Secondary mitral regurgitation

Article written and reviewed by Dr Luca Moretti

Secondary mitral regurgitation results from an alteration in the geometry or function of the left ventricle or atrium, while the leaflets are initially structurally normal. In the ventricular form, myocardial infarction or cardiomyopathy displaces the papillary muscles, increases tethering and reduces closing forces; in the atrial form, dilation of the atrium and annulus exceeds the adaptive capacity of the leaflets. The valve thus becomes part of a broader chamber disease.

Defining regurgitation as “functional” describes the mechanism, but does not mean that the lesion is harmless or entirely reversible. The backward volume reduces forward stroke volume, increases pressures and volume load, and may accelerate the heart failure that generated it; at the same time, however, severity may decrease after diuresis, neurohormonal therapy, resynchronization or revascularization. Intervening before optimizing the underlying substrate therefore risks treating a dynamic valve on the basis of an indication that is still unstable.

The secondary form must be distinguished from primary mitral regurgitation, in which repair eliminates the causal lesion. Here prognosis remains conditioned by cardiomyopathy, scar, right ventricular function and heart failure even after complete elimination of the regurgitant jet. The benefit of TEER or surgery therefore depends on stricter clinical selection.

This monograph focuses mainly on the ventricular form, both ischemic and nonischemic, to which most trials refer. Atrial functional mitral regurgitation is described separately because its mechanism, ventricular function and therapeutic evidence are not interchangeable.

Ventricular mechanisms and phenotypes

Mitral competence depends on the balance between systolic forces that drive the leaflets toward closure and chordal forces that anchor them. In a normal ventricle, the papillary muscles remain beneath the commissures and leaflet surface area is sufficient. With remodeling, lateral and apical papillary displacement stretches the chordae and lowers the point of coaptation into the ventricle.

In nonischemic dilated cardiomyopathy, remodeling is often global: ventricular dilation and sphericity, increased interpapillary distance and annular enlargement produce relatively symmetric tethering. The leaflets therefore assume a “tent-like” configuration above the papillary plane and the jet is often central; reduced contractility also decreases the forces and velocity with which the leaflets reach coaptation.

In the ischemic phenotype, an inferior or posterolateral infarction predominantly displaces the posteromedial papillary muscle and causes asymmetric tethering, often involving the posterior leaflet, with an eccentric jet. A large anterior infarction may cause global dilation and symmetric geometry. Transient ischemia and dyssynchrony can increase regurgitation without a new infarction.

Papillary muscle rupture, by contrast, is an acute structural lesion and is classified as primary ischemic mitral regurgitation, not as a secondary form. The distinction is clinically decisive: papillary dysfunction or displacement causes tethering and may improve with revascularization and remodeling, whereas rupture requires urgent correction by repair or replacement.

The annulus dilates mainly in the anteroposterior diameter, becomes flatter and loses systolic contraction. In the ventricular form, the annulus alone is rarely the sole mechanism: simple annuloplasty may fail if tethering persists. Tenting height and area and leaflet angles describe the deformation, but there are no isolated thresholds that automatically determine the technique.

The balance of forces explains the dynamic nature of the lesion. Acute increases in afterload, ischemia, dyssynchrony and volume overload amplify regurgitation; vasodilation, diuresis and improved contractility reduce it. Sedation and anesthesia may make it appear less severe. The examination guiding an intervention should therefore reflect stable clinical conditions and optimized therapy.

Dyssynchrony due to left bundle branch block alters the contraction sequence of the papillary muscles and reduces the rate of pressure rise. Resynchronization may immediately improve closing forces and, over time, reduce volumes and tethering. A favorable response may transform severe regurgitation into moderate regurgitation without valve intervention.

The leaflets do not remain biologically inert. They may increase in surface area in response to tethering, an adaptation that sometimes preserves coaptation; fibrosis and thickening may instead limit mobility. This valvular remodeling explains why the dichotomy between “normal” and “diseased” leaflets becomes less clear in chronic cardiomyopathy.

The atrial form develops with dilation of the atrium and annulus, often in long-standing atrial fibrillation or heart failure with preserved ejection fraction. The ventricle is not dilated to the same extent as in the ventricular phenotype; insufficient leaflet growth and posterior tethering may contribute. If ventricular remodeling develops, the phenotypes become mixed.

The severity of regurgitation and that of cardiomyopathy do not always progress in parallel. Some very large ventricles have moderate regurgitation, whereas others that are less dilated develop a large regurgitant orifice. The concept of “proportionate” or “disproportionate” regurgitation has attempted to describe this relationship, but it depends on variable measurements and does not replace validated selection criteria.

Pathophysiology, clinical features and natural prognosis

The regurgitant volume returns to the ventricle during diastole and increases preload. Forward output falls, while the atrium and pulmonary circulation receive a greater pressure and volume load. Ventricular dilation increases wall stress and oxygen consumption and amplifies tethering, creating a self-perpetuating cycle.

In cardiomyopathy with a low ejection fraction, a smaller EROA may represent a substantial proportion of total stroke volume. Absolute regurgitant volume may appear modest because total output is low, but the relative loss is clinically important. It is therefore inappropriate to interpret secondary regurgitation solely using thresholds derived from degenerative disease.

Increased atrial pressure causes dyspnea and congestion; a large atrium and atrial fibrillation further reduce efficiency. Pulmonary hypertension, tricuspid regurgitation and right ventricular dysfunction mark multichamber disease. Pressure may fall in terminal stages because the right ventricle can no longer generate flow, without indicating improvement.

Symptoms are those of heart failure: exertional dyspnea, orthopnea, fatigue, edema, weight gain, early satiety and hospitalizations. Angina suggests ischemia; palpitations may reflect atrial fibrillation or ventricular arrhythmias. Symptom intensity does not identify how much of the clinical picture is caused by regurgitation.

On examination, the murmur may be holosystolic but relatively soft when cardiac output is low. A third heart sound, a displaced and diffuse apex beat, crackles, jugular venous distension and edema reflect the underlying cardiomyopathy. A change in murmur after therapy is not sufficient to demonstrate a stable reduction in severity.

Moderate or severe secondary regurgitation is associated with higher mortality and more hospitalizations even after adjustment for ventricular function. This association does not prove that every mechanical reduction improves survival: trials have demonstrated benefit only in selected populations. In end-stage heart failure, regurgitation may be more a marker than a modifiable target.

Prognosis depends on age, ischemic etiology, ejection fraction and volumes, scar, renal function, BNP, NYHA class, hospitalizations, pulmonary pressure, right ventricular function and tricuspid regurgitation. An extremely dilated ventricle and severe right ventricular dysfunction reduce the likelihood that mitral correction alone will change the course of disease.

Regurgitation may increase during exercise because of greater tethering or afterload and produce dyspnea or edema not explained by the resting examination. A marked dynamic change has prognostic value, but the decision for TEER is based on persistent severity and clinical criteria under optimized conditions, not on provocation alone.

Repeated hospitalizations accelerate frailty, muscle loss, and renal and hepatic dysfunction. Intervention before stage D may interrupt part of the cycle; intervention when chronic inotropes or advanced support are already required may not provide benefit. Assessment of futility is part of patient selection, not a judgment based on age.

Diagnosis and integrated assessment

Transthoracic echocardiography should be performed with the patient euvolemic, blood pressure recorded and therapy as stable as possible. It defines dilation, sphericity, indirect evidence of scar, papillary position, tenting, annular geometry, jet direction, severity and the right heart. The presence of a primary lesion, even a minor one, should be sought before the term secondary is assigned.

Color Doppler may underestimate an eccentric or low-velocity jet. Linear vena contracta assumes a circular orifice, whereas the secondary regurgitant orifice is often elongated along the coaptation line. Three-dimensional imaging shows a crescent-shaped geometry and can measure the area directly, but requires adequate temporal and spatial resolution.

Two-dimensional PISA assumes a hemispheric flow-convergence surface and a relatively stable orifice, conditions that are often not met in secondary regurgitation. Flow convergence may be hemielliptic and EROA may vary during systole, with early and late peaks and a midsystolic reduction; a single measurement may therefore either underestimate or overestimate regurgitation. Regurgitant volume and fraction, pulmonary venous flow and chamber remodeling must be integrated into the final assessment.

The classic thresholds of EROA at least 40 mm² and regurgitant volume at least 60 mL identify severe regurgitation when present, but lower values may be significant in low-flow states. Previous lower thresholds should not be converted into an automatic definition of severity. Current guidelines emphasize a multiparametric approach, measurement quality and assessment after optimized therapy.

Comparison with total stroke volume is essential. A regurgitant fraction of at least 50% indicates that half of the stroke volume returns to the atrium and supports severe regurgitation. Cardiac magnetic resonance measures volumes, aortic flow, scar and viability and is particularly useful with multiple jets or discordant echocardiographic findings.

Geometric assessment includes end-systolic diameter and volume, tenting height and area, leaflet angles, interpapillary distance and posterior leaflet tethering. These data help predict repair, recurrence risk and response to remodeling, but do not replace clinical trial criteria. A report should distinguish symmetric from asymmetric mechanisms.

Three-dimensional transesophageal echocardiography defines anatomy for TEER: leaflet length, grasping zone, gap, calcium, clefts, valve area and gradient. A central A2-P2 jet is favorable, but modern systems can treat more complex anatomies. The goal remains substantial reduction in regurgitation without stenosis and with stable leaflet insertion.

Right ventricular assessment includes dimensions, TAPSE, S-wave velocity, fractional area change and, when possible, strain. Estimated pulmonary pressure may be unreliable with severe tricuspid regurgitation. Right heart catheterization is useful when pulmonary pressure, vascular resistance, cardiac output or candidacy for advanced therapy is uncertain.

Coronary angiography or CT identifies revascularizable disease; magnetic resonance or nuclear imaging assesses viability in selected scenarios. ECG defines QRS duration, bundle branch block and rhythm for CRT. BNP or NT-proBNP, renal function, iron status and hepatic profile quantify severity and potentially correctable conditions.

Cardiopulmonary exercise testing quantifies oxygen consumption, the VE/VCO₂ slope and exercise limitation. It is useful when symptoms and resting findings are discordant or when LVAD or transplantation is being considered. Exercise echocardiography may show the dynamic behavior of regurgitation and pulmonary pressure, but should not delay treatment of disease that is already severe and symptomatic.

Final assessment should be repeated after an adequate period of foundational therapy and after CRT when indicated, unless the patient is unstable. A reduction in grade changes the indication; persistent severe disease identifies the group to discuss for intervention. Review by heart failure specialists prevents therapy from being considered “optimal” in name only.

Heart failure therapy and interventions

Foundational therapy is the first intervention in the ventricular form with reduced ejection fraction. When tolerated and indicated, it includes an ARNI or ACE inhibitor/ARB, an evidence-based beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. Titration, blood pressure, potassium, renal function and adherence are checked; diuretics maintain euvolemia.

Intravenous iron for selected iron deficiency, rate or rhythm control, and treatment of hypertension, diabetes, sleep apnea and ischemia complete management. Therapy may reduce ventricular volumes and regurgitation over weeks or months. Failure to reach target doses does not equal failure to optimize when hypotension or renal dysfunction is limiting, but the reason should be documented.

Cardiac resynchronization therapy is indicated according to QRS duration, morphology, ejection fraction and symptoms. It improves papillary synchrony and closing forces early and induces reverse remodeling over time. Regurgitation should be reassessed after an adequate response; persistent severe regurgitation despite CRT identifies higher risk.

Revascularization treats ischemia and viable myocardium when indicated for coronary artery disease, but does not guarantee resolution of chronic regurgitation when scar and geometry are fixed. If bypass surgery is planned in a patient with severe ventricular regurgitation, the 2025 guidelines recommend concomitant mitral surgery. The choice between repair and replacement takes tethering and recurrence into account.

For patients without an indication for coronary surgery, the 2025 ESC/EACTS guidelines recommend TEER to reduce hospitalizations and improve quality of life when severe ventricular regurgitation persists despite optimized medical therapy and CRT, LVEF is below 50%, symptoms remain, and the clinical-anatomical profile predicts benefit.

The practical selection criteria reported in the guidelines include:

• Stable heart failure, NYHA class at least II despite optimized therapy and CRT when indicated.
• LVEF 20-50% and left ventricular end-systolic diameter no greater than 70 mm.
• Clinical risk documented by at least one hospitalization for heart failure in the previous year or BNP at least 300 pg/mL or NT-proBNP at least 1000 pg/mL.
• Suitable anatomy for TEER and systolic pulmonary pressure no greater than 70 mmHg.
• Absence of severe right ventricular dysfunction, stage D heart failure, coronary artery disease requiring revascularization, severe aortic or tricuspid disease, and hypertrophic, restrictive or infiltrative cardiomyopathy.

These criteria are not an automatic score. Biological age, frailty, anatomy, life expectancy, ability to adhere to therapy and patient goals complete the judgment. Stability implies absence of shock and the possibility of optimization; urgent TEER in shock belongs to observational evidence and expert pathways.

In the COAPT trial, adding TEER to maximally tolerated therapy reduced heart failure hospitalizations and mortality at two years; the hospitalization benefit and a survival difference persisted at five years, despite high absolute mortality. Centralized selection, optimization and a low degree of residual regurgitation are part of the result.

In the MITRA-FR trial, TEER did not reduce death or hospitalization compared with medical therapy at two years. On average, patients had more dilated ventricles and quantitatively less dominant regurgitation, but they also differed in selection criteria, optimization and procedural result. Reducing the divergence to the concept of “proportionality” alone is an oversimplification.

RESHAPE-HF2 extended the evidence to patients with moderate-to-severe or severe functional regurgitation and showed a reduction in the composite of recurrent hospitalizations or cardiovascular death, driven mainly by hospitalizations, together with improved health status at two years. The trial strengthens the evidence for TEER but does not remove the need to define severity and individual benefit.

MATTERHORN compared TEER with surgery in high-risk symptomatic patients with secondary regurgitation and demonstrated noninferiority for the clinical composite at one year, with fewer early safety events with TEER. Sample size and follow-up do not establish universal equivalence or identical durability. Anatomy and the need for other procedures remain decisive.

TEER creates one or more bridges between the leaflets, and success is not measured by device presence alone. The result is favorable when regurgitation is reduced to no more than mild-to-moderate, the gradient remains acceptable and leaflet insertion is stable; significant residual regurgitation and an elevated gradient are instead associated with worse outcomes. Follow-up must therefore assess the valve while continuing titration of heart failure therapy.

In symptomatic patients who do not meet criteria predicting benefit, TEER may be considered only after evaluation for LVAD or transplantation, for symptomatic improvement in selected patients who are ineligible for these therapies or awaiting them. In advanced disease, replacement therapies take priority when the patient is eligible. A clip may interfere with subsequent strategies and requires coordination.

Isolated surgery may be considered in patients with severe symptomatic regurgitation without advanced heart failure who are unsuitable for TEER, but the evidence is weaker. Restrictive annuloplasty carries a risk of recurrence when tethering is marked; chordal-sparing replacement offers more stable correction but introduces a prosthesis. Subvalvular techniques aim to realign the papillary muscles.

Severe symptomatic atrial regurgitation despite therapy may be treated surgically with annuloplasty, atrial fibrillation ablation and management of the atrial appendage when indicated. TEER may be an option in selected patients, but the evidence base is distinct. A very dilated annulus and short leaflets influence durability.

Follow-up, complications and advanced selection

After medical optimization, follow-up assesses tolerated doses, blood pressure, renal function, potassium, volume status, rhythm and devices. Serial echocardiography measures ventricular volumes, regurgitation severity, pulmonary pressure and the right heart. A patient initially excluded because of instability may become a candidate after compensation; one with rapid deterioration may move beyond the therapeutic window.

After TEER, regurgitation is assessed with color Doppler, pulmonary venous flow, continuous-wave Doppler and volumetric methods, recognizing that multiple orifices limit PISA. The mean gradient should be reported together with heart rate. A high gradient at rest or during exercise may produce functional stenosis and limit benefit.

Procedural complications include bleeding, vascular injury, pericardial effusion, stroke, renal injury, an interatrial defect and, rarely, embolization. Single-leaflet device attachment causes loss of leaflet grasp and recurrent regurgitation; leaflet injury may require surgery. Center experience reduces but does not eliminate risk.

An initial reduction in regurgitation promotes reverse remodeling, but the degree varies. If cardiomyopathy progresses, tethering and dilation may generate recurrence around the devices. Persistent moderate or severe regurgitation is associated with worse outcomes and requires multidisciplinary reassessment.

The right heart is a determinant of potential futility. Severe right ventricular dysfunction, severe tricuspid regurgitation and fixed pulmonary hypertension reduce the gain from an isolated mitral procedure. Very high pressures sometimes require catheterization to distinguish a reversible postcapillary component from elevated pulmonary vascular resistance.

Renal dysfunction, hepatic dysfunction, frailty and cachexia reflect the duration of heart failure. Symptomatic improvement may still be meaningful, but goals and expectations should be explicit. Selection should neither exclude patients because of chronological age nor include them merely because of a desire to “do something.”

The proportionate/disproportionate concept may help frame the relationship between EROA and end-diastolic volume, but it is affected by measurement errors, loading conditions and geometric simplifications. Subsequent trial analyses have not transformed a mathematical ratio into a standalone criterion. Validated clinical criteria remain the reference.

In patients with coronary artery disease, residual ischemia, viability and completeness of revascularization influence the choice. In nonischemic disease, genetic, inflammatory or infiltrative etiologies should be diagnosed because they change prognosis and treatment; severe infiltrative cardiomyopathy is a reason not to apply TEER criteria mechanically.

Benefit should be measured through hospitalizations, NYHA class, KCCQ, exercise capacity, diuretic dose and survival. Even after successful TEER, five-year mortality in COAPT remained high: the procedure modifies but does not cure heart failure. Continued specialist care remains essential.

The best strategy treats the valve and the system that distorted it at the same time. Foundational therapy and devices correct the ventricle; TEER or surgery interrupt regurgitant loss when it has become an independent therapeutic target; LVAD and transplantation replace function in end-stage disease. The sequence, more than any single technique, determines the result.