Etiology and Prevalence

Multiple valvular heart disease (MVD) is a highly prevalent condition, affecting 20% of all patients with native valve disease included in the Euro Heart Survey [1]. In a Swedish nationwide study, 11% of all patients with a first diagnosis of valvular heart disease presented with MVD [2]. Moreover, 17% of the patients undergoing intervention in the Euro Heart Survey had MVD [1]. In the Society of Thoracic Surgeons Database, 11% of all valvular surgeries were double valve procedures [3]. However, the heterogeneity of these conditions in terms of combinations, etiology, severity, surgical risk, reparability, and suitability for transcatheter therapies likely limits the availability of data and, therefore, contributes to the low level of evidence supporting the decision-making.

Most MVD are acquired, mainly resulting from rheumatic fever and degenerative etiologies (Fig. 13.1) [4, 5]. Much lesser commonly, it may result from infective endocarditis, radiation therapy, drug-induced valvular disease, and inflammatory diseases. As a consequence of ageing and of the overall decrease incidence of rheumatic fever, degenerative etiologies become increasingly prevalent in industrialized countries. Downstream valvular lesions may induce secondary mitral regurgitation (MR) and tricuspid regurgitation (TR). Although quite unusual, significant pulmonary regurgitation (PR) may occur, as a result from endocarditis or carcinoid disease, and, even more rarely, from left-sided valvular disease-related pulmonary hypertension. Because of the high prevalence of coronary artery disease and remote myocardial infarction in patients with degenerative valvular disease, ischemic MR is not uncommon in patients with aortic valve disease. Congenital etiologies are by far less frequent than acquired etiologies [4].

Fig. 13.1
figure 1

Degenerative calcified mitral and aortic valve disease observed in an elderly patient (systolic and diastolic frames, Panel a and b, respectively), and rheumatic valve disease in a young patient (systolic and diastolic frames, Panel c and d, respectively)

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Pathophysiology and Diagnosis

Hemodynamic and clinical consequences of a single valvular lesion may vary according to the concomitant presence of a stenotic or regurgitant lesion on another valve [4]. Several factors, including the specific combination of MVD, the severity and timing of onset of each individual lesion, the loading conditions, and the ventricular systolic and diastolic performance may modulate the expression of these lesions.

As in single valve disease, Doppler-echocardiography is the cornerstone of the diagnosis and, hence, of the management of MVD. It provides detailed and non-invasive information about the etiology, mechanisms, severity, progression and repercussions of each valvular lesion, and thus contributes to determine the indication and timing for intervention, as well as the choice of therapeutic procedure (surgical versus transcatheter approach). However, several methods routinely used to assess valvular disease have only been validated in single valve disease. If not correctly interpreted, echocardiography may be misleading in the setting of MVD. The main hemodynamic interactions and consequences of MVD, that may impact the echocardiographic diagnosis, are as follows: (1) Low flow, low gradient stenosis is frequent in the setting of MVD; (2) The continuity equation is inapplicable when transvalvular flows are unequal; (3) Any severe valvular lesion may induce or increase upstream MR and/or TR; and (4) Pressure half-time- derived methods may be invalid in the presence of altered left ventricular diastolic properties due to another valvular disease. The main diagnostic pitfalls are presented in Table 13.1 [4].

Table 13.1 Main diagnostic caveats in the echocardiographic diagnosis of multiple valve disease
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When non-invasive evaluation is inconclusive or discordant with clinical findings, cardiac catheterization remains a recommended alternative [6]. However, in patients with severe TR and/or with very low cardiac output, the calculation of aortic or of mitral valve area may be inaccurate with the Gorlin formula using cardiac output assessment by either the thermodilution or the Fick method [7].

When conventional echocardiography is inconclusive, other imaging modalities can be helpful. However, there is currently only limited data supporting a role for multimodality imaging in the setting of MVD. Alternative techniques may prove useful in selected challenging cases, particularly in the setting of low flow states. These include three-dimensional echocardiography, low dose dobutamine stress echocardiography, and multidetector computed tomography (MDCT). In patients with inadequate acoustic windows or in case of discrepant results, cardiac magnetic resonance (CMR) allows to assess the severity of valvular lesions, particularly in regurgitant lesions, as well as ventricular volumes and systolic function [8]. However, similarly to echocardiography, the assessment of regurgitant fraction and volume by calculating ventricular volumes may be inaccurate in the presence of MVD, as it assumes that only one valve is affected [9].

Aortic Stenosis and Mitral Regurgitation

The long-standing increased afterload associated with severe aortic stenosis (AS) may eventually result in LV dilatation, dysfunction, and hypertrophic remodeling. These morphological and functional changes may lead to mitral leaflet tethering and mitral annular dilatation, and thus, promote the development of secondary MR. In addition, concomitant coronary artery disease is highly prevalent in the elderly, and the combination of aortic valve disease and ischemic MR is not uncommon. Primary MR may result from degenerative and calcified mitral valve disease whose prevalence is also high in the elderly [10]. Less frequently, mitral valve prolapse may occur in patients with severe degenerative AS.

AS and MR jets should be differentiated. MR jet has a higher velocity than the AS jet, and includes the isovolumic contraction and relaxation periods, therefore starting earlier and lasting longer than the latter (Fig. 13.2, top panel).

Fig. 13.2
figure 2

Continuous wave Doppler flows recorded from the apex in a patient presenting a combination of mixed aortic valve disease and mixed mitral valve disease. Top panel: aortic flow demonstrating the timing of anterograde (peak aortic velocity 4 m/s) and regurgitant flows. Lower panel: mitral flow recorded from the apex, demonstrating the timing of mitral regurgitation (peak systolic velocity: 6.8 m/s) and forward flow. Unlike regurgitant flows, aortic and mitral forward flows do not include the isovolumic contraction and relaxation periods (red and yellow asterisks, respectively)

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AS increases LV systolic pressure, and, therefore, the systolic pressure gradient across the mitral valve also increases, resulting in a higher mitral regurgitant volume and a larger colour-flow mapping area, whereas mitral regurgitant orifice is usually lesser affected [11]. In addition, significant MR may decrease the net forward flow, thereby reducing the transaortic pressure gradient, and, among patients with AS and normal LV ejection fraction, is independently associated with low flow [12]. Three-dimensional echocardiography and MDCT may provide more accurate left ventricular outflow tract assessment, and thereby can be used to improve the accuracy of aortic valve area assessment [13]. Dobutamine stress echocardiography (if ejection fraction is reduced) and aortic valve calcium scoring by MDCT (if ejection fraction is preserved) can be used to distinguish true severe from pseudo-severe AS and to confirm its severity. A calcium scores of >2000 AU in men and >1200 AU in women are strongly suggestive of severe AS [6]. A typical example of a patient with a low flow state associated with coexistent MR in whom MDCT allowed to confirm severe AS is presented in Fig. 13.3.

Fig. 13.3
figure 3

Panel a: Mid-systolic transthoracic echocardiographic parasternal long-axis view showing severe mitral regurgitation due to mitral valve prolapse. Left ventricular (LV) ejection fraction is 70%. The aortic valve is severely calcified (Panel b). Panel c shows the continuous wave Doppler interrogation of the aortic valve, with a 26 mmHg mean pressure gradient and a 340 cm/s maximal velocity. With a LVOT diameter of 21 mm (Panel d) and a LVOT velocity-time integral of 13.7 cm by pulsed wave Doppler (Panel e), the calculated forward stroke volume in the LVOT is 47 mL (indexed stroke volume 30 mL/m2), consistent with a low flow state. Aortic valve area is 0.61 cm2. Panel f: Non-contrast multi-detector computed tomography shows severe valve calcification (aortic valve calcium score 4500 AU), consistent with true severe aortic stenosis. Thus, computed tomography allows confirming true severe paradoxical aortic stenosis, with the low gradient and the low flow state being related to the coexistence of severe mitral regurgitation

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Aortic Stenosis and Mitral Stenosis

The reduction in cardiac output, observed in combined AS and mitral stenosis (MS), is usually greater than what is seen in isolated AS or MS, and this infrequent combination is usually poorly tolerated. Due to their mutual effect, stroke volume may be markedly reduced and, hence, both aortic and mitral pressure gradients may be lower than expected even if LV ejection fraction is preserved. In this situation, aortic valve calcium scoring by MDCT can be used to confirm AS severity. Due to altered LV diastolic properties, the pressure half-time method is unreliable for assessing mitral valve area. In the absence of concomitant MR and/or AR, the assessment of mitral valve area should include the use of the continuity equation. In selected patients, 3D echocardiography can be used to measure mitral valve anatomic area and confirm MS severity [14].

Aortic Regurgitation and Mitral Stenosis

MS and AR induce opposed effects on LV preload. Indeed, preload is decreased by MS, while it is increased by AR. Hence, LV volumes [15], stroke volume, and regurgitant volume may be lower than in isolated AR [16], which may blunt the typical clinical signs of AR.

AR and MS jets should be differentiated. The AR jet has a higher velocity than the MS jet and includes the isovolumic relaxation and contraction periods, and therefore starts earlier and lasts longer than the latter (Fig. 13.2, lower panel). Both the continuity equation and the pressure half-time method to assess mitral valve area are unreliable in this setting. 3D echocardiography may be useful to determine MS severity [17].

Aortic Regurgitation and Mitral Regurgitation

Aortic regurgitation (AR) and MR both contribute to volume overload, which may result in marked LV dilatation and dysfunction [18]. Currently, normal mitral valve competence protects the left atrium from the deleterious effects of increased LV pressure in patients with AR. However, the presence of concomitant MR may contribute to poor clinical tolerance, resulting in pressure overload on left atrium, pulmonary circulation and right heart chambers. Postoperative LV dysfunction is frequent after AVR for AR [19], and although LV function may improve after surgery [20], persisting symptoms are more frequent than in patients operated for isolated AR. Survival rates are lower in combined AVR and MVR compared to patients operated for isolated symptomatic MR [21].

Both Doppler volumetric methods using left-sided assessment of forward flow and cardiac magnetic resonance imaging using volumetric methods are invalid in this setting.

Tricuspid Regurgitation and Left-Sided VHD

Secondary TR is highly prevalent among patients presenting with left-sided VHD, and may occur as a result of mitral and of aortic valve disease [22, 23]. Secondary TR impacts both long-term functional capacity and survival after treatment of the left-sided VHD [23]. In the setting of downstream VHD, many factors including pulmonary hypertension, atrial fibrillation, right ventricular dilatation and dysfunction, leaflet tethering, annular dilatation towards the right ventricular free wall, and/or right atrial enlargement may contribute to the occurrence and severity of TR. TR is highly sensitive to changes in loading conditions; therefore, rather than TR severity itself, annular dilatation and leaflet coaptation might be better predictors for the subsequent development of TR [24, 25].

Management Strategy

Current evidence on the management of MVD is limited, and most American Heart Association/American College of Cardiology (AHA/ACC) and European Society of Echocardiography/European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines have been given a C level of evidence [6, 26, 27]. The number of possible combinations, and the heterogeneity in terms of etiology and severity currently preclude a standardized approach, and the management of these patients remains particularly challenging. Nevertheless, three main clinical scenarios may be encountered [28] (Fig. 13.4):

  1. 1.

    When two or more severe lesions are present, the likelihood of severe functional intolerance is high if one of the lesions is left untreated, and all severe lesions are usually being addressed. Current ACC/AHA guidelines on the management of VHD have given to severe AS, AR, MS, primary MR, TR and TS a class I recommendation for concomitant procedure while undergoing other cardiac surgery [26, 27], whereas mitral valve surgery for severe secondary MR (stage C and D) in patients undergoing aortic valve replacement has received a class of recommendation IIa [27]. Similarly, 2017 ESC/EACTS guidelines have given a class of recommendation I for concomitant valve surgery in patients with severe AS, AR, secondary MR and TR [6].

  2. 2.

    When one severe lesion is associated with one or more non-severe lesion(s), the most severely diseased valve should be managed according to current guidelines. However, the management of the less-than severe lesion(s) is less straightforward, and, in most situations, a class II recommendation has been given for intervention [6, 26, 27] (Table 13.2).

  3. 3.

    Two or more moderate lesions may induce a significant overall hemodynamic burden and may cause symptoms and/or LV systolic dysfunction. The exact prevalence of this scenario is unknown, and it is not covered by current guidelines. Before considering intervention, it is of particular importance to determine the global consequences of all lesions, which may include the assessment of natriuretic peptides levels, of maximal exercise capacity and of peak oxygen consumption, in addition to conventional imaging parameters.

Fig. 13.4
figure 4

Clinical scenarios and decision-making in the management of patients with multiple valve disease

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Table 13.2 Indications for concomitant valve surgery on a less than severe valve lesion in patients undergoing surgery on another valve, according to the AHA/ACC and ESC/EACTS guidelines [6, 26, 27]
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Decision-Making in MVD, and the Role of the Heart Team

European guidelines recommend a Heart Team-based management strategy [6] and highlight the importance of a collaborative multidisciplinary inpatient team approach including cardiologists and cardiac surgeons in the setting of Heart Valve Centers [29], linked to dedicated and structured outpatient Heart Valve Clinics [30]. The decision-making in patients with MVD should include imaging and clinical factors and has to be individually tailored. For instance, whether or not leaving unoperated a less-than-severe valve lesion at the time of treating another valve requires the integration of numerous factors, which include the followings:

  • The natural history of an untreated valve may help to predict the likelihood and timing of a potential reoperation [31]. For instance, the progression rates of moderate AS are faster in patients with degenerative disease [32,33,34,35] than in those with rheumatic or congenital AS [36,37,38] as well as in patients with higher degree of valvular calcifications and higher degree of severity [35, 38]. The progression rate of isolated AR is low, in particular in rheumatic AR [37, 39, 40]. The rate of progression of MS of rheumatic etiology is highly variable, but is faster with higher transmitral pressure gradient and echocardiographic scores [41, 42]. Importantly, the expected progression rate of the non-severe lesion should be balanced again the estimated life expectancy, but inter-individual variability is high, and unexpected progression rate may occur (Fig. 13.5).

  • Treatment of a downstream valve lesion may impact the severity of MR and/or TR. Even severe MR may improve following surgical or transcatheter aortic valve replacement (TAVR). Although the degree of severity of secondary MR tends to decrease after aortic valve replacement—particularly in the absence of pulmonary hypertension, of left atrial dilatation, of atrial fibrillation and of low aortic mean gradient-, individual responses may be variable, and pre-procedural identification of the responders remains challenging (Fig. 13.6) [43]. A marked decrease in MR severity is unlikely for primary degenerative MR.

    Secondary TR is highly load-dependent. However, the presence of tricuspid annular dilatation despite moderate or lesser degrees of TR at the time of left-sided valve surgery is associated with a risk of TR progression and of redo surgery for severe TR. This has led to lower down the threshold for performing concomitant restrictive ring annuloplasty repair, despite limited evidence supporting current recommendations (Fig. 13.7). In addition to annular dilatation, evidence of right heart failure, leaflet tethering and atrial fibrillation should also be considered in the decision-making. Similarly, TR may spontaneously improve after transcatheter pulmonary valve replacement but predictors and long-term durability of this improvement remain largely unknown [44].

  • The individual surgical risk profile markedly influences the decision-making. Improved perioperative and postoperative care achieved in the last decades have contributed to better long-term survival after multiple valve surgery [45], but operative mortality of double valve replacement remains on average two-fold greater than that of single valve replacement [1, 3, 46,47,48]. Several risk factors influencing the operative risk and outcomes after multiple valve surgery have been identified, which include age, New York Heart Association class IV, pulmonary hypertension, reduced LV ejection fraction, atrial fibrillation, emergency presentation, reoperation and associated coronary artery disease [45, 46, 49,50,51]. Noticeably, both the Society of Thoracic Surgeons scoring system and EuroSCORE II have been shown to reliably assess operative mortality for single-valve surgery [52, 53], but their role in multiple valve surgery have not been validated [52].

  • The possibility of valve repair and the feasibility of transcatheter approaches should be evaluated. Mitral valve repair plus aortic valve replacement has been shown in some series to lower operative mortality and to improve late survival as compared to double-valve replacement [54] but this observation was not confirmed by others [55]. Therefore, repairing or replacing mitral valve in patients undergoing aortic valve surgery remains a matter of debate. As in single valve disease, a “case by case” management strategy should be followed, considering: valve anatomy and likelihood of successful and durable valve repair, the availability of surgical expertise, and patient’s condition [6].

Fig. 13.5
figure 5

At the time of mitral valve repair, this patient presented mild aortic regurgitation. Despite excellent mitral valve repair results (Panel a: normal diastolic opening of the MV valve; Panels b and c: trivial residual mitral regurgitation), moderate to severe aortic regurgitation developed during a 10 years follow up (Panel d and e: 3-Chamber apical TTE views showing aortic regurgitant jet; Panel f: Continuous wave Doppler demonstrating an aortic regurgitation slope of 3.5 m/s

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Fig. 13.6
figure 6

Examples of improvement (Panel a and b) and of deterioration in mitral regurgitation post TAVR (Panel c and d)

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Fig. 13.7
figure 7

Panel a: Moderate tricuspid regurgitation detected by color flow Doppler in apical 4 chamber view obtained in a patient with severe mitral regurgitation due to mitral valve prolapse. Panel b: End-diastolic tricuspid annulus measures 40 mm. This clinical situation represents a class IIa indication for concomitant tricuspid annuloplasty according to both the AHA/ACC and ESC/EACTS guidelines

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The role of transcatheter interventions in MVD is currently ill-defined. Small series on highly selected patients have shown the feasibility of combining TAVR and percutaneous edge-to-edge procedure, usually as staged procedures (Fig. 13.8). More recently, there has been some experience of concomitant TR and MR correction with the percutaneous edge-to-edge procedure [56]. The time delay between the two procedures might be longer for secondary as compared to primary MR, as further MR improvement may occur several months after the TAVR procedure. Patients whose severe MR persists after TAVR and presenting favorable anatomic conditions might benefit from percutaneous mitral procedures (Fig. 13.8) [57].

Fig. 13.8
figure 8

MitraClip procedure in a patient with persisting symptomatic severe mitral regurgitation due to flail anterior mitral leaflet after a TAVR procedure (Panel a), with minimal residual mitral regurgitation (Panel b). Panel c: fluoroscopic appearance of the aortic valvular prosthesis and of the MitraClip

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TAVI is usually targeted at degenerative AS and percutaneous mitral commissurotomy at rheumatic MS. Therefore, there is usually no indication for combining these two procedures. Preliminary reports have shown the feasibility of transcatheter mitral valve implantation in highly selected patients with MS or MR presenting with extensive mitral valve calcifications who had undergone previous aortic valve replacement [58]. Transcatheter implantation of both aortic and mitral valves might become an option for the treatment of severe degenerative AS and MS in patients with a prohibitive surgical risk [56, 59, 60].

Percutaneous mitral commissurotomy may be indicated in patients with severe MS and moderate aortic valve disease, thereby allowing postponing surgery. Although current guidelines list severe TR among unfavorable anatomical characteristics for performing percutaneous mitral commissurotomy [6], this procedure might be considered in patients presenting contraindications to- or being at high risk for- surgery.

Numerous new percutaneous techniques addressing mitral, aortic, and tricuspid VHD are currently under development and will likely change the therapeutic paradigm, but further studies are needed to clarify their respective role.