Functional Mitral Regurgitation

Functional (secondary) mitral regurgitation is regurgitation through structurally normal mitral leaflets, caused by left ventricular or left atrial remodelling. It is a disease of the ventricle or atrium, not the valve.

Two forms exist. Ventricular functional regurgitation follows left ventricular dilatation and dysfunction (dilated or ischaemic cardiomyopathy), with leaflet tethering. Atrial functional regurgitation arises from annular dilatation in atrial fibrillation or heart failure with preserved ejection fraction, with normal ventricular size and function.

Moderate or severe regurgitation is present in about 20 to 25% of patients with chronic heart failure with reduced ejection fraction, and it independently increases mortality and hospitalisation.

Severity is defined as severe when the effective regurgitant orifice area is 40 mm2 or more (some use 30 mm2 or more) and regurgitant volume 60 mL or more (some use 45 mL or more), because lower thresholds apply to secondary regurgitation.

Pathophysiology.

Ventricular enlargement displaces the papillary muscles, which tether the leaflets and pull them toward the apex. Annular dilatation, reduced closing force (low systolic pressure rise) and dyssynchrony add to poor coaptation.

Regurgitation adds volume load, which drives further remodelling, giving a self-reinforcing cycle. Regurgitation changes with loading conditions, and exercise can raise the regurgitant orifice and cause pulmonary oedema.

In atrial functional regurgitation, left atrial and posterior annular dilatation prevent leaflet closure despite a healthy ventricle.

Dyspnoea, orthopnoea, fatigue, oedema and exertional pulmonary oedema. The apical holosystolic murmur radiating to the axilla may be soft despite severe regurgitation. A third heart sound, displaced apex and signs of congestion are common. Atrial fibrillation is frequent.

• Transthoracic echocardiography with quantification: effective regurgitant orifice area by the proximal isovelocity method, vena contracta (7 mm or more suggests severe), regurgitant volume and fraction, plus tenting area, coaptation distance, left atrial size, left ventricular volumes and ejection fraction, and pulmonary pressure.
• Transoesophageal echocardiography when images are inadequate or intervention is planned.
• Exercise echocardiography when symptoms exceed resting severity: a rise in effective regurgitant orifice area of 13 mm2 or more is significant.
• Cardiac MRI: regurgitant fraction (40% or more is severe), volumes, scar and viability.
• NT-proBNP; coronary angiography or CT when ischaemic origin is possible.
• ECG for left bundle branch block (QRS 150 ms or more) and atrial fibrillation.

Differential diagnosis.

• Primary (degenerative, rheumatic or endocarditic) mitral regurgitation.
• Ischaemic mitral regurgitation with papillary muscle dysfunction.
• Hypertrophic cardiomyopathy with systolic anterior motion.
• Other causes of dyspnoea in heart failure, and acute regurgitation from chordal rupture.

Optimise heart failure therapy first (at least 3 months of maximally tolerated doses).

• Sacubitril/valsartan 24/26 mg orally twice daily, doubled every 2 to 4 weeks to 97/103 mg twice daily (maximum); potassium and creatinine at 1 to 2 weeks; start at 24/26 mg when eGFR is under 30 mL/min/1.73 m2; do not combine with an ACE inhibitor (36 hour washout). Alternative: ramipril 2.5 mg daily titrated to 10 mg daily.
• Beta blocker: bisoprolol 1.25 mg daily titrated to 10 mg (reduce in eGFR under 20 and severe hepatic impairment), or carvedilol 3.125 mg twice daily titrated to 25 mg twice daily (50 mg twice daily when weight is over 85 kg), or metoprolol succinate 12.5 to 25 mg daily titrated to 200 mg.
• Spironolactone 25 to 50 mg daily or eplerenone 25 to 50 mg daily (potassium under 5.0 mmol/L, eGFR over 30; check at 1 and 4 weeks).
• Dapagliflozin 10 mg daily (eGFR 25 or over) or empagliflozin 10 mg daily (eGFR 20 or over); monitor volume status and genital infection; stop 3 days before major surgery.
• Furosemide 40 to 160 mg orally daily for congestion, titrated to dry weight.
• Hydralazine 25 mg three times daily titrated to 75 mg three times daily with isosorbide dinitrate 20 mg three times daily titrated to 40 mg three times daily, when renin angiotensin drugs are not tolerated, or added in Black patients with persisting symptoms.
• Cardiac resynchronisation for ejection fraction 35% or under with left bundle branch block and QRS 150 ms or more (also 130 to 149 ms), and an implantable defibrillator for ejection fraction 35% or under after 3 months of therapy.
• Atrial fibrillation: restore sinus rhythm (catheter ablation reduces atrial functional regurgitation), anticoagulate (apixaban 5 mg twice daily, 2.5 mg when two of age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over).

Mitral valve intervention (after optimised therapy, by a heart team).

• Transcatheter edge-to-edge repair for symptomatic severe regurgitation with ejection fraction 20 to 50%, left ventricular end systolic diameter 70 mm or less, systolic pulmonary pressure under 70 mmHg, and a regurgitant orifice large for the ventricular size. Antiplatelet therapy (aspirin 75 to 100 mg daily) for at least 6 months, or oral anticoagulation when already indicated. Benefit is smallest when the regurgitant orifice is small, or ventricular dilatation is advanced.
• Surgery at the time of coronary bypass or other cardiac surgery when regurgitation is severe. Replacement with preservation of the chordae is more durable than undersized ring annuloplasty, which fails in up to half of patients with severe tethering.
• Advanced disease: ventricular assist device or transplantation.

Monitoring. Clinical review every 3 to 6 months, echocardiography at 3 months after optimisation and every 6 to 12 months, NT-proBNP, creatinine and potassium at each drug change.

Referral and escalation. Refer symptomatic severe regurgitation to a heart team (heart failure, imaging, interventional cardiology and surgery). Urgent referral for pulmonary oedema, cardiogenic shock or rapidly worsening regurgitation.

Special groups.

• Pregnancy: stop sacubitril/valsartan, ACE inhibitors, spironolactone and SGLT2 inhibitors before conception; use metoprolol and diuretics as needed.
• Older adults: lower starting doses, orthostatic hypotension monitoring; transcatheter repair is favoured over surgery.
• Kidney impairment: start sacubitril/valsartan at 24/26 mg twice daily when eGFR is under 30 mL/min/1.73 m2; use spironolactone or eplerenone only when eGFR is over 30 and potassium under 5.0 mmol/L; start dapagliflozin at eGFR 25 or over and empagliflozin at eGFR 20 or over; reduce bisoprolol when eGFR is under 20; use contrast sparingly.