result of the volume overload associated with AR. However, the increase in stroke volume resulting from the aortic regurgitant volume may further contribute to increase the transvalvular pressure gradient and thus the severity of LV pressure overload associated with AS (figure 1). Patients with MAVD may therefore be at higher risk to develop subclinical myocardial fibrosis and dysfunction compared with patients with isolated AR, and these patients may progress to symptoms and heart failure even though neither the AS nor the AR has yet reached the severe stage.9 They are also at higher risk to develop LV systolic dysfunction following valve intervention.10
Outcome of MAVD
There are limited data on the natural history of patients with MAVD, but the few studies available on this topic suggest similar or worse outcomes in patients with severe MAVD versus isolated severe AS or AR.2–4 6 11 Furthermore, the progression rate of AS was faster in patients with moderate MAVD compared with those with isolated moderate AS.4
Asymptomatic patients with severe MAVD generally have worse outcomes, whereas those with moderate MAVD have similar outcomes compared with patients with severe isolated AS.2 3 6 In asymptomatic patients with moderate AS, Sorajja et al 6 reported that the coexistence of a mild AR was associated with a significant negative impact on outcomes during follow-up. This finding may be related to the fact that patients with moderate AS primarily develop LV concentric hypertrophy and LV diastolic dysfunction, and they may thus not be able to tolerate an even mild aortic regurgitant volume. The main factors associated with higher risk of progression to symptoms and heart failure in MAVD are: older age, more severe AS and/or AR at baseline, larger LV mass index, more pronounced LV concentric remodelling and advanced LV diastolic dysfunction.3 4 10 12 13
These findings emphasise that patients with MAVD need careful surveillance with close clinical and echocardiographic follow-up, especially if the patient harbours the risk factors mentioned above. The determination of the optimal timing for intervention in these patients is challenging and should account for the composite severity of both AS and AR and their combined haemodynamic effects on cardiac function (figure 2 and table 1).
Diagnosis and grading severity of MAVD
Assessing the haemodynamic severity of MAVD
In patients with MAVD, one should assess the haemodynamic severity of each lesion: AS and AR and then the overall haemodynamic severity of the MAVD, that is, of the severity of the AS+AR combination (figure 2). Table 2 presents the caveats in the assessment of MAVD severity using Doppler echocardiography and other imaging modalities.
The peak aortic jet velocity and mean transvalvular gradient, which are highly flow dependent, may overestimate the severity of AS in the context of MAVD because of the high transvalvular flow state associated with AR (table 2, figures 1 and 3). The effective aortic valve area (AVA) by the continuity equation method and Doppler velocity index (ie, ratio of the velocity time integrals in LV outflow tract versus aortic jet) are the best parameters to quantitate the AS severity in the context of MAVD (table 2, figures 1–3). The anatomic AVA measured by planimetry using transoesophageal echocardiography, contrast multidetector CT (MDCT) or cardiac magnetic resonance (CMR) imaging may help to corroborate AS severity.14 15
Doppler echocardiography: the assessment of AR haemodynamic severity should rely on an integrative approach including structural, semiquantitative and quantitative parameters as recommended by the 2017 American Society guidelines for the non-invasive evaluation of native valvular regurgitation (table 2, figures 2 and 3).16 17 Patients with MAVD generally have less LV dilation and thus smaller LV end-diastolic volume and stroke volume, compared with patients with isolated AR. Hence, a moderate AR on the basis of effective regurgitant orifice area, vena contracta width and regurgitant volume may, in fact, correspond to a moderate-to-severe or severe AR in terms of regurgitant fraction. In patients with MAVD, it is thus preferable to put more weight on the regurgitant fraction than on other parameters to grade AR severity (table 2).
CMR: given that the feasibility and validity of several Doppler echocardiographic parameters of AR severity is compromised by the coexistence of AS, CMR imaging with phase-contrast performed at 10 mm above the aortic annulus may be helpful to confirm the AR volume and fraction in patients with MAVD (table 2; figure 4).18 In patients with MAVD, the regurgitant fraction appears to be the best parameter to corroborate AR severity; a fraction >33% has been associated with worse clinical outcomes in chronic isolated AR.18 CMR should be considered when the quantitative assessment of AR by Doppler echocardiography is not feasible or uncertain, which is more likely to occur in patients with MAVD (figures 2 and 4).17
Overall severity of MAVD
The peak aortic jet velocity and mean transvalvular gradient may be superior to other severity parameters of AS or AR to reflect the overall haemodynamic severity of MAVD (table 2, figures 1 and 3).5 The AVA and Doppler velocity index indeed reflect the severity of AS, whereas the effective regurgitant orifice area, vena contracta width of the AR jet, regurgitant volume and regurgitant fraction reflect the severity of AR but none of these parameters adequately assess the overall haemodynamic burden resulting from the combination of AS and AR. However, the peak aortic jet velocity and mean gradient increase with the severity of AS but also with that of AR due to the increase in transvalvular flow. Hence, these parameters may be useful to assess the overall haemodynamic severity of MAVD (table 2, figures 1 and 3) and have been shown to correlate with outcomes in these patients.2 4 Hence, a patient with moderate AS (according to AVA, indexed AVA and Doppler velocity index) and moderate AR (according to effective regurgitant orifice area, vena contracta width and regurgitant volume and fraction) should be considered having severe MAVD if they harbour a peak jet velocity ≥4 m/s and/or a mean gradient ≥40 mm Hg (figures 2 and 3). The coexistence of moderate AS and mild AR or vice versa moderate AR and mild AS generally corresponds to moderate MAVD (table 1 and figure 2). However, the overall haemodynamic severity of MAVD is more difficult to determine in patients with moderate AS (on the basis of AVA) and moderate AR harbouring a peak velocity <4 m/s and mean gradient <40 mm Hg (figure 4). The European Society of Cardiology guidelines suggest that, in such patients, the MAVD is likely severe (table 1). However, additional tests such as stress echocardiography or quantitation of aortic valve calcification by non-contrast MDCT, and quantitation of AR by phase-contrast CMR may be useful to differentiate a true severe versus a moderate MAVD in patients with low transvalvular gradient (figures 2 and 4).
MAVD with low flow, low gradient
Some patients with MAVD may have a decline in LV systolic dysfunction (LVEF <50%) and thus in stroke volume due to the haemodynamic burden related to the combination of AS and AR and/or to other cardiomyopathies, the most frequent being an ischaemic cardiomyopathy. In presence of low-flow state (stroke volume index <35 mL/m2, mean transvalvular flow rate <200 mL/s), the peak aortic velocity and mean gradient may underestimate the severity of the AS component as well as that of the MAVD (table 2). However, the AVA and Doppler velocity index may overestimate the severity of AS, and there is thus often a discordant grading pattern with AVA being in the severe range but with peak velocity and mean gradient being in the non-severe range.
Dobutamine stress echocardiography: in these patients, a low-dose dobutamine stress echocardiography may theoretically be helpful to assess the presence of LV contractile/flow reserve and to confirm the overall haemodynamic severity of MAVD (figures 2 and 4). There are currently no published data on the utilisation of dobutamine stress echocardiography in patients with MAVD. Nonetheless, by analogy with low-flow, low-gradient isolated AS, the MAVD could be considered severe if the peak jet velocity increases to ≥4 m/s and/or mean gradient to ≥40 mm Hg with dobutamine stress (figure 2). Stress echocardiography could also be applied to patients with moderate AS and moderate AR and low velocity/gradient to corroborate the overall severity of MAVD (figure 4).
Non-contrast MDCT: the quantitation of aortic valve calcium score by non-contrast MDCT and the modified Agatston method may also be used in patients with MAVD and low gradient to confirm the overall aortic valve disease severity (table 2, figures 2 and 4). A calcium score ≥2000 AU in men and ≥1200 AU in women would suggest severe MAVD.7 19 20
Assessing the clinical severity of MAVD
A haemodynamically severe MAVD may be well tolerated in some patients, whereas a moderate MAVD may have a detrimental impact on LV function and symptomatic status in others.21 This is why, besides the grading of the haemodynamic severity of MAVD, it is essential to assess the clinical severity, which reflects the repercussion of the haemodynamic burden associated with the AS+AR combination on cardiac chamber geometry and function and patient’s clinical status (figure 2).
One of the key aspects in the assessment of the clinical severity of MAVD and the indication for intervention is the presence of symptoms. As for isolated AS or AR, a treadmill exercise testing using a Bruce or modified Bruce protocol may be useful to unmask symptoms in apparently asymptomatic patients (figure 2).
Patients with MAVD and a preoperative LVEF <50% are also at higher risk of adverse clinical outcomes following AVR.10 Given that patients with MAVD may have a greater susceptibility to develop LV systolic dysfunction, the consideration of a higher cut-point of LVEF (ie, 60% vs 50%) for intervention, as recently suggested for patients with isolated AS,22–24 might also be relevant in these patients with MAVD. Global longitudinal strain has been shown to be useful to identify subclinical LV dysfunction and enhance risk stratification in patients with isolated AS or isolated AR,25 26 and this parameter may thus also be potentially helpful in those with MAVD. The onset of atrial fibrillation, pulmonary arterial hypertension and/or right ventricular dysfunction, which mark an impact on upstream cardiac chambers have also been associated with higher risk of adverse cardiac events both prior or after valve intervention in patients with aortic valve disease.27 Figure 2 presents the parameters and criteria that can be used to assess the haemodynamic and clinical severity of MAVD and therefore eventually trigger intervention. Some of these parameters and criteria are those proposed in the guidelines for isolated AS or AR and other emerging parameters and staging approach will need to be validated in the context of MAVD.
Therapeutic management of MAVD
The management of MAVD ideally requires the expertise and resources of multidisciplinary dedicated heart valve clinics in order to better address the numerous pitfalls and challenges in the grading of haemodynamic and clinical severity of MAVD and in the determination of the optimal timing for intervention (figure 2).28–30
Indication and type of intervention
According to current guidelines,1 7 the general principles for the management of MAVD are as follows: (1) when either AS or AR is predominant, management follows the recommendations related to the predominant lesion (table 1). (2) When the haemodynamic severity of both AS and AR is balanced (eg, moderate AS and moderate AR), indications for intervention should be based on symptoms and objective consequences on the LV (presence of LV dilatation or dysfunction), that is, clinical severity, rather than on the haemodynamic severity indices of AS or AR (figure 2 and table 1). The combination of moderate AS and moderate AR associated with high peak aortic jet velocity or mean gradient should be considered as severe MAVD (figures 1 and 3) and managed according to the guidelines recommendations for severe AS or severe AR. In patients with moderate AS and moderate AR associated with peak velocity <4 m/s and mean gradient <40 mm Hg (figure 4 and table 1), AVR may be considered if there is evidence that the overall severity of the MAVD is severe and if the MAVD is clinically significant: that is, the patient presents with symptoms, LV systolic dysfunction (LVEF ≤50%) or severe LV dilation (LV end-systolic diameter ≥50 mm). Although this is not mentioned in the guidelines, low-dose dobutamine stress echocardiography and/or aortic valve calcium scoring by MDCT may be useful to confirm the haemodynamic/anatomic severity of MAVD, especially if the patient is in low flow state (table 2). Once the indication of AVR is confirmed, the next step is to select the type of AVR (figure 2). Surgical aortic valve repair may be considered in patients with MAVD but is rarely feasible in these patients because of often extensive aortic valve calcification and fibrosis.7 Surgical AVR is thus the standard of care for patients with MAVD and low to intermediate surgical risk. Concomitant replacement of the aortic root and of the tubular ascending aorta should be performed at the time of AVR in patients with dilated aorta (≥45 mm, especially if the valve is bicuspid). Transcatheter AVR may be considered in patients with ≥intermediate surgical risk if the anatomy and size of the aortic root is suitable. This procedure may not be feasible in patients with large aortic annulus and dilated aortic root. Several studies reported that patients with MAVD have favourable outcomes (in terms of mortality, stroke, residual AR, LV mass regression and functional improvement) following surgical or transcatheter AVR and that these outcomes are comparable with patients with isolated AS.10 31
Asymptomatic patients with severe MAVD are at high risk for cardiac events in the short term, particularly if they have high gradient and significant LV hypertrophy. These patients may thus benefit from earlier intervention. However, this approach has not yet been validated and is not supported by the guidelines.
Knowledge gaps and future perspectives
As highlighted in this article, there is a considerable knowledge gap in the field of MAVD. More data are required on the natural history and the impact of intervention on outcomes in order to better define the indications for intervention. One of the priorities in the future would be to develop and validate a comprehensive algorithm including Doppler echocardiography, multimodality imaging and stress testing for an accurate and standardised evaluation of the haemodynamic and clinical severity of MAVD and for the determination of the optimal timing of valve intervention in this population. In particular, the staging scheme proposed by Généreux et al 27 in the context of isolated AS to assess the extent of associated cardiac damage will have to be tested and validated in the context of MAVD.
There are, to date, no data regarding the best timing of intervention to optimise outcomes in asymptomatic MAVD. Ongoing randomised trials such as the EARLY-TAVR trial or the EvoLVeD trial are comparing early AVR versus clinical surveillance with AVR performed when the patient develops symptoms or LV dysfunction. However, the vast majority of patients with moderate AS and concomitant AR are not eligible for the EARLY-TAVR trial, which requires a peak jet velocity ≥4 m/s and an AVA <1.0 cm2 for inclusion. There is thus a need for randomised trials specifically dedicated to asymptomatic patients with MAVD.
The diagnosis, severity grading and therapeutic management of MAVD are complex and challenging. The decision to intervene is based on an integrative evaluation of the overall haemodynamic severity, the AS+AR combination and the repercussions of the haemodynamic burden related to the MAVD on the function of the LV and other cardiac chambers and the patient’s clinical status.
In patients with mixed aortic valve disease (MAVD), an echocardiographic multiparameter approach, often associated with multimodality imaging (dobutamine stress echocardiography, multidetector CT (MDCT), cardiac magnetic resonance and exercise testing) should be implemented to assess: (1) the individual haemodynamic severity of each lesion: aortic stenosis (AS) and aortic regurgitation (AR); (2) the overall haemodynamic severity of the MAVD, that is, the global haemodynamic burden resulting from the combination of AS+AR; and (3) the clinical severity of the MAVD, that is, the repercussions of this haemodynamic burden on LV function and patient’s symptomatic status.
When either severe AS or severe AR is present, the management follows the guidelines recommendations related to the predominant severe lesion.
The combination of moderate AS and moderate AR associated with high peak aortic jet velocity or mean transvalvular gradient should be considered as severe MAVD and managed according to the recommendations for severe AS or severe AR.
In patients with combination of moderate AS and moderate AR associated with low gradient, additional tests such as dobutamine stress echocardiography or aortic valve calcium scoring by MDCT may be used to confirm overall haemodynamic severity and intervention should essentially be determined by the clinical severity of the MAVD, that is, presence of LV dilation/dysfunction or symptoms.
CME credits for Education in Heart
Education in Heart articles are accredited for CME by various providers. To answer the accompanying multiple-choice questions (MCQs) and obtain your credits, click on the ‘Take the Test’ link on the online version of the article. The MCQs are hosted on BMJ Learning. All users must complete a one-time registration on BMJ Learning and subsequently log in on every visit using their username and password to access modules and their CME record. Accreditation is only valid for 2 years from the date of publication. Printable CME certificates are available to users that achieve the minimum pass mark. Education in Heart articles are accredited for CME by various providers. To answer the accompanying MCQsmultiple choice questions (MCQs) and obtain your credits, click on the ‘Take the Test’ link on the online version of the article. The MCQs are hosted on BMJ Learning. All users must complete a one-time registration on BMJ Learning and subsequently log in on every visit using their username and password to access modules and their CME record. Accreditation is only valid for 2 years from the date of publication. Printable CME certificates are available to users that achieve the minimum pass mark.
Contributors GO did a review of literature on the topic and prepared the first draft of the initial and revised version. PP made critical revisions and prepared the figures and table.
Funding PP received funding from Edwards Lifesciences and Medtronic for echocardiography core laboratory analyses in the field of transcatheter aortic valve replacement with no direct personal compensation.
Competing interests PP holds the Canada Research Chair in Valvular Heart Disease and his research programme is funded by the Canadian Institutes of Health Research (grant numbers FDN-143225) (Ottawa, Ontario, Canada). PP received funding from Edwards Lifesciences for echo corelab analyses in the field of transcatheter valve therapy.
Provenance and peer review Commissioned; externally peer reviewed.
Patient consent for publication Not required.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.