Mitral Regurgitation

Mitral regurgitation is a pathological condition in which the mitral valve fails to ensure effective closure during ventricular systole, leading to retrograde blood flow from the left ventricle to the left atrium. This valve incompetence results in a volume overload of both left-sided chambers and a reduced forward output to the aorta, with potential consequences on pulmonary pressure and overall cardiac function.

Clinically and pathophysiologically, mitral regurgitation is classified as primary (organic), when it directly involves the valve leaflets, chordae tendineae, or mitral annulus, and as secondary (functional), when it arises from alterations in left ventricular geometry that prevent proper valve coaptation despite a structurally normal valve. Moreover, it can present in an acute or chronic form, with profoundly different hemodynamic and clinical characteristics.

Etiology, Pathogenesis, and Pathophysiology

The causes of mitral regurgitation are multiple and can be categorized into primary and secondary forms.

Primary forms, where the valvular apparatus is directly affected, include:

• Myxomatous degeneration (mitral valve prolapse): the most common cause in Western countries, characterized by leaflet thickening and redundancy with chordal rupture;
• Rheumatic disease: with leaflet retraction, commissural fusion, and post-inflammatory valvular deformity;
• Infective endocarditis: with destruction of the leaflets, perforations, chordal rupture, and vegetative lesions;
• Papillary muscle rupture: a rare but dramatic complication of acute myocardial infarction, typically causing severe acute regurgitation;
• Mitral annular calcifications: frequent in the elderly, causing leaflet rigidity and impaired coaptation;
• Connective tissue disorders (e.g., Marfan, Ehlers-Danlos): with structural alterations of the valvular components;
• Blunt chest trauma: potentially leading to rupture of subvalvular structures.

Secondary forms, or functional mitral regurgitation, occur when the valve is anatomically normal but ventricular conditions prevent its correct closure. Main causes include:

• Non-ischemic dilated cardiomyopathy: with annular dilatation and papillary muscle displacement;
• Ischemic heart disease: particularly inferior-posterior infarction that distorts the subvalvular geometry (ischemic mitral regurgitation);
• Global left ventricular dysfunction: in advanced heart failure with reduced ejection fraction, even in the absence of overt myocardial necrosis.

During systole, the left ventricle normally ejects blood into the aorta through the aortic valve. In mitral regurgitation, a variable portion of this volume regurgitates into the left atrium, which must accommodate blood from both the pulmonary veins and the leaking ventricle. This results in left atrial volume overload and increased size and pressure of the chamber.

Over time, the left atrium dilates to accommodate the increased volume, and in parallel, the left ventricle undergoes eccentric remodeling, dilating and developing hypertrophy to maintain effective output. This adaptation allows for long-term compensation, albeit at the cost of progressive structural and functional deterioration.

The reduced systemic output caused by the regurgitant flow is initially compensated by neurohormonal mechanisms that induce salt and water retention and increased circulating plasma volume. This exacerbates the volume overload on the left heart and contributes to pulmonary congestion. If untreated, ventricular dysfunction may become irreversible.

In acute forms, such as chordae tendineae or papillary muscle rupture, there is no time for adaptation. The left atrium is non-dilated and unable to handle the regurgitant volume: atrial pressure rises rapidly, leading to acute pulmonary edema, hypotension, and cardiogenic shock. Acute mitral regurgitation is a medical emergency with high mortality if not promptly treated.

Clinical Manifestations

The clinical presentation of mitral regurgitation varies based on the rate of onset, severity of regurgitation, and the heart's compensatory capacity.

In chronic mild to moderate forms, patients may remain asymptomatic for years due to progressive left-sided chamber dilation and remodeling.
With increasing severity, symptoms of reduced cardiac output and pulmonary congestion appear:

• Fatigue and exercise intolerance;
• Dyspnea on exertion, progressing to rest dyspnea, orthopnea, and paroxysmal nocturnal dyspnea;
• Palpitations in case of atrial fibrillation (less common than in mitral stenosis);
• Acute pulmonary edema in decompensated cases.

In acute forms, the presentation is dramatic: sudden onset of severe dyspnea, widespread rales, tachycardia, hypotension, shock, and occasionally sudden death. Prompt diagnosis and treatment are crucial for survival.

On auscultation, the hallmark finding is a holosystolic murmur, best heard at the apex and radiating to the axilla. Depending on severity, the murmur may be mid- or late-systolic in mild or intermediate forms. In severe cases, murmur intensity may paradoxically diminish due to rapid pressure equalization between the atrium and ventricle.

Other findings include:

• Third heart sound (S3) from rapid ventricular filling in advanced stages;
• Mid-diastolic rumble due to excessive transmitral flow;
• Soft or split second heart sound (S2) due to early aortic valve closure;
• Signs of pulmonary congestion: rales, tachypnea;
• Signs of right-sided failure in terminal stages: jugular venous distension, hepatomegaly, peripheral edema.

Diagnosis

Electrocardiogram may show indirect signs of left chamber overload: notched and enlarged P waves due to left atrial enlargement, left axis deviation, and high-voltage QRS complexes indicating left ventricular hypertrophy. In atrial fibrillation, atrial activity is replaced by fibrillatory waves.

Chest X-ray reveals enlarged cardiac silhouette from left atrial and ventricular dilation. On lateral projection, esophageal compression may be seen. In acute cases, cardiac findings may be absent, but pulmonary edema with butterfly-pattern hilar opacities is present.

Transthoracic echocardiography with Doppler is the reference examination. It allows morphological assessment of the valves and cardiac chambers, evaluation of systolic function, and quantification of regurgitation.

Key quantitative parameters include:

• Vena contracta: narrowest segment of the regurgitant jet. ≥0.7 cm indicates severe regurgitation;
• EROA (Effective Regurgitant Orifice Area): ≥0.4 cm² indicates severe regurgitation;
• RVol (Regurgitant Volume): ≥60 mL denotes severe regurgitation;
• RF (Regurgitant Fraction): ≥50% defines severe regurgitation.

Additional severity indicators:

• Reversed pulmonary vein flow on Doppler;
• Significant left chamber dilation;
• Left atrial appendage pulsatility;
• High pulmonary systolic pressure (>60 mmHg).

Echocardiography also assesses valve reparability. Favorable criteria include:

• Isolated prolapse of one or two scallops (e.g., segment P2);
• Intact subvalvular apparatus with good leaflet mobility;
• Mitral annulus not excessively dilated (<55 mm);
• Absence of diffuse calcifications or retractions.

With these characteristics, mitral valve repair is the preferred intervention, offering better outcomes than replacement in terms of survival and preservation of left ventricular function.

Transesophageal echocardiography is helpful in doubtful cases or for preoperative planning. Stress echocardiography is indicated to assess exertion-induced regurgitation. Cardiac catheterization is reserved for complex cases, surgical candidates, or concurrent coronary evaluation.

Treatment

Management of mitral regurgitation depends on the severity of regurgitation, symptom presence, left ventricular function, and valve reparability potential. Options include medical therapy, surgical repair, valve replacement, or percutaneous interventions.

Medical therapy is indicated in asymptomatic patients or those awaiting intervention:

• Diuretics: to manage congestion symptoms;
• Vasodilators: useful for afterload reduction in hypertension;
• Beta-blockers and digoxin: for rate control in atrial fibrillation;
• Oral anticoagulants: in atrial fibrillation or prior embolic events.

Valve intervention follows ESC 2021 and ACC/AHA 2020 guidelines, with recommendations including:

• Class I: symptomatic patients with severe mitral regurgitation and EF >60%;
• Class I: asymptomatic patients with EF <60% or end-systolic diameter >40 mm;
• Class IIa: patients with new-onset atrial fibrillation or pulmonary pressure >50 mmHg at rest;
• Class IIb: asymptomatic high-risk patients if surgery carries low operative risk.

In these patients, mitral valve repair is preferred over replacement when feasible. Valve replacement with a mechanical or bioprosthetic valve is reserved for non-repairable cases.

In secondary (functional) mitral regurgitation, especially with reduced ejection fraction, the surgical role is less clear. In these cases, percutaneous repair with MitraClip is a valid option for patients unsuitable for conventional surgery and with favorable anatomy.

Two landmark trials evaluated this option:

• COAPT (2018): showed that in patients with severe regurgitation, not excessively dilated ventricles, and optimized therapy, MitraClip reduces mortality and hospitalizations;
• MITRA-FR (2018): showed no benefit, likely due to selection of patients with already severely compromised ventricles and less significant regurgitation.

These studies introduced the concept of disproportionate MR: only patients with regurgitation disproportionate to ventricular dilatation benefit from percutaneous intervention.

Treatment choice must always be evaluated by a multidisciplinary Heart Team, considering symptoms, valve morphology, ventricular function, and comorbidities.

Prognosis and Follow-up

The prognosis of mitral regurgitation strongly depends on timely intervention and preservation of left ventricular function. Early surgery before advanced ventricular dilatation is associated with excellent long-term survival. Progression to systolic dysfunction represents a point of no return with negative prognostic implications.

Follow-up includes:

Complications

Complications of mitral regurgitation are linked to disease progression and delayed intervention:

References
1. Baumgartner H et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022;43(7):561–632.
2. Nishimura RA et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease. J Am Coll Cardiol. 2021;77(4):e25–e197.
3. Bonow RO et al. Valvular Heart Disease: A Companion to Braunwald’s Heart Disease. Elsevier. 2nd ed, 2021.
4. Otto CM et al. Practice of Clinical Echocardiography. Elsevier. 6th ed, 2022.
5. Zoghbi WA et al. Recommendations for evaluation of native valvular regurgitation with echocardiography and Doppler ultrasound. J Am Soc Echocardiogr. 2017;30(4):303–71.
6. Stone GW et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med. 2018;379(24):2307–18.
7. Obadia JF et al. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med. 2018;379(24):2297–2306.
8. Grayburn PA et al. Proportionate and Disproportionate Functional Mitral Regurgitation. J Am Coll Cardiol. 2019;74(2):196–208.
9. Lancellotti P et al. Evaluation of ischemic mitral regurgitation. J Am Soc Echocardiogr. 2013;26(10):1057–92.
10. Carabello BA. The current therapy for mitral regurgitation. J Am Coll Cardiol. 2008;52(5):319–26.