Mitral stenosis, in general, is due to rheumatic heart disease. [70 ] – [77 ] Nonrheumatic causes of mitral stenosis or LV inflow obstruction include severe mitral annular and/or leaflet calcification, congenital mitral valve deformities, malignant carcinoid syndrome, neoplasm, left atrial thrombus, endocarditic vegetations, certain inherited metabolic diseases, and cases related to a previous commissurotomy (surgical or percutaneous) or implanted prosthetic heart valve [74 ] , [76 ] – [79 ] (Fig. 32-4) . A definite clinical history of rheumatic fever can be obtained in only about 50 to 60 percent of patients; women are affected more often than men by a 2 to 3:1 ratio. Nearly always acquired before age 20, rheumatic heart disease becomes clinically evident 10 to 30 years later.
Approximately 20 million cases of rheumatic fever occur in third world countries annually, with a correspondingly high incidence of advanced mitral stenosis later in life. [80 ] In the United States and other developed countries, the frequency of mitral stenosis has decreased markedly. The etiologic agent for acute rheumatic fever is group A beta-hemolytic streptococcus, but the specific mechanisms leading to the valvulitis are unknown. [80 ] Streptococcal antigens cross-react with human tissues and can modify immune mechanisms. Differences in the cellular and extracellular proteins in the many strains of group A streptococcus may be important in the development of rheumatic heart disease. The virulence of the organism may include the hyaluronic acid capsule and the serotype of the antigenic capsular M protein, which resists phagocytosis and opsonization. [80 ] Along with the individual patient's immune responsiveness, other genetic factors are likely to be involved in the susceptibility to disease development or progression.
Rheumatic heart disease involves more structures than just the cardiac valves; it is a pancarditis affecting to various degrees the endocardium, myocardium, and pericardium [70 ] , [73 ] , [74 ] (Fig. 32-5) . In rheumatic valvulitis, the mitral valve is the one most commonly involved (isolated mitral stenosis is found in 40 percent of cases), followed by combined aortic and mitral valve disease, and least frequently, isolated aortic valve disease. Distinct pathoanatomic changes characteristic of mitral valvulitis include commissural fusion, leaflet fibrosis with stiffening and retraction, and chordal fusion and shortening. [73 ] One common finding is fusion of the valve cusps. Leaflet stiffening and fibrosis become exacerbated by increased blood flow turbulence. Associated mitral regurgitation (MR) can develop due to chordal fusion and shortening. The chordae tendineae occasionally become so retracted that the leaflets appear to insert directly into the papillary muscles. The amount of calcification varies; it is more common and of greater severity in men, older patients, and those with a higher transvalvular gradient. [74 ] Rheumatic myocarditis can lead to cardiac dilatation and progressive heart failure.
Not uncommonly, mitral annular calcification progressing to mitral sclerosis and eventually stenosis becomes clinically important in elderly patients. [71 ] , [79 ] In this situation, the anterior leaflet remains relatively normal structurally but usually is thick and immobile; LV inflow obstruction results from a calcified “shelf” beneath the posterior mitral valve leaflet. Mitral stenosis also may result from protrusion of the calcific mass into the ventricle, narrowing the valve orifice; additionally, extension of the calcium into the leaflets may result in a rigid leaflet, leading to stenosis. [79 ] Anatomically, the left ventricle is typically small, hypertrophied, and noncompliant.
With mitral stenosis, a diastolic gradient develops between the left atrium and ventricle [75 ] , [81 ] – [83 ] (Fig. 32-6) . As the degree of mitral stenosis worsens, a progressively higher transvalvular pressure gradient becomes necessary to maintain adequate cardiac output. The mean left atrial pressure in patients with severe mitral stenosis may be in the range of 15 to 20 mmHg at rest, with a mean transvalvular gradient of 10 to 15 mmHg. [81 ] , [83 ] The high left atrial pressure and gradient rise substantially with exercise. LV end-diastolic pressure is usually in the normal range.
An important physiologic measurement in patients with mitral stenosis is the (derived) cross-sectional valve area, which is calculated from the mean transvalvular pressure gradient and cardiac output. The transvalvular pressure gradient is a function of the square of the transvalvular flow rate; for example, doubling the flow quadruples the gradient. At a given flow rate, a smaller valve area corresponds to a higher pressure gradient. Mitral transvalvular flow depends on cardiac output and heart rate; an increase in heart rate decreases the duration of transvalvular LV filling during diastole, reducing forward cardiac output; the transvalvular gradient increases and, consequently, so does left atrial pressure [82 ] , [85 ] (Fig. 32-7) . A high transvalvular gradient may be associated with a normal cardiac output; conversely, if the cardiac output is reduced, a low transvalvular gradient may be present.
In patients with mitral stenosis and normal sinus rhythm, effective atrial contraction is associated with a lower mean left atrial pressure compared with individuals in atrial fibrillation. [86 ] , [87 ] In addition, sinus rhythm can augment flow through the stenotic valve and thereby help to maintain adequate forward cardiac output. The development of atrial fibrillation decreases cardiac output by 20 percent or more; atrial fibrillation with a rapid ventricular response can lead to acute dyspnea and pulmonary edema. [70 ] , [86 ] , [87 ]
In patients with isolated mitral stenosis who have restricted LV inflow, LV chamber size (end-diastolic volume) is normal or decreased, and LV end-diastolic pressure is typically low. [75 ] , [88 ] , [89 ] LV peak filling rate is reduced, as is stroke volume. Decreased cardiac output due to mitral stenosis is usually the result of inflow obstruction rather than LV pump failure. [90 ] LV mass is normal or slightly subnormal in the majority of patients with mitral stenosis [88 ] ; however, approximately 25 to 50 percent of patients with severe mitral stenosis have LV systolic dysfunction due to associated diseases (e.g., mitral regurgitation, aortic valve disease, ischemic heart disease, or rheumatic myocarditis and/or myocardial fibrosis). [75 ] , [83 ] , [89 ] In these patients, LV end-systolic and end-diastolic volumes may be increased. Although LV ejection fraction increases with exercise, LV filling is compromised by the shorter diastolic periods at higher heart rates that cause smaller LV end-diastolic and stroke volumes and a blunted increase (or even decrease) in cardiac output. [89 ]
Additionally, as right ventricular afterload increases secondary to the development of pulmonary hypertension, right ventricular ejection performance may fall. [75 ] , [91 ] Clinically, however, increased right ventricular afterload as a result of mitral stenosis is frequently associated with normal right ventricular contractility. [75 ]
In patients with mitral stenosis who are in normal sinus rhythm, the left atrial pressure tracing is characterized by an elevated mean left atrial pressure with a prominent a wave, which is followed by a gradual pressure decline after mitral valve opening. [70 ] , [87 ] The a wave pressure largely reflects the kinetic energy dissipated in overcoming the resistance across the valve. Because of the stenotic valve, left atrial contraction is important in terms of maintaining transvalvular flow. [87 ] The high left atrial pressure gradually leads to left atrial hypertrophy, atrial fibrillation, and mural thrombi formation. [74 ] , [89 ] , [92 ] The degree of left atrial enlargement and fibrosis does not correlate with the severity of the valvular stenosis; this is due in part to the marked variation in duration of the stenotic lesion and atrial involvement by the underlying rheumatic inflammatory process. [89 ] Disorganization of atrial muscle fibers is associated with abnormal conduction velocities and inhomogeneous refractory periods. Premature atrial activation due to increased automaticity or reentry eventually can result in atrial fibrillation, which is present in over one-half of patients with either pure mitral stenosis or mixed mitral stenosis and regurgitation. [92 ] , [93 ] Major determinants of atrial fibrillation in patients with rheumatic heart disease include older age and larger left atrial diameter. [92 ]
In patients with mild to moderate mitral stenosis, pulmonary vascular resistance may not increase, and pulmonary arterial pressure may be normal at rest, rising only with exertion or increased heart rate. [81 ] In severe chronic mitral stenosis with elevated pulmonary vascular resistance, pulmonary arterial pressure is usually elevated at rest and may exceed systemic pressure. A pulmonary arterial systolic pressure greater than 60 mmHg significantly elevates impedance to right ventricular emptying and produces elevated right ventricular end-diastolic and right atrial pressures.
Left atrial hypertension produces pulmonary vasoconstriction and increased pulmonary vascular resistance. [74 ] , [91 ] As mean left atrial pressure exceeds 30 mmHg above oncotic pressure, transudation of fluid into the pulmonary interstitium occurs to cause reduced lung compliance. Pulmonary hypertension develops due to passive transmission of high left atrial pressure, pulmonary venous hypertension, pulmonary arteriolar constriction, and eventual pulmonary vascular obliterative changes. Early changes in the pulmonary vascular bed may be considered “protective” in that the elevated pulmonary vascular resistance protects the pulmonary capillary bed from excessively high pressures; however, the pulmonary hypertension progressively worsens, which leads to right-sided heart failure, tricuspid insufficiency, and sometimes pulmonic valve insufficiency. [75 ] , [91 ] Severe mitral stenosis ultimately causes irreversible pulmonary vascular changes; cardiac output may be low at rest and remain subnormal during exercise. [81 ]
Because of the gradual development of mitral stenosis, patients may remain asymptomatic for years. [70 ] , [72 ] , [81 ] , [93 ] Characteristic symptoms of mitral stenosis eventually develop and are associated primarily with pulmonary venous congestion or low cardiac output, e.g., dyspnea on exertion, orthopnea, or paroxysmal nocturnal dyspnea and fatigue. Dyspnea is often precipitated by events that elevate left atrial pressure, such as physical or emotional stress or atrial fibrillation. In patients with mild mitral stenosis, symptoms usually occur only with extreme exertion. With progressive stenosis (valve area between 1 and 2 cm 2 ), patients become symptomatic with less exertion. When mitral valve area decreases to about 1 cm 2 , symptoms become more severe. With pulmonary hypertension and right-sided heart failure, the patient may have signs of tricuspid regurgitation, hepatomegaly, edema, and ascites.
Although rare, hemoptysis can occur in patients with mitral stenosis. [70 ] , [91 ] As a result of high left atrial pressure and increased pulmonary blood volume in the earlier phases of the disease, massive hemoptysis may develop secondary to rupture of dilated bronchial veins (or submucosal varices). Over time, pulmonary vascular resistance increases and the likelihood of hemoptysis decreases. Hemoptysis also may result from pulmonary infarction, which is a late complication of chronic heart failure. Acute pulmonary edema with pink frothy sputum can occur due to rupture of alveolar capillaries.
Systemic thromboembolism, occurring in approximately 20 percent of cases, may be the first symptom of mitral stenosis; recurrent embolization occurs in 25 percent of patients. [70 ] , [72 ] , [94 ] , [95 ] The incidence of thromboembolic events is higher in patients with mitral stenosis or mixed mitral stenosis—regurgitation than in those with pure mitral regurgitation. At least 40 percent of all clinically important embolic events involve the cerebral circulation, approximately 15 percent involve the visceral vessels, and 15 percent affect the lower extremities. [70 ] , [72 ] , [96 ] Embolization to coronary arteries may lead to angina, arrhythmias, or myocardial infarction; renal embolization can result in hypertension. [70 ] , [72 ] Risk factors for thromboembolic events include low cardiac output, left atrial dilatation, atrial fibrillation, the absence of tricuspid or aortic regurgitation, and the presence of left atrial echocardiographic “smoke,” an indicator of stagnant flow. Patients with these risk factors should be considered for prophylactic anticoagulation. [70 ] , [72 ] , [94 ] – [96 ] If an episode of systemic embolization occurs in patients in sinus rhythm, infective endocarditis, which is more common in mild than in severe mitral stenosis, should be considered.
Patients with chronic mitral stenosis are often thin and frail (“cardiac cachexia”), indicative of long-standing low cardiac output, congestive heart failure, and inanition. [70 ] The peripheral arterial pulse is generally normal, except in patients with a decreased LV stroke volume, in which case the pulse amplitude is diminished. Heart size is usually normal, with a normal apical impulse on palpation; a forceful apical impulse suggests LV hypertrophy secondary to associated mitral insufficiency, aortic valvular disease, or hypertension. An apical diastolic thrill may be present. In patients with pulmonary hypertension, a right ventricular lift can be palpable in the left parasternal region.
Characteristic auscultatory findings include a presystolic murmur, an increased first sound, an opening snap, and an apical diastolic rumble. [70 ] , [97 ] – [99 ] The presystolic murmur, which occurs due to closing motion of the anterior mitral leaflet, is a consistent finding and begins earlier in those in sinus rhythm compared with patients in atrial fibrillation. [99 ] The first heart sound (S1) is accentuated in mitral stenosis when the leaflets are pliable but diminished in later phases of the disease when the leaflets are thickened or calcified. As pulmonary artery pressure becomes elevated, S 2 becomes prominent. [100 ] With progressive pulmonary hypertension, the normal splitting of S 2 narrows because of reduced pulmonary vascular compliance. Other signs of pulmonary hypertension include a murmur of tricuspid and/or pulmonic regurgitation and an S 4 originating from the right ventricle. Best heard at the apex, the early diastolic mitral opening snap is due to sudden tensing of the pliable leaflets during valve opening and is absent when the leaflets are rigid or immobile. [70 ] , [97 ] , [98 ] In mild mitral stenosis, the diastolic murmur is soft and of short duration; a long diastolic murmur indicates severe mitral stenosis. The intensity of the murmur does not necessarily correlate with the severity of the stenosis; indeed, no murmur may be detectable in patients with severe stenosis and calcified leaflets. [99 ]
In patients with mitral stenosis, left atrial enlargement is the earliest change found on chest radiography; it is suggested by posterior bulging of the left atrium, a double contour of the right heart border, and elevation of the left mainstem bronchus. [71 ] , [81 ] , [101 ] Overall cardiac size is often normal; prominence of the pulmonary arteries coupled with left atrial enlargement obliterates the normal concavity between the aorta and left ventricle to produce a “straight” left heart border. In the lung fields, pulmonary congestion may be recognized as distension of the pulmonary arteries and veins and pleural effusions. If mitral stenosis is severe, engorged pulmonary lymphatics are seen as distinct horizontal linear opacities in the lower lung fields (Kerley B lines).
The electrocardiogram (ECG) is not accurate in assessing the severity of the mitral stenosis and in many cases may be completely normal. In patients with severe mitral stenosis and in normal sinus rhythm, left atrial enlargement is the earliest change (a wide notched P wave in lead II and a biphasic P wave in lead V 1). [81 ] , [102 ] Atrial arrhythmias are more common in patients with advanced degrees of mitral stenosis. [81 ] In those with pulmonary hypertension, right ventricular hypertrophy (RVH) may develop and is associated with right-axis deviation, a tall R wave in V 1 , and secondary ST-T wave changes; however, the ECG is not a sensitive indicator of RVH or the degree of pulmonary hypertension. [102 ] Because multivalvular disease may be present in patients with rheumatic heart disease, signs of left and right ventricular hypertrophy can be identified on the ECG in cases of combined mitral and aortic stenosis. However, right atrial enlargement and right ventricular dilatation and hypertrophy also can mask the changes indicative of LV hypertrophy in patients with multivalvular disease. [102 ]
Echocardiography has emerged as an invaluable noninvasive technique for assessing mitral valve pathology and pathophysiology. [71 ] , [103 ] – [106 ] Cross-sectional valve area and left atrial and LV dimensions can be quantified using two-dimensional echocardiography. Best appreciated in the parasternal long-axis view, features of rheumatic mitral stenosis include reduced excursion of the leaflets and thickening or calcification of the valvular and subvalvular apparatus ( Figs. 32-8 and 32-9 ). M-mode findings include thickening, reduced motion, and parallel movement of the anterior and posterior leaflets during diastole. The mitral valve area can be planimetered directly in the short-axis view, but this measurement does not have much clinical importance, particularly in patients with heavily calcified valves and fibrotic commissures, in whom planimetered valve areas are inaccurate.
Doppler echocardiography accurately determines maximal and mean transvalvular mitral pressure gradients that correlate closely with cardiac catheterization measurements [71 ] , [104 ] (Fig. 32-10) . To obtain mitral valve area, the pressure half-time (time required for the initial diastolic gradient to decline by 50 percent) is employed [104 ] ; the more prolonged the half-time, the more severe is the reduction in orifice area. Using the pressure half-time determination, mitral valve area is equal to 220 (an empirical value) divided by the pressure half-time. In patients with combined aortic regurgitation and mitral stenosis, the pressure half-time method may be unreliable because the regurgitant jet may interfere with the valve area calculation. [104 ]
Transesophageal echocardiography can provide even more information in the evaluation of mitral stenosis; it is better than the transthoracic approach for visualizing details of valvular pathology, such as valve mobility and thickness, subvalvular apparatus involvement, and extent of leaflet or commissural calcification. [104 ] – [106 ] In addition, transesophageal echocardiography is more reliable in detecting left atrial thrombi.
Cardiac catheterization is not necessary to establish the diagnosis of mitral stenosis nor essential prior to surgical intervention; however, it can provide valuable data regarding secondary processes or associated cardiac diseases such as pulmonary hypertension or coronary artery disease. [71 ] , [101 ] Left ventriculography permits assessment of the mitral valve, LV contractility, and the subvalvular apparatus and calculation of ejection fraction but generally is unnecessary. Left-sided heart catheterization allows determination of LV end-diastolic pressure; right-sided heart catheterization is performed to measure cardiac index and the degree of pulmonary hypertension. In the past, fluoroscopy detected calcification of the mitral valve leaflets and annulus. Today, the only real need for cardiac catheterization in patients with mitral stenosis is to study coronary arteries or, rarely, to evaluate the reversibility of severe pulmonary hypertension.
Therapeutic options include medical therapy, commissurotomy (percutaneous balloon valvuloplasty or surgical), and mitral valve replacement (MVR). [73 ] , [75 ] , [107 ] – [111 ] Mild heart failure symptoms are managed with diuretics and salt restriction. If atrial fibrillation develops, attempts should be made to reestablish normal sinus rhythm by pharmacologic means or cardioversion. Digoxin remains the drug of choice for control of ventricular rate in patients with atrial fibrillation, although beta blockers and calcium-channel blockers may be more effective during exercise or stress. Digoxin does not significantly alter the adverse hemodynamics and usually is of no benefit to patients with mitral stenosis in sinus rhythm; however, it may be useful in treating symptoms of right-sided heart failure. Measures that reduce pulmonary venous pressure, including sedation, an upright posture, and aggressive diuresis, are used if the patient has hemoptysis. Endocarditis prophylaxis is mandated in all patients with valvular disease and a murmur. Unless contraindicated, anticoagulation should be considered in patients with atrial fibrillation and those with a history of embolism; however, anticoagulation-related mortality and morbidity increase with age, and the relative risks versus benefits should be weighed on an individual basis. [71 ] , [75 ]
Whereas indexes of LV function are used to determine the natural history and surgical outcome of patients with other valvular lesions, there are few data linking LV function to outcome in those with mitral stenosis. The best indicator is likely related to the amount of clinical impairment. From the time of diagnosis, the natural history of medical management of patients with mitral stenosis includes a survival estimate of roughly 45 to 50 percent at 5 years, 34 percent at 10 years, and 14 percent after 20 years. [107 ] , [108 ] In patients without symptoms (New York Heart Association class I), the expected 10-year survival rate is 85 percent. [75 ] For patients in functional class II, the 10-year survival estimate is 50 percent; however, for individuals in class III, only 20 percent are alive after 10 years. For patients who have deteriorated markedly (NYHA class IV), none can be expected to be alive at 5 years. [75 ] Survival is lower in older patients, since increasing age generally implies more advanced disease. Surgical intervention (mitral valvotomy or MVR) substantially improves the functional capacity and long-term survival of patients with mitral stenosis; over 90 percent of patients (functional class III and IV preoperatively) are alive at 10 years and 89 percent at 15 years. [112 ] , [113 ]
Although the mildly symptomatic patient may be managed medically for years, this valvular disease is relentlessly progressive, and there is a constant risk of systemic embolization. Prophylactic operation should be considered in an asymptomatic female patient who wishes to become pregnant. In those who have sustained systemic emboli, operation should be performed because of the high risk of recurrent thromboemboli with potentially catastrophic complications. [75 ] , [94 ] With current diagnostic and surveillance modalities, e.g., transesophageal echocardiography, however, a suggested alternative is to detect left atrial thrombi, institute anticoagulation, and defer operation if resolution of the thrombus is documented. [75 ]
Once patients with mitral stenosis become symptomatic, they become candidates for operation. In general, a valve area of 1 cm 2 is considered “critical” and is associated with significant symptoms and morbidity. In physically active or larger patients, somewhat larger valve areas (>11.2 cm 2 ) may produce symptoms. [75 ] Intervention in elderly patients is individualized; although a small minority in this age group may benefit from percutaneous mitral balloon valvuloplasty, most are better served by MVR. [109 ] – [111 ] In mitral stenosis, the LV may become foreshortened and more globular; these morphologic changes, however, rarely dictate operative timing and do not influence surgical outcome. Despite a higher operative risk in those with pulmonary hypertension and right-sided heart failure, these patients usually improve postoperatively with a reduction in pulmonary vascular pressures. [75 ] , [114 ]
Mitral stenosis is generally due to rheumatic heart disease. Rheumatic heart disease is a pancarditis affecting the endocardium, myocardium, and pericardium; the mitral valve is most commonly involved in rheumatic valvulitis, followed by combined aortic and mitral valve disease. Rheumatic myocarditis can lead to cardiac dilatation and progressive heart failure. In mitral stenosis, a diastolic gradient develops between the left atrium and the left ventricle. With worsening mitral stenosis, a progressively higher transvalvular pressure gradient becomes necessary to maintain adequate cardiac output. Mitral transvalvular flow depends on cardiac output and heart rate; an increase in heart rate decreases the duration of transvalvular LV filling during diastole and reduces forward cardiac output. Decreased cardiac output due to mitral stenosis is usually the result of inflow obstruction rather than LV pump failure. In mild to moderate mitral stenosis, pulmonary vascular resistance may not be increased, and pulmonary arterial pressure may be normal at rest and rise only with exertion or increased heart rate. In severe mitral stenosis with elevated pulmonary vascular resistance, pulmonary arterial pressure is usually elevated at rest and may exceed systemic pressure. Characteristic symptoms of mitral stenosis are primarily associated with pulmonary venous congestion or low cardiac output. Dyspnea is often precipitated by events that elevate left atrial pressure, such as stress or atrial fibrillation. Echocardiography (transthoracic and transesophageal) has emerged as a valuable noninvasive technique for assessing mitral valve pathology and pathophysiology. The cross-sectional valve area and transvalvular gradients can be quantified using echocardiography. Therapeutic options include medical therapy, commissurotomy (percutaneous balloon valvuloplasty or surgical), and mitral valve replacement. Endocarditis prophylaxis is mandated in all patients with valvular disease. Once patients with mitral stenosis become symptomatic, they become candidates for operation. Surgical intervention (mitral valvotomy or mitral valve replacement) can substantially improve the functional capacity and long-term survival of patients with mitral stenosis. Intervention in elderly patients is individualized; although a small minority in this age group may benefit from percutaneous mitral balloon valvuloplasty, most are better served by valve replacement. Despite a higher operative risk in those with pulmonary hypertension and right-sided heart failure, these patients usually improve postoperatively, and pulmonary vascular pressures decrease.