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Multivalvular disease (MVD) — the combination ofstenotic or regurgitant lesions, or both, on two or morecardiac valves — is a highly prevalent clinical condi-tion among patients with valvular heart disease. In theEuroHeart Survey, 20.2% of the patients with native

 valve disease, and 14.6% of the patients undergoing valvular surgery, had MVD1. Multiple-valve surgeryaccounted for 10.9% of the 623,039 patients undergoing

 valve surgery and included in the Society of Thoracic Surgeons (STS) database between 1993 and 2007 (REF. 2).Among these patients, 57.8% underwent surgery on theaortic and mitral valves, 31.0% on the mitral and tricus-pid, 3.3% on the aortic and tricuspid, and 7.9% under-

went triple-valve surgery 2,3. In the PARTNER trials4–6,the incidence of concomitant moderate-to-severe mitralregurgitation in patients with severe aortic stenosis wasapproximately 20%, and the incidence of moderate-to-severe tricuspid regurgitation was 27%. In theEuroHeart Survey, the mean age of patients presentingwith MVD (n = 712) was 64 years, and 83.6% of theseindividuals were male1.

Rheumatic heart disease has long been consideredthe main cause of primary (or organic) MVD7, but theincidence of this aetiology has dramatically declinedover the past 5 decades8. However, no concomitantdecline in the prevalence of all valvular heart disease

has occurred, because degenerative valve disease hasbecome more prevalent in developed countries owingto ageing of the population8. In the EuroHeart surveyconducted in 2001, rheumatic heart disease was themost frequent aetiology (51.4%) of MVD, followed bydegenerative valve disease (40.6%)1. Other, less frequent,causes of primary MVD include endocarditis, thoracicand mediastinal radiation therapy, and the adverseeffects of drugs. Even less frequently, connective tissuedisorders, and aortic root and myxomatous mitral andtricuspid valve disease linked to genetic syndromes, canbe associated with MVD9. Mitral and tricuspid regurgi-tation can also develop in the presence of a structurally

normal valve owing to malcoaptation. These commonforms of mitral and tricuspid regurgitation, classified assecondary regurgitation, result from alterations of thegeometry of the left or right ventricle, respectively 10.In a review published in 2014, mitral regurgitation wassecondary in approximately 50% of patients with mitralregurgitation undergoing transcatheter aortic valveimplantation (TAVI)11. Coronary artery disease and ahistory of myocardial infarction are highly prevalentin patients with degenerative valve disease, and ischae-mic mitral regurgitation is, therefore, common in theageing population12–15 and, therefore, in elderly patientswith degenerative valve disease. Aortic root dilatation

1Cardiology Department, CHU

Saint-Pierre, Université Libre

de Bruxelles, 322 rue Haute,

B-1000, Brussels, Belgium.2Quebec Heart & Lung

Institute, Department ofMedicine, Laval University,

Chemin Sainte-Foy, Quebec

City, QC, G1V 4G5, Canada.3Cardiovascular Division,

Washington University School

of Medicine, 660 South Euclid

 Avenue, St. Louis,

Missouri 63110, USA.

Correspondence to P.U. and P.P.

 [email protected]; 

 philippe.pibarot@

med.ulaval.ca

doi:10.1038/nrcardio.2016.57

Published online 28 April 2016

Pathophysiology and managementof multivalvular diseasePhilippe Unger 1, Marie-Annick Clavel 2, Brian R. Lindman3, Patrick Mathieu2 

and Philippe Pibarot 2

Abstract | Multivalvular disease (MVD) is common among patients with valvular disease, and has a

complex pathophysiology dependent on the specific combination of valve lesions. Diagnosis is

challenging because several echocardiographic methods commonly used for the assessment of

stenosis or regurgitation have been validated only in patients with single-valve disease. Decisions

about the timing and type of treatment should be made by a multidisciplinary heart valve team,on a case-by-case basis. Several factors should be considered, including the severity and

consequences of the MVD, the patient’s life expectancy and comorbidities, the surgical risk

associated with combined valve procedures, the long-term risk of morbidity and mortality

associated with multiple valve prostheses, and the likelihood and risk of reoperation.

The introduction of transcatheter valve therapies into clinical practice has provided new

treatment options for patients with MVD, and decision-making algorithms on how to combine

surgical and percutaneous treatment options are evolving rapidly. In this Review, we discuss the

pathophysiology, diagnosis, and treatment of MVD, focusing on the combinations of valve

pathologies that are most often encountered in clinical practice.

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can cause functional aortic regurgitation with anatomi-cally normal aortic valve cusps16. Moreover, primary andsecondary aetiologies can coexist.

Despite the prevalence of MVD, limited data exist

in the literature to guide the management of patientswith this disease. The large number of possible patho-physiological combinations contributes to the scarcityof studies. In this Review, we assess the available dataon the pathophysiological complexity of MVD, discussthe diagnostic pitfalls, and consider potential manage-ment strategies for these challenging clinical scenarios.We do not examine the specific problems of mixed heart

 valve disease, that is, the combination of stenosis andregurgitation of the same valve.

Pathophysiology

The clinical effect of MVD depends on a complex inter-play of pathophysiological factors, including the severityof each individual valve lesion, which combination of

 valves are diseased, the type (primary versus second-ary) and chronicity of the lesions, loading conditions,and ventricular compensation. The severity and clin-ical effect of one valve lesion can be altered if loadingconditions change or if another valve is repaired. Thesehaemodynamic interactions can promote, exacerbate, or,by contrast, blunt the clinical expression of each singularlesion. For example, in some patients, a rapid decreasein the severity of mitral regurgitation occurs after mech-anical correction of aortic stenosis. Similarly, one con-comitant valve lesion can modify the clinical effect ofanother. For example, two patients with equally severe

aortic regurgitation might experience the ventricularand clinical consequences of the aortic regurgitationat different time points if one patient has concomitantmitral stenosis (which can protect from the volume loadof aortic regurgitation) and the other patient has con-comitant mitral regurgitation (which exacerbates the

 volume load). The complex and dynamic pathophysio-logy of MVD makes the evaluation, diagnosis, andmanagement of these patients challenging. Althougheach case of MVD is different and precludes general-ization, we review some general pathophysiologicalprinciples that should be considered with the followingcombinations of valve lesions.

 Aortic stenosis and mitral regurgitation

Long-standing increased afterload resulting from aor-tic stenosis leads to hypertrophic remodelling of the left

 ventricle. However, a substantial proportion of patientswith aortic stenosis develop left ventricular (LV) dilata-tion and systolic dysfunction as a result of LV afterloadmismatch, concomitant cardiomyopathy (frequently ofischaemic origin), or both. In turn, LV dilatation andadverse remodelling can be accompanied by secondarymitral regurgitation owing to mitral annular dilatationand leaflet tethering17  (FIG. 1). Elderly patients (aged>70 years) with aortic stenosis often also have coronaryartery disease, thus explaining the high prevalence of con-comitant secondary ischaemic mitral regurgitation in thispopulation11,18. Alternatively, patients with aortic steno-sis can have concomitant primary mitral regurgitation.The systolic transmitral pressure gradient is inherentlyincreased in the presence of aortic stenosis and, therefore,the regurgitant flow rate (and the regurgitant volume) willbe increased for any given mitral regurgitant orifice area19.

The presence of moderate or severe mitral regurgita-

tion, whether primary or secondary, can alter the clin-ical presentation of patients with aortic stenosis. Mitralregurgitation contributes to a low-flow state, resulting ina low transaortic pressure gradient despite a small aortic

 valve area (FIG. 1). Atrial fibrillation, which frequentlyresults from mitral valve diseases, can exacerbate theclinical condition, because loss of the atrial kick is poorlytolerated in patients with aortic stenosis. Furthermore,atrial fibrillation is an independent risk factor for heartfailure, stroke, and death in patients with aortic steno-sis20,21. In addition, aortic stenosis and mitral regurgita-tion have opposite effects on ejection phase indices ofmyocardial performance17. Therefore, unlike patientswith isolated mitral regurgitation, those with aorticstenosis and mitral regurgitation can experience animprovement in LV ejection fraction (LVEF) after mitral

 valve replacement if the stenotic aortic valve is concomi-tantly replaced (FIG. 2). Conversely, the early detection ofLV dysfunction in patients with aortic stenosis can beimpeded by the presence of mitral regurgitation.

 Aortic stenosis and mitral stenosis

The combination of severe aortic and mitral stenosis isinfrequent in developed countries, because this conditionis usually very poorly tolerated from a haemodynamicstandpoint, and treatment is sought early during thecourse of the disease22. When both stenoses are severe,

a greater reduction in cardiac output occurs than with just one severe stenosis, decreasing the flow rate andpressure gradients across both valves, which can lead tounderestimation of the severity of both aortic and mitralstenosis23 (FIG. 3). Whereas physical findings are mainlycaused by the aortic stenosis, several clinical manifest-ations resulting from the mitral stenosis — includingatrial fibrillation, haemoptysis, and peripheral emboli-zation — can occur. If concomitant severe aortic steno-sis is not recognized24, percutaneous balloon mitral

 valvuloplasty could impose a sudden preload increase toa small, hypertrophied, and stiff left ventricle, resulting inpulmonary oedema25.

Key points

• Multivalvular disease (MVD) is a prevalent form of valvular heart disease; rheumatic

heart disease is the predominant aetiology in developing countries, whereas

degenerative aetiologies are increasingly common in developed countries

• Haemodynamic interactions between valve lesions can promote, exacerbate, or,

by contrast, blunt the clinical expression of each singular lesion

• Several diagnostic tools used for the assessment of valve stenosis or regurgitation

have been validated in patients with single-valve disease, but such tools might not be

valid for MVD

• Therapeutic decisions should be made by a heart valve team, considering the severity

of MVD, the patient’s life expectancy and comorbidities, and the risks of multiple

prostheses and eventual reoperation

• The introduction of transcatheter valve therapies is changing the therapeutic

paradigm, but further studies are needed to guide therapeutic decision-making

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Degenerative (or calcific) mitral stenosis is pre-dominantly found in elderly individuals and is usuallythe result of progressive mitral annular calcificationinvolving the base of the leaflets. Degenerative mitralstenosis causes progressive reduction in the functional

 valvular orifice, without commissural fusion26. Theresulting valvular stenosis is generally less severe thanin rheumatic valve disease, thereby decreasing the preva-lence of combined critical aortic and mitral stenosis inthis population22.

 Aortic regurgitation and mitral stenosis

The combination of aortic regurgitation and mitralstenosis imposes opposite loading conditions on theleft ventricle. Both LV end-diastolic and end-systolic

 volume are lower than with isolated aortic regurgita-tion27. Therefore, the increase in stroke volume typicallyassociated with aortic regurgitation might be bluntedin the presence of mitral stenosis, and the clinical signsassociated with increased pulse pressure might notbe observed28.

 Aortic regurgitation and mitral regurgitation

This condition, characterized by severe volume over-load caused by the two regurgitations and some pressureoverload typically associated with aortic regurgitation,is usually poorly tolerated. LV dilatation can be severeand the pattern of hypertrophic remodelling is eccentric(that is, a low ratio of wall thickness to cavity diameter).Furthermore, premature mitral valve closure — a protec-tive mechanism limiting the amount of backward flowinto the left atrium and the pulmonary veins in acuteand severe aortic regurgitation — does not occur, whichcontributes to poor clinical tolerance in patients withconcomitant aortic and mitral regurgitation. Patientswith this combination of valve lesions who are sympto-matic have worse LV performance than those with iso-lated aortic or mitral regurgitation29, resulting in a highincidence of postoperative LV dysfunction30. However,

over long-term follow-up, LV function can eventuallyimprove31. Nonetheless, patients with aortic and mitralregurgitation have significantly reduced postoperativesurvival and more frequently persistent symptoms aftersurgery than those with single-valve disease29.

Tricuspid regurgitation and left-sided valve disease

Secondary tricuspid regurgitation is highly prevalent inpatients presenting with mitral valve disease32,33 (FIG. 4),and is also common in patients undergoing surgical ortranscatheter aortic valve replacement for aortic steno-sis. Secondary tricuspid regurgitation is associated withreduced postoperative survival6,34,35. As with secondarymitral regurgitation, a complex interplay of factors —including free wall annular dilatation, right ventricularenlargement and dysfunction, pulmonary hyperten-sion, and right atrial enlargement — underlies the pres-ence and severity of secondary tricuspid regurgitationin the setting of left-sided valve disease. However, nosingle factor is independently associated with second-ary tricuspid regurgitation. Importantly, the severity of

tricuspid regurgitation is highly sensitive to changes inloading conditions, and the absence of regurgitation atthe time of treatment of the left-sided valve lesion doesnot guarantee long-term freedom from tricuspid regur-gitation (that is, annular dilatation alone can be a har-binger of future tricuspid regurgitation). More studiesare needed to elucidate the pathophysiology and deter-minants of secondary tricuspid regurgitation in the set-ting of left-sided valve disease and to identify predictorsof development or progression of tricuspid regurgitationif the tricuspid valve is not treated.

Diagnosis

The haemodynamic consequences of MVD on bloodflow, and on ventricular size, shape, and function,as well as the specific combination of valve lesionscan influence the diagnostic process in many ways9.Physical examination can be misleading both in terms

Figure 1 | Pathophysiology of combined aortic stenosis and mitral regurgitation. Mitral valve deformation andtethering, as well as an increase in transmitral pressure gradient caused by aortic stenosis, all contribute to mitralregurgitation. Increased left ventricular (LV) afterload related to aortic stenosis, combined with mitral regurgitation, resultin a decrease in forward LV stroke volume and, therefore, often to a low-flow, low-gradient pattern. Both aortic stenosisand mitral regurgitation can, in the long-term, induce LV myocardial fibrosis and dysfunction. However, the extent of LVsystolic dysfunction in such cases is underestimated by LV ejection fraction owing to the LV concentric remodellingrelated to aortic stenosis and the retrograde flow (mitral regurgitant volume) related to mitral regurgitation.

Aortic stenosis

Poor functional tolerance

Mitral regurgitation

Low-flow, low-gradientaortic stenosis

 Forwardstroke volume

Atrialfibrillation

LV systolic dysfunction(underestimated byLV ejection fraction)

LV diastolicdysfunction

 Filling pressurePulmonary hypertension

LV remodelling

Mitral valvedeformationLeaflet tethering

 LV systolicpressure

 Transmitralsystolic pressuregradient

 Mitral valveregurgitantvolume

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of the timing and intensity of murmurs heard duringauscultation, and of other signs such as pulse pressure.Echocardiography is the cornerstone of the diagnosis of

 valvular heart disease. However, several Doppler meth-ods commonly used for the assessment of stenosis orregurgitation have been validated only in patients withsingle-valve disease and might not be valid in the set-ting of MVD. Echocardiographic assessment shouldinclude quantification of the stenosis or regurgitation,and evaluation of valve anatomy and function, integratedin a multiparametric analysis36. Left and right ventricular

 volume and function and pulmonary pressure shouldalso be assessed. As a general rule, measurements thatare not dependent on loading conditions, such as directplanimetry of a stenotic valve or, for regurgitant lesions,assessment of the effective regurgitant orifice or the venacontracta, are preferred.

A low-flow, low-gradient stenosis is common in

MVD (FIG. 3). Indeed, any severe valve lesion can reduceflow and, therefore, the gradient across another stenotic

 valve. A low-flow, low-gradient pattern makes the accu-rate assessment of stenosis severity difficult. Conversely,the presence of concomitant regurgitation on a stenotic

 valve (mixed lesion) will have the opposite effect — thatis, increase the transvalvular flow and, therefore, the pres-sure gradient. Mitral valve area should not be evaluatedusing the continuity equation method in the presence ofaortic regurgitation, because the transmitral flow differsfrom the transaortic flow. Pressure half-time-derivedechocardiographic methods are invalid in the presenceof altered LV compliance or relaxation. Therefore, mitral

pressure half-time in the presence of aortic valve dis-ease should be interpreted with caution37,38. These andother diagnostic echocardiographic caveats of MVD aresummarized in TABLE 1.

Aortic or pulmonary valve disease can lead toremodelling of the left and right ventricles and, there-fore, of the respective atrioventricular valve and sub-

 valvular apparatus. In turn, secondary mitral or tricuspidregurgitation can result. In addition, the increased driv-ing pressure across the atrioventricular valve in thepresence of aortic or pulmonary stenosis will increasethe regurgitant volume. In this context, the regurgitant

 volume accurately reflects the haemodynamic burden ofthe regurgitation and correlates with symptoms, but willtend to be disproportionately elevated as compared withthe effective regurgitant orifice. Conversely, the effectiveregurgitant orifice area is more useful to guide decisionsabout whether to perform concomitant correction of theregurgitation of the atrioventricular valve if the patientundergoes replacement of the aortic or pulmonary valve.

Catheterization is recommended when discordant or

inconclusive results are obtained on physical examina-tion and with noninvasive testing39. In the EuroHeartSurvey, catheterization was performed in 30% of patientswith MVD1. However, right-heart catheterization cannotbe used accurately in this setting because the stroke vol-ume obtained using this technique does not equal thestroke volume across the aortic or the mitral valve in thepresence of mixed aortic or mitral valve disease, respec-tively. In addition, thermodilution can be misleading inthe assessment of cardiac output and, therefore, valvearea in patients with severe tricuspid regurgitation,

 very low cardiac output, or both — situations that arecommon in patients with MVD40,41.

Multimodality imaging

Echocardiography is the primary imaging modality usedto establish a diagnosis and monitor patients with MVD,but other imaging modalities can be helpful when theinformation obtained using echocardiography is notsufficient or is inconclusive to determine the severityof each individual valvular lesion. Determination ofthe severity of stenotic lesions can be hampered by thefrequent occurrence of low-flow states with resulting‘pseudonormal’ low gradients or ‘pseudosevere’ valvestenosis. Nevertheless, an accurate diagnosis is critical,often with implications for treatment decisions. Thecontinuity equation, on which the estimation of aortic

 valve area is based, assumes a circular shape of the LVoutflow tract. However, 3D analysis has demonstratedthat the annulus often has an oval shape42. Therefore,LV outflow tract area, as measured by 3D echocardio-graphy, MRI, or multidetector CT is often larger than thearea calculated from a single LV outflow tract diameterobtained using transthoracic echocardiography 43. Thislarger LV outflow tract area will translate into a differ-ent (and often larger) aortic valve area when 3D meth-ods are used44. However, these measurements of aortic

 valve area by hybrid methods (for example, LV outflowtract area measured using multislice CT and flow velo-cities measured using Doppler echocardiography) have

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Figure 2 | A patient with aortic stenosis and mitral regurgitation. a  | This patient hassevere, symptomatic aortic stenosis with a mean transaortic gradient of 48 mmHg and anaortic valve area of 0.7 cm2 on Doppler echocardiography. Left ventricular ejectionfraction is 45%. b | Colour Doppler shows that moderate-to-severe mitral regurgitation isalso present (see Supplementary information S1 (video)). c,d | The same patient, 6 monthsafter transcatheter aortic valve implantation. The mean transaortic pressure gradient is11 mmHg with only mild residual mitral regurgitation (see Supplementary information S2 (video)). Left ventricular ejection fraction is 65%.

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to be used with technique-specific validated thresh-olds that might be >1 cm2 (the validated thresholdfor echocardiography)45.

Dobutamine stress echocardiography should be per-formed in patients with low flow and a low transaorticgradient, but a small valve area, to exclude pseudosevereaortic stenosis46. In these difficult cases, particularlywhen the results of echocardiography are inconclu-sive, multislice CT can be used to assess the aortic valvecalcium score (severe stenosis: >2,000 AU in men and>1,200 AU in women)47,48.

Real-time 3D transoesophageal echocardiographycan be useful to measure mitral valve area in rheumaticmitral stenosis49, whereas real-time 3D echocardio-graphy with colour-defined planimetry can be usefulin selected patients with degenerative calcified mitralstenosis50. However, with the exception of interventionalcardiology 51, the role of multimodality imaging in thesetting of MVD is currently limited.

Treatment

Evidence on medical, surgical, and interventionalmanagement of patients with MVD is scarce. Most

recommendations from both US39 and European52 guidelines are, therefore, given a level of evidence C(TABLE 2). Several factors should, however, be taken intoaccount when determining the optimal managementstrategy. First, the increased surgical risk of combinedprocedures and the long-term increase in morbidityassociated with multiple prosthetic valves. Second, therisk of eventual reoperation and the prognostic effectof not correcting a less-than-severe lesion. Third, thelikelihood of spontaneous changes in mitral or tricus-pid regurgitation after surgery on a downstream valvularlesion. Fourth, the choice of surgical technique. Fifth, theemerging role of percutaneous approaches, and sixth,the crucial role of a heart valve team. We consider eachof these factors in turn.

Surgical risk and long-term morbidity 

Combined surgical procedures on multiple valves areassociated with increased operative risk. Among patientswith MVD included in the EuroHeart Survey, in-hospitalmortality was 6.5%, compared with 0.9% to 3.9% for

single- valve surgery 1. In a series of 513 patients under-going multiple-valve surgery, in-hospital mortality was12.5%, and 5-year mortality was 32.9%53. Postoperatively,80% of the patients discharged from hospital improvedto NYHA functional class I or II, with only 0.6% remain-ing in functional class IV. The 5-year rate of freedomfrom late combined valve-related morbidity and mor-tality was 71.7%53. Pulmonary artery hypertension wasone of the main risk factors for postoperative mortality 53.Among the 623,039 patients undergoing valvular surgerybetween 1993 and 2007 included in the STS database,10.9% had multiple-valve procedures3. Overall, operativemortality almost doubled compared with single-valveprocedures (10.7% versus 5.7%)3. However, a higherproportion of patients with NYHA class III/IV conges-tive heart failure and a higher incidence of nonelectivesurgery with multiple-valve procedures might havecontributed to the increased mortality in these patients3.In this large series, unadjusted operative mortality was10.7% for the combination of aortic and mitral surgery,13.2% for aortic plus tricuspid, 9.7% for mitral plustricuspid, and 14.0% for triple-valve surgery, whereasunadjusted operative mortality was 4.9%, 6.9%, and10.0% for isolated aortic, mitral, and tricuspid surgery,respectively 3. Results are improving noticeably overtime, with a decrease in mortality between 1993 and2007, despite worsening in preoperative risk profiles2.

In another analysis, risk factors significantly associatedwith operative mortality included emergency presenta-tion, increasing age, renal failure, reoperation, endo-carditis, diabetes mellitus, severe chronic lung disease,peripheral vascular disease, coronary artery disease, andfemale sex54. In a series of 871 patients with rheumaticheart disease undergoing triple-valve surgery, 30-dayhospital mortality was 8%55. NYHA class IV functionalstatus, ascites, and reduced LVEF were identified as inde-pendent risk factors for in-hospital mortality. Overalllong-term survival was 71 ± 3% at 5 years, and 59 ± 5%at 10 years, with 74% of surviving patients remaining inNYHA class I or II55.

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Figure 3 | A patient with aortic and mitral stenosis. a | Parasternal long-axisechocardiographic view of a patient with rheumatic aortic and mitral stenosis and severe

symptoms (NYHA class III; see Supplementary information S3 (video)). Left ventricularejection fraction is 60%. b | The mean pressure gradient across the aortic valve is21 mmHg. c | Stroke volume, measured in the left ventricular outflow tract (velocity-timeintegral [green line tracing in top image] multiplied by the cross-sectional area[calculated from diameter: green line in bottom image]), is 42 ml (26 ml/m2 of bodysurface area). The aortic valve area is 0.62 cm2, consistent with a low-flow, low-gradientaortic stenosis. d | The mean pressure gradient across the mitral valve is 8 mmHg, and themitral valve area estimated from the pressure half-time method (red diagonal line) is1.65 cm2. e | Mitral anatomical orifice area (green outline) as measured by directplanimetry is 1.2 cm2. This case highlights the inaccuracy of the pressure half-timemethod to assess mitral valve effective area in the presence of severe aortic valvedisease. Moreover, this patient exemplifies the frequent and challenging situation oflow-flow, low-gradient stenosis, present here at both the aortic and the mitral valves.This situation can lead to underestimation of the severity of aortic and mitral stenoses.

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Together, the results from these studies demon-strate that, at the price of an increased operative risk,acceptable clinical improvement and late survival canbe expected after a multiple-valve operation. In addition,these data also indicate that the risk of late mortality aftermultiple-valve surgery can be reduced by early surgicaltreatment, before pulmonary hypertension, progressionto NYHA class IV, or deterioration of LVEF occur.

Risk of reoperation

Treatment decisions for patients with MVD requireknowledge of the natural history of each specific valvularlesion. The risk of eventual reoperation and the prog-nostic implications of not correcting a less-than-severelesion should also be taken into account. Increasedoperative mortality and poor long-term survival are tobe expected after a ‘redo’ valve procedure56. Patient ageand the aetiology of the secondary valve lesion are themain factors influencing operative mortality and long-term survival56. Therefore, the likelihood and timing ofreoperation for the secondary valve lesion should be

considered when planning the initial surgical procedure.Moderately severe valve lesions have variable

rates of progression; some progress in severity moreoften and more quickly than others. In patients withmild-to-moderate aortic stenosis, the average yearlyincrease in transaortic velocity and mean gradient is0.3 m/s and 7 mmHg, respectively, whereas the decreasein valve area is 0.1 cm2 per year57. However, the patternof progression varies according to its aetiology; aorticstenosis progresses faster in patients with degenerativedisease than in those with a rheumatic or congenital

aetiology 58,59. A higher degree of valvular calcification isindependently associated with faster stenosis progres-sion and worse outcome60. Aortic regurgitation is slow toprogress. Patients with aortic regurgitation and normalLV systolic function who are asymptomatic have a lowlikelihood of progression to asymptomatic LV systolicdysfunction (

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hypertension (consistent with lesser chronic repercus-sions of mitral regurgitation), and higher preoperativetransaortic pressure gradient and lesser postoperativeprosthesis–patient mismatch (consistent with a greaterpostoperative reduction in systolic transmitral gradi-ent)11,17. In addition, the use of self-expanding valvesseems to be associated with less improvement in mitralregurgitation than balloon-expandable valves72,73. Thisfinding might be explained by anatomical or functionalinterference with mitral leaflet excursion annulus geom-etry, or by the increased incidence of LV dyssynchronyresulting from left bundle branch block or pacemakerinsertion. Balloon aortic valvuloplasty has been shownto reduce the severity of mitral regurgitation in nearlyhalf of patients with severe aortic stenosis and coexistentmitral regurgitation74, but no specific data exist to sup-port the routine use of this procedure to select patients

who should not receive an additional mitral procedureduring aortic valve replacement.

Secondary tricuspid regurgitation is an independ-ent predictor of long-term mortality 6,32–35,75. Mitral andaortic valve replacement tend to decrease pulmonary

 vascular pressures and so reduce right ventricular over-load; therefore, conservative management of moderatesecondary tricuspid regurgitation has been postulated76.However, as discussed, the pathophysiological linksbetween left-sided valve disease and secondary tricus-pid regurgitation are not linear or predictable. Severalstudies have demonstrated that the presence of untreatedmoderate-to-severe tricuspid regurgitation at the time

of aortic or mitral valve surgery is associated withreduced postoperative survival6,32. Moreover, late onsetof tricuspid regurgitation is associated with poor func-tional tolerance and reduced exercise capacity 77. Redosurgery for secondary tricuspid regurgitation is associ-ated with operative mortality of 10–25%78. Accordingly,patients with severe secondary tricuspid regurgitation,or those with mild-to-moderate secondary tricuspidregurgitation and evidence of right-sided heart fail-ure or annular dilatation (>40 mm when measured inend-diastole in the four-chamber view, or >70 mm whenassessed by a surgeon in the operating room) are gener-ally recommended to undergo tricuspid valve surgery atthe time the left-sided valve lesion is fixed39,52,79 (FIGS 4,5).

Choice of surgical technique

Whether valve repair or replacement is the optimal

surgical strategy should be considered when makingmanagement decisions for patients with MVD. In apropensity-matched analysis of patients with aorticand mitral valve lesions, aortic valve replacement andmitral valve repair improved late survival compared withreplacement of both valves80. Similarly, in another studyof patients with rheumatic heart disease, mitral valverepair plus aortic valve replacement improved event-free survival compared with double-valve replacement81.In the STS database, 23,404 patients underwent concomi-tant aortic valve replacement and mitral valve surgerybetween 1993 and 2007 (REF. 82). Mitral valve repairwas performed in 46%, and these patients had a 39%

Table 1 | Echocardiographic caveats in the diagnosis of multivalvular disease

Combinationof valve lesions

Aortic stenosis Aortic regurgitation Mitral stenosis Mitral regurgitation

Aortic stenosis NA • Pressure half-timemethod unreliable

• Pressure half-timemethod unreliable

• Low-flow,low-gradient mitralstenosis can occur

• High mitral regurgitant volume• Increased area of mitral regurgitant

 jet using colour-flow mapping• Mitral effective regurgitant orifice

less affected than mitral regurgitantvolume and colour-flow mappingparameters

Aorticregurgitation

• Simplified Bernoulli formula mightnot be applicable if left ventricularoutflow tract velocity is elevated

• Gorlin formula usingthermodilution is invalid

• Continuity equation is applicable• Peak aortic jet velocity reflects

severity of both aortic stenosis andaortic regurgitation

NA • Aortic regurgitant jetcan be mistaken for amitral stenosis jet

• Continuity equation isunreliable

• Doppler volumetric method invalid

Mitral stenosis • Low-flow, low-gradient aorticstenosis is common

• Mitral stenosis canblunt the increasein pulse pressureassociated with

aortic regurgitation

NA • Not affected

Mitralregurgitation

• Low-flow, low-gradient aorticstenosis is common

• Mitral regurgitant jet should notbe mistaken for the aortic stenosis jet

• Doppler volumetricmethod inapplicable

• Pressure half-timemethod can beunreliable

• Continuity equationunreliable

• Pressure half-timemethod unreliable

• Gorlin formula usingthermodilution invalid

NA

This Table presents the caveats in the echocardiographic diagnosis of a given valvular lesion (vertical columns) in the presence of a concomitant valvular lesion(horizontal rows). NA, not applicable. Modified from Unger, P. et al. Management of multiple valve disease. Heart 97 (4), 272–277© (2011), with permission from BMJPublishing Group Ltd.

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reduction in the risk of operative mortality comparedwith those undergoing mitral valve replacement, despitethem being of older age, with a lower LVEF, and a higherincidence of concomitant CABG surgery 82. Therefore,efforts should be directed towards improving rates ofmitral valve repair, even if prosthetic valve replacementof another valve decrease the willingness of a surgeon torepair the mitral valve.

Controversy exists, however, as to whether repair orreplacement of the mitral valve is preferred in patientswho have moderate-to-severe secondary mitral regurgita-tion and are undergoing aortic valve replacement. In onestudy, reduced in-hospital mortality was reported withmitral valve repair (11% versus 18% for replacement),but survival after discharge from hospital did not differsignificantly between the two strategies83. Conversely,other studies that included patients with primary or

secondary mitral regurgitation reported no survivalbenefit of mitral valve repair with aortic valve replace-ment over double-valve replacement, and an increasedlong-term incidence of mitral valve failure in patientsundergoing mitral repair was observed84,85. In a propen-sity matched analysis86 and in the Cardiothoracic SurgeryNetwork randomized trial87, mitral valve replacement wasassociated with better freedom from recurrent second-ary ischaemic mitral regurgitation during follow-upcompared with mitral valve repair.

When a patient is to undergo double-valve replace-ment, using the same type of prosthesis in both locations(bioprosthesis or mechanical) has been recommended soas not to lose the advantages of each valvular option. Thatis, to avoid superimposing the risk of anticoagulationand the risk of bioprosthesis deterioration7. No data areavailable on which type of valve prosthesis is preferable.

Table 2 | Indications for concomitant valve surgery in patients undergoing surgery on another valve

Valve lesion AHA/ACC guidelines (2014)39 ESC/EACTS guidelines (2012)52

Aorticstenosis • AVR is indicated for patients with severe aortic stenosis undergoingother cardiac surgery (class I, LOE B)• AVR is reasonable for patients with moderate aortic stenosis

undergoing other cardiac surgery (class IIa, LOE C)

• AVR is indicated in patients with severe aortic stenosisundergoing CABG surgery, or surgery on the ascendingaorta or another valve (class I, LOE C)

• AVR should be considered in patients with moderateaortic stenosis undergoing surgery on the ascendingaorta or another valve (class IIa, LOE C)

Aorticregurgitation

• AVR is indicated for patients with severe aortic regurgitation (stage Cor D) undergoing cardiac surgery for other indications (class I, LOE C)

• AVR is reasonable in patients with moderate aortic regurgitationundergoing other cardiac surgery (class IIa, LOE C)

• Surgery is indicated in patients with severe aorticregurgitation undergoing surgery on another valve(class I, LOE C)

Mitralstenosis

• Concomitant mitral valve surgery is indicated for patients with severemitral stenosis undergoing other cardiac surgery (class I, LOE C)

• Concomitant mitral valve surgery may be considered for patients withmoderate mitral stenosis (mitral valve area 1.6–2.0 cm2) undergoingother cardiac surgery (class IIb, LOE C)

• Surgery is preferable to PMC in patients with severemitral stenosis combined with severe aortic valve disease

• In patients with severe mitral stenosis and moderateaortic valve disease, PMC can be performed to postponethe surgical treatment of both valves

• Severe concomitant aortic valve disease is acontraindication to PMC

Mitralregurgitation

• Concomitant mitral valve repair or replacement is indicated inpatients with chronic severe primary mitral regurgitation undergoingcardiac surgery for other indications (class I, LOE B)

• Concomitant mitral valve repair is reasonable in patients with chronicmoderate primary mitral regurgitation (stage B) undergoing cardiacsurgery for other indications (class IIa, LOE C)

• Mitral valve surgery (repair or replacement) is reasonable for patientswith chronic severe secondary mitral regurgitation (stages C and D)undergoing AVR (class IIa, LOE C)

• Mitral valve repair may be considered for patients with chronicmoderate secondary mitral regurgitation (stage B) undergoing othercardiac surgery (class IIb, LOE C)

• No clear position

Tricuspidstenosis

• Tricuspid valve surgery is recommended for patients with severetricuspid stenosis at the time of operation for left-sided valve disease

(class I, LOE C)

• Tricuspid valve surgery is indicated in patients withsevere tricuspid stenosis undergoing left-sided valve

intervention (class I, LOE C)• Percutaneous balloon valvuloplasty can be attempted if

PMC can be performed on the mitral valve

Tricuspidregurgitation

• Tricuspid valve surgery is recommended for patients with severetricuspid regurgitation (stages C and D) undergoing left-sided valvesurgery (class I, LOE C)

• Tricuspid valve repair can be beneficial for patients with mild,moderate, or greater functional tricuspid regurgitation (stage B) at thetime of left-sided valve surgery with either tricuspid annular dilatationor prior evidence of right-sided heart failure (class IIa, LOE B)

• Tricuspid valve repair may be considered for patients with moderatefunctional tricuspid regurgitation (stage B) and pulmonary arteryhypertension at the time of left-sided valve surgery (class IIb, LOE C)

• Tricuspid valve surgery is indicated in patients withsevere primary or secondary tricuspid regurgitationundergoing left-sided valve surgery (class I, LOE C)

• Surgery should be considered in patients with moderateprimary tricuspid regurgitation undergoing left-sidedvalve surgery (class IIa, LOE C)

• Surgery should be considered in patients with mildor moderate secondary tricuspid regurgitation withannular dilatation (≥40 mm or >21 mm/m2) undergoingleft-sided valve surgery (class IIa, LOE C)

AVR, aortic valve replacement; LOE, level of evidence; PMC, percutaneous mitral commissurotomy. Modified from Unger, P. et al. Management of multiple valvedisease. Heart 97 (4), 272–277© (2011), with permission from BMJ Publishing Group Ltd.

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Tricuspid annuloplasty is the preferred techniquefor the surgical treatment of tricuspid regurgitation atthe time of left-sided valve surgery, because tricuspidregurgitation is usually the result of annulus dilata-tion with ensuing lack of leaflet coaptation. Moreover,tricuspid annuloplasty valve replacement is associ-ated with a lower rate of complications than tricuspid

 valve replacement33,78,88,89.

Percutaneous approaches

Percutaneous treatment of aortic stenosis and mitralregurgitation is increasingly used in patients at highsurgical risk. Limited series of combined transcathetertreatment of aortic stenosis and mitral regurgitation havebeen reported90,91. In carefully selected patients, a stagedapproach has been proposed — the valve stenosis istreated first by TAVI, followed by subsequent implant-ation of a MitraClip® (Evalve, Inc., USA) if moderate-to-severe mitral regurgitation with symptoms persists.This strategy has been associated with good proceduralsuccess rates and, at 6 months, acceptable functional

outcomes and survival91.In patients with severe aortic stenosis undergoing

TAVI, the concomitant mitral stenosis is generally ofdegenerative aetiology (that is, mitral annulus calcifi-cation) with significant thickening and calcificationof the subvalvular apparatus, and absence of com-missural fusion, and is, therefore, not suitable forpercutaneous mitral commissurotomy 92. However, inexceptional circumstances, circular mitral annular cal-cification is severe enough to cause haemodynamicallysignificant mitral stenosis and can offer enoughsupport to allow stable anchoring of a percutaneousmitral prosthesis93,94.

In the past 5 years, several percutaneous procedureshave been developed and successfully used to treatsecondary tricuspid regurgitation88,95. These emergingtechniques provide a valuable alternative to surgeryto correct tricuspid regurgitation at the time of otherpercutaneous intervention on the aortic or mitral valve,or as a staged procedure after surgical or percutaneoustreatment of another valve. More studies are neededto clarify these treatment pathways and to incorpor-ate evolving transcatheter options for mitral valvereplacement and tricuspid repair.

The heart valve team

The evaluation and treatment of patients with MVDcan be incredibly complex. The numerous diagnos-tic pitfalls, emergence of innovative transcathetertherapies, and treatment of elderly high-risk patientswith multiple comorbidities require the expertise of amultidisciplinary heart valve team (BOX 1). Expertisein cardiac surgery, transcatheter interventions, cardiacimaging, haemodynamics, anaesthesia, and geriatrics

is critical to making the best recommendations andtailoring treatment strategies to optimize outcomes forindividual patients96.

Clinical scenarios

Three main clinical scenarios are encountered in clin-ical practice — patients with two or more severe lesions,patients with one severe lesion plus at least one non-severe lesion, and patients with two or more nonseverelesions. The recommendations for concomitant valvesurgery in patients undergoing surgery on another

 valve, as outlined in the AHA/ACC39 and ESC/EACTS52 guidelines, are presented in TABLE 2.

Symptomatic severeaortic stenosis withconcomitant mitralregurgitation

Moderate

Secondary

Primary

Secondary

Primary

Severe

Mild

High

Low

Mitral regurgitation Treatment according to operative risk

Severity AetiologyLikelihood of improvement

Low/intermediate

SAVR SAVR or TAVI

Double valvesurgery

Double valvesurgery

Double valvesurgery or TAVI*

Double valvesurgery

Double valvesurgery

High Prohibitive

TAVI

TAVI*

TAVI ormedicaltherapy*

Medicaltherapyor TAVI*Double valve

surgery or TAVI*

TAVI*

Figure 5 | Management of severe aortic stenosis requiring surgery, with concomitant mitral regurgitation.Mitral regurgitation is highly likely to improve with aortic valve replacement in the absence of atrial fibrillation, left atrial

dilatation, or pulmonary hypertension. This algorithm requires validation by further studies. *A staged approach is

possible, consisting of TAVI followed by implantation of a MitraClip® (Evalve, Inc., USA) if symptomatic mitral regurgitationpersists. SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation. Modified from

Nombela-Franco, L. 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. 63 (24),2643–2658© (2014), with permission from Elsevier.

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Two or more severe lesions

The general recommendation for patients with two ormore severely stenotic or regurgitant lesions, and who

are symptomatic or have ventricular dysfunction ordilatation, is for all lesions to be surgically correctedconcomitantly 39,52. However, for patients at high or pro-hibitive risk of surgery, alternative treatment pathwayshave been proposed. In such cases, the staged percu-taneous approach involving the MitraClip® outlinedabove might be considered. This rapidly evolving areawill become only more complex with the emergence oftranscatheter options for tricuspid disease.

One severe lesion plus at least one nonsevere lesion

The decision to perform an intervention should bebased on the recommendations for the predominant

 valvular lesion52. Whether an additional procedure ona coexistent nonsevere valvular lesion is required can be

difficult to determine. The surgical risk of a combined valve procedure and the long-term increase in mor-bidity associated with multiple valve prostheses shouldbe balanced against the risk of eventual reoperationand the prognostic implications of not correcting theless-severe lesion during the initial procedure. In addi-tion, life expectancy, comorbidities, and patient wishesshould all be taken into account.

In the current AHA/ACC39  and ESC/EACTS52 guidelines, moderate aortic stenosis, moderate aorticregurgitation, moderate primary mitral regurgitation,and moderate primary or secondary tricuspid regurgi-tation (provided that tricuspid annulus is dilated) areall class IIa recommendations for performing a sec-ond surgical valve procedure in patients undergoingsurgery for another valve lesion or other cardiac sur-gery. Moderate mitral stenosis, moderate secondarymitral regurgitation, and moderate tricuspid regur-gitation (in the presence of pulmonary artery hyper-tension) are considered class IIb indications in theAHA/ACC guidelines39.

In patients with one severe and one moderately-severe valve lesion who are asymptomatic, the increasedoperative risk associated with a double-valve proce-dure is an incentive to postpone surgery until symp-toms develop or another class I indication for surgeryexists. Decisional algorithms for patients with aorticstenosis presenting with concomitant mitral regurgita-tion have been proposed. These algorithms take intoaccount the severity and mechanism of mitral regurgi-tation, the likelihood of spontaneous improvement ifisolated aortic valve replacement is performed, as wellas the individual surgical risk 11,17 (FIG. 5). In patients withsevere mitral stenosis and concomitant moderate aor-tic valve disease, percutaneous mitral commissurotomycan be performed to postpone double-valve surgery.Indeed, only a minority of these patients will requiresubsequent aortic valve replacement on long-termfollow-up, emphasizing the limited progression of aorticregurgitation in this setting97.

The management of tricuspid regurgitation inpatients undergoing left-sided valve surgery as rec-ommended in the AHA/ACC39 and ESC/ EACTS52 guidelines is depicted in FIG. 6. Tricuspid valve repairor replacement is recommended (class I) in patientswith severe tricuspid regurgitation undergoing surgeryfor aortic or mitral valve disease. Tricuspid valve repairshould be considered in patients undergoing left-sided

 valve surgery if they have mild or moderate tricuspidregurgitation and tricuspid annulus dilatation (class IIa)or pulmonary hypertension with tricuspid annulusdilatation (class IIb)39,52.

Importantly, in some elderly patients, performingan intervention to improve quality of life can be moreimportant than prolonging life. Procedures that arebeneficial only after a long period of survival mightbe less suitable or appropriate for very elderly patients.Single-valve procedures that are less demanding andcarry a lower risk than double-valve or triple-valve pro-cedures should be considered for these individuals, evenat the cost of incomplete repair.

Box 1 | Heart valve team considerations

• Life expectancy of the patient

• Nature and severity of symptoms

• Which valve lesion is dominant

• Aetiology and severity of each valve lesion

• Size and function of the left and right ventricles

• Presence and severity of pulmonary hypertension

• Anticipated progression of a secondary valve lesion

if left untreated

• Transcatheter options

• Staged procedures versus all-at-once treatment

• Procedural risk

• Local experience of the treatment team

• Patient wishes

Figure 6 | Management of tricuspid regurgitation in patients undergoingleft-sided valve surgery. Indications for surgery on the tricuspid valve according tothe severity and aetiology (primary versus secondary) of tricuspid regurgitation, and

to the presence of tricuspid annulus dilatation or pulmonary hypertension39,52.

MildSevere

Le-sided valvular surgery

+

Tricuspid regurgitation

Moderate

Primary Secondary

Dilated tricuspid annulus

Tricuspid surgery No tricuspid surgeryTricuspid surgery(preferably repair)

Pulmonary hypertensionYes NoClass I Class IIa(ESC)

Class IIa Class IIb (AHA/ACC)(moderate tricuspidregurgitation)

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Two or more nonsevere lesions

In patients with nonsevere MVD, determining the globalconsequences of all lesions is of the utmost importance.Even moderate lesions, when combined, can lead tosevere functional intolerance, symptoms, LV dilatation ordysfunction, and pulmonary hypertension. This combin-ation of lesions is the most challenging in terms of thera-peutic decision-making. The consequences of the overallhaemodynamic burden on the cardiac chambers, pulmo-nary circulation, and patient’s functional capacity shouldbe assessed. Therefore, maximal exercise capacity andpeak oxygen consumption, parameters of ventricularfunction (such as LV global longitudinal strain, RV tri-cuspid annulus plane excursion, or free-wall strain), aswell as natriuretic peptide levels and pulmonary arterialpressure at rest and during exercise should be meas-ured98,99. Surgery might be appropriate for selected patientsin whom the combination of moderate lesions has ameaningful effect on the functional parameters men-tioned above. However, further studies are neededto identify and validate criteria for intervention in this

subset of patients.

Conclusions

Degenerative aetiologies have replaced rheumatic heartdisease as the predominant causes of MVD, the preva-lence of which is increasing in developed countries owingto ageing of the population. Clinicians must be aware ofspecific pitfalls associated with the evaluation of MVD;diagnosis and treatment of this condition depend onthe individual patient’s presentation and combination of

 valve pathologies. Patient-centred therapeutic decisionsshould be made by a multidisciplinary heart valve team,with integration of numerous factors to optimize clinicaloutcomes. Much work remains to be done to develop evi-dence to guide treatment decisions for these complex clin-ical cases. Several randomized trials are currently ongoingto assess the benefit of performing concomitant tricuspidannuloplasty at the time of mitral valve surgery in patientswith mild or moderate tricuspid regurgitation. Similarstudies will also be needed for patients undergoing aortic

 valve surgery. Randomized trials are also needed to deter-mine whether concomitant treatment of moderate mitralregurgitation at the time of surgical or percutaneous

aortic valve procedure improve patient outcomes.

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 AcknowledgementsB.R.L. is supported by NIH K23 HL116660. P.P. holds the

Canada Research Chair in Valvular Heart Disease, and his

research programme is funded by the Canadian Institutes

of Health Research (grant numbers FDN-143225, MOP

126072, MOP 114997 and MOP 102737) (Ottawa, Ontario,

Canada).

 Author contributionsP.U. researched data for the art icle. P.U., M.-A.C., B.R.L., and

P.M. contributed substantially to discussion of content, and

P.U. and P.P. wrote the manuscript. All the authors reviewed

and edited the manuscript before submission.

Competing interests statementB.R.L. has received research support from, and served on the

scientific advisory board for, Roche Diagnostics. P.P. has Core

Lab contracts with Edwards Lifesciences, for which he receives

no direct compensation, and has received research grants

from Ionis. The other authors declare no competing interests.

FURTHER INFORMATIONSociety of Thoracic Surgeons (STS) database:

http://www.sts.org/national-database

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