Pathophysiology and clinical features of Mitral Stenosis
Philip J Podrid, MD
Mitral stenosis (MS), resulting from the thickening and immobility of the mitral valve leaflets, causes an obstruction in blood flow from the left atrium to left ventricle. There is therefore an increase in pressure within the left atrium, pulmonary vasculature, and right side of the heart, while the left ventricle is unaffected in pure MS. However, mitral stenosis often coexists with mitral regurgitation and occasionally with aortic valve dysfunction, which may cause left ventricular dysfunction.
The major cause of MS is rheumatic fever and the majority of patients with rheumatic MS are female. Other rare etiologies include congenital disease (almost exclusively seen in infants and children), a complication of malignant carcinoid or methysergide therapy which cause fibrosis of the valve, systemic lupus erythematosus, and rheumatoid arthritis. In addition, obstruction of the mitral valve, simulating mitral stenosis, can occur with a left atrial myxoma or an uncommon congenital abnormality known as cor triatriatum in which there is a membrane within the left atrium producing two left atrial chambers. However, the mitral valve itself is normal in these disorders.
In patients with a prosthetic or tissue mitral valve, stenosis of the leaflet or prosthesis may result in the clinical picture of "mitral stenosis" and the symptoms are often rapid in onset. The valve dysfunction in this setting may result from acute or chronic thrombosis, fibrosis, or calcification.
PATHOPHYSIOLOGY –Rheumatic fever results in a number of pathologic changes affecting the mitral valve apparatus, one or all of which may be present:
• Fusion of the leaflet commissures
• Thickening, fibrosis, and calcification of the leaflet cusps
• Thickening, fusion and shortening of the chordae tendineae
These changes become progressive over time and result in a stenotic mitral valve which is funnel shaped, often called"fish mouthed."
The normal mitral valve orifice has a cross sectional area of 4 to 6 cm2. When the orifice is reduced to 2 cm2, mitral stenosis is mild and there is a small pressure gradient between the left atrium and ventricle. An orifice area of < or =1 cm2 is considered to represent critical mitral stenosis, and is associated with a significant pressure gradient which is necessary to maintain adequate filling of the left ventricle. However, the rate of progressive mitral valve narrowing varies and cannot be predicted by the initial mitral valve area or transmitral gradient . In addition, right heart dysfunction can progress independent of the degree of mitral stenosis.
Cardiac hemodynamics– With pure mitral stenosis, the left ventricular systolic and diastolic pressures are usually normal. However, when the stenosis is very severe, there may be a decrease in left ventricular filling and end-diastolic volume (or preload) which will cause a reduction in stroke volume and cardiac output.
An earlier change is an elevation in left atrial pressure due to the obstruction to blood flow. This is reflected backward, causing an increase in pulmonary venous, capillary and arterial pressures and resistance. With mild to moderate mitral stenosis, these abnormalities are often only apparent with exercise or other conditions that increase heart rate; they eventually are seen at rest as the severity of the stenosis increases.
In addition to exercise, the onset of atrial fibrillation can also lead to clinical decompensation. With atrial fibrillation, which is very common in patients with mitral valve disease, there is loss of atrial contraction which plays an important role in the generation of adequate left atrial pressure to maintain blood flow across the stenotic valve. Atrial fibrillation has other deleterious effects including an increase in heart rate and, due to the reduction in the duration of diastole, a decrease in the time available for filling of the left ventricle.
Pulmonary hypertension and right-sided heart failure– Pulmonary hypertension is a common complication of more advanced MS. Several factors contribute to the development of pulmonary hypertension in this setting:
• Passive backward transmission of the elevated left atrial pressure
• Pulmonary artery and arteriole vasoconstriction due to the elevated pulmonary venous pressures (reactive pulmonary hypertension)
• Hypertrophy of the pulmonary artery muscular layer as a result of the increased pressure
• Organic obliterative changes in the pulmonary vascular bed due to the chronically elevated pressures
Pulmonary hypertension eventually leads to right ventricular hypertrophy and enlargement, tricuspid regurgitation, increased right atrial pressure, and the development of right-sided congestive heart failure.
CLINICAL SYMPTOMS– Mitral stenosis can be associated with a variety of symptoms that are primarily related to the severity of the valvular stenosis as reflected by the cardiac output and pulmonary pressures and pulmonary vascular resistance.
Dyspnea– The principal and often only symptom of MS is dyspnea due both to the reduced compliance of the lungs and to the decrease in vital capacity resulting from vascular congestion and interstitial edema. Dyspnea initially occurs with any condition that causes an increase in blood flow across the mitral valve or reduces the time for such blood flow to occur (ie, diminishes the duration diastole). These conditions include exertion, emotional stress, fever, pulmonary infection, sexual intercourse, atrial fibrillation, and pregnancy. In addition, a pulmonary viral infection can result in shortness of breath, cough, and bronchitic symptoms which persists for many months and actually represent mild congestive heart failure.
As the degree of MS increases, dyspnea occurs with very little effort and orthopnea may also occur. A common complaint at this time is fatigue due to the reduction in cardiac output.
Hemoptysis –The increased pulmonary pressures and vascular congestion can lead to hemoptysis which may have a variety of clinical manifestations:
• Sudden hemorrhage (pulmonary apoplexy) due to the rupture of thin walled and dilated bronchial veins when there is a sudden increase in left atrial pressure. This complication is rarely life-threatening, despite the large amount of blood.
• Blood tinged sputum induced by severe coughing associated with paroxysmal nocturnal dyspnea or bronchitis.
• Pink frothy sputum resulting from pulmonary edema.
• Pulmonary infarction due to an embolism or associated with congestive heart failure.
Thromboembolism –Not infrequently, the first presentation of mitral stenosis (which may be mild and asymptomatic) is an embolic event, most commonly cerebral. Prior to surgical treatment and the widespread use of anticoagulation with warfarin, as many as 30 percent of patients with mitral stenosis experienced an embolic event during the course of the disease.
Various studies have found that predictors of embolism in patients with mitral stenosis are cardiac output, size of the left atrium and its appendage, and the presence of atrial fibrillation.Over 80 percent of patients with mitral stenosis who have an embolism are in atrial fibrillation. In these patients, previous embolism is a predictor of increased risk (relative risk 3.1), while early percutaneous balloon mitral commissurotomy prevents systemic embolism in patients with and without atrial fibrillation .
One study of 534 patients with mitral stenosis and a valve area less than2 cm2 assessed the risk factors for embolism in patients in sinus rhythm . There were three major clinical and echocardiographic predictors of embolism :
• Presence of left atrial thrombus (relative risk 37)
• Degree of reduction in mitral valve area (relative risk 16.9)
• Presence of significant aortic regurgitation (relative risk 22.4)
Transient atrial fibrillation and infective endocarditis should also be considered when embolization occurs in patients with mitral stenosis who are in sinus rhythm.
Most emboli originate from the left atrium . Themost common site for embolism from this site is the cerebral circulation, but any organ may be involved, especially spleen, kidneys, and the coronary circulation, resulting in a myocardial infarction. Emboli can also arise from the right atrium when there is pulmonary hypertension and right ventricular and atrial dilatation. Emboli from this site lead to pulmonary embolism and infarction.
Chest pain –Patients with MS infrequently experience chest pain. Although the pain often resembles angina and may be due to underlying coronary artery disease or a coronary artery embolism, it is most commonly the result of pulmonary hypertension and right ventricular hypertrophy . An atrial tachyarrhythmia with left atrial and pulmonary vascular distension is another cause of intermittent chest pain in MS.
Infective endocarditis –Since the mitral valve is deformed, there is the potential for infective endocarditis. This complication is primarily associated with mild mitral stenosis when the valve is stiff and fibrotic. Endocarditis is uncommon once the valve becomes calcified and very rigid .
Right sided congestive heart failure –Chronic pulmonary hypertension eventually leads to increased right ventricular and right atrial pressures, right ventricular enlargement, tricuspid regurgitation, and signs of right sided congestive heart failure including :
• Neck vein distension.
• Edema of both legs which may progress to involve the upper thighs, sacral area, and abdominal wall; ascites and pleural effusions can also occur.
• Hepatomegaly in which the liver may be pulsatile if tricuspid regurgitation is present
Hoarseness –If the left atrium becomes very large there may be compression of the recurrent laryngeal nerve leading to hoarseness (Ortner's syndrome) or coughing.
PHYSICAL EXAMINATION –The physical examination, especially examination of the arterial and venous pulses and the heart, is often diagnostic for mitral stenosis.
• The arterial pulses are normal but reduced in volume due to the decreased stroke volume.
• When MS is severe and cardiac output is diminished, there is vasoconstriction resulting in pinkish-purple patches on the cheeks (mitral facies).
• Pulmonary hypertension and right ventricular hypertrophy can lead to a prominent "a" wave (atrial contraction or systole) in jugular venous pulsations, reflecting elevated right atrial pressure.The "a" wave is absent in patients with atrial fibrillation and only a prominent "v" wave (atrial filling during ventricular systole when the tricuspid valve is closed) is seen. If present, tricuspid regurgitation can lead to a prominent "c-v" wave (reflecting regurgitation of blood into the right atrium) and the neck veins are very pulsatile.
• Palpation and percussion of the chest wall reveals an apical impulse that is generally normal, although it may be reduced in intensity, reflecting the decreased left ventricular filling.
• Dullness to percussion and aprominent pulsation at the second left intercostal space reflects an enlarged pulmonary artery. When the right ventricle is hypertrophied and enlarged, there is dullness to percussion along the sternal border and the presence of a right ventricular lift at the left parasternal region.
As noted above, advanced disease may be associated with the signs of right heart failure .
CARDIAC AUSCULTATION –Cardiac auscultation is often diagnostic for mitral stenosis if the listener is sufficiently skilled. The following findings are characteristically heard:
Heart sounds– As a result of the elevated left atrial pressure, the stenotic (but noncalcified) mitral leaflets are still widely separated at the onset of ventricular contraction. Thus, the first heart sound (S1) is loud, reflecting the increased excursion of the leaflets . As the leaflets become more rigid and calcified, their motion is limited and S1 becomes soft.
The second heart sound is initially normal but, with the development of pulmonary hypertension, P2 becomes increased in intensity and may be widely transmitted. As pressure increases further, splitting of S2 is reduced and ultimately it becomes a single sound.
A third heart sound of left ventricular origin is never heard in pure mitral stenosis because of the obstruction to flow across the mitral valve. It may, however, be present if there is coexisting aortic or mitral regurgitation or may be generated from the right ventricle.
A fourth heart sound may be heard, most often originating from the right ventricle when it is hypertrophied and dilated.
Opening snap– An opening snap (OS) of the mitral valve is heard when the mitral stenosis is mild-moderate and the leaflets are still mobile . The OS is due to the high left atrial pressure and the vigorous opening of the leaflets as the left ventricular pressure falls below that of the left atrium. It is best heard at the apex and lower left sternal border.
As the mitral stenosis progresses and left atrial pressure is higher, the OS occurs earlier after S2 or A2. Thus,the shorter the A2-OS interval, the more severe the mitral stenosis.
Another indicator of severity is the Q-S1 interval. As the stenosis becomes more severe, left atrial pressure rises and mitral valve closure, which occurs when left ventricular pressure exceeds left atrial pressure, becomes delayed. The onset of left ventricular contraction and pressure increase (isovolumetric contraction) is the Q wave and the Q-S1 interval is therefore an indicator of the time for mitral valve closure after the onset of ventricular systole. Prior to the widespread use of echocardiography, the severity of mitral stenosis was determined with simultaneous phonocardiography and ECG recording and was called Well's index– (Q-S1) minus (A2-OS).
Diastolic murmur– The murmur caused by mitral stenosis is a low pitched diastolic rumble which is heard best at the apex, using the bell of the stethoscope. It can often be heard best by lying the patient on the left side. Although the intensity of the diastolic murmur does not correlate with the severity of the stenosis, the duration of the murmur is helpful since it reflects the transvalvular gradient and the duration of blood flow across the valve. When MS is mild, the gradient is confined to atrial systole and hence the murmur is heard late in diastole, just before S1,and is termed "presystolic accentuation" . As the stenosis becomes more severe, there is a gradient at the very onset of diastole, immediately following an OS. This early diastolic murmur is decrescendo, becoming softer as the left atrial pressure falls and the transvalvular gradient decreases. With more severe MS, there is a continuous gradient throughout all of diastole and the diastolic murmur is holodiastolic with a presystolic accentuation if the patient is in sinus rhythm. The diastolic murmur may be inaudible or absent when mitral stenosis is very severe, due to the very slow and reduced flow across the mitral valve.
Several maneuvers are helpful in evaluating the murmurs and heart sounds in MS.
• The diastolic murmur and OS are diminished with inspiration, but augmented with expiration (in contrast to tricuspid stenosis). With inspiration the A2-OS interval widens and a distinct P2 may also be heard.
• Increasing venous return, eg, by lying the patient down and lifting the legs, augments the gradient; as a result, the diastolic murmur lengthens while the A2-OS intervals shortens. Similar changes are seen in response to exercise. In contrast, reducing venous return with amyl nitrate, the Valsalva maneuver, or squatting shortens the murmur and lengthens the A2-OS interval.
There are other murmurs or sounds that may be heard in patients with mitral stenosis, particularly when pulmonary hypertension is present.
• A pulmonary ejection sound which diminishes with inspiration when the pulmonary arteries dilate
• With the development of tricuspid regurgitation, there is a holosystolic murmur best heard along the right sternal border which increases with inspiration
• A faint and brief murmur of pulmonary insufficiency (Graham Steel) may be heard at the base
Murmurs of mitral or aortic regurgitation may also be present if these valve lesions coexist with mitral stenosis.
TESTING –In 1998, an ACC/AHA Task Force published recommendations for the use of echocardiography in patients with symptomatic and asymptomatic murmurs (Table 1A-1B) and the use of echocardiography, transesophageal echocardiography, and cardiac catheterization in patients with mitral stenosis ( Table 2A-2C) .
Electrocardiogram –The findings on the surface ECG reflect the hemodynamic alterations that are present. The QRS amplitude and morphology are normal unless there is mitral regurgitation or coexistent aortic valve disease. Left atrial hypertrophy and enlargement results in a P wave which becomes broader (duration in lead II>0.12 sec), is of increased amplitude, and is notched (due to the delay in left atrial activation). This is termed "P-mitrale." It also produces a prominent negative terminal portion of the P wave in lead V1.
TheP waves changes are not seen in patients with atrial fibrillation. The fibrillatory waves are coarse, generally >0.1 mV in amplitude, reflecting left atrial hypertrophy.
Additional changes occur with the development of pulmonary hypertension and right ventricular hypertrophy. In this setting, the frontal axis shifts to the right (S>R in lead I and aVL) and a tall R wave develops in V1 and V2 (R>S or R/S ratio >1).
Chest x-ray –The chest x-ray in mild mitral stenosis may be normal, although there is often evidence of some enlargement of the left atrium and appendage. Left atrial enlargement may produce a "double density", the left heart border becomes straightened, the left bronchus is elevated, and on the lateral projection the left atrium is displaced posteriorly, impinging on the esophagus (show radiograph 1).
The size of the left atrium does not correlate with the severity of the mitral stenosis or the transvalvular gradient. In general, a very large left atrium suggests combined mitral stenosis and regurgitation.
Other findings that may be seen include:
• Calcification of the mitral valve and annulus with an overpenetrated film (show radiograph 2).
• Enlargement of the main pulmonary artery, while the aorta and left ventricle are often small.
• Pulmonary vascular congestion with redistribution or "cephalization" of pulmonary blood flow to the upper lobes, dilated pulmonary vessels, Kerley B lines at the bases, and interlobar effusions (Kerley C lines) (show radiograph 2). In more severe cases, Kerley A lines (straight dense lines running toward the hilum) may be seen.
Echocardiography –Echocardiography, when combined with color flow Doppler, can establish the severity of mitral stenosis and quantify the gradient (show table 3A-3B) . The M-mode echo provides information about the valve thickness and motion. The 2-D echo permits assessment of valvular spatial relationships, measurement of valve orifice, and evaluation of subvalvular structures, particularly the chordae and papillary muscles. Doppler echo provides an assessment of the hemodynamics and transvalvular gradient.
Valve leaflet motion is significantly altered on M-mode echo. The usual "M" shaped configuration during diastole is altered and there is a reduced E-F slope and a reduced or absent "a" wave. The leaflet opening is reduced during diastole and there is absent leaflet closure during mid-diastole (show echocardiogram 1and show echocardiogram 2). When the stenosis is more severe and the two leaflets are fused, they move in the same direction, rather than away from each other. The leaflets are frequently thickened and multiple dense echoes are seen. Associated findings are a large left atrium, reduced opening of the aortic valve leaflets, and decreased motion of the aortic root, reflecting the decreased stroke volume. The degree of pulmonary hypertension may also be assessed by imaging the pulmonic valve.
With 2-D echo (transthoracic or transesophageal), the mitral leaflets are thickened, have reduced motion during diastole, and show doming, indicative of leaflet fusion . Estimates of the degree of calcification of the leaflets and mitral valve annulus and assessment of the subvalvular apparatus are helpful for establishing the role for surgical or balloon valvotomy. The degree of pulmonary hypertension and the presence of thrombus in the left atrium or atrial appendage can be established.
Doppler echocardiography provides an accurate assessment of the hemodynamic effects of the stenosis (show echocardiogram 3 ). Measurements of the peak velocity of blood flow across the valve, pressure half-time, flow convergence region, flow areas, and the fall of velocity in early diastole are useful for determining the gradient and, along with two-dimensional planimetry, the valve area (show echocardiogram 4). . The extent of pulmonary hypertension can also be evaluated.
The use of color flow Doppler has augmented the ability to determine valve area and also to provide an estimate of the amount of mitral regurgitation. (show echocardiogram 5).
Cardiac catheterization and angiography –Cardiac catheterization and direct measurement of intracardiac pressures permit a precise determination of the gradient across the mitral valve and the severity of mitral stenosis (show figure 1 and show figure 2). However, the widespread availability of echocardiography has led to a very limited role for left ventricular angiography in mitral stenosis (show table 4) . Angiography can determine movement of the mitral valve and the presence of mitral regurgitation, and may give some additional information about the subvalvular apparatus.
1. Sagie, A, Freita, N, Padial, LR, et al. Doppler echocardiographic assessment of long-term progression of mitral stenosis in 103 patients: Valve area and right heart disease. J Am Coll Cardiol 1996; 28:472.
2. Chiang, C-W, Lo, S-K, Ko, Y-S, et al. Predictors of systemic embolism in patients with mitral stenosis: A prospective study. Ann Intern Med 1998; 128:885.
3. Bonow, RO, Carabello, B, de Leon, AC, Jr., et al. Guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 1998; 32:1486
4. Faletra, F, Pezzana, A, Fusco, R, at al. Measurment of mitral area in mitral stenosis: Four echocardiographic methods compared with direct measurements of anatomic orifices. J Am Coll Cardiol 1996; 28:1190.
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