CHAPTER 50: MITRAL STENOSIS

Worldwide, most cases of mitral stenosis (MS) are caused by rheumatic heart disease (RHD) (Fig. 50–1).¹ However, rheumatic fever has become quite rare in developed nations and so too has MS. Indeed, most MS in the United States occurs in patients who have emigrated here from countries where rheumatic fever is still commonplace. Why rheumatic fever has waned in developed nations is unclear. Although antibiotic use almost certainly plays a role,² the decline in disease incidence began before antibiotics were widely available, suggesting that socioeconomic factors also play a key role in the disease process. In addition, the organism responsible (group A Streptococcus) itself may have mutated to a less rheumatologic agent. Degenerative calcific MS may be confused with rheumatic MS. Although the incidence of degenerative calcific MS increases in the very elderly, the MS is most often mild to moderate, and does not require intervention.

RHD remains prevalent in developing countries. Using echocardiographic screening, the prevalence of RHD ranged from 20 to 30 per 1000 school children.^3,4 This leads to a large pool of rheumatic MS. Forty percent of patients with RHD have isolated MS, but only 60% of these patients report a past history of rheumatic fever.^4,5

Rheumatic MS is a progressive disease. The time interval between rheumatic fever and the clinical appearance of MS varies considerably among various countries. In developed countries, the disease appears to take two to four decades before symptoms appear.^5,6,7,8 Thus, presentation in the west is in the fifth to sixth decades of life.^{5,6,7,8,9,10,11} In developing countries, the disease may progress much more rapidly, leading to symptoms by the age of 20 years (juvenile MS), often within 5 years of the initial attack of RF.¹² This is likely a result of recurrences of RF (either clinical or subclinical). The mean age of symptom onset in developing countries is between the third and fourth decades.^11,13 Progression from mild to severe disability takes a decade.^6,8 Once symptoms develop, the prognosis becomes poor if left untreated. Among 271 symptomatic patients,⁷ the 10-year survival of patients in functional class II, III, and IV was 69%, 33%, and 0%, respectively. Only half of the patients in functional class II remained alive at 20 years, with none among class III patients. Overall, the mortality was 70% over an average period of 11 years.⁷

There is a progressive reduction in the valve area by an average of 0.09 cm² per year.^14,15 There is considerable inter-individual variability, with 27% of the patients having no change and one-third of the patients having a more rapid decrease (> 0.1cm²/y).¹⁴ Those with a larger initial valve area had a greater rate of decrease in valve area.¹⁴ Another study noted that those with a Wilkin’s echocardiographic score greater than 8 were more likely to have a progressive course.¹⁵ Eighty percent of those with a score ≥ 8 had a progressive course, compared with only 5% with a score < 8.¹⁵ Although it is clear that rheumatic fever causes the disease, the exact mechanisms are still controversial. It is generally agreed that rheumatic fever occurs after infection with group A Streptococcus.^16,17,18 The bodily defense against the organism attacks “M” protein antigens shared by the bacterium and the heart in some patients.¹⁷ Thus, there is an inflammatory response that leads to cardiac damage, potentially of all three cardiac layers, the pericardium, myocardium, and endocardium. However, it is the endocardium, from which the cardiac valves are derived, that is most severely affected. Although all four valves may become damaged, the mitral valve is virtually always affected, but the reasons for this propensity are unclear. Perhaps greater mechanical stress on the mitral valve causes the inflammatory process to be manifested more severely there than on other valves.

The initial attack causes inflammation, thickening, and retraction of the mitral leaflets, usually causing mild mitral regurgitation (MR), which may disappear as the attack subsides. Why MS develops later is not entirely clear, but at least three factors contribute to the process: gender, the severity of carditis in the first attack, and the number of subsequent attacks. MS is primarily a disease of women, with a 3:1 female preponderance. If after the initial attack there is little evidence of valvulopathy and no subsequent attacks occur, the chance that the patient will develop severe MS later in life is probably less than 5%.¹⁹ Subsequent attacks can be prevented by faithful adherence to antibiotic prophylaxis. However, what pathologic processes occur between the initial attack of acute rheumatic fever and eventual development of MS (when it does occur) are uncertain. At the time of surgery for MS there are active Aschoff nodules (the pathognomonic lesion of rheumatic fever) in the left atrial appendages (LAAs) of many patients, suggesting that a smoldering rheumatic process persists years after the last acute attack.²⁰ Alternatively, it may be that after the initial lesion is created by rheumatic fever, hemodynamic stress on the valve may lead to continued inflammation and scarring. In fact, C-reactive protein is elevated in many MS patients, indicative of ongoing inflammation from either or both processes.^21,22

Occasionally MS develops from nonrheumatic causes. Extensive annular calcification in the elderly may limit valve area.²³ Approximately 50% of such patients progress to more severe disease over time. Radiation and restrictive mitral valve repair for MR are additional rare causes.^24,25 At the other end of the age spectrum, congenital malformation is another cause of MS.

The main pathology in rheumatic MS is commissural fusion, leaflet thickening, and choral fusion and shortening leading to a typical “fish-mouth” appearance. In normal subjects, mitral valve area (MVA) is 4.0 to 5.0 cm², such that in diastole there is hemodynamically a common chamber of the left atrium (LA) and left ventricle (LV). Thus, as shown in Fig. 50–2A, there is an initial small gradient across the mitral valve that rapidly dissipates so that throughout most of diastole, pressures in the LA and LV are equal. However, in MS, as the mitral valve becomes progressively narrowed, a gradient develops across the valve (Fig. 50–2B) so that LA pressure exceeds LV pressure.²⁶ As MS worsens, LA pressure becomes progressively higher, in turn creating progressively more pulmonary congestion The force needed to overcome the increased LA pressure and to drive blood past the stenotic mitral valve is generated by the right ventricle (RV), such that right ventricular pressure and pulmonary pressure become elevated. As MS becomes severe, secondary vasoconstriction in the pulmonary bed causes a further increase in pulmonary artery (PA) pressure, and pulmonary hypertension may become extreme. The exact cause of pulmonary vasoconstriction in MS is unknown. It is known that pulmonary hypertension is almost always reversed by relief of MS²⁷ and also can be reversed by administration of phosphodiesterase inhibitors such as sildenafil²⁸ or by nitric oxide inhalation.²⁹ These data suggest that the nitric oxide pathway is in some way involved in the mechanism of pulmonary vasoconstriction and pulmonary hypertension in MS. Occasional patients have structural changes in the pulmonary bed leading to a disproportionate pulmonary hypertension that is not completely resolved with relief of MS.

The 2014 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines³⁰ for the management of valvular heart disease have provided a new staging system for rheumatic MS along with a revision of the grades of severity (Table 50–1). The definition of “severe” MS has been based on the severity at which symptoms occur and at a level when interventional treatment improves symptoms. Severe MS has now been defined as ≤ 1.5 cm², unlike previous guidelines³¹ where it was ≤ 1.0 cm² (Table 50–2). This will make comparisons with historical cohorts problematic. Further, a large number of patients remain asymptomatic even with valve areas of 1.3 to 1.4 cm² and the guidelines make it clear that intervention is not indicated in such patients.

Heart Failure and Left Ventricular Function

It is generally held that MS “protects” the LV from damage. That is, unlike other left-sided valve lesions, MS creates no overload on the LV and in fact may decrease preload by impairing LV filling. It is of interest then that approximately one-third of patients with MS have reduced indexes of LV ejection performance.^32,33,34 The mechanism of reduced LV ejection has been the subject of controversy for many years, and some have invoked a “myocardial factor” (myocardial damage from rheumatic fever) as the cause. Although rheumatic fever may cause LV damage in developing countries where the rheumatic process may be very aggressive,³⁵ in developed countries, LV contractility in MS appears to be normal. Instead, reduced LV performance is caused by abnormal loading conditions. Unexpectedly, afterload may be abnormally high in some patients with MS.³⁴ Increased afterload accrues in part from arterial vasoconstriction caused by sympathetic reflexes to decreased cardiac output. In addition, the LV in some MS patients remodels in such a way that the LV is thinner than normal, increasing wall stress (afterload).^34,35 In most other cardiac diseases, increased afterload is offset by increased preload to maintain stroke volume. However, MS limits LV filling, preventing full utilization or preload reserve, and thus ejection fraction is reduced. Proof of this concept follows from the changes seen immediately after balloon mitral valvotomy, where acute relief of LV inflow obstruction results in rapid correction of LV ejection indexes, indicating that loading abnormalities rather than a myocardial factor must have been involved.³⁶

Diastolic function in MS may also be abnormal. Reverse LV remodeling to smaller than normal volume and regional tethering caused by distortion of the subvalvular apparatus lead to abnormal LV compliance. Like the systolic abnormalities noted earlier, these are also reversed rapidly after balloon valvotomy.³⁷

Right Ventricular Function

The pulmonary hypertension that develops in MS causes RV pressure overload and eventual RV failure. Although the irregular shape of the RV makes assessment of contractility difficult, most studies have concluded that RV failure, like LV failure, in MS is mostly caused by afterload excess rather than contractile dysfunction.^38,39 This is in contradistinction to experimental RV pressure overload, where contractile dysfunction has been well documented. Thus, MS causes reduced cardiac output and pulmonary congestion typical of LV failure, yet these abnormalities are more the consequence of abnormal loading and LV remodeling than of myocardial dysfunction. Likewise, RV failure also seems to be a consequence of increased afterload rather than of myocardial dysfunction.

History

Most patients with mild MS are asymptomatic. Indeed, many women are unaware that they have the disease until the increased cardiac demands of pregnancy cause symptoms to appear. Conditions that increase cardiac output and/or heart rate, such as infection, hyperthyroidism, anemia, or atrial fibrillation (AF), may precipitate symptoms. As MS worsens, symptoms typical of left-sided heart failure occur. Thus, dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea are common. Pulmonary edema may be precipitated. If pulmonary hypertension develops, ascites and edema may follow. The development of pulmonary hypertension may paradoxically reduce dyspnea by creating a proximal obstruction. A symptom seen in MS but rare in other causes of heart failure is hemoptysis, usually during activity. As predicted by the Gorlin formula,⁴⁰ if exercise causes cardiac output to double, the transmitral gradient will quadruple, causing a sudden increase in LA pressure. This increase is thought to cause rupture of small pulmonary vein anastomoses, leading to frank hemoptysis to be distinguished from the pink frothy sputum seen in pulmonary edema. In cases where the LA becomes so large that it impinges on the left recurrent laryngeal nerve, hoarseness appears (Ortner syndrome).

Physical Examination

Physical examination of the patient with MS may reveal a plethora of signs, many of which are subtle, so that the exam should take place in a quiet, undisturbed setting. If the patient is experiencing rapid AF, many signs may be inaudible, obscuring the diagnosis. The sensitivity, specificity and predictive value of these cardiac findings, either singly or in combination, has never been examined, most of which were described in the era preceding that of evidence-based medicine. Cardiac examination may find the irregularly irregular pulse of AF, common in older patients with MS. The pulse pressure may be reduced, indicating a low stroke volume. This may lead to the typical “mitral” faces with plethoric cheeks with bluish patches. The jugular venous pulse may show a prominent a wave in the presence of pulmonary hypertension. With AF, the “a” wave and “x” descent are absent. The apex beat is usually in its normal position of a tapping nature, but palpation may reveal a diastolic thrill when the patient is examined in the left lateral decubitus position. Palpation of the sternum may find an RV lift in the presence of pulmonary hypertension. A loud P₂ may be palpable in the second intercostal space. S₁ is typically quite loud because the transmitral gradient holds the valve open throughout diastole rather than allowing the valve to drift closed just before systole, as it normally does. Thus systole closes the valve from its fully open (albeit stenotic) position, creating a loud S₁. However, in far advanced disease, the valve may have little motion and S₁ becomes soft. S₂ may be normal, or its P₂ may be loud if pulmonary hypertension has developed. S₂ is then followed by an opening snap (OS), and the S₂-OS interval gives a good clue to the severity of the MS. As severity worsens, the LA pressure increases so that LA pressure exceeds LV pressure (the force that opens the valve) relatively soon after S₂, and the S₂-OS interval is short, approximately 60 ms, just a bit longer than the normal splitting interval of A₂ and P₂ during inspiration. Conversely, in mild disease, the S₂-OS interval is long, approaching 120 ms, similar in cadence to an S₃. It should be noted that S₃ and S₄, sounds produced by rapid LV filling, are typically absent in this disease that impairs the transfer of blood from LA to LV. After the OS, the typical low-pitched rumble of MS is heard best at the LV apex with the bell of the stethoscope in the left lateral position with the breath held in expiration. If the patient is in sinus rhythm, there may be presystolic accentuation of the murmur. The murmur may be very soft in obese patients, those with emphysema, and those with a low cardiac output and fast ventricular rate. The duration of the murmur correlates with severity of MS. In mild MS, the murmur is short, while in severe MS it heard throughout diastole. With the onset of AF, the intensity of S₁ becomes variable with louder S₁ in short cycles. The A2-OS interval varies directly with the previous cycle length in MS with AF. In AF, following short diastoles, the presystolic accentuation may persist.⁴¹ This is seen in pliable valves only. Persistence of the mid-diastolic murmur up to S₁ during long RR cycles indicates significant MS. Examination of the lungs may detect rales, although it is remarkable that some patients with very high LA pressure have clear lung fields upon auscultation. It is thought that lymphatic hyperfunction clears the alveoli of transudated fluid that would be expected to form from high LA pressure.⁴²

If pulmonary hypertension has ensued, the high-pitched murmur of pulmonary insufficiency (Graham-Steell) may be heard in the pulmonic area. However, the concomitant presence of aortic insufficiency is often mistaken for this murmur.⁴³ Neck vein distension, ascites, hepatomegaly, and edema reflect RV failure.

Complications

AF is the most common complication, developing in approximately 40% patients.⁴⁴ It is initially paroxysmal (often subclinical) and subsequently becomes permanent. Development of AF has a profound effect on the course of MS, leading to hemodynamic deterioration (discussed later) and placing the patient at risk of thrombus formation and systemic embolism. Age and the severity of MS are the most important determinants for development of AF.⁴⁵ AF is related to LA enlargement, the latter often a result rather than the cause of AF.⁴⁶

Systemic embolism occurs in up to 20%^31,47,48,49 of patients, with 60% to 75% occurring to the brain. Increasing age and presence of AF are main predictors. Previous thromboembolism is positively associated with risk of embolism. When embolization occurs in the presence of sinus rhythm (as seen in up to 20% cases^47,50), transient AF and infective endocarditis should be considered.⁴⁹ Transient subclinical AF⁵¹ has been shown to be a major predictor for systemic embolic events. The risk of infective endocarditis in isolated MS is low. Other complications include hemoptysis (sometimes massive), pulmonary embolism, and respiratory infections.⁵²

In the presurgical era, 62% of the deaths were caused by heart failure, 22% from thromboembolic complications and 8% from infections.⁷

The electrocardiogram and the chest X-ray provide valuable insights into the anatomic changes affecting the various chambers of the heart and the lungs in MS. They should be carefully assessed but they are by no means diagnostic. The echocardiogram is the imaging modality of choice to diagnose MS.

Electrocardiogram

If the patient is in sinus rhythm, large p-waves may be present, indicating LA enlargement (p mitrale). Tall “R” waves in the right precordial leads may be a clue to RV hypertrophy. These electrocardiographic findings have high specificity but low sensitivity. AF is often present.

Chest X-Ray

Before the easy applicability of echocardiography, the chest x-ray was often the key diagnostic study. Important features include a double density along the right heart border reflecting the shadow of the enlarged LA outside the image of the right atrium. The PA segment is enlarged, a consequence of pulmonary hypertension. Straightening of the left heart border (as a result of prominent LAA, dilated PA, and an underfilled aortic knuckle), widening of the carinal angle, and posterior displacement of the esophagus (on lateral view) may be seen. Redistribution of blood flow to the lung apices (cephalization of blood flow) and Kerley B lines in the lung fields reflect chronic pulmonary venous hypertension and hypertrophy of lung septae. Loss of the retrosternal air space in the lateral view indicates RV enlargement.

Echocardiography

The echocardiogram is the modality of choice in the assessment of MS. It establishes the diagnosis, determines the etiology, quantifies the severity, detects concomitant valve involvement, assesses suitability for balloon mitral valvotomy (BMV) and enables serial follow-up.^53,54 Valve images show the typical “hockey-stick” appearance of the mitral valve, immobility of the posterior leaflet, and “fish-mouth” narrowing of the valve orifice (Fig. 50–3).⁵¹ Valve area can be estimated by direct planimetry (two-dimensional [2D] or three-dimensional [3D]), by the continuity equation, by the pressure half-time technique (dividing an empirical constant of 220 by the mitral inflow pressure half-time), and the proximal isovelocity surface area (PISA) method. In some cases these measures are concordant, but in others, all measures must be taken into account and clinical judgment used to decide on MS severity. Planimetry by 3D echocardiography has better reproducibility and intraobserver variability than 2D echocardiography and has the closest agreement with invasive Gorlin-derived MVA.⁵⁵ It provides better evaluation of commissural anatomy in patients undergoing BMV (Fig. 50–4). The mean pressure gradient across the mitral valve can be determined using the continuous-wave Doppler signal. Although this parameter is affected by flow and heart rate, it correlates well with invasive measurement. In the presence of AF, an average of 5 beats with least variation should be taken. LA dimension and volume also give clues to the impact of the disease on that chamber. If tricuspid insufficiency is present, the jet velocity across the tricuspid valve can be used to estimate peak PA pressure. Assuming a right atrial pressure of 10 mm Hg, PA pressure is estimated as 4v² +10, where v = the tricuspid jet velocity. Recalculation of mitral valve gradient and PA pressure during exercise may be helpful in explaining exercise-induced symptoms when right-sided pressures are normal or nearly normal at rest. Although no longer considered an indication for intervention in the AHA/ACC guidelines, because it may occur in normal subjects, an exercise-induced PA pressure (PASP) > 60 mm Hg should warrant further investigation as to its cause.

Echocardiography is also important in evaluating patients for BMV, the therapy of choice for suitable valves, as well as for guiding BMV (see below).⁵⁶ Valve leaflet thickness, leaflet mobility, valve calcification, and subvalvular apparatus deformity are scored from 1 to 4, where 1 indicates mild abnormality and 4 indicates severe pathology. Valves scored 8 or less generally respond well to BMV, although this rule is not invariable, and some patients with higher scores still achieve a good result with BMV.⁵⁷ Other echocardiographic scores have been developed, but none has proven to be superior to another.⁵³ All have a limited value in predicting the success (or complications) of BMV. Rather, scoring systems should be considered complementary to one another. Because the mechanism of BMV is splitting of commissures, assessment of commissural calcium is vital. Bicommissural calcification is a contraindication for BMV. The presence and severity of concomitant MR is also assessed because BMV may worsen existing MR. More than mild (1+) MR is usually considered a relative contraindication to BMV. BMV may be safely performed in patients with grade 2 MR, especially if the MR is central. Grade 3–4 MR is usually considered an absolute contraindication.¹⁰ If after transthoracic echocardiography, BMV is contemplated, transesophageal echocardiography is then performed to examine for thrombus in the LA and LAA. Presence of LA/LAA thrombus has traditionally been a contraindication to BMV.³⁰ If thrombus is detected, warfarin anticoagulation is initiated and the patient is reimaged in 3 months.³⁰ Theoretically, this may entail placing the patient at an increased risk of systemic embolism during the 3-month period (as opposed to performing a mitral valve replacement [MVR]/open mitral valvotomy immediately). This needs to be weighed against the potential long-term complications associated with a prosthetic valve. If the thrombus has resolved, BMV may then be performed. Persistence of thrombus after anticoagulation has been an indication for open mitral valve surgery. Of late, some studies have shown that it is feasible to perform BMV in selected patients with LA/LAA thrombus after 8 to 12 weeks of anticoagulation.⁵⁸ The LA/LAA thrombus was classified into five types based on the location (Table 50–3). 108 patients with LA/LAA thrombus type Ia, Ib, and IIa underwent BMV using a modified over the wire technique that virtually excluded the LA from the track of the septal dilator and balloon catheter exchanges.^58,59 BMV was successfully performed in 98% of cases. Only one patient had a transient ischemic attack 6 hours after the procedure, and recovered completely. It is to be noted that BMV was performed by experienced operators (> 500 procedures) in this study.

Post BMV, echocardiography enables assessment of commissural splitting, the degree and mechanism of MR, mitral valve gradients, MVA by planimetry, and any complications (pericardial effusion). Follow-up echocardiography is recommended among asymptomatic individuals at intervals of 3 to 5 years in those with MVA > 1.5 cm², every 1 to 2 years with MVA ≤ 1.5 cm², and yearly in those with MVA < 1 cm².³⁰

Cardiac Catheterization

In most cases, MS evaluation can be completely assessed noninvasively. However, if after echocardiography the issue of MS severity is still in doubt, the diagnosis may be resolved during cardiac catheterization. Data from invasive hemodynamics are used in the Gorlin formula (MVA = CO/dfp × hr/38.5 √h₂ – h₁), where MVA = mitral valve area (cm²), CO = cardiac output (mL/min), dfp = diastolic filling period (seconds), hr = heart rate, and h₁ – h₂ = the mean transmitral gradient.²⁵ Simultaneous measurement of the LV and LA pressures by means of transseptal puncture are needed (Fig. 50–5). A carefully obtained pulmonary capillary wedge pressure (PCWP, time adjusted) may be substituted for LA pressure in measuring the transvalvular gradient.⁶⁰ If resting hemodynamics are unrevealing, dynamic or handgrip exercise may show significant elevation in PCWP and PA pressure, demonstrating the cause of the patient’s symptoms.

Because most patients with MS in whom cardiac surgery is contemplated are of an age to be at risk for coronary artery disease, coronary angiography or multislice computed tomography examination is usually performed before operation to preoperatively evaluate coronary anatomy.

Rate Control in Atrial Fibrillation

The onset of AF with a rapid ventricular response may have markedly severe clinical consequences. Transit of blood flow from LA to LV is obviously impaired in MS patients, even in sinus rhythm. As heart rate accelerates, diastolic filling period is shortened, further impairing LA emptying. Hemodynamically, shortened diastolic filling time and loss of atrial systole result in further increases in LA pressure and a decrease in cardiac output. Thus, the patient may experience acute pulmonary edema and shock. The speed at which rate control must be achieved is dictated by clinical circumstances. In very ill patients, immediate direct current cardioversion is indicated to restore sinus rhythm. If the consequences of rapid AF are less severe, rate control may be accomplished by intravenous administration of a β-blocker such as metoprolol or esmolol, a calcium channel blocker (CCB) such as diltiazem, or digoxin. The latter agent gains rate control less rapidly but may be preferable if blood pressure is tenuous. Intravenous amiodarone can be used to control the heart rate in patients where β-blockers or heart-rate–regulating CCBs cannot be used or have not been effective.³⁰

When elective cardioversion is planned for AF lasting > 24 hours, anticoagulation should be given for 3 weeks prior or transesophageal echocardiography should be performed immediately to rule out an atrial thrombus. The decision for cardioversion should take into consideration the duration of AF, the hemodynamic response to AF, the LA size, the past history of AF, and the limitation to exercise capacity. As MS progresses, it becomes more difficult to maintain sinus rhythm.

In chronic AF, adequate rate control is also a cornerstone of good therapy. Control should be evaluated both at rest and during modest activity, such as walking down the clinic corridor. Too often the patient is only assessed on the examining table and found to have a satisfactory heart rate, yet during activity heart rate may be quite rapid, potentially leading to rate-related cardiomyopathy.⁶¹ β-blockers and heart-rate–regulating CCBs are the mainstay, while digoxin may be added if optimal heart rate control is not achieved.³⁰ A resting heart rate < 80 beats per minute and an exercise (moderate) heart rate < 100 beats per minute is recommended for symptomatic patients.^62,63

At the time of mitral valve surgery (replacement or repair), the performance of a biatrial maze or pulmonary vein isolation enabled more than 60% of patients to remain in sinus rhythm at 1 year.⁶⁴ Successful BMV enables patients in sinus rhythm to persist in sinus rhythm.⁶⁵ However, BMV does not promote reversion to sinus rhythm in patients with chronic AF.⁶⁶ In a subgroup of patients (LA size < 45 mm, duration of AF < 1 year), successful BMV was associated with increased probability of cardioversion (chemical with/or without electrical).⁶⁷

Anticoagulation

The MS patient with AF has a very high risk of stroke, approaching 15% per year unless adequately anticoagulated.⁶⁸ Faster heart rates in AF contribute to an increased clotting tendency.⁶⁹ Because of the high stroke risk, only dire contraindications such as active bleeding should prevent anticoagulation in such patients. Anticoagulation with vitamin K antagonist (VKA) is recommended for MS patients with AF (paroxysmal, persistent, or permanent), those with a prior embolic event, and those with a left atrial/left atrial appendage thrombus to maintain an international normalized ratio of 2.5 (range 2-3) for an indefinite duration.³⁰ The use of anticoagulation in patients in sinus rhythm with large LA (diameter > 55 mm)⁷⁰ or those with spontaneous echo contrast may be beneficial, but this has not been adequately studied. Low-dose aspirin (81 mg/d) may be added to the regimen safely to further lower the risk of stroke. Newer oral anticoagulants dabigatran, apixaban, and rivoraxaban have been approved for prevention of systemic embolism in nonvalvular AF. They are currently not approved for patients with MS with indications for anticoagulation.³⁰ The RE-ALIGN study that compared dabigatran with warfarin in patients with mechanical heart valves was terminated early because of excess thromboembolic and bleeding events in the dabigatran arm.⁷¹

Infective Endocarditis Prophylaxis

Among valve lesions, patients with MS are at relatively low risk for developing infective endocarditis. The ACC/AHA¹⁰ and the National Institute for Health and Clinical Excellence (NICE)⁷² guidelines currently do not recommend preprocedural antibiotic therapy for the prevention of infective endocarditis in patients with MS unless the patient has had a previous episode of infective endocarditis. The new guidelines are based on the lack of evidence that prophylaxis is effective and the fact that bacteremia occurs routinely with eating, yet prophylaxis for that activity would be impossible. Not all international societies are in agreement with this recommendation. The Brazilian⁷³ and the Australasian guidelines (indigenous Australians)⁷⁴ continue to recommend antibiotic prophylaxis for RHD given that this condition is still rampant and many of these patients would have poor oral hygiene. Two recent studies from the United States⁷⁵ and UK⁷⁶ have shown a disturbing increase in the incidence of infective endocarditis following the change in guidelines. As such, individual judgement should be used in advising prophylaxis.

Secondary prevention of rheumatic fever (preferably long-acting benzathine penicllin G) should be continued. The risk of for recurrence of rheumatic fever declines with increasing age and the number of years from the last attack.

Heart Failure

Although, the ultimate therapy for symptomatic MS is mechanical relief of the obstruction to LV inflow, loop diuretics and dietary salt restriction are usually effective in treating congestive symptoms. Digoxin may be useful in patients with LV and/or RV dysfunction. Whether β-blockers are useful in treating heart failure symptoms remains controversial.⁷⁷ Slowing of the heart rate reduces mean transvalvular gradient by allowing more time for LA emptying. However, β-blockers also tend to increase LV diastolic pressure so that mean LA pressure changes little at rest. However, for patients prone to a robust sinus tachycardia with exercise, β-blockade may be effective in controlling exercise-induced symptoms. Ivabradine, a negative chronotropic agent, may have an advantage over β-blockers in patients with sinus rhythm, as it has no effect on myocardial contractility. Studies have demonstrated that ivabradine is better or at least as effective β-blockers in improving exercise tolerance in patients with mild-to-moderate MS in sinus rhythm.^78,79 Anemia, fever, infections, and hyperthyroidism should be corrected.

Three procedures are routinely practiced for the relief of MS: BMV, open commissurotomy (OMV), and MVR. In some areas, closed commissurotomy (CMV) is still practiced quite effectively and does not entail the cost of the catheters and balloons needed for BMV. Because BMV is less morbid and carries a lower mortality than surgery, the timing for BMV is more liberal than for the surgical procedures at both ends of the clinical spectrum. It may be applied for mild symptoms caused by severe MS or in late-stage disease in patients at high risk for surgery from various comorbidities. Advanced symptoms worsen prognosis (Fig. 50–6), and thus BMV or surgery should be performed before the patients reaches New York Heart Association (NYHA) class III.⁸⁰ Additionally, pulmonary hypertension defined as a peak systolic pressure > 50 mm Hg at rest also worsens prognosis and increases surgical risk.⁸¹ Thus mechanical relief of obstruction should ideally take place before this degree of severity has developed.

Balloon Mitral Valvotomy

BMV was first performed by Inoue in 1984,⁸² followed by Lock in 1985.⁸³ BMV is the procedure of choice for relieving MS,³⁰ with surgery being reserved only for patients who are not candidates for BMV. It is recommended for the following groups of patients³⁰: (1) symptomatic patients (class II-IV) with severe MS (MVA ≤ 1.5 cm²) (class 1 indication) or asymptomatic patients with very severe MS (MVA ≤ 1.0 cm²) (class 2a indication) with a favorable valve morphology in the absence of LA thrombus and moderate-to-severe MR; (2) asymptomatic patients with severe MS (MVA ≤ 1.5 cm²) with new-onset AF and suitable valve anatomy (class 2b indication); (3) symptomatic patients with MVA > 1.5 cm² and hemodynamically significant MS during exercise (mean mitral valve gradient > 15, PCWP > 25 mm Hg, class 2b indication; and (4) severely symptomatic patients (NYHA class III-IV) with severe MS (MVA ≤ 1.5 cm²) with suboptimal valve anatomy and high risk for surgery (class 2b indication).

The steps for BMV are demonstrated in Fig. 50–7. First, a transseptal puncture is performed (Fig. 50–7A), and the inter-atrial septum is dilated with a dilator (Fig. 50–7B). A balloon is then advanced across the septum, into the LA across the mitral valve. Stepwise inflation causes commissures separation (Fig. 50–7C, D; Fig. 50–5B), permitting a dramatic increase in leaflet motion and valve area. BMV can be performed using a hourglass-shaped balloon (triple lumen Inoue balloon⁸² or double lumen Accura balloon^84,85), a single⁸³ or double peripheral angioplasty balloon,⁸⁶ or a reusable valvulotome.⁸⁷ Although the three techniques produce a similar outcome,^86,88 currently the hourglass-shaped balloons are preferred. The procedure should be performed by experienced, skilled operators. The mortality is approximately 1% in experienced centers. Other complications include severe MR requiring surgery (2%), embolic events (1%), and cardiac perforation (1%).¹⁰ Retrograde BMV without transseptal puncture using a steerable guidewire is an alternative to conventional BMV.^89,90

Randomized trials have shown BMV to be superior to CMV, with a larger postprocedure valve area when the two procedures were compared in patients with valves suitable for BMV,^91,92,93,94 and similar results have been shown for BMV and OMV.⁹⁵ Although successful BMV is usually defined as a postprocedure valve area > 1.5 cm² (without > grade 2 MR), valve area often exceeds 1.8 cm² and is durable for a decade or more. There is an immediate reduction in transmitral gradient, LA mean pressure, and PA pressure. Even patients with systemic or suprasystemic PA pressure have an immediate significant drop in PA pressure after successful BMV.⁹⁶ Reduction in PA pressure is associated with improvement in tricuspid regurgitation (TR) in some, but not all, patients. Successful BMV has been shown to reduce systemic embolism,⁴⁹ but does not appear to revert AF.⁶⁶ Long-term studies with follow-up for up to 20 years are available.^97,98 Among 912 patients with a median age of 48 years,⁹⁷ cardiovascular survival without reintervention and cardiovascular survival without surgery was 38% and 46%, respectively, at 20 years. For patients aged < 50 years, the figures were 45% and 57%, respectively.⁹⁷ The overall survival and cardiovascular survival at 20 years was 75% and 85%, respectively.⁹⁷ In another study of 547 patients with a mean age of 31 years,⁹⁸ freedom from restenosis at 10 and 19 years was 78% and 26%, respectively.

The BMV technique and hardware has remained essentially unchanged over the past three decades, but the indications of BMV have expanded to encompass patients with calcified valves, severe submitral disease, LA/LAA clot, moderate MR (grade 2), mitral valve restenosis (post BMV/CMV/OMV/MVR), pregnancy, children, and those with difficult anatomy (anomalous inferior vena cava connections, dextrocardia, kyphoscoliosis).

Cardiac Surgery

Relief of MS by surgery may be done either by CMV, OMV, or MVR. CMV, via transatrial or transventricular route, is still practiced successfully in many developing countries. However, the results of BMV are superior to CMV, with lower morbidity. As such, CMV is indicated only if BMV is not available. OMV is done under cardiopulmonary bypass and enables direct visual inspection of the mitral valve, enabling direct splitting of commissures, splitting of fused chordae tendinae and papillary muscles, and debridement of calcific deposits. LA thrombi may be removed and the LAA amputated to reduce future thromboembolic events. Further, moderate to severe TR can be repaired. The results are dependent on the surgical skills, and the main advantage of OMV is that it avoids a prosthetic valve. When extensive calcification and severe subvalvular disease make BMV/OMV unfeasible, MVR is the surgical treatment of choice. The indication for MVR are as follows³⁰: (1) severely symptomatic patients (NYHA class III/IV) with severe MS (MVA < 1.5 cm²) who are not high risk for surgery and who are not candidates for, or have failed, previous BMV (class 1 indication); (2) severe MS (MVA < 1.5 cm²) undergoing other cardiac surgery (eg, aortic valve surgery, coronary artery bypass grafting) (class 2a indication); and (3) mitral valve surgery and LAA excision may be considered for patients with severe MS (MVA ≤ 1.5 cm², stages C and D) with recurrent embolic events despite adequate anticoagulation (class 2b indication). Further, patients with moderate to severe TR do better after surgery that includes a tricuspid valve repair.⁹⁹ Given the morbidity and mortality associated with MVR and the potential long-term complications associated with a prosthetic valve (prosthetic valve thrombosis, infective endocarditis, prosthesis mismatch, bleeding complications with anticoagulation), the threshold for MVR is higher than for BMV and is limited to NYHA class III and IV patients. The operative mortality is 3% to 8%, but it may reach as high as 10% to 20% with NYHA class IV patients.¹⁰⁰ Therefore the patient should not be allowed to reach NYHA class IV during postponement of surgery. Even if the patient does present in NYHA class IV, surgery should not be denied, as the outlook without surgery is very poor. BMV can be an alternative in such cases after careful discussion.³⁰ The type of valve inserted will depend on the patient’s age and the risk of anticoagulation, but is increasingly more dictated by patient choice. However, if the patient has long-standing AF and must be anticoagulated anyway, a mechanical valve may be inserted. On the other hand, a young patient in sinus rhythm may opt for a bioprosthetic valve to avoid the hazards of anticoagulation, with an understanding of the need for future redo surgery for valve deterioration. If AF is less chronic, a maze procedure may be used at the time of MVR,⁶⁴ although its success in a purely rheumatic population is less certain than in a nonrheumatic population. Although it is often hoped that relief of MS will result in restoration of sinus rhythm, AF in MS is due not only to increased LA size but also to rheumatic scarring and histologic changes in the LA.¹⁰¹ Thus, relief of mitral obstruction may⁶⁵ or may not prevent AF¹⁰² or allow for return to sinus rhythm.

Pregnancy

As noted earlier, MS is primarily a disease of women and may become manifest during pregnancy when the cardiac output demands on the heart increase by 70%. As predicted by the Gorlin formula, an increase in cardiac output of 1.7-fold would increase the transvalvular gradient by 1.7² or 2.89-fold. Thus, a small pregravid transmitral gradient of 4 mm Hg might become 11 mm Hg during the second trimester and cause symptoms to appear. Typically, symptomatic status follows the rule of one class. That is, the patient’s symptoms will increase by one NYHA class during pregnancy. Thus the asymptomatic patient may develop class II symptoms, whereas a class II patient may become class III. Effects on the fetus include intrauterine growth retardation, low birthweight, preterm delivery, and fetal loss.¹⁰³ Ideally, asymptomatic patients with severe MS (MVA ≤ 1.5 cm²) with suitable valve should undergo BMV before conception.³⁰ Diuretics can usually be used safely to control mild symptoms. Overaggressive use of diuretics can lead to placental hypoperfusion. Therapy is targeted to reduce heart rate and prolong diastolic filling period. This includes restriction of physical activity and use of β-blockers (those with selective β-1 activity are preferred). Metoprolol is preferred over atenolol, as it has a lower incidence of intrauterine growth retardation.³⁰ In patients with AF, digoxin can be safely used. Pregnant patients with severe MS (MVA ≤ 1.5 cm²) who continue to remain symptomatic (NYHA class III-IV) despite medical therapy should undergo BMV if the valve is suitable.³⁰ A combined analysis of 515 patients who underwent BMV during pregnancy found a success rate of 98% (94%-100% in large-volume centers).¹⁰⁴ Maternal mortality was 1%. In the largest of these studies, the average fluoroscopic time was 3.6 ± 3.2 minutes.¹⁰⁵ The radiation to fetus is estimated to be less than 0.2 rad. Long-term follow-up of these children up to 7 years revealed no fetal anomalies.¹⁰⁶ The procedure should be performed by experienced operators. It is best performed after 20 weeks in the second trimester if the patient’s symptoms permit. Technical aspects include use of minimal fluroscopy with avoidance of right heart study and LV angiogram, utilization of echo guidance, stepwise dilation technique, and use of pelvic and abdominal shield.

For symptomatic patients with valve anatomy unsuitable for BMV, mitral valve surgery is indicated if there are refractory NYHA class IV heart failure symptoms.¹⁰⁷ However, valve operation in pregnancy has a high risk, with 30% to 40% fetal loss and maternal mortality of up to 9%.¹⁰⁸

Pregnant patients with MS who have or develop AF will need anticoagulation. The use of warfarin during the first trimester (6-12 weeks) is associated with a high risk of embryopathy.¹⁰⁹ However, pregnancy is a prothrombotic state, and the risk of stroke in a pregnant woman with both AF and MS is presumably quite high. The risk of warfarin-associated embryopathy appears to be dose-related. The incidence is < 3% with a daily dose ≤ 5 mg, but increases to > 8% with a warfarin dose > 5 mg/d.¹¹⁰ Direct current cardioversion after transesophageal echocardiography that reveals no atrial thrombus is preferable. If thrombus is present or cardioversion fails, then clear-cut options are limited. Options include (as for mechanical heart valves) continuing warfarin (if dose < 5 mg/d) or the use of unfractionated heparin (intravenous infusion or subcutaneous injections twice daily) or low molecular weight heparin (monitored with factor Xa levels) in the first 6 to 12 weeks followed by a switch to warfarin.^30,111 The decision regarding the choice of the regimen should be made after a thorough discussion with the patient.¹¹¹

Juvenile MS

Rheumatic MS presenting below 20 years is termed juvenile MS.¹² This condition is uncommon in developed countries, but may constitute up to a quarter of cases of all rheumatic MS in developing countries.¹² Unlike in adults, boys are more commonly affected.¹² Heart failure/pulmonary edema is a frequent finding, while AF is uncommon. Severe pulmonary arterial hypertension with gross pulmonary vascular obstruction is common. Although mitral valve calcification and LA thrombi are absent, the valve morphology is associated with severe subvalvular disease and thickened leaflets. BMV has been successfully preformed with acute success rates of 94% to 100%^112,113,114 (comparable to adult series). Event-free survival at intermediate to long-term follow-up ranged from 75% to 79% at 5 to 10 years follow-up.^115,116 Restenosis rates were 14% to 16%.¹¹⁶ Important procedural aspects include the use of stepwise graded dilatation, the use of a balloon size 2 to 4 mm less than the calculated size, and indexing the MVA to BSA to define procedural success (MVA > 1.0 cm² /m² BSA).^112,115 There was significant drop in the PA pressure immediately after the procedure¹¹⁵ followed by further substantial regression over long-term follow-up.¹¹⁶

Concomitant Valve Disease

As noted, rheumatic fever may affect all four heart valves. Perhaps the most common lesion is mixed MS and MR. The lesions are almost never balanced, with one more prominent than the other. From the standpoint of management, LV remodeling gives the best clue regarding which lesion is dominant and, therefore, which to treat. If the LV is dilated, MR is the dominant lesion, and strategies for MR therapy should be followed, whereas if the LV remains normal in volume, MS predominates, and the patient should be treated accordingly.

Aortic insufficiency is the next most common accompanier of MS, and its evaluation may be misleading. The aortic valve can only regurgitate what it receives from the mitral valve. MS reduces cardiac output and LV volume. Thus, many of the clinical clues to aortic insufficiency severity may be missing in the MS patient, both upon clinical and echocardiographic examination.¹¹⁷

Perhaps the most important concomitant lesion is TR. Although rheumatic deformity of the tricuspid valve does occur, most TR is functional, resulting from RV dilatation secondary to pulmonary hypertension. It is often believed that once the MS is corrected and pulmonary hypertension disappears, the TR will also improve. Although this does occur in some cases,¹¹⁸ it fails to materialize in others, and the need to address TR surgically as a second operation after successful mitral surgery carries a high operative risk.¹¹⁹ Therefore, it is preferable to perform ring tricuspid annuloplasty at the time of mitral surgery if even mild TR is present, because TR may paradoxically worsen if left unattended. On the other hand, it is probably acceptable to gauge TR before BMV and follow the patient for regression of TR. If TR does not improve, tricuspid repair as a first cardiac surgery seems reasonable.