Sage Journals: Discover world-class research

Abstract

Multiple and mixed valvular heart disease (MMVD) is defined as the combination of stenotic or regurgitant lesions occurring on ≥2 cardiac valves (ie, multiple valvular heart disease [VHD]) or the combination of stenotic and regurgitant lesions on the same valve (ie, mixed VHD). This condition is frequent in clinical routine, with a notable shift in epidemiology over recent years, marked by a decline in rheumatic heart disease and an increase in degenerative causes. Even if echocardiography stands as the cornerstone for diagnosing VHD, practicians need to remain cautious because some echocardiographic parameters might be invalid in the context of MMVD. Considering echocardiography's pitfalls, MMVD needs to be assessed using multiparametric perspective, including cardiovascular magnetic resonance, cardiac computed tomography, biomarkers, and the assessment of comorbidities. Multimodality imaging seems to be a promising approach to assess patient's prognosis, by providing a precise analysis of cardiac remodeling and an accurate evaluation of MMVD severity. Due to the heterogeneity of this clinical scenario, studies are typically conducted in single centers with a limited number of patients. Therefore, there is a lack of dedicated guidelines regarding the severity assessment and the clinical decision-making for these MMVD patients. The aim of this review is to provide a state-of-the-art using the available evidence on the management of MMVD considering the interactions between different valve lesions, the diagnostic pitfalls, and the strategies that should be considered including the role of multimodality imaging in the presence of MMVD.

Graphical abstract

This is a visual representation of the abstract.

Keywords

cardiac computed tomography cardiovascular magnetic resonance diagnosis and imaging echocardiography mixed valvular disease multimodality imaging specific heart valve disease conditions valve disease severity grading

Key points

Transthoracic echocardiography is the first-line tool for the assessment of VHD. However, some echocardiographic parameters are unreliable in MMVD.

Cardiac CT plays an important role in AS not only by assessing the aortic valve calcium score but also by measuring the aorta and describing the valve morphology.

2D-flow CMR is a powerful technique for assessing valvular regurgitation but is more limited for valvular stenosis. 4D-flow CMR, through direct quantification of the regurgitant jet, appears to be promising in MMVD. However, further studies are needed to confirm its usefulness.

Ventricular remodeling is associated with the presence of LGE on CMR, which is associated with increased mortality and cardiovascular outcomes in patients with single VHD. The value of LGE in MMVD should be evaluated.

There is a severe lack of evidence regarding diagnostic tools, prognostic elements, and treatment recommendations for patients with MMVD. In this context, EACVI-MMVD, a real-life registry of MMVD patients, is currently conducted to provide unique descriptive and prognostic data. This study will be followed by the MULTIVALVE registry that will use a standardized cardiovascular imaging protocol.

Introduction

Multiple and mixed valvular heart disease (MMVD) is a complex pathology with high morbidity and mortality rates.^1,2 Multiple and mixed valvular heart disease is defined as the combination of stenotic or regurgitant lesions occurring on at least 2 cardiac valves (also called multiple valvular heart disease [VHD]) or the combination of stenotic and regurgitant lesions on the same valve (also called mixed VHD). Although this is a highly prevalent condition, there remains a significant lack of data and recommendations, for both diagnosis and treatment.² The complexity of MMVD is mainly due to the difficulty to assess its severity, with unreliable echocardiographic parameters, and the multitude of factors influencing his investigation (loading conditions, timing of their onset, ejection fraction…).³ Thus, many diagnostic challenges remain to be overcome for better therapeutic guiding.

The aim of this review is to provide a state-of-the-art about MMVD, considering etiologies and pathophysiology, multimodality imaging, and treatments.

General Principles

Etiology

Rheumatic heart disease

Despite a big decline in industrialized countries in the past decades,^4,5 rheumatic heart disease (RHD) remains the most common type of VHD worldwide with approximately 40.5 million of people affected, primarily impacting middle- and low-income countries. The peak prevalence of RHD is between 20 and 29 years and after 15 years old, women have a higher prevalence.⁶ Rheumatic heart disease disproportionately affects the most vulnerable and marginalized populations, highlighting the urgent need to improve access to antibiotics and enhance sanitary conditions. Additionally, active efforts are underway to develop Group A Streptococcus vaccines.⁷

Degenerative VHD

By contrast, the burden of degenerative valve disease is constantly increasing in developed countries due to the increase in life expectancy (Figure 1).⁸ In the EURObservational Research Programme Valvular Heart Disease II survey, degenerative cause was the most frequent etiology (>60%) of multiple VHD, followed by RHD (<20%).⁸ Indeed, in this aging population, a degenerative and calcified aortic valve can coexist with a variable degree of calcifications of the mitral annulus.⁹

Figure 1.

Epidemiology of Multiple Valvular Heart Disease (VHD) (modified from Tribouilloy et al⁷).

Other etiologies

Other causes of acquired MMVD include the sequelae of infective endocarditis,¹⁰ thoracic radiotherapy,¹¹ adverse effects of some medications such as ergot-derived agonists or anorectic agents,¹² or Ehlers-Danlos syndromes (Table 1).¹³ Bicuspid aortic valve is one of the main causes of mixed aortic valve disease (MAVD) combining aortic regurgitation (AR) and aortic stenosis (AS).¹⁴ Attention should be paid to cases where MMVD is associated with congenital heart disease, as this is a distinct condition requiring specific recommendations.

Table 1.

Etiologies of Multiple and Mixed Valvular Heart Disease.

Acquired etiologies
Primary valvular heart disease
Cardiovascular disease	Rheumatic heart disease ¹⁷⁴
	Degenerative
	Prior endocarditis ¹⁰
Iatrogenicity	Thoracic or mediastinal radiation therapy¹¹
Iatrogenicity	Side effects of medications: ergot-derived agonists or anorectic agents ¹²
Noncardiovascular	Metastatic carcinoid syndrome ¹⁷⁵
Noncardiovascular	Chronic kidney disease on hemodialysis
Secondary valvular heart disease
Cardiovascular disease	LA and/or LV dilatation/dysfunction for MR
Cardiovascular disease	RA and/or RV dilatation/dysfunction for TR
Congenital etiologies
Congenital aortic valve	Bicuspid aortic valve ¹⁴
Connective tissue diseases	Marfan syndrome
Connective tissue diseases	Ehlers-Danlos syndrome
Others	Trisomy 18, 13 or 15 ¹⁷⁶
	Ochronosis (alkaptonuria)
	Shone's anomaly ¹⁷⁷
	Others including congenital MMVD without trisomy ¹⁷⁸

Abbreviations: LA, left atrium; LV, left ventricle; MMVD, multiple and mixed valvular heart disease; MR, mitral regurgitation; RA, right atrium; RV, right ventricle; TR, tricuspid regurgitation.

Finally, secondary mitral regurgitation (MR) and tricuspid regurgitation (TR) are frequently linked to left ventricle (LV) and right ventricle (RV) dilatation and/or dysfunction, respectively.^15,16 Among patients referred for transcatheter aortic valve implantation (TAVI), approximately 20% have at least moderate secondary MR.¹⁷ In addition, primary and secondary etiologies of MMVD can coexist.¹⁸

Pathophysiology of MMVD

The hemodynamic consequences and the clinical presentation of a VHD are influenced by a concomitant lesion on the same valve (mixed VHD) or on another valve (multiple VHD). Pathophysiology is complex, depending on affected valves, time of onset, severity of each individual valvular defect, pathogenesis, loading conditions, and overall ventricular function.¹⁹ For example, secondary MR can result from leaflet tethering and mitral annular dilatation due to increased afterload in AS, or from left ventricular dilatation in AR.³ Similarly, secondary TR can be classified as ventricular, associated with primary or secondary MR, or atrial, associated with concomitant atrial fibrillation, which is common in VHD.

Adaptive mechanisms and ventricular remodeling help to maintain equilibrium until heart failure and first symptoms develop. A key pathophysiological feature is that some valvular lesions may exacerbate or, on the contrary, alleviate a concomitant VHD. For example, the clinical expression of AR is different with mitral stenosis (MS), which limits volume overload, and with MR, which may exacerbate it.^13,20 Similarly, the treatment of a valvular lesion can influence another, as seen in the treatment of AS, which often leads to a reduction in the severity of MR.^17,18

Global Evaluation and Management

As already mentioned, the hemodynamic impact of MMVD on blood flow, ventricular dimensions, and function can significantly influence the diagnostic process. When valvular lesions exhibit comparable severity, the presence of a proximal VHD may attenuate the full expression of a concurrent distal VHD. For example, in a scenario where a patient presents with severe mitral and tricuspid VHD, the clinical manifestations related to the right-sided lesion will likely be more pronounced.¹³ Physical examination findings may be misleading, particularly regarding the timing and intensity of murmurs detected upon auscultation. In this review, we will detail the importance of a multiparametric approach in echocardiography for accurately quantifying stenoses or regurgitation.²¹ Besides echocardiography, multimodality imaging has become essential in the evaluation of MMVD,²¹ through 2-dimensional (2D) flow and 4-dimensional (4D) flow sequences in cardiovascular magnetic resonance (CMR) for the evaluation of regurgitant lesions, and the quantification of the aortic valve calcifications as marker of AS severity or to detect an aortic root dilatation using cardiac computed tomography (CT).²²

Cardiovascular Multimodality Imaging

Cardiovascular Imaging in MMVD Patients

Echocardiography

Echocardiography is the main tool for assessing VHD, especially given its accessibility and routine use in clinical practice. It plays a crucial role in the diagnosis, assessment of the etiology (Table 1), severity and clinical impact of the disease, as well as in the evaluation of the feasibility of surgical or percutaneous interventions. Moreover, echocardiography is essential in guiding treatment decisions and determining the optimal timing for intervention.

While echocardiography stands as the cornerstone for assessing VHD, some echo techniques routinely employed to assess stenosis or regurgitation have been validated primarily in patients with single-VHD, potentially limiting their validity in the context of MMVD (Tables 2 and 3).

Table 2.

Multimodality Imaging in Multiple Valvular Heart Diseases.

		TTE-TOE		CT	CMR (a)
		Reliable	Unreliable	CT	CMR (a)
Left-sided VHD	AS + MR	Planimetry of the mitral regurgitant orifice area EROA (PISA method) Mitral vena contracta	Mitral regurgitant volume (PISA method) Mitral color flow jet area Mitral regurgitant jet should not be mistaken for the AS jet Aortic pressure gradient (underestimated) Dobutamine TTE for low-flow, low-gradient AS	Aortic valve calcium score	Mitral regurgitant volume by indirect method (b) – exercise caution in stroke volume calculation 2D and 4D flow methods in progress
	AR + MR	Planimetry of the mitral regurgitant orifice aera EROA and mitral regurgitant volume (PISA method) EROA and aortic regurgitant volume (PISA method) Vena contracta for AR and MR	Volumetric method for AR and MR Mitral-to-aortic VTI ratio PHT (underestimated) Cardiac output underestimated (usable only if high cardiac output)		Aortic regurgitant volume and fraction by 2D flow Mitral regurgitant volume by indirect method (c) 4D flow method in progress
	AS + MS	2D/3D mitral valve anatomic area MVA by the continuity equation MVA by the PISA method AVA by the continuity equation	PHT (underestimate the mitral valve aera) Mitral pressure gradient (underestimated) Aortic pressure gradient (underestimated)	Aortic valve calcium score Annular calcification Mitral valve area
Left-sided VHD + TR ¹⁷⁹		EROA (PISA method) Regurgitant volume (PISA method) Vena contracta Density and jet contour of the doppler trace Systolic flow reversal in the hepatic vein	Systolic pulmonary artery pressure in case of laminary TR	Tricuspid annulus measurement	Tricuspid regurgitant volume by indirect method (d) – not applicable in case of associated AR Mitral regurgitant volume by indirect method (b) 2D and 4D flow methods in progress RV volume RV function

Abbreviations: AR, aortic regurgitation; AS, aortic stenosis; AVA, aortic valve area; CMR, cardiovascular magnetic resonance; CT, computed tomography; EROA, effective regurgitant orifice area; LV, left ventricle; MMVD, multiple and mixed valvular heart disease; MR, mitral regurgitation; MS, mitral stenosis; MVA, mitral valve area; PHT, pressure half-time; PISA, proximal isovelocity surface area; RV, right ventricle; TOE, transesophageal echocardiography; TR, tricuspid regurgitation; TTE, transthoracic echocardiography; VHD, valvular heart disease; VTI, velocity-time integral.

(a) For any combination of MMVD, LV volume, mass and function can be accurately assessed by CMR.

(b) Mitral regurgitant volume = (LV end-diastolic volume – LV end-systolic volume) – aortic systolic ejection volume.

(c) Mitral regurgitant volume = (LV end-diastolic volume – LV end-systolic volume) – aortic systolic ejection volume – AR volume.

(d) Tricuspid regurgitant volume = (RV end-diastolic volume – RV end-systolic volume) – pulmonary artery systolic ejection volume.

Table 3.

Multimodality Imaging in Mixed Valvular Heart Diseases.

	TTE-TOE		CT	CMR (a)
	Reliable	Unreliable	CT	CMR (a)
AR + AS	Peak aortic jet velocity and doppler mean gradient (prediction of event-free survival)³² AVA by the continuity equation Regurgitant volume and fraction (PISA method) Vena contracta Diastolic flow reversal in the descending aorta – abdominal aorta – femoral arteries	PHT	Aortic valve calcium score	AR regurgitant volume and fraction by 2D flow 4D flow method in progress
MR + MS	EROA (PISA method) Volumetric method Vena contracta Doppler mitral gradient (good reflect of the global severity) ³ 2D/3D mitral valve anatomic area	PHT MVA by the continuity equation (underestimated) Mitral-to-aortic VTI ratio	Mitral valve area	Mitral regurgitant volume by indirect method (b) 2D and 4D flow methods in progress

Abbreviations: AR, aortic regurgitation; AS, aortic stenosis; AVA, aortic valve area; CMR, cardiovascular magnetic resonance; CT, computed tomography; EROA, effective regurgitant orifice area; LV, left ventricle; MMVD, multiple and mixed valvular heart disease; MR, mitral regurgitation; MS, mitral stenosis; MVA, mitral valve area; PHT, pressure half-time; PISA, proximal isovelocity surface area; RV, right ventricle; TOE, transesophageal echocardiography; TTE, transthoracic echocardiography; VTI, velocity-time integral.

(a) For any combination of MMVD, LV volume and function can be accurately assessed by CMR.

(b) Mitral regurgitant volume = (LV end-diastolic volume – LV end-systolic volume) – aortic systolic ejection volume.

To avoid measurement errors, the assessment can be supplemented with transesophageal echocardiography (TOE) and 3D echocardiography methods, which provide a more reliable analysis of volumes and anatomy. However, it represents a real technical challenge and a recent international survey showed a relatively low level of skills and knowledge in TOE among young cardiologists in this situation.²³

Cardiac CT

Cardiac CT has become a crucial tool for assessing both AS severity and preprocedural work-up of TAVI. Aortic stenosis severity can be assessed by quantifying valvular calcium burden using the Agatston score.²⁴ Women exhibit less calcification but more fibrosis than men at equivalent levels of AS severity, necessitating distinct thresholds for defining severe AS: >1200 Agatston units (AU) for women, and >2000 AU for men.²⁵ However, the assessment of AS severity should not solely rely on one parameter. In RHD or in cardiac amyloidosis without severe calcifications, these thresholds may not accurately reflect the severity of AS.²⁶ Mitral annulus calcification (MAC) is common in patients with MMVD, being observed in 50% of patients with concomitant severe AS.²⁷ Although there is currently no validated standardized scoring system for its quantification,²⁸ cardiac CT appears to be a relevant tool for defining the severity of MAC and predicting valve embolization/migration during valve-in-MAC procedures.²⁹

Cardiovascular Magnetic Resonance

Cardiovascular magnetic resonance uniquely allows for direct measurement of flow using the “phase contrast” method, bypassing the complex equation-based calculations required by echocardiography. It also provides flexibility in the selection of imaging plane positioning, independently of probe placement or of the limitations imposed by the acoustic windows that can restrict echocardiography. Direct measurement of regurgitation volume in AR, performed through 2D-flow measurements at the aortic root, is generally unaffected by concomitant aortic or MS, or MR. However, in cases of concurrent AS, the measurement of aortic flow can be underestimated due to intravoxel signal dephasing caused by the stenosis jet.^30,31 Direct phase-contrast imaging at the mitral valve for measuring forward and backward flow is not recommended to assess MR.³² The preferred indirect method for calculating the MR volume employs the following formula: regurgitant volume = (LV end-diastolic volume – LV end-systolic volume) – aortic systolic ejection volume. This approach remains valid in the presence of AR but the presence of AS may compromise the accuracy of this method in determining systolic ejection volume.³² Notably, CMR using 2D-flow is not a good method to assess the severity of valvular stenosis, due to the slick image slice, partial volume effects, lower temporal resolution compared to Doppler echo, and signal loss due to turbulence.³³ Indeed, several studies have shown the risk of underestimation of valvular stenoses.^34,35

In centers with local expertise, 2D flow can be replaced by 4D-flow to measure transvalvular flow. The latter is a relatively novel CMR technique, which offers time-resolved 3-dimensional (3D) imaging and enables the measurement of blood flow within a 3D volume in a single acquisition, covering the entire heart.^36,37 This allows for the quantification of flow across all 4 valves using the same 4D-flow dataset, which may be highly beneficial in assessing MMVD³⁸ as no assumptions on regurgitant jet morphology are required. However, current literature in 4D flow CMR is mainly related to single valve disease, and there are limited data on the specific additional value of 4D-flow compared to 2D-flow in this context.³⁹ Cardiovascular magnetic resonance is currently recommended for single VHD when transthoracic echocardiography (TTE) data are unreliable (inadequate echocardiographic quality or discrepant results, eccentric, multiple, and late-systolic regurgitant jets) and for assessing LV/RV volumes and fibrosis. Although CMR appears to reliably assess valvular regurgitation in complex cases such as MMVD (grade I recommendation),²⁵ its use is currently limited by its accessibility.

Interpretation of Cardiovascular Imaging for Each Combination of MMVD

Aortic stenosis and MR

Aortic stenosis with MR is the most common MMVD scenario, accounting for 54% of left-sided multiple VHD.⁸ As with any VHD, the initial assessment is made by TTE. However, the increased afterload resulting from AS complicates the assessment of MR severity. While regurgitant volume and the area of the color flow jet are anticipated to be higher, the effective mitral regurgitant orifice and vena contracta are less affected (Table 2). The advent of CMR using 2D and 4D flow to measure regurgitant volume is a promising method.^32,40 However, 2D and 4D flow may also be susceptible to inaccuracies in the setting of AS and requires further investigation.

Mitral regurgitation influences the clinical presentation of AS by reducing forward flow and contributing to a low-flow state. The transaortic pressure gradient is often low despite a small aortic valve area (AVA), resulting in a low-flow low-gradient AS.^3,18 Current guidelines recommend dobutamine stress echocardiography to assess low-flow low-gradient AS.²⁵ However, when resulting from MR, low-flow low-gradient AS is often associated with preserved left ventricular ejection fraction, and dobutamine stress TTE is not recommended in these cases; secondly, inasmuch as even if there is contractile reserve, there will be no significant effect on forward stroke volume. In this setting, cardiac CT can be used to assess the aortic valve calcium score which is correlated with the degree of AS (Figure 2).²⁵

Figure 2.

Association of Aortic Stenosis with Mitral and Tricuspid Regurgitation. Clinical context: a 73-year-old female with degenerative aortic stenosis, and mitral and secondary tricuspid regurgitation. (A) Three-chamber transthoracic echocardiography (TTE) showing a calcified aortic valve and P2 prolapse. (B) Four-chamber view with and without color Doppler showing enlargement of the left and right atria, prolapse of the posterior mitral valve with mitral regurgitation and a large vena contracta and secondary tricuspid regurgitation with a large vena contracta. (C) Severe pulmonary hypertension estimated at 55 mm Hg + right atrial pressure. (D) Severe low-gradient aortic valve stenosis (peak jet velocity of 3 m/s and aortic valve area estimated at 0.49 cm²). (E) Reversal of subhepatic vein flow in favor of severe tricuspid regurgitation. (F) Noncontrast computed tomography (CT) scan showing a heavily calcified tricuspid aortic valve (aortic valve calcium score 2300 Agatston units [AU]).

Aortic Regurgitation and MR

Although the diagnosis and quantification of associated AR/MR severity are primarily echocardiography-based, the quantitative assessment of both valve diseases remains challenging (Table 2). Whereas clinicians frequently use the pressure half-time (PHT) for assessing the AR severity, PHT is less reliable in the presence of MR due to the altered LV diastolic properties. Furthermore, the semiquantitative assessment of the severity of isolated MR by the mitral to aortic velocity-time integral ratio cannot be used in the presence of significant AR.⁴¹

Cardiovascular magnetic resonance could be very useful to assess the AR/MR severity (Figure 3). Indeed, it can directly quantify regurgitant volume and fraction of AR using 2D-flow measurements at the aortic root. This method is not affected by the coexisting MR, which is evaluated by subtracting the systolic (forward) flow above the aortic valve from the LV stroke volume.^30,31 The MR severity can also be assessed using an indirect method for calculating the regurgitation volume with the following formula: regurgitant volume = (LV end-diastolic volume – LV end-systolic volume) – aortic systolic ejection volume – AR volume.³² This approach to quantify MR severity remains valid in the presence of AR. Left ventricle dilatation or impaired function are strong indicators of a poor prognosis,⁴² and CMR is the gold standard for their assessment.⁴³

Figure 3.

Association of Aortic and Mitral Regurgitation. Clinical context: a 66-year-old patient with severe degenerative aortic and mitral regurgitation. (A) Three-chamber transthoracic echocardiography (TTE) showing P2 prolapse with a flail leaflet. (B) Eccentric jets of aortic and mitral regurgitation. (C) Proximal isovelocity surface area (PISA) radius of the mitral valve of 13 mm at an aliasing velocity of 31 cm/s (effective regurgitant orifice area of 60 mm², regurgitant volume of 67 mL). (D) Aortic valve PISA radius of 10 mm at an aliasing velocity of 31 cm/s (effective regurgitant orifice area of 45 mm², regurgitant volume of 65 mL). (E-G) Cardiac MRI assessment of the severity of mitral and aortic regurgitations including: a regurgitant volume of 55 mL (regurgitant fraction 55%) for mitral regurgitation, and 65 mL (regurgitant fraction 39%) for aortic regurgitation (left ventricular stroke volume: 165 mL, aortic flow forward [phase contrast]: 110 mL, and aortic backward flow [phase contrast]: 65 mL).

Aortic Stenosis and MS

The combination of AS and MS is not uncommon (19% of patients with 2 severe left-sided VHD without severe TR⁸) and represents a real diagnostic challenge. Indeed, in this low-flow situation, both aortic and mitral pressure gradients can be low despite a small surface area.⁴⁴ Furthermore, the mitral flow PHT may underestimate the mitral valve area due to the reduced LV compliance caused by AS. The continuity equation and mitral valve area planimetry remain solid methods, but calcifications complicate measurement in cases of degenerative MS (Table 2). The degenerative cause is becoming more prevalent than the rheumatic cause, increasing the role of the cardiac CT. Computed tomography also provides important information on annular calcification and mitral valve area,⁴⁵ which correlates with the severity of MS (Figure 4).⁴⁶

Figure 4.

Association of Aortic Stenosis and Mitral Stenosis. Clinical context : a 78-year-old female patient with degenerative calcified aortic stenosis and mitral stenosis. (A and B) Severe calcification of the mitral annulus, mitral valve, and aortic valve. (C and D) Low-flow, low-gradient severe aortic stenosis with a peak aortic jet of 3 m/s, estimated aortic valve area of 0.45 cm² and a calculated indexed systolic ejection volume of 18 mL/m². (E) Mean mitral valve gradient elevated to 9 mm Hg. (F) Planimetry of the aortic valve using multiplanar reconstruction in 3D transoesophageal echocardiography, measured at 0.8 cm². (G) 3D “en-face” view of the mitral valve showing severe annular calcifications. (H) Contrast-enhanced computed tomography (CT) planimetry of the aortic valve, measured at 0.95 cm².

Aortic Stenosis and AR (Mixed Aortic Valvular Disease)

Echocardiography is a key diagnostic tool for MAVD (Figure 5), but conventional parameters for assessing isolated AS or AR have limitations (Table 3). Peak aortic jet velocity and mean gradient increase not only with AS but also with AR due to a greater stroke volume. Even with an AVA greater than 1 cm², severe pressure overload occurs.³ Yet, the continuity equation remains a reliable estimate of AVA in this setting.⁴⁷ The impaired LV relaxation secondary to the LV hypertrophy makes the PHT method unreliable for AR assessment.⁴⁸ Usually, MAVD results in less pronounced LV dilatation due to AS-induced remodeling. As a result, even a moderate regurgitant volume may be clinically more significant in a normal or slightly dilated LV compared with a markedly dilated LV. For that reason, Unger et al suggested to use the regurgitation fraction rather than the regurgitant volume in this situation.⁴⁹ If feasible, the use of vena contracta remains valid, such as femoral diastolic flow reversal or abdominal flow reversal, which are even more specific for AR severity than descending aortic flow reversal.

Figure 5.

Aortic Stenosis and Aortic Regurgitation (Mixed Aortic Valvular Disease). Clinical context: a 55-year-old patient with severe mixed aortic valve disease. Transthoracic echocardiography shows severe aortic regurgitation and high gradient aortic stenosis despite persistent aortic valve opening. (A) The aortic valve is moderately calcified, and the aortic annulus is large (26 mm). (B) Short-axis view showing a bicuspid aortic valve with a raphe between the right and noncoronary cusps (red arrow) and persistent aortic valve opening. (C and D) Presence of severe aortic regurgitation with a high end-diastolic velocity (31 cm/s) in the descending aorta (C) and a large proximal isovelocity surface area (PISA) radius of 10 mm at an aliasing velocity of 30 cm/s (D). (E) High gradient aortic stenosis with peak jet velocity greater than 5 m/s. (F) Increase in cardiac output estimated at 10.5 l/min. The aortic valve area is calculated at 1.3 cm² by the continuity equation.

More generally, the aortic mean pressure gradient is a good reflection of the MAVD severity with a value > 40 mm Hg suggesting severe MAVD.

The role of dobutamine stress echocardiography in low-flow low-gradient AS is to discriminate pseudo severe from true severe AS by calculating AVA at a normal flow rate. Aortic valve area <1.0 cm² at a normal flow rate indicates true severe AS. In some cases, at very high flow rates, the same aortic valve could reach an AVA ≥ 1 cm², secondary to the residual valvular compliance.⁵⁰ The same scenario may apply to MAVD because of greater transaortic flow. Some patients may have an AVA ≥1 cm², indicating moderate AS, but that would correspond to <1 cm² at a normal flow rate, in line with severe AS.⁴⁹

Cardiac CT may help to differentiate between true severe and pseudo severe AS by assessment of the aortic valve calcium score (true severe if ≥2000 AU in men and ≥1200 AU in women).⁵¹

Mitral Stenosis and MR (Mixed Mitral Valvular Disease)

The association of MS and MR is not frequent representing 5% of VHD patients.⁵² Rheumatic heart disease and degenerative etiology with MAC are the main causes.⁵³ Interestingly, MR elevates the flow rate through the mitral valve, leading to an increase in left atrial (LA) pressure, particularly in individuals with associated MS.³ Echocardiographic assessment of MR severity is challenging, particularly with severe calcifications that obscure the jet area.²⁰ Nevertheless, both the proximal isovelocity surface area (PISA) and volumetric method remain applicable (Table 3). For MS assessment, the estimated mitral valve area from PHT is not accurate due to the presence of a significant MR that alters LV compliance. Similarly, the continuity equation is unreliable and may overestimate the severity of MS.^3,20 The Doppler mitral gradient reflects the global severity of mixed mitral VHD, and a value greater than 10 mm Hg could be a good criterion of severity.²⁰ Finally, planimetric area is probably the most reliable technique to evaluate the MS severity if feasible. The impact of exercise echocardiography on clinical decision-making is unclear. Although it has been recommended for isolated MS,²⁵ there are currently only limited data in patients with mixed mitral valve disease.^54,55

Cardiac CT using the latest generation scanners has shown acceptable feasibility, accuracy, and reproducibility in assessing mitral valve orifice area measurements and can be helpful in cases of mixed valvular disease with difficulties in performing planimetric area in echocardiography.⁴⁵ Atrial fibrillation, which is common in this population, leads to artifacts limiting its use. In the case of MAC-related mitral valve, the mitral annulus calcium score is not yet recommended in clinical practice.^28,29 Finally, the assessment of MR by CMR is helpful using the indirect method, already mentioned above.^32,56

Left-Sided VHD with TR

Secondary TR frequently complicates left-sided VHD²⁵ through pulmonary hypertension, RV dilatation and dysfunction, and annular dilatation.^3,18,57 Furthermore, increased RV filling pressure may contribute to the development of right atrial dilatation and atrial fibrillation, both of which can cause and exacerbate TR.⁵⁸

Tricuspid regurgitation evaluation is commonly made by echocardiography (Figure 2, Table 2).^25,59 However, a multimodal approach could be used, with CMR for the regurgitant volume, RV volume and function, and catheterization to estimate pulmonary pressure. Regurgitant volume calculated with 2D PC CMR by using indirect volumetric assessment has been less evaluated than for the mitral valve and RV stroke volume obtained from the RV delineation is more challenging; 4D flow appears to be an interesting technique with a direct measurement avoiding RV delineation.^60,61 Secondary TR may develop late after treatment of the left-sided VHD⁶² and is associated with the worst long-term prognosis.⁶³

In the case of RHD, particular attention should be paid to the assessment of the tricuspid valve and RV function, as well as the pulmonary valve.

Case of MMVD Patients with Prosthetic Valves

Prosthetic dysfunction involving concurrently multiple valves, whether prosthetic and/or native, is not uncommon.⁵⁹ A study assessing the risk of redo valve surgery after bioprosthethic valve replacement found that the most common concurrent cardiac procedure was on a valve other than the failed bioprosthesis, occurring in 27% of cases. Aortic valve replacement was performed in 20% of cases of patients referred for mitral prosthesis dysfunction, and tricuspid annuloplasty or replacement in 21% of cases.⁶⁴

More recently, real-life registries have provided interesting and novel data. The Valve-In-Valve (ViV) International Data registry examined outcomes of transcatheter ViV procedures in 459 patients, of whom about 30% had mixed lesions, involving either the aortic or mitral valve.⁶⁵ Moreover, in a recent study comparing the clinical and echocardiographic outcomes after surgical redo mitral valve replacement and transcatheter mitral ViV therapy among patients with mitral bioprosthesis degeneration, the authors showed that nearly 60% of patients had at least moderate associated MR, 8% had at least moderate AR, and 60% had at least moderate associated TR.⁶⁶ Finally, in the VIVA registry, which evaluated patients referred for aortic in-valve surgery, 21% of patients had a mixed VHD combining AR and AS.⁶⁷

Cardiac Remodeling Due to MMVD

Several studies using CMR have already identified dynamic changes within the myocardial structure during the progression of VHD.⁶⁸ This phenomenon, called ventricular remodeling, not only is necessary to maintain a balance between valve disease severity and cardiac output but also serves as a gateway to heart failure,⁶⁹ worsening secondary valve regurgitations,⁷⁰ and increased mortality and outcomes. Ventricular remodeling is associated with late gadolinium enhancement (LGE) on CMR,^71,72 which is linked to mortality in AS⁷³ and to ventricular arrhythmias in primary MR.⁷⁴ Beyond LGE, T1 mapping, and extracellular volume mapping can be used to better quantify the diffuse interstitial fibrosis.^40,68 Interestingly, recent studies have suggested an important role of LA and LV coupling through a combined index in the left remodeling of ischemic heart disease and some cardiomyopathies.^75,76 Although several important determinants of left atrioventricular coupling index are linked to VHD,⁷⁷ no study has yet evaluated the interest of a combined index evaluating LA and LV coupling in VHD patients. Finally, significant innovations, including high-resolution LGE can better characterize myocardial fibrosis.⁷⁸

Treatments

Current Guidelines

Due to the lack of data to support and direct clinical decision-making, current European and American guidelines on MMVD are still limited and primarily based on small retrospective studies or expert consensus opinion and are therefore mostly Level C recommendations.^25,59 In most cases, one lesion is predominant, and management should follow recommendations for this lesion. However, when 2 or more lesions are moderate, their combined effect may lead to a worse prognosis, even in the absence of associated severe VHD. This often leads to delays in patient management. In such cases, symptom evolution and global assessment—including clinical assessment, LV/RV dilation and dysfunction, and pulmonary hypertension—are key factors in guiding therapeutic decisions, and intervention may be considered.³ However, the increased risk of combined intervention should be evaluated for each patient. Some lesions may benefit from a staged approach. The MMVD's relationships are not yet fully understood, and our understanding of their coexistence in terms of current management remains limited, emphasizing the role of the “Heart valve team.”³ This highlights the unmet need for studies that will help the clinician to tailor the therapeutic strategy in each individual MMVD patients.^8,19

Surgical Valve Replacement

A recent study reported that among patients with severe multiple VHD, only 26% had undergone surgery, among which 57% involved more than one valvular procedure (35% valve replacement and 22% valve repair).⁵⁸ Based on literature data and expert consensus, the main principles guiding the decision to proceed to surgical management of MMVD patients should be the following:

Multiple surgical valve surgery is associated with an increased operative risk.^3,79–81 In particular, triple valve surgery (TVS) remains a high-risk procedure with in-hospital mortality rates ranging from 7% to 11% and significant long-term morbidity, which varies according to population and underlying etiology.^82,83 In younger patients (Middle Eastern countries), RHD is the primary cause of TVS, with diabetes and hypertension being important prognostic factors.⁸⁴ In older populations (Western countries), degenerative valve disease predominates, with factors such as New York Heart Association class IV, renal failure, and redo sternotomy having a significant impact on surgical outcomes.⁸⁵ Furthermore, when feasible, valve repair should be privileged.^86,87

The durability of mechanical prosthesis is advantageous for young patients.⁸⁸ However, this should be balanced against the higher risk of anticoagulation in patients with multiple mechanical valve prostheses.⁸⁹

Assessment of the operative risk is instrumental in the choice of surgical, transcatheter approach, combined, or medical treatment strategy. Some risk scores such as the STS score have been validated for MMVD patients, but lack external validation.^81,90

Minimally invasive surgery is usually limited by its inability to address MMVD.⁸⁸

Surgery is most often advised when at least 2 VHDs are severe unless the patient is at high surgical risk and all lesions are amenable to transcatheter procedures.⁴⁵

When a patient presents a severe VHD requiring surgery, the decision to address another concurrent moderate lesion should be made on an individual basis and should include the likelihood to improvement after treatment of the severe lesion and the natural history of an untreated moderate VHD.³

Percutaneous Valve Replacement

Few studies have assessed the percutaneous management of MMVD with most data from TAVI registries for AS.⁹¹ While AS and AR may increase the risk of transcatheter heart valve (THV) migration due to the hyperdynamic jet during TAVI procedure, the presence of mitral or tricuspid VHD does not pose a significant challenge to TAVI implantation. Although the clinical impact of concomitant baseline VHD on post-TAVI outcomes varies depending on the specific type of baseline VHD,^92,93 there is limited evidence to recommend transcatheter intervention for MMVD. Indeed, while TAVI is becoming a dominant therapeutic option in patients with severe AS and moderate to severe surgical risk, percutaneous valve replacement or transcatheter edge-to-edge repair (TEER) for MR, MS, and TR are still reserved for patients at high surgical risk. Recent TAVI trials emphasize careful preprocedural MR and TR assessment. While functional MR often improves after TAVI due to left ventricular unloading,^94,95 primary MR and significant TR may persist, requiring additional interventions.⁹⁶ Considering the latest data, the evolution of MR remains unpredictable and the superiority of a staged or concomitant mitral-tricuspid approach over isolated TAVI is not established, warranting close imaging follow-up.^97–100 For concomitant severe MS, combining transcatheter mitral valve replacement with TAVI (TMVI) may be an alternative, particularly in cases unsuitable for percutaneous mitral balloon commissurotomy (PMC).^101,102 While concomitant TR as an independent predictor of mortality after TAVI remains controversial,^96,103 staged interventions for TR may still be warranted if symptomatic. Similarly, the efficacy of additional TR procedures in high-risk patients with severe MR undergoing TMVI or TEER repair still needs further investigation.

Valve Repair

Surgical Valve Repair

Whether valve repair or replacement is the optimal surgical strategy should be considered in the decision-making for MMVD patients. Hence, echocardiography is critical not only in determining the indication and timing for surgery but also in predicting the likelihood of successful valve repair.³ Between 2001 and 2017, the rate of surgical valve repair increased from 46% to 51% for MR and from 2% to 22% for AR.² In the STS registry, 23 404 patients underwent concomitant aortic valve replacement and mitral valve surgery between 1993 and 2007.¹⁰⁴ In the context of AS and MR, mitral valve repair should be preferred, if possible, to replacement as studies have suggested late survival improvement.¹⁰⁵ Therefore, efforts should be directed toward improving rates of mitral valve repair, even if prosthetic valve replacement of another valve decreases the willingness of a surgeon to repair the mitral valve. Controversy exists, however, as to whether repair or replacement of the mitral valve should be preferred in patients undergoing aortic valve replacement who have moderate-to-severe secondary M.In this setting, 2 studies showed no benefit from mitral valve repair with aortic valve replacement over double-valve replacement on survival, and an increased long-term incidence of mitral valve failure in patients undergoing mitral repair was even observed.^106,107 Concomitant tricuspid valve repair at the time of left-sided valve surgery is the preferred technique with a lower rate of complications than transcatheter tricuspid valve replacement (TTVR).^57,108–110

Percutaneous Mitral Commissurotomy

Commissurotomy can be performed surgically or percutaneously. It can be used in the context of valvular stenosis, often mitral.²⁵ Double surgical valve replacement is preferable to isolated PMC in patients with severe MS combined with severe aortic valve disease. However, in patients with severe MS and moderate aortic valve disease, percutaneous ballon valvuloplasty can be performed to postpone the surgical treatment of both valves.

Transcatheter Edge-to-Edge Repair

Transcatheter edge-to-edge repair is a minimal-invasive solution that is increasingly used in primary or secondary MR. It has been evaluated against optimal medical therapy, resulting in an upgrade of the recommendation.²⁵ Regarding the tricuspid valve, experience with transcatheter tricuspid valve interventions suggests a potential role in high-risk patients.¹¹¹ In the specific setting of MMVD, multiple transcatheter procedures are feasible, but clinical experience remains limited for robust recommendations.¹¹² In high-risk patients with severe AS and severe secondary MR, combined or often sequential TAVI and TEER may be feasible.¹¹³ In inoperable with severe primary MR, TEER is a safe alternative and should be considered early if symptoms persist and MR is still severe after TAVI. Finally, the efficacy of more recent TEER system iterations will be investigated in high-risk (MITRA-HR study) and intermediate-risk patients (REPAIR-MR study).^114,115

Antithrombotic Management

No international guidelines specify the antithrombotic management for MMVD patients.^25,59

Native Valves

In patients with native valves, antithrombotic treatment depends on associated comorbidities. For atrial fibrillation, which is frequent in MMVD, direct oral anticoagulants (DOACs) are the first-line treatment,^116,117 except in case of MS. Indeed, the INVICTUS study showed that vitamin K antagonists (VKAs) led to a lower rate of a composite of outcomes than rivaroxaban.¹¹⁸

Transcatheter Bioprosthesis

There is no difference in antithrombotic management between single VHD and MMVD, possibly due to a lack of evidence in MMVD patients. Indeed, in patients with aortic transcatheter bioprosthesis, aspirin therapy is recommended as recent studies showed a significant decrease in major bleeding with aspirin over dual antiplatelet therapy.^119,120 After implantation of transcatheter mitral bioprosthesis (TMVI; eg, ViV, valve-in-ring, valve-in-MAC), anticoagulation for 3 months is commonly prescribed. The use of DOACs after TMVI, compared with VKAs, appears to reduce the risk of bleeding complications,^121,122 even though we currently have no data from randomized trials. Vitamin K antagonists are widely used over DOACs for the first 6 months after percutaneous mitral or TTVR (dedicated devices).

Surgical Bioprosthesis or Valve Repair

After aortic valve surgery, if there is no indication of anticoagulation, aspirin is preferable to anticoagulation.^123–125 After mitral/tricuspid valve surgery, anticoagulation for at least 3 months is recommended.^126,127 Although few data are available on the use of DOACs in the 3 months following surgery, there are no alarm signals even while DOACs are widely prescribed.^128,129

Mechanical Valves

Mechanical valves require lifelong treatment with VKAs guided by the international normalized ratio (INR). Direct oral anticoagulants failed to show any benefit and are even harmful.^130,131 Target INR varies between 2.5 and 3.5 and should be based upon prosthesis thrombogenicity and patient-related risk factors. The use of self-monitoring INR must be favored to reduce VKA-related complications.

Multiple and Mixed Valvular Heart Disease Associated with Specific Conditions

Atrial and Ventricular Arrhythmia

Valvular heart disease is independently associated with atrial fibrillation with a prevalence of 30%.¹³² However, while patients with moderate to severe MS and/or mechanical prosthetic should undergo anticoagulation with VKAs, current evidence does not suggest that the presence of other forms of VHD should influence the choice of oral anticoagulation therapy.¹³³ According to a recent study, MMVD in patients with atrial fibrillation does not increase thrombotic risk.¹³⁴ The decision to use oral anticoagulation to prevent thromboembolic events, using either VKAs or DOACs, should be determined through a shared decision-making process. Vitamin K antagonists remain the preferred anticoagulants for patients with rheumatic MS and/or mechanical heart valves. Importantly, the evaluation of these MMVD patients with atrial fibrillation could be very challenging but feasible using an optimized imaging protocol.¹³⁵

Cardiac Implantable Electronic Device–Related VHD

Cardiac implantable electronic device, including pacemakers, implantable cardioverter defibrillator (ICD) may have the potential to induce specific VHDs and may be implanted as a consequence of long-term, untreated VHDs.

Valvular-induced ventricular arrhythmias or even sudden cardiac death, which are more commonly associated with MR, with¹³⁶ or without mitral valve prolapse^137,138 and with AS,¹³⁹ might account for an important number of defibrillator implantations for primary and secondary prevention of sudden cardiac death. Tricuspid regurgitation is the most common complication of device implantation and can be classified into 2 distinct categories: lead-induced TR caused by lead-leaflet interaction,¹⁴⁰ and lead-associated TR, which occurs when preexisting TR is aggravated by devices,^141,142 right ventricular apical pacing only might produce MR due to left ventricular dyssynchronous contraction.^143,144 On the other hand, LV resynchronization could serve as a tool for lowering the degree of MR.¹⁴⁵ Alternative leadless strategies that have demonstrated no worsening of TR after implantation should be considered.¹⁴¹ These include leadless pacemakers or subcutaneous ICDs.^146,147

Finally, for the evaluation of these patients using CMR, although the presence of a defibrillator causes important artifacts, it is important to mention the good feasibility of the CMR exam including 2D-flow in patients with a pacemaker.¹⁴⁸

Cardiac Amyloidosis

Amyloid deposition can involve any cardiac structure, including the valves. The most common VHD in cardiac amyloidosis is AS, particularly in transthyretin amyloidosis,¹⁴⁹ where it often presents with a low-flow, low-gradient pattern. Mitral regurgitation and MS are the next most prevalent VHD.^150,151 The mechanism remains unclear but may involve direct deposit, chronic inflammation, and oxydative stress caused by amyloid infiltration, which ultimately results in calcification, rigidity, fibrosis, and leaflet sclerosis.^152,153 Multivalvular involvement places a significant hemodynamic load on a stiff and dysfunctional myocardium, which negatively contributes to the LV remodeling. Mohty et al demonstrated that mitral and/or aortic valve thickening was associated with higher all-cause mortality.¹⁵¹ The tricuspid valve can also be affected, typically with regurgitation.¹⁵⁴ However, mitral and tricuspid VHD are rarely more than mild or moderate and rarely require valve intervention. Cardiac amyloidosis screening could be interesting in MMVD patients with suggestive signs.¹⁵⁵

Perspectives

Transcatheter Mitral and TVR

Transcatheter mitral valve replacement might serve as an alternative invasive treatment option to overcome the current anatomical constraints of percutaneous repair with the potential to treat mixed mitral valve disease.¹⁵⁶ Multiple devices (using either transseptal or transapical access and using single or multistep approaches depending on devices), specifically designed for this purpose are being evaluated in early feasibility studies as well as pivotal trials. Nonetheless, to date, only one device, the Tendyne (Abbott Structural) system, has received a European conformity mark. The cornerstone of investigating patient eligibility relies on preprocedural planning, which necessitates multimodality imaging assessment. Yet, this process poses a challenge in clinical practice, given the high screening failure rates of around 90%, which emphasize the critical importance of optimizing candidacy.¹⁵⁷ Patients with severe MAC pose a particular challenge and are frequently excluded from most studies evaluating new mitral THVs. This unmet clinical need has been partially addressed by the off-label use of aortic THVs with transseptal access, albeit showing poor outcomes at 1 year therefore raising the question of the futility.^158,159

Similarly, TTVR has emerged as an alternative to isolated TR surgery which is associated with high morbidity and mortality. Several novel percutaneous transcatheter methods for tricuspid valve repair and replacement have been extensively studied in recent years, showing promising clinical results in terms of mortality and rehospitalization within the initial year of follow-up.¹⁶⁰ To date, only one device has been recently approved by both the FDA and CE for commercial use, the Evoque Tricuspid Valve (Edwards Lifesciences).

Risk Stratification Using Machine Learning

To improve decision-making for VHD patients, emphasis should be on identifying factors and developing risk models that will guide clinical decisions.^161,162 To meet this need, traditional risk assessment tools, such as the STS score, have been tailored for VHD and, to a certain extent, MMVD, demonstrating utility in clinical decision-making.^81,163 Nonetheless, many clinical prediction models lack external validation⁹⁰ and fail to fully grasp the intricate dynamics of MMVD. This is particularly concerning given the multidimensional nature of multimodality imaging data in MMVD patients.³ This underscores the need for a paradigm shift toward more personalized decision-making processes.¹⁶²

Machine learning emerges as a promising solution, offering sophisticated tools for handling the nonlinearities inherent in cardiology, and enhancing prognostication and decision-making in cardiovascular disease. Supervised ML improves prediction score,¹⁶⁴ while unsupervised learning is used to perform clustering^165,166 and provides insights into patient phenotypes and risk continuums.¹⁶⁷ Recent advancements have led to ML-driven scores for AS, MR, and TR that surpass traditional models in predicting outcomes.^168–173 However, a specific ML score for MMVD patients, integrating the interactions between valves, remains undeveloped.

Presentation of the EACVI-MMVD Study

Due to this lack of evidence about MMVD, we advocate for the initiation of the first international MMVD registry to: (1) assess the prevalence of MMVD; (2) evaluate management strategies using multimodality cardiovascular imaging; and (3) prognosticate outcomes for MMVD patients. Indeed, the Heart Imagers of Tomorrow of the EACVI is performing the “European Association of Cardiovascular Imaging – Multiple and Mixed Valvular heart Diseases” (EACVI-MMVD) study (ClinicalTrials: NCT06235385) as a large prospective, multicenter, observational “real-life” study including all consecutive patients diagnosed with MMVD using TTE over a 6-month recruitment period in more than 100 centers from more than 20 different countries (Figure 6). The entire spectrum of multimodality imaging data performed in clinical routine will be collected. All patients will be followed to assess the occurrence of cardiovascular events and valvular intervention needed within a year. Notably, 3 dedicated core laboratories (MIRACL.ai, Lariboisiere Hospital, Paris for CMR; CORELAB ECHO, Rennes Hospital for Echo; and VaRMI Core Lab, Laval Hospital, Canada for cardiac CT) will analyze cardiovascular imaging data from participating centers.

Figure 6.

EACVI-MMVD Study Design (ClinicalTrials: NCT06235385). (*) Clinical outcomes: hospitalization for heart failure, cardiac death, myocardial infarction, pulmonary embolism, stroke. MMVD, multiple and mixed valvular heart disease.

Presentation of the MULTIVALVE Study

While the EACVI-MMVD study will provide unique data on a global scale for MMVD patients, we can fear a lack of granularity in the cardiovascular imaging data linked to the absence of a standardized protocol and the heterogeneity of practices across countries. To achieve a highly standardized MMVD registry for cardiovascular imaging, the French Society of Cardiology will begin in 2025 the “MULTIVALVE” registry as a prospective multicenter study in France including all consecutive patients diagnosed with MMVD using TTE over a 12-month recruitment period. The strengths of this study include: (1) carrying out a more interventional study with a standardized cardiovascular imaging protocol for TTE and CMR mandatory for all patients; (2) analysis of all images of TTE and CMR by 2 centralized analysis core lab (MIRACL.ai, Lariboisiere Hospital, Paris for CMR and cardiac CT; and CORELAB ECHO, Rennes Hospital for Echo); and (3) matching with French social security data allowing exhaustive monitoring of valve interventions, drug treatments and outcomes for 5 years.

Conclusion

Multiple and mixed VHD are very common conditions, with an increasing incidence of degenerative cause, especially in developed countries. Considering each patient singularity and echocardiography pitfalls, multiparametric evaluation with multimodality imaging, symptoms, and biomarkers, supported by machine learning score, appears promising to make personalized care approaches. However, given these difficulties, there are a paucity of data concerning MMVD patient and treatment recommendation. To provide adequate answers to this daily clinical and therapeutic challenge, the “EACVI MMVD” (international observational and “real life” study) is underway, and the “MULTIVALVE” study (prospective multicenter study in France) will start in 2025.

Footnotes

Abbreviations

ORCID iDs

Andreea Sorina Afana

Alexandre Unger

Trecy Gonçalves

Théo Pezel

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Dreyfus

Komar

Attias

, et al. Tricuspid regurgitation: frequency, clinical presentation, management and outcome among patients with severe left-sided valvular heart disease in Europe. Insights from the ESC-EORP valvular heart disease II survey. Eur. J. Heart Fail. 2024;26(4):994–1003.

Iung

Delgado

Rosenhek

, et al. Contemporary presentation and management of valvular heart disease: the EURObservational research programme valvular heart disease II survey. Circulation. 2019;140(14):1156–1169.

Unger

Pibarot

Tribouilloy

, et al. Multiple and mixed valvular heart diseases. Circ. Cardiovasc. Imaging. 2018;11(8):e007862.

Iung

Baron

Butchart

, et al. A prospective survey of patients with valvular heart disease in Europe: the Euro heart survey on valvular heart disease. Eur. Heart J. 2003;24(13):1231–1243.

Goldbarg

Elmariah

Miller

Fuster

. Insights into degenerative aortic valve disease. J. Am. Coll. Cardiol. 2007;50(13):1205–1213.

Roth

Mensah

Johnson

, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J. Am. Coll. Cardiol. 2020;76(25):2982–3021.

Ajay Castro

Dorfmueller

. Update on the development of group A Streptococcus vaccines. NPJ Vaccines. 2023;8(1):135.

Tribouilloy

Bohbot

Kubala

, et al. Characteristics, management, and outcomes of patients with multiple native valvular heart disease: a substudy of the EURObservational research programme valvular heart disease II survey. Eur. Heart J. 2022;43(29):2756–2766.

Aronow

. Heart disease and aging. Med. Clin. North Am. 2006;90(5):849–862.

10.

Mihaljevic

Byrne

Cohn

Aranki

. Long-term results of multivalve surgery for infective multivalve endocarditis. Eur. J. Cardiothorac. Surg. 2001;20(4):842–846.

11.

Carlson

Mayfield

Normann

Alexander

. Radiation-associated valvular disease. Chest. 1991;99(3):538–545.

12.

Horvath

Fross

Kleiner-Fisman

, et al. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov. Disord. 2004;19(6):656–662.

13.

Unger

Rosenhek

Dedobbeleer

Berrebi

Lancellotti

. Management of multiple valve disease. Heart. 2011;97(4):272–277.

14.

Thiene

Rizzo

Basso

. Bicuspid aortic valve: the most frequent and not so benign congenital heart disease. Cardiovasc. Pathol. 2024;70 (May–June 2024):107604.

15.

De Bonis

Maisano

La Canna

Alfieri

. Treatment and management of mitral regurgitation. Nat. Rev. Cardiol. 2011;9(3):133–146.

16.

Adamo

Chioncel

Benson

, et al. Prevalence, clinical characteristics and outcomes of heart failure patients with or without isolated or combined mitral and tricuspid regurgitation: an analysis from the ESC-HFA heart failure long-term registry. Eur. J. Heart Fail. 2023;25(7):1061–1071.

17.

Nombela-Franco

Ribeiro

Urena

, et al. Significant mitral regurgitation left untreated at the time of aortic valve replacement: a comprehensive review of a frequent entity in the transcatheter aortic valve replacement era. J. Am. Coll. Cardiol. 2014;63(24):2643–2658.

18.

Unger

Clavel

Lindman

Mathieu

Pibarot

. Pathophysiology and management of multivalvular disease. Nat. Rev. Cardiol. 2016;13(7):429–440.

19.

Berti

Bonanni

D’agostino

Celi

Mariani

. Treatment of multiple valve disease: surgery, structural intervention, or both? Eur. Heart J. Suppl. 2023;25(Suppl B):B21–B24.

20.

Venneri

Khattar

Senior

. Assessment of complex multi-valve disease and prosthetic valves. Heart Lung Circ. 2019;28(9):1436–1446.

21.

Lancellotti

Tribouilloy

Hagendorff

, et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European association of cardiovascular imaging. Eur. Heart J. Cardiovasc. Imaging. 2013;14(7):611–644.

22.

Tops

Wood

Delgado

, et al. Noninvasive evaluation of the aortic root with multislice computed tomography implications for transcatheter aortic valve replacement. JACC Cardiovasc. Imaging. 2008;1(3):321–330.

23.

Pezel

Coisne

Michalski

, et al. EACVI SIMULATOR-online study: evaluation of transoesophageal echocardiography knowledge and skills of young cardiologists. Eur. Heart J. Cardiovasc. Imaging. 2023;24(3):285–292.

24.

Agatston

Janowitz

Hildner

Zusmer

Viamonte

Detrano

. Quantification of coronary artery calcium using ultrafast computed tomography. J. Am. Coll. Cardiol. 1990;15(4):827–832.

25.

Vahanian

Beyersdorf

Praz

, et al. 2021 ESC/EACTS guidelines for the management of valvular heart disease. Eur. Heart J. 2022;43(7):561–632.

26.

Hussain

Hanna

Rodriguez

, et al. Subthreshold aortic valve calcium scores in severe aortic stenosis and transthyretin cardiac amyloidosis. JACC Case Rep. 2020;2(14):2205–2209.

27.

Abramowitz

Kazuno

Chakravarty

, et al. Concomitant mitral annular calcification and severe aortic stenosis: prevalence, characteristics and outcome following transcatheter aortic valve replacement. Eur. Heart J. 2017;38(16):1194–1203.

28.

Sabbagh A

Parikh

Ray

, et al. Mitral annulus calcium score in patients with calcific mitral stenosis undergoing invasive hemodynamic assessment. J. Am. Heart Assoc. 2024;13(3):e030540.

29.

Guerrero

Wang

Pursnani

, et al. A cardiac computed tomography-based score to categorize mitral annular calcification severity and predict valve embolization. JACC Cardiovasc. Imaging. 2020;13(9):1945–1957.

30.

Muzzarelli

Monney

O’Brien

, et al. Quantification of aortic flow by phase-contrast magnetic resonance in patients with bicuspid aortic valve. Eur. Heart J. Cardiovasc. Imaging. 2014;15(1):77–84.

31.

Nordmeyer

Riesenkampff

Messroghli

, et al. Four-dimensional velocity-encoded magnetic resonance imaging improves blood flow quantification in patients with complex accelerated flow. J. Magn. Reson. Imaging. 2013;37(1):208–216.

32.

Uretsky

Argulian

Narula

Wolff

. Use of cardiac magnetic resonance imaging in assessing mitral regurgitation: current evidence. J. Am. Coll. Cardiol. 2018;71(5):547–563.

33.

Myerson

. Heart valve disease: investigation by cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 2012;14(1):7.

34.

Kerr

O’Brien

Gabriel

Cowan

Young

. Underestimation of aortic flow by CMR in aortic stenosis—implications for aortic valve area assessment. Heart Lung Circ. 2009;18(Suppl 3):S57–S58.

35.

O’Brien

Gabriel

Greiser

Cowan

Young

Kerr

. Aortic valve stenotic area calculation from phase contrast cardiovascular magnetic resonance: the importance of short echo time. J. Cardiovasc. Magn. Reson. 2009;11(1):49.

36.

Markl

Frydrychowicz

Kozerke

Hope

Wieben

. 4D flow MRI. J. Magn. Reson. Imaging. 2012;36(5):1015–1036.

37.

Gorecka

Bissell

Higgins

Garg

Plein

Greenwood

. Rationale and clinical applications of 4D flow cardiovascular magnetic resonance in assessment of valvular heart disease: a comprehensive review. J. Cardiovasc. Magn. Reson. 2022;24(1):49.

38.

Roes

Hammer

van der Geest

, et al. Flow assessment through four heart valves simultaneously using 3-dimensional 3-directional velocity-encoded magnetic resonance imaging with retrospective valve tracking in healthy volunteers and patients with valvular regurgitation. Invest. Radiol. 2009;44(10):669–675.

39.

Blanken

CPS

Farag

Boekholdt

, et al. Advanced cardiac MRI techniques for evaluation of left-sided valvular heart disease. J. Magn. Reson. Imaging. 2018;48(2):318–329.

40.

Pavon

Guglielmo

Mennilli

, et al. The role of cardiovascular magnetic resonance in patients with mitral regurgitation. J. Cardiovasc. Dev. Dis. 2022;9(11):399.

41.

Hagendorff

Helfen

Brandt

, et al. Expert proposal to analyze the combination of aortic and mitral regurgitation in multiple valvular heart disease by comprehensive echocardiography. Clin. Res. Cardiol. 2024;113(3):393–411.

42.

American College of Cardiology, American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease), Society of Cardiovascular Anesthesiologists, Bonow

Carabello

Chatterjee

, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J. Am. Coll. Cardiol. 2006;48(3):e1–148.

43.

Grothues

Smith

Moon

JCC

, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am. J. Cardiol. 2002;90(1):29–34.

44.

Unger

Lancellotti

de Cannière

. The clinical challenge of concomitant aortic and mitral valve stenosis. Acta Cardiol. 2016;71(1):3–6.

45.

Messika-Zeitoun

Serfaty

Laissy

, et al. Assessment of the mitral valve area in patients with mitral stenosis by multislice computed tomography. J. Am. Coll. Cardiol. 2006;48(2):411–413.

46.

Mahnken

Mühlenbruch

Das

, et al. MDCT detection of mitral valve calcification: prevalence and clinical relevance compared with echocardiography. AJR Am. J. Roentgenol. 2007;188(5):1264–1269.

47.

Grayburn

Smith

Harrison

Gurley

DeMaria

. Pivotal role of aortic valve area calculation by the continuity equation for Doppler assessment of aortic stenosis in patients with combined aortic stenosis and regurgitation. Am. J. Cardiol. 1988;61(4):376–381.

48.

de Marchi

Windecker

Aeschbacher

Seiler

. Influence of left ventricular relaxation on the pressure half time of aortic regurgitation. Heart. 1999;82(5):607–613.

49.

Unger

Clavel

. Mixed aortic valve disease: a diagnostic challenge, a prognostic threat. Struct. Heart J. 2020;4(6):468–474.

50.

Blais

Burwash

Mundigler

, et al. Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low-flow, low-gradient aortic stenosis: the multicenter TOPAS (truly or Pseudo-severe aortic stenosis) study. Circulation. 2006;113(5):711–721.

51.

Henning

. The current diagnosis and treatment of patients with aortic valve stenosis. Future Cardiol. 2021;17(6):1143–1160.

52.

Andell

Martinsson

, et al. Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study. Heart. 2017;103(21):1696–1703.

53.

Churchill

Yucel

Deferm

Levine

Hung

Bertrand

. Mitral valve dysfunction in patients with annular calcification: JACC review topic of the week. J. Am. Coll. Cardiol. 2022;80(7):739–751.

54.

Tischler

Battle

Saha

Niggel

LeWinter

. Observations suggesting a high incidence of exercise-induced severe mitral regurgitation in patients with mild rheumatic mitral valve disease at rest. J. Am. Coll. Cardiol. 1995;25(1):128–133.

55.

Lev

Sagie

Vaturi

Sela

Battler

Shapira

. Value of exercise echocardiography in rheumatic mitral stenosis with and without significant mitral regurgitation. Am. J. Cardiol. 2004;93(8):1060–1063.

56.

Zoghbi

Adams

Bonow

, et al. Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American society of echocardiography developed in collaboration with the society for cardiovascular magnetic resonance. J. Am. Soc. Echocardiogr. 2017;30(4):303–371.

57.

Dreyfus

Corbi

Chan

KMJ

Bahrami

. Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair? Ann. Thorac. Surg. 2005;79(1):127–132.

58.

Unger

Tribouilloy

. Aortic stenosis with other concomitant valvular disease: aortic regurgitation, mitral regurgitation, mitral stenosis, or tricuspid regurgitation. Cardiol. Clin. 2020;38(1):33–46.

59.

Otto

Nishimura

Bonow

, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. 2021;143(5):e72–227.

60.

Bollache

van Ooij

Powell

Carr

Markl

Barker

. Comparison of 4D flow and 2D velocity-encoded phase contrast MRI sequences for the evaluation of aortic hemodynamics. Int. J. Cardiovasc. Imaging. 2016;32(10):1529–1541.

61.

David

Le Touze

Warin-Fresse

, et al. In-vitro validation of 4D flow MRI measurements with an experimental pulsatile flow model. Diagn. Interv. Imaging. 2019;100(1):17–23.

62.

Kwak

Kim

, et al. Development of tricuspid regurgitation late after left-sided valve surgery: a single-center experience with long-term echocardiographic examinations. Am. Heart J. 2008;155(4):732–737.

63.

Lindman

Maniar

Jaber

, et al. Effect of tricuspid regurgitation and the right heart on survival after transcatheter aortic valve replacement: Insights from the placement of aortic transcatheter valves II inoperable cohort. Circ. Cardiovasc. Interv. 2015;8(4):e002073. 10.1161/CIRCINTERVENTIONS.114.002073

64.

Akins

Buckley

Daggett

, et al. Risk of reoperative valve replacement for failed mitral and aortic bioprostheses. Ann. Thorac. Surg. 1998;65(6):1545–1551. discussion 1551–1552.

65.

Dvir

Webb

Bleiziffer

, et al. Transcatheter aortic valve implantation in failed bioprosthetic surgical valves. JAMA. 2014;312(2):162–170.

66.

Kamioka

Babaliaros

Morse

, et al. Comparison of clinical and echocardiographic outcomes after surgical redo mitral valve replacement and transcatheter mitral valve-in-valve therapy. JACC Cardiovasc. Interv. 2018;11(12):1131–1138.

67.

Kornowski

Chevalier

Verhoye

, et al. Transcatheter aortic valve implantation for failed surgical aortic bioprostheses using a self-expanding device (from the prospective VIVA post market study). Am. J. Cardiol. 2021;144(April 2021):118–124.

68.

Pezel

Viallon

Croisille

, et al. Imaging interstitial fibrosis, left ventricular remodeling, and function in stage A and B heart failure. JACC Cardiovasc. Imaging. 2021;14(5):1038–1052.

69.

Stassen

Ewe

Hirasawa

, et al. Left ventricular remodelling patterns in patients with moderate aortic stenosis. Eur. Heart J. Cardiovasc. Imaging. 2022;23(10):1326–1335.

70.

Chehab

Roberts-Thomson

Ng Yin Ling

, et al. Secondary mitral regurgitation: pathophysiology, proportionality and prognosis. Heart. 2020;106(10):716–723.

71.

Azevedo

Nigri

Higuchi

, et al. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J. Am. Coll. Cardiol. 2010;56(4):278–287.

72.

Pezel

des Horts T

Schaaf

, et al. Predictive value of early cardiac magnetic resonance imaging functional and geometric indexes for adverse left ventricular remodelling in patients with anterior ST-segment elevation myocardial infarction: a report from the CIRCUS study. Arch. Cardiovasc. Dis. 2020;113(11):710–720.

73.

Balciunaite

Skorniakov

Rimkus

, et al. Prevalence and prognostic value of late gadolinium enhancement on CMR in aortic stenosis: meta-analysis. Eur. Radiol. 2020;30(1):640–651.

74.

Kitkungvan

Nabi

Kim

, et al. Myocardial fibrosis in patients with primary mitral regurgitation with and without prolapse. J. Am. Coll. Cardiol. 2018;72(8):823–834.

75.

Pezel

Venkatesh

De Vasconcellos

, et al. Left atrioventricular coupling Index as a prognostic marker of cardiovascular events: the MESA study. Hypertension. 2021;78(3):661–671.

76.

Pezel

Ambale-Venkatesh

Quinaglia

, et al. Change in left atrioventricular coupling Index to predict incident atrial fibrillation: the multi-ethnic study of atherosclerosis (MESA). Radiology. 2022;303(2):317–326.

77.

Pezel

Venkatesh

Vasconcellos

HDD

, et al. Determinants of left atrioventricular coupling index: the multi-ethnic study of atherosclerosis (MESA). Arch. Cardiovasc. Dis. 2022;115(8–9):414–425.

78.

Toupin

Pezel

Bustin

Cochet

. Whole-Heart high-resolution late gadolinium enhancement: techniques and clinical applications. J. Magn. Reson. Imaging. 2022;55(4):967–987.

79.

Mehr

Karam

Taramasso

, et al. Combined tricuspid and mitral versus isolated mitral valve repair for severe MR and TR: an analysis from the TriValve and TRAMI registries. JACC Cardiovasc. Interv. 2020;13(5):543–550.

80.

Vassileva

Thourani

, et al. Outcome characteristics of multiple-valve surgery: comparison with single-valve procedures. Innovations (Phila). 2014;9(1):27–32.

81.

Jacobs

Shahian

Badhwar

, et al. The society of thoracic surgeons 2021 adult cardiac surgery risk models for multiple valve operations. Ann. Thorac. Surg. 2022;113(2):511–518.

82.

Fadel

Alsoufi

Manlhiot

, et al. Determinants of short- and long-term outcomes following triple valve surgery. J. Heart Valve Dis. 2010;19(4):513–522. discussion 523.

83.

Al-Zubaidi

Hussein

Smith

, et al. 20 Years of triple-valve surgery in the UK: demographic and outcome trends. Eur. J. Cardiothorac. Surg. 2024;66(1):ezae268.

84.

Davarpasand

Hosseinsabet

. Triple valve replacement for rheumatic heart disease: short- and mid-term survival in modern era. Interact. Cardiovasc. Thorac. Surg. 2015;20(3):359–364.

85.

Pagni

Ganzel

Singh

, et al.

Clinical outcome after triple-valve operations in the modern era: are elderly patients at increased surgical risk?

Ann. Thorac. Surg. 2014;97(2):569–576.

86.

Gillinov

Faber

Houghtaling

, et al. Repair versus replacement for degenerative mitral valve disease with coexisting ischemic heart disease. J. Thorac. Cardiovasc. Surg. 2003;125(6):1350–1362.

87.

Fan

Cao

Zhang

. Outcome of mitral valve repair or replacement for non-ischemic mitral regurgitation: a systematic review and meta-analysis. J. Cardiothorac. Surg. 2021;16(1):175.

88.

Bombace

Meucci

Fortuni

, et al. Beyond aortic stenosis: addressing the challenges of multivalvular disease assessment. Diagnostics (Basel). 2023;13(12):2102.

89.

Cannegieter

Rosendaal

Wintzen

van der Meer

Vandenbroucke

Briët

. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N. Engl. J. Med. 1995;333(1):11–17.

90.

Wessler

Lundquist

Koethe

, et al. Clinical prediction models for valvular heart disease. J. Am. Heart Assoc. 2019;8(20):e011972.

91.

Khan

Okuno

Malebranche

, et al. Transcatheter aortic valve replacement in patients with multivalvular heart disease. JACC Cardiovasc. Interv. 2020;13(13):1503–1514.

92.

Hayashida

Lefèvre

Chevalier

, et al. Impact of post-procedural aortic regurgitation on mortality after transcatheter aortic valve implantation. JACC Cardiovasc. Interv. 2012;5(12):1247–1256.

93.

Witberg

Codner

Landes

, et al. Effect of transcatheter aortic valve replacement on concomitant mitral regurgitation and its impact on mortality. JACC Cardiovasc. Interv. 2021;14(11):1181–1192.

94.

Mavromatis

Thourani

Stebbins

, et al. Transcatheter aortic valve replacement in patients with aortic stenosis and mitral regurgitation. Ann. Thorac. Surg. 2017;104(6):1977–1985.

95.

Salem

Stankowski

Aboul-Hassan

, et al. Transfemoral aortic valve implantation in patients with severe aortic stenosis and coexisting mitral valve regurgitation. J. Surg. Res. 2024;304(December 2024):101–111.

96.

Barbanti

Binder

Dvir

, et al. Prevalence and impact of preoperative moderate/severe tricuspid regurgitation on patients undergoing transcatheter aortic valve replacement. Catheter Cardiovasc. Interv. 2015;85(4):677–684.

97.

Hahn

Pibarot

Otto

. Transcatheter interventions spark a paradigm change for management of patients with mixed valve disease. Eur. Heart J. 2022;43(29):2767–2769.

98.

Kische

D’Ancona

Paranskaya

, et al. Staged total percutaneous treatment of aortic valve pathology and mitral regurgitation: Institutional experience. Catheter Cardiovasc. Interv. 2013;82(4):E552–E563.

99.

Donal

Unger

Coisne

, et al. The role of multimodality imaging in multiple valvular heart diseases. A clinical consensus statement of the European Association of Cardiovascular Imaging (EACVI) of the ESC. Eur. Heart J. Cardiovasc. Imaging. 2025;26(4):593–608.

100.

Giannini

Baldetti

Gallone

Tzanis

Latib

Colombo

. Transcatheter valve replacement in Asia pacific: current practice and perspectives. J. Am. Coll. Cardiol. 2018;72(24):3189–3199.

101.

Ribeiro

Doyle

Urena

, et al. Transapical mitral implantation of a balloon-expandable valve in native mitral valve stenosis in a patient with previous transcatheter aortic valve replacement. JACC Cardiovasc. Interv. 2014;7(10):e137–e139.

102.

Elkharbotly

Delago

El-Hajjar

. Simultaneous transapical transcatheter aortic valve replacement and transcatheter mitral valve replacement for native valvular stenosis. Catheter Cardiovasc. Interv. 2016;87(7):1347–1351.

103.

Löw

Steffen

Lux

, et al. Atrial functional tricuspid regurgitation in patients undergoing transcatheter aortic valve replacement. JACC Cardiovasc. Interv. 2024;17(1):76–87.

104.

Thourani

Suri

Rankin

, et al.

Does mitral valve repair offer an advantage over replacement in patients undergoing aortic valve replacement?

Ann. Thorac. Surg. 2014;98(2):598–603. discussion 604.

105.

Gillinov

Blackstone

Cosgrove

, et al. Mitral valve repair with aortic valve replacement is superior to double valve replacement. J. Thorac. Cardiovasc. Surg. 2003;125(6):1372–1387.

106.

Hamamoto

Bando

Kobayashi

, et al. Durability and outcome of aortic valve replacement with mitral valve repair versus double valve replacement. Ann. Thorac. Surg. 2003;75(1):28–33. discussion 33–34.

107.

Kuwaki

Kawaharada

Morishita

, et al. Mitral valve repair versus replacement in simultaneous mitral and aortic valve surgery for rheumatic disease. Ann. Thorac. Surg. 2007;83(2):558–563.

108.

Chikwe

Itagaki

Anyanwu

Adams

. Impact of concomitant tricuspid annuloplasty on tricuspid regurgitation, right ventricular function, and pulmonary artery hypertension after repair of mitral valve prolapse. J. Am. Coll. Cardiol. 2015;65(18):1931–1938.

109.

Arsalan

Walther

Smith

Grayburn

. Tricuspid regurgitation diagnosis and treatment. Eur. Heart J. 2017;38(9):634–638.

110.

Gatti

Dell’Angela

Morosin

, et al. Tricuspid annuloplasty for tricuspid regurgitation secondary to left-sided heart valve disease: immediate outcomes and risk factors for late failure. Can. J. Cardiol. 2016;32(6):760–766.

111.

Dreyfus

Martin

Chan

KMJ

Dulguerov

Alexandrescu

. Functional tricuspid regurgitation: a need to revise our understanding. J. Am. Coll. Cardiol. 2015;65(21):2331–2336.

112.

Ando

Takagi

Briasoulis

, et al. A systematic review of reported cases of combined transcatheter aortic and mitral valve interventions. Catheter Cardiovasc. Interv. 2018;91(1):124–134.

113.

Cortés

Amat-Santos

Nombela-Franco

, et al. Mitral regurgitation after transcatheter aortic valve replacement: prognosis, imaging predictors, and potential management. JACC Cardiovasc. Interv. 2016;9(15):1603–1614.

114.

Chakravarty

Makar

Patel

, et al. Transcatheter edge-to-edge mitral valve repair with the MitraClip G4 system. JACC Cardiovasc. Interv. 2020;13(20):2402–2414.

115.

Piriou

Al Habash

Donal

, et al. The MITRA-HR study: design and rationale of a randomised study of MitraClip transcatheter mitral valve repair in patients with severe primary mitral regurgitation eligible for high-risk surgery. Eurointervention. 2019;15(4):e329–e335.

116.

Breithardt

Baumgartner

Berkowitz

, et al. Clinical characteristics and outcomes with rivaroxaban vs. Warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial. Eur. Heart J. 2014;35(47):3377–3385.

117.

Avezum

Lopes

Schulte

, et al. Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial. Circulation. 2015;132(8):624–632.

118.

Connolly

Karthikeyan

Ntsekhe

, et al. Rivaroxaban in rheumatic heart disease-associated atrial fibrillation. N. Engl. J. Med. 2022;387(11):978–988.

119.

Maes

Stabile

Ussia

, et al. Meta-analysis comparing single versus dual antiplatelet therapy following transcatheter aortic valve implantation. Am. J. Cardiol. 2018;122(2):310–315.

120.

Brouwer

Nijenhuis

Delewi

, et al. Aspirin with or without clopidogrel after transcatheter aortic-valve implantation. N. Engl. J. Med. 2020;383(15):1447–1457.

121.

Pagnesi

Moroni

Beneduce

, et al. Thrombotic risk and antithrombotic strategies after transcatheter mitral valve replacement. JACC Cardiovasc. Interv. 2019;12(23):2388–2401.

122.

Bèze N

Himbert

Suc

, et al. Comparison of direct oral anticoagulants vs vitamin K antagonists after transcatheter mitral valve replacement. J. Am. Coll. Cardiol. 2024;83(2):334–346.

123.

Brennan

Edwards

Zhao

, et al. Early anticoagulation of bioprosthetic aortic valves in older patients: results from the Society of Thoracic Surgeons Adult Cardiac Surgery National Database. J. Am. Coll. Cardiol. 2012;60(11):971–977.

124.

Mérie

Køber

Skov Olsen

, et al. Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding. JAMA. 2012;308(20):2118–2125.

125.

Christersson

James

Lindhagen

, et al. Comparison of warfarin versus antiplatelet therapy after surgical bioprosthetic aortic valve replacement. Heart. 2020;106(11):838–844.

126.

Russo

Grigioni

Avierinos

, et al. Thromboembolic complications after surgical correction of mitral regurgitation incidence, predictors, and clinical implications. J. Am. Coll. Cardiol. 2008;51(12):1203–1211.

127.

Butnaru

Shaheen

Tzivoni

Tauber

Bitran

Silberman

. Diagnosis and treatment of early bioprosthetic malfunction in the mitral valve position due to thrombus formation. Am. J. Cardiol. 2013;112(9):1439–1444.

128.

Skogseid

Batra

Westerbergh

Held

Christersson

. Thromboembolic and bleeding events after valvular intervention in patients with atrial fibrillation. Open Heart. 2024;11(1):e002602.

129.

Guimarães

Lopes

de Barros E Silva

PGM

, et al. Rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve. N. Engl. J. Med. 2020;383(22):2117–2126.

130.

Eikelboom

Connolly

Brueckmann

, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N. Engl. J. Med. 2013;369(13):1206–1214.

131.

Wang

Svensson

Wen

, et al. Apixaban or warfarin in patients with an on-X mechanical aortic valve. NEJM Evid. 2023;2(7):EVIDoa2300067.

132.

Nkomo

Gardin

Skelton

Gottdiener

Scott

Enriquez-Sarano

. Burden of valvular heart diseases: a population-based study. Lancet. 2006;368(9540):1005–1011.

133.

Hindricks

Potpara

Dagres

, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur. Heart J. 2021;42(5):373–498.

134.

Philippart

Brunet-Bernard

Clementy

, et al. Prognostic value of CHA2DS2-VASc score in patients with « non-valvular atrial fibrillation » and valvular heart disease: the Loire valley atrial fibrillation project. Eur. Heart J. 2015;36(28):1822–1830.

135.

Pezel

Sanguineti

Kinnel

, et al. Feasibility and prognostic value of vasodilator stress perfusion CMR in patients with atrial fibrillation. JACC Cardiovasc. Imaging. 2021;14(2):379–389.

136.

Essayagh

Sabbag

El-Am

Cavalcante

Michelena

Enriquez-Sarano

. Arrhythmic mitral valve prolapse and mitral annular disjunction: pathophysiology, risk stratification, and management. Eur. Heart J. 2023;44(33):3121–3135.

137.

Engin

Cevik

Deniz

Orta

Elitok

. Ventricular arrhythmias in mitral valve prolapse syndrome and their relationship with electrocardiographic repolarization parameters. North Clin. Istanb. 2023;10(2):205–211.

138.

Olafiranye

Hochreiter

Borer

, et al. Nonischemic mitral regurgitation: prognostic value of nonsustained ventricular tachycardia after mitral valve surgery. Cardiology. 2013;124(2):108–115.

139.

Cambise

Gnan

Tremamunno

, et al. Impact on clinical outcome of ventricular arrhythmias in patients undergoing transcatheter aortic valve implantation. J. Cardiovasc. Med. (Hagerstown). 2024;25(4):327–333.

140.

Addetia

Harb

Hahn

Kapadia

Lang

. Cardiac implantable electronic device lead-induced tricuspid regurgitation. JACC Cardiovasc. Imaging. 2019;12(4):622–636.

141.

Andreas

Burri

Praz

, et al. Tricuspid valve disease and cardiac implantable electronic devices. Eur. Heart J. 2024;45(5):346–365.

142.

Saito

Iannaccone

Kaye

, et al. Effect of right ventricular pacing on right ventricular mechanics and tricuspid regurgitation in patients with high-grade atrioventricular block and Sinus rhythm (from the protection of left ventricular function during right ventricular pacing study). Am. J. Cardiol. 2015;116(12):1875–1882.

143.

Chango Azanza

Munín

Raggio

Perea

Carbajales

. Different phenotypes of mitral regurgitation in patients with right apical ventricular pacing: an echocardiographic approach in a heterogeneity of clinical scenarios. Arch. Peru Cardiol. Circ. Cardiovasc. 2021;2(2):112–120.

144.

Sassone

De Simone

Parlangeli

Tortorici

Biancoli

Di Pasquale

. Pacemaker-induced mitral regurgitation: prominent role of abnormal ventricular activation sequence versus altered atrioventricular synchrony. Ital. Heart J. 2001;2(6):441–448.

145.

Auricchio

. Pacing-correctable mitral regurgitation: something old, something new. Circ. Arrhythm. Electrophysiol. 2016;9(11):e004736.

146.

Yuyun

Joseph

Erqou

, et al. Evolution and prognosis of tricuspid and mitral regurgitation following cardiac implantable electronic devices: a systematic review and meta-analysis. Europace. 2024;26(7):euae143.

147.

Leong

Dokainish

Mondésert

, et al. Effects of implantable cardioverter-defibrillator leads on the tricuspid valve and right ventricle: a randomized trial. JACC Clin. Electrophysiol. 2024;10(9):2088–2096.

148.

Pezel

Lacotte

Horvilleur

, et al. Safety, feasibility, and prognostic value of stress perfusion CMR in patients with MR-conditional pacemaker. Eur. Heart J. Cardiovasc. Imaging. 2023;24(2):202–211.

149.

Ternacle

Krapf

Mohty

, et al. Aortic stenosis and cardiac amyloidosis: JACC review topic of the week. J. Am. Coll. Cardiol. 2019;74(21):2638–2651.

150.

Kristen

Schnabel

Winter

, et al. High prevalence of amyloid in 150 surgically removed heart valves—a comparison of histological and clinical data reveals a correlation to atheroinflammatory conditions. Cardiovasc. Pathol. 2010;19(4):228–235.

151.

Mohty

Pradel

Magne

, et al. Prevalence and prognostic impact of left-sided valve thickening in systemic light-chain amyloidosis. Clin. Res. Cardiol. 2017;106(5):331–340.

152.

Jaiswal

Agrawal

Khulbe

, et al. Cardiac amyloidosis and aortic stenosis: a state-of-the-art review. Eur. Heart J. Open. 2023;3(6):oead106.

153.

Bonelli

Paris

Nardi

, et al. Aortic valve stenosis and cardiac amyloidosis: a misleading association. J. Clin. Med. 2021;10(18):4234.

154.

Randhawa

Vakamudi

Phelan

, et al. Mitral and tricuspid stenosis caused by light chain cardiac amyloid deposition. ESC Heart Fail. 2020;7(3):1130–1135.

155.

Duca

Kronberger

Willixhofer

Bartko

Bergler-Klein

Nitsche

. Cardiac amyloidosis and valvular heart disease. J. Clin. Med. 2023;13(1):221.

156.

Urena

Lurz

Sorajja

Himbert

Guerrero

. Transcatheter mitral valve implantation for native valve disease. Eurointervention. 2023;19(9):720–738.

157.

Ben Ali

Ludwig

Duncan

, et al. Characteristics and outcomes of patients screened for transcatheter mitral valve implantation: 1-year results from the CHOICE-MI registry. Eur. J. Heart Fail. 2022;24(5):887–898.

158.

Guerrero

Wang

Eleid

, et al. Prospective study of TMVR using balloon-expandable aortic transcatheter valves in MAC: MITRAL trial 1-year outcomes. JACC Cardiovasc. Interv. 2021;14(8):830–845.

159.

Urena

Brochet

Lecomte

, et al. Clinical and haemodynamic outcomes of balloon-expandable transcatheter mitral valve implantation: a 7-year experience. Eur. Heart J. 2018;39(28):2679–2689.

160.

Taramasso

Benfari

van der Bijl

, et al. Transcatheter versus medical treatment of patients with symptomatic severe tricuspid regurgitation. J. Am. Coll. Cardiol. 2019;74(24):2998–3008.

161.

Lindman

Arnold

Bagur

, et al. Priorities for patient-centered research in valvular heart disease: a report from the national heart, lung, and blood institute working group. J. Am. Heart Assoc. 2020;9(9):e015975.

162.

Sengupta

Kluin

Lee

Smits

AIPM

. The future of valvular heart disease assessment and therapy. Lancet. 2024;403(10436):1590–1602.

163.

Nashef

SAM

Roques

Sharples

, et al. EuroSCORE II. Eur. J. Cardiothorac. Surg. 2012;41(4):734–744. discussion 744–745.

164.

Pezel

Sanguineti

Garot

, et al. Machine-Learning score using stress CMR for death prediction in patients with suspected or known CAD. JACC Cardiovasc. Imaging. 2022;15(11):1900–1913.

165.

Shah

Katz

Selvaraj

, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131(3):269–279.

166.

Pezel

Bonnet

Kinnel

, et al. Clustering of patients with inconclusive non-invasive stress testing referred for vasodilator stress cardiovascular magnetic resonance. Arch. Cardiovasc. Dis. 2022;115(12):627–636.

167.

Rajkomar

Dean

Kohane

. Machine learning in medicine. N. Engl. J. Med. 2019;380(14):1347–1358.

168.

Kwak

Lee

, et al. Unsupervised cluster analysis of patients with aortic stenosis reveals distinct population with different phenotypes and outcomes. Circ. Cardiovasc. Imaging. 2020;13(5):e009707.

169.

Kwiecinski

Dabrowski

Nombela-Franco

, et al. Machine learning for prediction of all-cause mortality after transcatheter aortic valve implantation. Eur. Heart J. Qual. Care Clin. Outcomes. 2023;9(8):768–777.

170.

Huttin

Girerd

Jobbe-Duval

, et al. Machine learning-based phenogrouping in MVP identifies profiles associated with myocardial fibrosis and cardiovascular events. JACC Cardiovasc. Imaging. 2023;16(10):1271–1284.

171.

Hausleiter

Lachmann

Stolz

, et al. Artificial intelligence-derived risk score for mortality in secondary mitral regurgitation treated by transcatheter edge-to-edge repair: the EuroSMR risk score. Eur. Heart J. 2024;45(11):922–936.

172.

Rao

Giczewska

Chiswell

, et al. Long-term outcomes of phenoclusters in severe tricuspid regurgitation. Eur. Heart J. 2023;44(21):1910–1923.

173.

Bodenhofer

Haslinger-Eisterer

Minichmayer

Hermanutz

Meier

. Machine learning-based risk profile classification of patients undergoing elective heart valve surgery. Eur. J. Cardiothorac. Surg. 2021;60(6):1378–1385.

174.

Roberts

Sullivan

. Clinical and necropsy observations early after simultaneous replacement of the mitral and aortic valves. Am. J. Cardiol. 1986;58(11):1067–1084.

175.

Bhattacharyya

Gujral

Toumpanakis

, et al. A stepwise approach to the management of metastatic midgut carcinoid tumor. Nat. Rev. Clin. Oncol. 2009;6(7):429–433.

176.

Matsuoka

Misugi

Goto

Gilbert

Ando

. Congenital heart anomalies in the trisomy 18 syndrome, with reference to congenital polyvalvular disease. Am. J. Med. Genet. 1983;14(4):657–668.

177.

Brauner

Laks

Drinkwater

Scholl

McCaffery

. Multiple left heart obstructions (shone’s anomaly) with mitral valve involvement: Long-term surgical outcome. Ann. Thorac. Surg. 1997;64(3):721–729.

178.

Kowal-Vern

Bharati

Melnyk

Husain

. Congenital polyvalvular cardiac disease without chromosomal abnormalities. Pediatr. Pathol. Lab. Med. 1995;15(2):299–308.

179.

Hahn

Thomas

Khalique

Cavalcante

Praz

Zoghbi

. Imaging assessment of tricuspid regurgitation severity. JACC Cardiovasc. Imaging. 2019;12(3):469–490.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

Multiple and Mixed Valvular Heart Disease: State-of-the-Art

Abstract

Keywords

Key points

Introduction

General Principles

Etiology

Rheumatic heart disease

Degenerative VHD

Other etiologies

Pathophysiology of MMVD

Global Evaluation and Management

Cardiovascular Multimodality Imaging

Cardiovascular Imaging in MMVD Patients

Echocardiography

Cardiac CT

Cardiovascular Magnetic Resonance

Interpretation of Cardiovascular Imaging for Each Combination of MMVD

Aortic stenosis and MR

Aortic Regurgitation and MR

Aortic Stenosis and MS

Aortic Stenosis and AR (Mixed Aortic Valvular Disease)

Mitral Stenosis and MR (Mixed Mitral Valvular Disease)

Left-Sided VHD with TR

Case of MMVD Patients with Prosthetic Valves

Cardiac Remodeling Due to MMVD

Treatments

Current Guidelines

Surgical Valve Replacement

Percutaneous Valve Replacement

Valve Repair

Surgical Valve Repair

Percutaneous Mitral Commissurotomy

Transcatheter Edge-to-Edge Repair

Antithrombotic Management

Native Valves

Transcatheter Bioprosthesis

Surgical Bioprosthesis or Valve Repair

Mechanical Valves

Multiple and Mixed Valvular Heart Disease Associated with Specific Conditions

Atrial and Ventricular Arrhythmia

Cardiac Implantable Electronic Device–Related VHD

Cardiac Amyloidosis

Perspectives

Transcatheter Mitral and TVR

Risk Stratification Using Machine Learning

Presentation of the EACVI-MMVD Study

Presentation of the MULTIVALVE Study

Conclusion

Footnotes

Abbreviations

ORCID iDs

Funding

Conflicting interests

References

Supplementary Material