Multiple valve disease

Article written and reviewed by Dr Luca Moretti

Multiple valve disease is the concomitant presence of clinically relevant abnormalities affecting at least two different cardiac valves. It does not simply mean two findings listed in the same echocardiogram: each lesion changes flow, pressures and chamber geometry, thereby altering the expression of the other lesion and the overall risk. Aortic stenosis with secondary mitral regurgitation, combined rheumatic mitral-aortic disease and degenerative aortic disease associated with mitral prolapse are therefore all multivalvular conditions, but they are not equivalent.

The term must be distinguished from mixed aortic valve disease and mixed mitral valve disease, in which stenosis and regurgitation coexist in the same valve. A patient may have both conditions, for example mixed mitral disease and tricuspid regurgitation, but the specific question in multiple valve disease is how two different valves interact and which should be treated, by which technique and in what sequence.

Severity is not obtained by adding labels. Two moderate lesions may produce substantial cardiac damage, whereas apparently severe regurgitation may be secondary and decrease after correction of the dominant valve. Conversely, always expecting spontaneous regression risks leaving behind a lesion that has become autonomous. The distinction between an organic lesion, in which the valve tissue itself is diseased, and a secondary lesion, generated by remodeling, is the first key step in the strategy.

The 2025 ESC/EACTS guidelines address multiple valve disease as a distinct entity and recommend discussion in a Heart Valve Centre. The scarcity of randomized trials requires combining pathophysiology, multimodality imaging, biventricular damage, likelihood of reversibility and the risk of each procedure. The goal is not to correct as many valves as possible, but to remove the hemodynamic drivers without leaving a prognostically relevant lesion.

Definition, etiologies and classification of lesions

In high-income countries, aging commonly brings together aortic calcification, mitral degeneration, annular calcification and remodeling-related tricuspid regurgitation. The valves may become diseased independently, or one primary lesion may generate another. Aortic stenosis raises ventricular and atrial pressure, promoting functional mitral regurgitation and pulmonary hypertension; pulmonary hypertension then dilates the right ventricle and may cause tricuspid regurgitation. The three abnormalities may therefore belong to the same cascade, but only the first is necessarily organic.

Rheumatic heart disease remains the dominant cause of multivalvular disease in many regions. Commissural fusion, thickening and retraction affect primarily the mitral valve, followed by the aortic and tricuspid valves; stenosis and regurgitation may coexist in each. The tricuspid component may be organic, secondary to pulmonary hypertension or mixed. Defining the tissue lesion is crucial, because mitral commissurotomy does not reverse a retracted rheumatic tricuspid valve.

Endocarditis may involve multiple valves simultaneously or spread by continuity, producing vegetations, perforations, abscesses and fistulas with acute regurgitation. Bacteremia and emboli help define urgency, but a second regurgitant lesion may also be functional because of sepsis, ischemia or overload. Transesophageal mapping must therefore distinguish anatomical destruction from hemodynamic consequences, because surgery must treat all relevant infected tissue rather than chase an isolated Doppler grade.

Mediastinal radiation therapy may cause thickening and calcification of the aortic and mitral valves, calcification of the aortomitral curtain, coronary artery disease, pericardial disease and myocardial fibrosis. The risk of multivalve surgery depends not only on the valves but also on the irradiated mediastinum, aorta and lungs. Carcinoid disease predominantly involves the tricuspid and pulmonary valves; connective tissue disorders, serotonergic drugs, infiltrative diseases and congenital heart disease produce rarer combinations that require an etiologic strategy.

Classification should assign four attributes to each valve: type of dysfunction, severity, mechanism and etiology. Writing “severe aortic stenosis, moderate ventricular secondary mitral regurgitation and severe mixed secondary tricuspid regurgitation” is more useful than “triple-valve disease.” Rhythm, pulmonary pressure, biventricular function, annular dimensions, shunts, prostheses and devices must also be described because they determine reversibility and procedural feasibility.

A previously repaired or replaced valve may coexist with native disease at another site. In that case the problem is no longer entirely “native”: mismatch, thrombosis, degeneration or paravalvular leak may alter flow and mimic progression of the remaining native valve. Comparison with the baseline post-procedural study prevents symptoms caused by an obstructed aortic bioprosthesis from being attributed to new mitral stenosis.

Etiologic hierarchy avoids two opposite errors. The first is operating on a potentially reversible secondary regurgitation as though it were an independent disease; the second is assuming that every atrioventricular regurgitation will regress after treatment of the left-sided valve. Marked annular dilatation, chronic atrial fibrillation, tethering, right ventricular dysfunction, fixed pulmonary hypertension and organic valve disease reduce the likelihood of regression.

Hemodynamic interactions and clinical hierarchy

When aortic stenosis coexists with mitral regurgitation, the regurgitation diverts volume away from forward stroke output. Aortic velocity and gradient may therefore be low despite a severely narrowed orifice. At the same time, high ventricular pressure increases the systolic gradient toward the atrium and may amplify the mitral jet. Jet area and aortic gradient thus describe opposite effects of the same system and cannot be interpreted separately.

Secondary mitral regurgitation caused by afterload and remodeling may improve after aortic valve replacement, whereas prolapse, flail, calcification or rheumatic disease are not corrected by TAVI. Atrial fibrillation, a large annulus, fibrosis, pulmonary hypertension and a dilated ventricle favor persistence. Regression is probabilistic: observational studies show improvement in a substantial proportion, but residual regurgitation continues to be associated with a worse prognosis.

In combined mitral and aortic stenosis, mitral obstruction limits filling and reduces flow through the aortic valve, masking its gradient and velocity. Correcting the mitral lesion abruptly increases ventricular preload and may reveal hemodynamically more severe aortic stenosis; treating the mitral valve alone in the presence of critical aortic obstruction may cause pulmonary edema or low output. Planimetry, aortic calcium and measurements that are less flow-dependent become particularly important.

When aortic and mitral regurgitation coexist, the left ventricle receives volume from both the atrium and the aorta and ejects it through two retrograde pathways. It may therefore become markedly dilated while maintaining only modest effective systemic output; for this reason, the difference between ventricular stroke volume and arterial flows cannot automatically assign the excess volume to one valve. Independent flow measurements and separate quantification are required, remembering that correcting either lesion immediately changes the load and the apparent severity of the other.

Mitral valve disease associated with tricuspid regurgitation links the two ventricles through the pulmonary circulation. Left atrial pressure and pulmonary hypertension increase right ventricular afterload, tethering and annular dilatation. After mitral correction, pressure and regurgitation may decrease, but a dilated tricuspid annulus and atrial fibrillation may continue to progress. The tricuspid valve should therefore not be judged solely by the grade measured after diuresis or anesthesia.

Severe tricuspid regurgitation lowers pulmonary flow and left-sided preload, potentially reducing mitral and aortic gradients. Apparent low-flow aortic stenosis may reflect right ventricular dysfunction rather than left ventricular contractility alone. In turn, severe congestion impairs kidney and liver function and diuretic response, increasing the risk of any procedure. An upstream valve may therefore mask the burden imposed by a downstream valve while simultaneously determining how well treatment can be tolerated.

Identifying the dominant lesion means establishing which defect explains symptoms, low flow and damage and which lesion drives the cascade. It does not always correspond to the highest severity grade: severe low-gradient aortic stenosis may dominate torrential tricuspid regurgitation on color Doppler, whereas acute primary mitral regurgitation may be the emergency in a patient with stable chronic aortic stenosis. Chronology, morphology and consequences define the hierarchy.

Symptoms are shared and poorly localizing. Dyspnea may result from stenosis, regurgitation, pulmonary hypertension or heart failure; edema reflects right-sided failure but does not identify the initial cause; angina and syncope suggest aortic stenosis without excluding multivalvular low output. Cardiopulmonary exercise testing measures overall limitation, whereas biomarkers and signs of end-organ injury indicate disease stage rather than the single valve responsible.

Diagnostic hierarchy and multimodality imaging

Transthoracic echocardiography is the first level of assessment, but it should follow a sequence. Anatomy and mechanism are defined for each valve, stenosis and regurgitation are quantified with multiple methods, flow is measured, and only then are chamber response, pulmonary pressure and damage assessed. A report that lists four grades without stating flow, loading conditions and physiologic consistency does not solve the multivalvular problem.

Gradients and velocities are flow-dependent; pressure half-time depends on compliance and filling; jet area depends on pressure and machine settings. The continuity equation is valid only when the compared volumes are truly equal: shunts or intervening regurgitation make them different. Mitral regurgitation, for example, reduces forward output through the aortic valve but not total ventricular stroke volume. Indiscriminate use of formulas designed for a single valve produces impossible classifications.

The most robust measurements depend on the specific combination. Anatomical planimetry helps in mitral stenosis when the gradient is altered by flow; CT calcium supports true aortic stenosis in low-flow states; vena contracta, morphology, venous flow reversal and three-dimensional area strengthen regurgitation assessment. No parameter is completely independent of loading conditions, so agreement among anatomy, quantitative measurements and chamber response remains central.

Three-dimensional transesophageal echocardiography clarifies organic lesions, commissures, calcification, perforations, the subvalvular apparatus and repair feasibility. It is essential in endocarditis and for mitral or tricuspid planning, but sedation and ventilation alter pressure and regurgitation. The intraprocedural grade should not erase the outpatient examination performed under physiologic conditions; anatomy and load must be reported together.

Cardiac magnetic resonance is particularly useful when multiple regurgitant lesions make the assumption that all stroke volumes are equivalent unreliable. Combining biventricular volumes with phase-contrast flow in the aorta and pulmonary artery helps separate multiple regurgitations and shunts, while mapping and late enhancement may reveal fibrosis capable of explaining disproportionate dysfunction. Arrhythmias, complex jets and plane selection still require rigorous quality control, especially when CMR is used to resolve echocardiographic discordance.

CT assesses aortic valve calcium, mitral annular calcification, the aortomitral curtain, aorta, coronary arteries and vascular access. In a transcatheter strategy it simulates prostheses and possible device interactions: TAVI may alter access or geometry for a future mitral procedure, whereas TMVR may threaten the left ventricular outflow tract. Planning should therefore cover the entire treatment pathway, not only the first device.

Exercise testing and stress echocardiography uncover symptoms, increases in gradients, pulmonary hypertension and biventricular reserve; they do not by themselves determine which valve should be treated. NT-proBNP, bilirubin, albumin, renal function and markers of hemolysis or infection complete staging. An apparently asymptomatic patient with reduced exercise capacity, rising pulmonary pressure and declining right ventricular function already has biologically advanced disease.

Catheterization should be reserved for clinically relevant discordance, definition of pulmonary hypertension and coronary planning. Simultaneous pressures may clarify serial stenoses, but sedation, diuresis and indirect measurements alter physiology; moreover, in low-flow states or severe tricuspid regurgitation, thermodilution and the Fick method using estimated oxygen consumption may be inaccurate. Even invasive testing must therefore pass a consistency check and cannot be regarded as an infallible arbiter.

The diagnostic conclusion should state not only severity but also the degree of certainty and alternative scenarios. If aortic stenosis is definitely severe while secondary mitral regurgitation varies with loading conditions, it may be reasonable to treat the aortic valve first and reassess; when both lesions are organic and severe, uncertainty is lower and combined correction becomes more logical. Making uncertainty explicit therefore enables rational sequencing rather than masking it with false precision.

Indications and sequencing of interventions

A lesion that independently meets criteria for intervention is treated according to recommendations for the corresponding valve, but the modality must account for the entire system. In multiple valve disease with relevant primary lesions, surgery allows simultaneous correction and generally remains the reference strategy. The 2025 guidelines recommend concomitant treatment of severe lesions and consideration, during surgery for another valve, of moderate aortic stenosis or selected moderate tricuspid regurgitation.

The decision regarding a moderate lesion is not automatic. Probability of progression, age, etiology, annular size, repairability, procedure duration and the difficulty of future reintervention are weighed. Adding a mitral prosthesis to aortic valve replacement increases cross-clamp time, anticoagulation burden and prosthesis-related risk; leaving rheumatic mitral stenosis that is likely to progress may, however, negate the benefit and make a second intervention much riskier.

During mitral surgery, severe primary or secondary tricuspid regurgitation should be treated concomitantly; moderate regurgitation is considered according to recommendations and anatomy. In the CTSN trial, adding annuloplasty to surgery for degenerative mitral regurgitation reduced a two-year composite outcome driven by progression of tricuspid regurgitation, but increased pacemaker implantation from 2.5% to 14.1%, without yet demonstrating a survival benefit. Prevention and conduction-system risk must be discussed together.

When severe aortic stenosis coexists with severe primary mitral regurgitation, an operable patient is generally a candidate for simultaneous aortic valve replacement and mitral repair or replacement. If regurgitation is secondary, correction of afterload may reduce it and the decision is more individualized. Mixed mechanism, annular calcium, coronary disease, ejection fraction and center expertise determine whether the benefit of double-valve surgery outweighs the expectation of regression.

In high-risk patients, the 2025 guidelines favor a staged transcatheter strategy, generally starting with the downstream lesion: aortic first, then mitral and finally tricuspid. Treating aortic stenosis first removes the fixed obstruction, changes afterload and flow and allows reassessment of regurgitation. Reversing the sequence may abruptly increase flow against a still critically stenotic aortic valve and cause hemodynamic deterioration.

After TAVI, the mitral valve is reassessed once volume status and medical therapy have stabilized, not only before discharge. If severe symptomatic regurgitation persists with favorable anatomy, TEER or other mitral therapy may be considered according to etiology and specific indications. A primary lesion is less likely to regress; a secondary lesion may improve, but failure to regress identifies a high-risk population that should not simply be left under observation.

After mitral treatment, tricuspid regurgitation must be reassessed in light of the new right ventricular function, pulmonary pressure, annular size and congestion. A secondary form with still-limited remodeling may decrease, whereas marked tethering, atrial fibrillation, devices, right ventricular damage or organic disease favor persistence. If regurgitation remains severe and symptomatic despite therapy, a tricuspid procedure may complete the pathway: successful mitral treatment does not automatically guarantee tricuspid recovery.

When both mitral and tricuspid regurgitation are severe and secondary, reassessment of the upstream valve about three months after the first intervention is a pragmatic interval indicated by the guidelines, not a deadline for every combination; it is brought forward in case of instability and may be deferred if remodeling is still evolving. Waiting is inappropriate with refractory edema or low output. Simultaneous procedures are reserved for exceptionally selected patients and increase technical interactions and uncertainty regarding the contribution of each correction.

Rheumatic mitral stenosis and aortic stenosis may be treated with percutaneous commissurotomy and TAVI if anatomy, risk and absence of relevant mitral regurgitation permit, but the order must be simulated hemodynamically. Mitral annular calcification and degenerative stenosis are much less favorable for commissurotomy. In isolated aortic and mitral regurgitation, the absence of aortic calcium may limit anchoring of conventional devices and preserve surgery as the more comprehensive strategy.

Formal operative risk scores do not fully capture a multivalve procedure. Frailty, an irradiated mediastinum, aortic disease, right ventricular function, pulmonary pressure, liver and kidney function, coronary disease and the possibility of repair rather than replacement all modify the balance. The Heart Team must compare not only immediate mortality, but also the likelihood of leaving severe residual disease, durability, access to future procedures and the antithrombotic burden of the entire pathway.

Follow-up, post-intervention reassessment and prognosis

Before intervention or during surveillance, at least the interval required by the most severe lesion is used, often shortened because of the cumulative burden. No follow-up frequency is validated for every combination: severity, symptoms, rhythm, biventricular function, remodeling rate and feasibility of intervention determine timing. In stable cases with at least moderate disease, follow-up often falls within a six- to twelve-month range, but values close to thresholds or an unfavorable trajectory require shorter intervals.

Each visit records real-world activity, NYHA class, angina, syncope, weight, diuretic dose, rhythm, blood pressure, edema and ascites. Echocardiography compares all valves, not only the one designated dominant, together with chamber volumes, biventricular function, atrial size and pulmonary pressure. NT-proBNP, creatinine, sodium, bilirubin and albumin help identify a systemic trajectory that may precede a change in any single Doppler grade.

After the first intervention in a staged strategy, a new baseline must be established. Correction changes flows and loading conditions, so previous measurements cannot be mechanically transferred to the new circuit; an early study documents the result and complications, whereas the study that determines whether a second intervention is needed is scheduled after adequate stabilization. When both atrioventricular regurgitations are secondary, this point often falls around three months, but clinical deterioration requires earlier reassessment.

Improvement in an untreated regurgitant lesion is favorable but does not guarantee stability. Meta-analyses after aortic valve replacement associate regression of mitral regurgitation with better survival, without proving that the difference is entirely valve-mediated: persistent regurgitation may be a marker of more advanced myocardial and pulmonary vascular disease. A decision to perform TEER should therefore demonstrate suitable anatomy, symptom causality and an expected benefit.

Tricuspid regurgitation likewise does not follow a uniform trajectory after TAVI. In a recent cohort, some cases of at least moderate regurgitation regressed, whereas others persisted or developed during follow-up; persistence and progression were associated with more events. Pulmonary pressure, right ventricular function, atrial fibrillation and annular size explain part of the variability. Monitoring only the aortic prosthesis would miss the stage at which the tricuspid valve becomes the dominant therapeutic target.

After multivalve surgery, a baseline echocardiogram documents repairs, prostheses, gradients and residual regurgitation. Bioprosthetic valves are checked within three months, at one year and then annually according to recommendations; repairs require serial comparison. A high gradient from the outset suggests mismatch or a technical issue, whereas a later increase points toward thrombosis or degeneration. Anticoagulation and endocarditis prophylaxis depend on the complete set of prostheses and indications.

Prognosis worsens with the number of lesions, cumulative severity, biventricular dysfunction, pulmonary hypertension and hepatorenal injury. In the European registry, patients with multiple valve disease had high complexity and were often undertreated; in TAVI registries, persistent severe mitral or especially tricuspid disease identifies higher risk. These associations do not make every procedure automatically beneficial, but they make a strategy without reassessment inadequate.

A good outcome does not mean indiscriminate treatment of every valve. The goal is to restore forward output and functional capacity, reduce pressures and congestion, preserve both ventricles and avoid leaving a residual lesion that remains causally important. In some patients this requires simultaneous surgery, in others correction of the dominant lesion followed by observation, and in still others a sequence of transcatheter procedures. The precision with which this sequence is constructed is the true disease-specific therapy for multivalvular heart disease.