Mitral stenosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mohammed A. Sbeih, M.D. [2]; Rim Halaby, M.D. [3]; Yamuna Kondapally, M.B.B.S[4]

Mitral stenosis is a valvular heart disease characterized by narrowing of the orifice of the mitral valve of the heart. In normal cardiac physiology, the mitral valve opens during left ventricular diastole, to allow blood to flow from the left atrium to the left ventricle. Blood flows in the proper direction because during this phase of the cardiac cycle, the pressure in the left ventricle is lower than the pressure in the left atrium, and the blood flows down the pressure gradient. In the case of mitral stenosis, the valve does not open completely, and to transport the same amount of blood, the left atrium needs a higher pressure than normal to overcome the increased gradient. Mitral stenosis typically progresses slowly (over decades) from the initial signs of mitral stenosis to NYHA functional class II symptoms to the development of atrial fibrillation to the development of NYHA functional class III or IV symptoms. Once an individual develops NYHA class III or IV symptoms, the progression of the disease accelerates and the patient’s condition deteriorates. Severe mitral stenosis (MS) is eventually lethal disease unless treated with valvotomy or valve replacement, it may progress to serious complications like pulmonary hypertension, heart failure and death. Most of the cases are due to rheumatic heart disease.

Nonrheumatic calcific (degenerative) MS is found with increasing frequency in elderly populations in high-income countries, resulting from calcification of the mitral annulus extending into the leaflet bases. This is a distinct entity from rheumatic MS and is not amenable to commissurotomy.^[1]

Stage A = at risk (mild valve doming);

Stage B = progressive MS (MVA >1.5 cm²);

Stage C = asymptomatic severe MS (MVA ≤1.5 cm²);

Stage D = symptomatic severe MS (MVA ≤1.5 cm²).

This staging framework is the current standard for guiding management decisions.

Rheumatic MS is much more common in women (approximately 80% of cases) than in men. In high-prevalence regions, patients present at a young age (teens to age 30) with pliable noncalcified valves, whereas in low-prevalence regions, presentation occurs in older patients (age 50-70) with calcified fibrotic leaflets.^[1]

Mitral stenosis (MS) is most commonly secondary to acute rheumatic fever. Generally, the initial valvulitis is associated with valvular regurgitation but over a period of 2 or more years, the commissures fuse and the valves thicken and calcify. The chordal supporting structure also calcifies and retracts. The result is the typical “fish mouth deformity”. 70% of the time; the mitral valve is involved in isolation, and 25% of the time; the aortic valve is involved as well. The tricuspid and pulmonic valves are involved less commonly.

Patients with MVA >2.5 cm² are generally asymptomatic, those with MVA between 1.5-2.5 cm² may exhibit mild symptoms, and MVA ≤1.5 cm² is considered severe MS — the threshold at which significant symptoms typically develop and intervention is considered. ^[2], the transmitral gradient is highly dependent on heart rate and transvalvular flow. Conditions that increase heart rate or cardiac output (exercise, fever, pregnancy, hyperthyroidism, anemia, atrial tachyarrhythmia) accentuate symptoms by shortening diastolic filling time and increasing LA pressure.^[1]

The majority of cases of mitral stenosis result from rheumatic heart disease, which occurs as a complication of group A streptococcal infection in genetically susceptible individuals. Some cases may be congenital.

Nonrheumatic calcific (degenerative) MS as an increasingly recognized cause in elderly patients in high-income countries, resulting from mitral annular calcification (MAC) extending into the leaflets. This entity has a different pathophysiology and is generally not amenable to PMBC or surgical commissurotomy^[1]

Other causes include carcinoid heart disease, systemic lupus erythematosus, mucopolysaccharidoses, radiation-induced valve disease, and drug-induced valve disease (e.g., ergot derivatives). ^[3]

The possible causes, and other conditions that may present similarly, should be evaluated for when there is suspicion of mitral stenosis.

The incidence of rheumatic MS is low in high-income countries and has been slowly declining in low- and middle-income countries, but MS remains a major cause of valve disease worldwide. The Global Burden of Disease study estimated approximately 40-55 million prevalent cases of RHD globally, with the highest burden in Oceania, South Asia, and sub-Saharan Africa.^[4][5][6]

The prevalence ranges from approximately 3.4 cases per 100,000 in nonendemic countries to >1,000 cases per 100,000 in endemic countries^[7]

After the initial episode of rheumatic fever, there is a latent period of 20 years before the onset of symptoms in mitral stenosis. Complications of mitral stenosis are left and right heart failure, endocarditis and embolization (stroke) and pulmonary embolism. Survival in asymptomatic patients is 80% at 10 years. Once symptoms develop, if mitral stenosis is left untreated, survival at 10 years is only 15%. The majority of patients die due to complications of pulmonary hypertension (which is associated with a mean survival of 3 years after its onset) and right heart failure.

atrial fibrillation develops in approximately 30-40% of patients with significant MS and is associated with an 18-fold increased risk of stroke compared to age-, sex-, and hypertension-matched populations without AF^[8]

Staging of mitral stenosis (MS) is of utmost importance because it dictates the appropriate management plan for the affected patients. The stages of MS are determined based on the valve morphology, the valve hemodynamics characteristics, the consequences of MS on the left atrium and the pulmonary arterial system, and on the presence or absence of symptoms.

ACC/AHA staging with specific hemodynamic criteria^[1]:

Stage A (At risk): Mild valve doming during diastole; normal transmitral flow velocity

Stage B (Progressive MS): Commissural fusion and diastolic doming; MVA >1.5 cm²; pressure half-time <150 ms; mild-moderate LA enlargement; normal pulmonary pressure at rest

Stage C (Asymptomatic severe MS): MVA ≤1.5 cm²; pressure half-time ≥150 ms; severe LA enlargement; elevated PASP >50 mm Hg; no symptoms

Stage D (Symptomatic severe MS): Same hemodynamics as Stage C with decreased exercise tolerance and exertional dyspnea

After the initial episode of rheumatic fever, there is an approximate 20 year latent period before symptoms develop in mitral stenosis. Approximately half the patients will not have a recollection of having rheumatic fever. In regions with low disease prevalence, presentation occurs more often in older patients (age 50 to 70 years) who present decades after the initial rheumatic fever episode. ^[1]. Initial symptoms are worsened by exercise or tachycardia. Symptoms may begin with an episode of atrial fibrillation, or may be triggered by pregnancy or other metabolic stress, such as an infection. The symptoms are initially those of left heart failure, and subsequently are those of right heart failure.

Mitral stenosis is associated with a rumbling mid-diastolic murmur that is associated with an opening snap, best heard at the cardiac apex, and radiating to the axilla. While the murmur increases when lying down, raising the legs, and with exercise, it decreases upon performing the valsalva maneuver. The pulse pressure might be decreased among patients with mitral stenosis. Later in the course of the disease there may be signs of right heart failure such as pedal edema, ascites, and congestive hepatopathy.

The electrocardiogram (ECG) in mitral stenosis might have no significant abnormalities. Findings suggestive of left atrial enlargement and hypertrophy might be present, such as a broad, bifid P wave in lead II (referred to as P mitral) and an enlarged terminal negative portion of the P wave in V1. The ECG might demonstrate findings of pulmonary hypertension and right ventricular hypertrophy. Atrial fibrillation is not an uncommon finding among patients with mitral stenosis.

Chest X-ray in a patient with mitral stenosis might reveal left atrial enlargement. Chest X-ray findings include double right heart border, a prominent pulmonary artery (suggestive of an elevation in the pulmonary artery pressure), and kerley lines (suggestive of interstial pulmonary edema).

Transthoracic echocardiography (TTE) should be performed among patients with suspected mitral stenosis to confirm the diagnosis and to establish the baseline severity of disease. It should then be performed to monitor the course of disease over time. Echocardiography findings of mitral stenosis include decreased opening of the mitral valve leaflets and increased blood flow velocity during diastole. Per the 2020 ACC/AHA guidelines and 2023 ASE recommendations, hemodynamic severity is best characterized by the planimetered mitral valve area (by 2D or 3D echocardiography), not the transmitral gradient. The gradient is highly dependent on heart rate and transvalvular flow and should always be reported with heart rate^[1][9]. The gradient has not been included in the criteria for severity staging precisely because of this variability. TEE should also be performed prior to percutaneous mitral balloon commissurotomy for the evaluation of the presence of left atrial thrombus.

3D echocardiography (either TTE or TEE) provides greater accuracy of MVA measurement than 2D methods and is recommended when available. ^[1]

Moreover there is a significant role of echocardiographic morphology scoring systems (Wilkins score and commissural morphology assessment) in predicting suitability for PMBC. A Wilkins score ≤8 predicts favorable outcomes. Commissural morphology and calcification further predict suitability for commissurotomy.^[1][10]

When symptoms and resting echocardiographic data are discordant, exercise echocardiography is indicated to assess the hemodynamic significance of MS. Threshold values for consideration of intervention include a mean transmitral gradient >15 mm Hg during exercise or a PASP >60 mm Hg during exercise.^[11]

Cardiac magnetic resonance (CMR) may be beneficial to evaluate the structure and function of the left atrium and left ventricle as well as the severity of the mitral stenosis when echocardiography findings are inconclusive. It may help in identifying changes in left ventricular volume and masses in patients with valvular dysfunction.CMR may overestimate MVA (i.e., underestimate MS severity) compared to 3D echocardiography, particularly in severe MS, due to translational motion of the heart. CMR is therefore a second-line modality for MVA assessment when echocardiography is inconclusive.^[12][13][14]

While echocardiography remains the diagnostic imaging modality of choice, cardiac catheterization is useful to evaluate mitral stenosis when the results of the non-invasive testing are insufficient. Simultaneous left and right heart catheterization demonstrate a pressure gradient such that the pulmonary capillary wedge pressure (a surrogate of the left atrial pressure) exceeds the left ventricular end diastolic pressure.

Per the 2020 ACC/AHA guidelines, cardiac catheterization with hemodynamic assessment is recommended when there is a discrepancy between symptoms and the severity of MS assessed by TTE. Only the American guidelines (not ESC) specifically highlight invasive hemodynamic assessment for this purpose.^[15]

Medical therapy for mitral stenosis includes anticoagulation and rate control (to increase diastolic filling time) in those patients with atrial fibrillation. Medical therapy can relieve symptoms, but the patient may need surgery to relieve the blood flow obstruction by mitral stenosis. Surgical treatment in the symptomatic patient reduces the mortality rate of mitral stenosis compared to medical treatment. The interventional and surgical treatments for mitral stenosis include Percutaneous mitral balloon valvotomy (PMBV), Closed commissurotomy, Open commissurotomy (valve repair) and Mitral valve replacement.

Medical treatment for mitral stenosis includes anticoagulation and rate control in patients with atrial fibrillation.Per the 2020 ACC/AHA guidelines:

• Anticoagulation with a VKA (warfarin) is indicated (Class I) in patients with rheumatic MS and: (1) AF, (2) a prior embolic event, or (3) an LA thrombus. ^[1]
• DOACs are NOT recommended for patients with rheumatic MS and AF. The INVICTUS trial demonstrated that patients with rheumatic heart disease and AF treated with VKA had significantly better outcomes than those treated with rivaroxaban. ^[8]
• Heart rate control (beta-blockers, calcium channel blockers, or ivabradine) is recommended (Class IIa) in patients with MS in sinus rhythm with symptomatic tachycardia to lengthen diastolic filling time and lower LA pressure. Both ACC/AHA and ESC/EACTS guidelines recommend beta-blockers or ivabradine for rate control in sinus rhythm. ^[1][15]

Surgical treatment in the symptomatic patient reduces the mortality rate of mitral stenosis compared to medical treatment. The interventional and surgical treatments for mitral stenosis include: percutaneous mitral balloon valvotomy (PMBV), closed commissurotomy, open commissurotomy (valve repair), and mitral valve replacement.

The development of this approach was done by Inoue in 1984 and Lock in 1985 for the treatment of mitral stenosis. For a long time, surgical commissurotomy and open valve replacement were the only methods by which mitral stenosis could be corrected. PMBV can be performed in chronically symptomatic patients, patients who present emergently with cardiac arrest or pulmonary edema and in asymptomatic patients who plan on childbearing or major noncardiac surgery. There is improvement in the mortality rates for mitral stenosis by intervention by percutaneous mitral balloon valvotomy or surgery.

• Class I (A): Symptomatic patients (NYHA II-IV) with severe rheumatic MS (MVA ≤1.5 cm²) and favourable valve morphology with <2+ MR, in the absence of LA thrombus, at a Comprehensive Valve Center. JACC[1]

• Class IIa (B-NR): Asymptomatic patients with severe rheumatic MS and favourable morphology who have elevated pulmonary pressures (PASP >50 mm Hg). JACC[1]
• Class IIb (C-LD): Asymptomatic patients with severe MS and favourable morphology who have new-onset AF; symptomatic patients with MVA >1.5 cm² with hemodynamically significant MS on exercise (PAWP >25 mm Hg or mean gradient >15 mm Hg); severely symptomatic patients with suboptimal anatomy who are not surgical candidates.

PMBC should be performed only at experienced centers (Comprehensive Valve Centers per ACC/AHA). In the United States, there has been a 7.5% decrease in PMBC use accompanied by a 15.9% increase in complication rate, highlighting the importance of operator experience. ^[1]

70-80% of patients with an initial good result after PMBC are free of recurrent symptoms at 10 years, and 30-40% are free of recurrent symptoms at 20 years. ^[1][16]

The mainstay of treatment for mitral stenosis is not medical therapy.

Per the 2020 ACC/AHA guidelines^[1], mitral valve surgery (repair, commissurotomy, or valve replacement) is indicated

(Class I, B-NR) in severely symptomatic patients (NYHA III-IV) with severe rheumatic MS who:

(1) are not candidates for PMBC,

(2) have failed previous PMBC,

(3) require other cardiac procedures, or

(4) do not have access to PMBC. .

Beside percutaneous mitral balloon valvotomy (PMBV), surgical treatments for mitral stenosis include closed commissurotomy, open commissurotomy (valve repair) and mitral valve replacement.surgical commissurotomy at experienced centers may have better long-term outcomes than PMBC, but surgical commissurotomy is not routinely or widely performed by most surgeons in the United States.^[1]

Mitral valve replacement should be described as an option only when there is no other option and the patient has severe limiting symptoms, particularly if valve repair is not feasible due to severe valvular thickening and subvalvular fibrosis^[1]

In open surgery, the surgeon makes a large cut in the sternum to reach the heart. Minimally invasive mitral valve surgery is done through much smaller surgical cuts than the large cuts needed for open surgery.

Per the 2020 ACC/AHA guidelines, recommended echocardiographic surveillance intervals for asymptomatic MS are:

1. Progressive MS (Stage B, MVA >1.5 cm²): every 3-5 years
2. Severe asymptomatic MS (Stage C, MVA 1.0-1.5 cm²): every 1-2 years
3. Very severe asymptomatic MS (MVA <1.0 cm²): every year

At a minimum, a yearly history and physical examination are necessary for all patients with significant MS^[1]

Prevention of rheumatic fever (the most common cause of mitral stenosis) is the best way to prevent development of this valvular heart disease. Any child who has a sore throat should see a doctor to treat any case of strep throat infections (by antibiotics) before it progresses to rheumatic fever.

Secondary prevention of recurrent ARF with continuous antibiotic prophylaxis, which is recommended for patients with a definite history of ARF or diagnosis of definite RHD. Continuous antimicrobial prophylaxis is recommended because recurrent ARF can be triggered by GAS infection even if asymptomatic.^[17]

Per the 2008 ACC/AHA focused update and the 2020 ACC/AHA guidelines, prophylaxis is recommended only for the highest-risk groups (prosthetic valves, previous IE, unrepaired cyanotic CHD, cardiac transplant with valve regurgitation). This is distinct from secondary prophylaxis against recurrent rheumatic fever^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mohammed A. Sbeih, M.D. [2]; Cafer Zorkun, M.D., Ph.D. [3]

Mitral stenosis (MS) is most commonly secondary to acute rheumatic fever. Generally, the initial valvulitis is associated with valvular regurgitation but over a period of 2 or more years, the commissures fuse and the valves thicken and calcify. The chordal supporting structure also calcifies and retracts. The result is the typical “fish mouth deformity”. 70% of the time; the mitral valve is involved in isolation, and 25% of the time; the aortic valve is involved as well. The tricuspid and pulmonic valves are involved less commonly. Patients develop symptoms when the mitral vavle area is 2 to 2.5 cm².

Almost all cases of mitral stenosis are due to disease in the heart secondary to rheumatic fever and the consequent rheumatic heart disease (a condition that may develop after strep throat or scarlet fever). Around 90% of cases of rheumatic heart disease are associated with mitral stenosis.^[1]

The valve problems develop 5 – 10 years after the rheumatic fever, a tiny nodule forms along the valve leaflets ^[2], the leaflets eventually thicken with deposition of fibrin. The cusps may become fibrosed, calcified and thickened over a span of a decade.^[3][4] Chronic turbulent flow through a deformed valve appears to cause these changes and as a result the valve looses it’s normal morphology.^[5] The degree of leaflet thickening and calcification and the severity of chordal involvement are variable. Rheumatic fever is becoming rare in the United States, so mitral stenosis is also less common.^[6][7]

• The severity of mitral stenosis depends on the pressure gradient between the left atrium and ventricle which depends on the cross sectional area of the mitral valve.
• The normal mitral valve orifice has a cross sectional area of about 4.0 cm².
  • Mitral stenosis is mild if the cross sectional area is about 2 cm² and the pressure gradient is small.
  • Mitral stenosis is moderate if the cross sectional area is about 1.0 to 1.5 cm².
  • Mitral stenosis is severe if the cross sectional area is ≤1.0 cm² and the pressure gradient between the left atrium and left ventricle is significant.

Usually, the rate of decrement in the valve area is about 0.1 cm²/year once mitral stenosis is present.^[8][9]

• The normal mitral valve orifice area is 4-6 cm².
• Mitral stenosis occurs when the orifice area is reduced to at least 2.2 cm².
• This degree of narrowing results in a gradient across the mitral valve.
• The opening is surrounded by a fibrous ring known as the mitral valve annulus.^[10]
• The anterior cusp covers approximately two-thirds of the valve area (imagine a crescent moon within the circle, where the crescent represents the posterior cusp).
• These valve leaflets are prevented from prolapsing into the left atrium by the action of tendons attached to the posterior surface of the valve, the chordae tendineae.
• The inelastic chordae tendineae are attached at one end to the papillary muscles and at the other end to the valve cusps.
• Papillary muscles are fingerlike projections that extend from the wall of the left ventricle.
• Chordae tendineae from each muscle are attached to both leaflets of the mitral valve.
• Thus, when the left ventricle contracts, the intraventricular pressure forces the valve to close, while the tendons keep the leaflets coapting together and prevent the valve from opening in the wrong direction; thus preventing blood to flow back to the left atrium.
• Each chord has a different thickness. The thinnest ones are attached to the free leaflet margin, whereas thickest ones are attached quite away from the free margin. This disposition has important effects on systolic stress distribution physiology.^[11]

When the mitral valve cross sectional area is about 2 cm² and the pressure gradient is small.^[12]

When the mitral valve area goes below 2 cm², the valve causes an impediment to the flow of blood into the left ventricle, creating a pressure gradient across the mitral valve. This gradient may be increased by increases in the heart rate or cardiac output. As the gradient across the mitral valve increases, the amount of time necessary to fill the left ventricle with blood increases. Eventually, the valve is so tight and the gradient is so high that the atrial kick is required to fill the left ventricle with blood. As the heart rate increases, the amount of time that the ventricle is in diastole and can fill up with blood (called the diastolic filling period) decreases. When the heart rate goes above a certain point, the diastolic filling period is insufficient to fill the ventricle with blood and pressure builds up in the left atrium, leading to pulmonary congestion. The patient may experience dyspnea on exertion at this point.^[12]

When the mitral valve area goes less than 1 cm², there will be a further increase in the left atrial pressures. Since the normal left ventricular diastolic pressures is about 5 mm Hg, a pressure gradient across the mitral valve of 20 mm Hg due to severe mitral stenosis will cause a left atrial pressure of about 25 mm Hg. This left atrial pressure is transmitted to the pulmonary vasculature and causes an elevated pulmonary capillary wedge pressure. Pulmonary capillary pressures in this level cause an imbalance between the hydrostatic pressure and the oncotic pressure, leading to extravasation of fluid from the vascular tree and pooling of fluid in the lungs (congestive heart failure causing pulmonary edema). Increases in the heart rate will allow less time for the left ventricle to fill, also causing an increase in left atrial pressure and further pulmonary congestion causing Hemoptysis may develop. The constant pressure overload of the left atrium will cause the left atrium to increase in size. As the left atrium increases in size, it becomes more prone to develop atrial fibrillation. When atrial fibrillation develops, the atrial kick is lost.

In individuals with severe mitral stenosis, the left ventricular filling is dependent on the atrial kick. The loss of the atrial kick due to atrial fibrillation can cause a precipitous decrease in cardiac output and sudden congestive heart failure. Mitral stenosis may cause left ventricular dysfunction if it is associated with mitral regurgitation.^[5][12]

The elevated pressures in the left atrium are transmitted into the pulmonary circuit, and pulmonary hypertension may develop. Due to hypoxemia, there may be pulmonary vasoconstriction as well that further elevates right heart pressures. The elevated pulmonary capillary wedge pressure leads to a rise in interstitial edema which also increases the load on the right ventricle. Finally, intimal hyperplasia and medial hypertrophy develop in the pulmonary vascular bed.

All the aforementioned changes lead to a rise in the pulmonary arterial pressure and the right ventricle begins to dilate and fail. As a result of the dilation of the right ventricle, tricuspid regurgitation develops. The jugular venous pressure may be elevated. Other signs of right heart failure such as hepatic congestion and pedal edema may also eventually develop.^[13]

A chronic smouldering rheumatic myocarditis may further reduce left ventricular function. Patients with mitral stenosis also often have aortic stenosis. Some patients will also have mixed mitral regurgitation/stenosis.^[14][15]

In pregnancy, the pressure gradient between the left atrium and ventricle is usually increased due to the increase in the heart rate and cardiac output during pregnancy. This can lead to the diagnosis of previously asymptomatic case of mitral stenosis, or worsening of the symptoms of previously diagnosed case.^[16]

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Amyloidosis Ankylosing spondylitis Bicuspid aortic valve Carcinoid tumor[7] Coarctation of aorta Congenital[8] Cor triatriatum Double orifice mitral valve Endomyocardial fibrosis Ergotamines Fabry disease Hemodialysis

Hunter syndrome[9] Hurler syndrome Hypoplastic left heart syndrome Infective endocarditis[10] Left atrial myxoma Left atrial thrombus Loeffler endocarditis Lutembacher syndrome Methysergide Mitral annular calcification[11] Mucopolysaccharidosis

Parachute mitral valve Post AV canal defect repair Prosthetic mitral valve Pulmonary veno-occlusive disease Radiation Rheumatic fever Rheumatoid arthritis Shone’s syndrome Supravalve mitral membrane Systemic lupus erythematosus Whipple disease