ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Rheumatic mitral stenosis: Overview of management

Rheumatic mitral stenosis: Overview of management
Literature review current through: Jan 2024.
This topic last updated: Sep 07, 2022.

INTRODUCTION — Mitral stenosis (MS) is a progressive condition characterized by obstruction of blood flow across the mitral valve from the left atrium to the left ventricle. The mechanical obstruction leads to increases in pressure within the left atrium, pulmonary vasculature, and right side of the heart. Most cases of MS are caused by rheumatic heart disease with mitral commissural adhesion; thickened, immobile mitral valve leaflets; and fibrosis, thickening, shortening, fusion, and calcification of the chordae tendineae. Infrequent causes of MS include mitral annular calcification and congenital MS. (See "Rheumatic mitral stenosis: Clinical manifestations and diagnosis" and "Pathophysiology and natural history of mitral stenosis".)

The medical management and indications for intervention for rheumatic MS will be reviewed here. Outcomes and management of patients undergoing percutaneous mitral balloon commissurotomy and mitral valve surgery for MS are discussed separately. (See "Percutaneous mitral balloon commissurotomy in adults" and "Surgical and investigational approaches to management of mitral stenosis".)

Management of MS caused by mitral annular calcification is discussed separately. (See "Management and prognosis of mitral annular calcification".)

ROLE OF HEART TEAM AND EXPERIENCED VALVE CENTERS — Evaluation and management of MS may be optimized by a multidisciplinary heart valve team approach used for a variety of valve conditions [1,2]. This multidisciplinary approach incorporates clinical evaluation and risk assessment to determine if mitral valve intervention is indicated and to guide choice of intervention. (See "Percutaneous mitral balloon commissurotomy in adults", section on 'Evaluation of candidates for PMBC' and "Estimating the risk of valvular procedures" and "Preoperative evaluation for anesthesia for cardiac surgery".)

Interventions for MS (percutaneous mitral balloon commissurotomy [PMBC] and mitral valve surgery) in adults are most commonly performed in countries with high prevalence of rheumatic heart disease; valve centers in such settings often have high procedure volume and extensive operator experience.

On the other hand, interventions for MS are less commonly performed in countries in which acute rheumatic fever is rare (eg, the United States); patients presenting with rheumatic MS in countries with low prevalence of rheumatic fever are often immigrants from other countries where rheumatic fever persists [3]. Given the very low volume of patients with rheumatic MS treated by most clinical practices in resource-abundant countries, professional societies have recommended that PMBC be performed at selected experienced valve centers (termed Comprehensive Valve Centers by the American College of Cardiology/American Heart Association [1,4] and Heart Valve Centres by the European Society of Cardiology [2]) where expertise and experience for low-volume procedures such as PMBC can be concentrated.

GENERAL MANAGEMENT — Management of rheumatic MS includes patient education regarding the need for ongoing care, periodic monitoring, rheumatic fever prophylaxis, management of heart failure, management of atrial fibrillation (AF), prevention of thromboembolism, endocarditis prophylaxis, counseling on physical activity, management of risk associated with pregnancy, management of risk of noncardiac surgery, and cardiovascular risk reduction.

Monitoring — For all patients with MS, follow-up should include yearly history and physical examination to assess for symptoms and signs of disease progression and development of indications for intervention [1]. Careful clinical evaluation is required since some patients may not report symptoms due to the gradual progression of disease.

Follow-up transthoracic echocardiography should be performed with frequency based upon the severity of disease. We agree with the 2020 American College of Cardiology/American Heart Association (ACC/AHA) valve guideline recommendation for echocardiography every three to five years if the mitral valve area (MVA) is >1.5 cm2, every one to two years if the MVA is 1.0 to 1.5 cm2, and every year if the MVA is <1.0 cm2 [1].

The long interval between testing in asymptomatic, stable, mild disease is based in part upon the natural history of MS, as MVA declines at a mean of approximately 0.1 cm2 per year. However, the rate of progression is highly variable, especially in younger populations with recurrent rheumatic fever [5]. More frequent monitoring may be required in these patients and in those with concurrent mitral regurgitation or disease affecting other valves. All patients should undergo reevaluation whenever there is a change in clinical status. (See "Pathophysiology and natural history of mitral stenosis", section on 'Rate of progression'.)

The rationale for monitoring is to optimize timing of mitral valve intervention. The timing of surgical or percutaneous intervention for MS is crucial for the following reasons:

If performed too early, the patient may be put at unnecessary risk of a procedure-related complication with little or no benefit because MS (in the absence of intervention) may remain asymptomatic and stable for many years.

Delaying intervention may cause irreversible pulmonary hypertension (PH) and/or right heart failure. Delaying intervention might also increase the risk of AF, although there are few data addressing this issue. The risk of failure to receive necessary corrective intervention was illustrated by a report that included patients in whom valve surgery was indicated but refused [6]. Patient survival with medical therapy was 44 percent at five years, 32 percent at 10 years, and 19 percent at 15 years.

Monitoring and evaluation prior to and during pregnancy are discussed separately. (See "Pregnancy in women with mitral stenosis".)

Secondary prevention of rheumatic fever — Patients with rheumatic MS should receive antibiotic prophylaxis for secondary prevention of rheumatic fever. Acceptable regimens and issues related to the duration of prophylaxis are discussed separately. Regardless of whether or not prophylaxis is continued, there should always be a low threshold to test and treat these patients for acute group A streptococcal pharyngitis. (See "Acute rheumatic fever: Treatment and prevention", section on 'Secondary prevention (antibiotic prophylaxis)'.)

Nearly all cases of MS are the result of rheumatic involvement of the mitral valve. Although chronic degenerative changes associated with MS may represent a response to turbulent blood flow through the rheumatically deformed valve [7], there is also evidence that repeated episodes of rheumatic carditis contribute to the natural history of MS even when no clinical signs of acute rheumatic fever have been present [8,9]. Thus, preventing repeated attacks of rheumatic fever may play a role in delaying the progression of MS.

The likelihood of recurrence of rheumatic fever is correlated with a higher number of previous attacks and the presence and severity of preexisting rheumatic heart disease [10]. The risk for recurrence of rheumatic fever declines with increasing age and the number of years since the patient's most recent attack. Recurrences of rheumatic fever tend to mimic previous attacks for that patient, such that the absence of carditis during the initial attack usually means it will not be a feature during future attacks. However, the diagnosis of recurrent rheumatic fever may be difficult since classical criteria for first episodes may not be present. (See "Acute rheumatic fever: Clinical manifestations and diagnosis".)

Prevention of infective endocarditis — As noted in the 2007 AHA guidelines on the prevention of bacterial endocarditis, only patients with the highest risk of the development of endocarditis (eg, patients with prosthetic heart valves, patients with prior endocarditis) are advised to receive antimicrobial prophylaxis [11]. Most patients with native valvular heart disease, including those with MS, are not included in this group and therefore do not require antimicrobial prophylaxis. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

Physical activity and exercise — Most patients with severe MS are symptomatic with exertion, leading them to adopt a more sedentary lifestyle. However, all patients should be encouraged to participate in at least a low-level exercise regimen to maintain cardiovascular fitness. Patients should be informed that sudden death in MS is extremely rare, which may alleviate certain fears about exercising. Each patient's exercise tolerance will vary depending upon the severity of their disease (table 1) and the intensity and type of exercise [12].

The following recommendations were included in the 2014 AHA/ACC recommendations for competitive athletes with MS [13] (figure 1):

Annual evaluation should be performed in athletes with MS to determine whether sports participation can continue.

In athletes with MS, exercise testing to at least the level of activity achieved in competition and training is useful in confirming asymptomatic status.

For athletes with MS with MVA >2.0 cm2 and mean gradient <10 mmHg at rest, participation in all competitive sports is reasonable.

Athletes with severe MS (MVA ≤1.5 cm2) should not participate in competitive sports, with the possible exception of low-intensity (class IA) sports.

Individuals with MS with AF treated with anticoagulation should not participate in sports involving risk of bodily contact.

Management of risk of pregnancy — Pregnancy is associated with hemodynamic changes that may be poorly tolerated in patients with MS, particularly in those with more advanced disease. Management of MS during pregnancy is discussed in detail separately. (See "Pregnancy in women with mitral stenosis".)

MEDICAL MANAGEMENT OF HEART FAILURE — The role of medical therapy for heart failure caused by MS is limited. The onset of symptoms is an indication for intervention in patients with severe MS (see 'Indications for intervention' below). Pharmacologic therapy is appropriate to improve symptoms and hemodynamic conditions prior to intervention, for persistent symptoms after intervention, and for management of symptoms precipitated by an intercurrent illness or during pregnancy. (See "Pregnancy in women with mitral stenosis", section on 'Clinical management'.)

Diuretic therapy (usually with a loop diuretic such as furosemide) and dietary salt restriction are appropriate when there are manifestations of pulmonary vascular congestion such as exertional shortness of breath, orthopnea, and/or paroxysmal nocturnal dyspnea [14]. At a later stage of MS, right heart failure can occur, with hepatic congestion and peripheral edema. Loop diuretics acutely improve such manifestations of the congestive state [15]. However, diuresis may also reduce cardiac output and thus cause or worsen fatigue [16]. (See "Use of diuretics in patients with heart failure".)

Agents for heart rate control (in patients in sinus rhythm or AF) include beta blockers, nondihydropyridine calcium channel blockers, and ivabradine. These agents are used to reduce the heart rate and improve dyspnea, although their effect on exercise tolerance is uncertain. These agents can significantly decrease heart rate and cardiac output at rest, causing a decrease in the transmitral gradient, pulmonary venous pressure, and mean pulmonary artery pressure in patients with MS [17]. Beta blockers can blunt the heart rate and cardiac output responses to exercise, while attenuating the rise in transmitral gradient that normally occurs [18]. However, the impact of beta blockers on exercise tolerance is uncertain, with conflicting results from small trials [18,19].

A meta-analysis of five small randomized trials comparing the effects of beta blockers and ivabradine in patients with MS in sinus rhythm found a longer exercise duration in patients treated with ivabradine (n = 147) compared with patients treated with beta blocker (n = 149; mean difference 32.73 s; 95% CI 12.19-53.27) [20]. The maximal heart rate achieved was lower with ivabradine (mean difference -3.87 beats per minute; 95% CI -5.88 to -1.86). Resting heart rate was higher with ivabradine, but results differed among the three included studies (mean difference 1.83 beats per minute; 95% CI 0.39-3.28).

The role of digoxin in patients with MS is limited since most patients have preserved ventricular systolic function [21,22]. Digoxin may be helpful in selected patients who have symptomatic left and/or right ventricular systolic dysfunction, as in patients with other causes of systolic heart failure. Digoxin may also be helpful in controlling a rapid ventricular rate during AF, although digoxin is not a first-line drug for this indication for most patients. (See 'Management of atrial fibrillation' below and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Optional therapies'.)

MANAGEMENT OF ATRIAL FIBRILLATION — In general, the medical management of AF for patients with MS does not significantly differ from general treatment guidelines. However, because of the exaggerated adverse hemodynamic effects caused by MS, prompt therapy is often necessary. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and 'Prevention of thromboembolism' below.)

In many patients with MS, the onset of AF contributes to the onset of symptoms. When MS is hemodynamically significant (valve area ≤1.5 cm2), flow across the mitral valve is maintained by two factors: adequate diastolic filling time and higher-than-normal pulmonary venous pressure. AF in patients with MS may be poorly tolerated for two reasons, with the hemodynamic consequences depending upon the severity of the stenosis:

If AF is associated with a rapid ventricular rate, the shortened diastolic filling time causes left atrial and pulmonary pressures to rise, potentially leading to pulmonary edema. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".)

The loss of atrial contraction contributes to a decrease in left ventricular filling and an increase in left atrial pressure.

Initial management — In patients who are hemodynamically unstable, immediate electrical cardioversion is indicated. (See "Atrial fibrillation: Cardioversion".)

For hemodynamically stable patients, the initial management consists of controlling the ventricular rate (with a beta blocker, calcium channel blocker [verapamil or diltiazem], or, less preferably, digoxin) and anticoagulation. (See 'Prevention of thromboembolism' below and 'Medical management of heart failure' above and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".)

As discussed above, some experts suggest percutaneous mitral balloon commissurotomy (PMBC) in patients with MS with new AF based upon limited evidence suggesting that PMBC may favorably alter electrocardiographic and echocardiographic parameters associated with risk of AF [23]. (See 'Our approach' below.)

Rate versus rhythm control — A rate control strategy is generally preferred because, based upon studies in patients with nonvalvular AF, outcomes are as good as or perhaps better than with a rhythm control strategy and, with a rhythm control strategy, long-term anticoagulation is still required in most patients and long-term rhythm control may not be feasible as MS progresses. Conversion to sinus rhythm may be necessary if heart rate cannot be adequately controlled with medications. In patients not requiring urgent cardioversion, the decision for rate control versus rhythm control is based upon multiple factors including the duration of AF, hemodynamic response to AF, symptoms, and left atrial size. (See "Management of atrial fibrillation: Rhythm control versus rate control".)

For patients in whom a rhythm control strategy is chosen, issues related to the method of restoration of sinus rhythm, anticoagulation before, during, and after cardioversion, and antiarrhythmic drug therapy to maintain sinus rhythm are discussed separately. (See "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".)

Regardless of the initial response to antiarrhythmic therapy, it may become increasingly difficult, if not impossible, to maintain sinus rhythm as the severity of MS progresses. Catheter AF ablation is an option in selected patients with MS [24]. Patients with indications with mitral valve surgery may undergo concomitant surgical AF ablation. (See "Overview of catheter ablation of cardiac arrhythmias" and "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy" and "Atrial fibrillation: Surgical ablation" and 'Indications for intervention' below.)

PREVENTION OF THROMBOEMBOLISM — The risk of thromboembolism is addressed primarily by anticoagulation in selected patients with rheumatic MS. Monitoring patients for the development of an indication for PMBC may also help manage the thromboembolic risk since timely percutaneous intervention appears to reduce the risk of systemic embolism in patients with and without AF [25]. (See 'Indications for intervention' below and "Percutaneous mitral balloon commissurotomy in adults".)

Indications for anticoagulation — We recommend anticoagulation for patients with rheumatic MS (stage B, C, or D) (table 1) and AF (paroxysmal, persistent, or permanent) [1,26].

Patients with rheumatic MS and left atrial thrombus or an embolic event require anticoagulation whether or not AF is detected. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'Transesophageal echocardiography-based approach' and "Echocardiography in detection of cardiac and aortic sources of systemic embolism", section on 'Intracardiac sources of emboli'.)

The above approach is in broad agreement with antithrombotic recommendations for MS in major society guidelines [1,2,27].

Indications for antithrombotic therapy in patients with MS and AF are primarily supported by observational studies in patients with MS and extrapolation of anticoagulant trial data in patients with AF without MS. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Effects of anticoagulation'.)

Systemic thromboembolism is a major complication of rheumatic MS and is the presenting event in some patients. Prior to widespread anticoagulant therapy and surgical treatment in patients with MS, as many as 30 percent of patients with MS experienced an embolic event during the course of the disease. The presence of AF is a risk factor for thromboembolic events in patients with MS [28,29]. The risk of stroke in unanticoagulated patients with MS and AF has been estimated as approximately 5 to 6 percent per patient-year [28,29]. In later prospective studies in anticoagulated patients, the risk of stroke or systemic embolism ranged from 0.4 to 4 percent per patient-year. In one series of patients with rheumatic valve disease with systemic embolic events, the incidence of recurrent embolism was 3.4 percent per patient year in those treated with anticoagulation and 9.6 percent per patient year in those not treated with anticoagulation [30]. (See "Rheumatic mitral stenosis: Clinical manifestations and diagnosis", section on 'Thromboembolism' and "Atrial fibrillation in adults: Use of oral anticoagulants".)

The utility of anticoagulation in patients with MS in normal sinus rhythm with left atrial enlargement or spontaneous echocardiographic contrast but no thrombus on transesophageal echocardiography is uncertain. When embolization occurs in patients with MS who are in sinus rhythm, potential causes include transient AF and infective endocarditis. Transient subclinical AF occurs in some patients with MS, and transient AF is a predictor of stroke and systemic embolism [31]. Although left atrial enlargement and spontaneous echocardiographic contrast (SEC; along with AF and smaller mitral valve area) have been identified as predictors of thromboembolism in patients with MS [25,32,33], the risks and benefits of anticoagulation for left atrial enlargement or SEC in patients with MS in sinus rhythm are uncertain. SEC is a marker of blood stasis associated with decreased atrial contractile function and increased risk of left atrial thrombus in patients with MS [34,35]. Among patients with MS, SEC is more frequent among patients in AF although some patients in sinus rhythm also have SEC, other evidence of decreased atrial function, and atrial thrombus. A transesophageal echocardiographic study of 848 patients in sinus rhythm with MS with MVA ≤1.5 cm2 (mean MVA 0.78 cm2) found left atrial thrombus in 7 percent [36].

Choice of anticoagulant — For patients with MS requiring anticoagulation (for AF, left atrial thrombus, or an embolic event), we recommend a vitamin K antagonist (VKA; eg, warfarin) rather than a direct oral anticoagulant (DOAC). (See "Warfarin and other VKAs: Dosing and adverse effects".)

This recommendation is supported by the results of the INVICTUS trial, which enrolled 4565 adults from 23 countries in Asia, Africa, and Latin America and found lower rates of stroke and death with VKA compared with rivaroxaban [37]. Enrollment criteria included presence of rheumatic heart disease, AF, and at least one of the following additional criteria: a CHA2DS2-VASc score of ≥2 (table 2), a mitral valve area of ≤2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. The subjects were randomly assigned to receive rivaroxaban (20 mg daily for patients with an estimated creatinine clearance of ≥50 mL per minute; 15 mg daily in patients with an estimated creatinine clearance <50 mL per minute) or dose-adjusted VKA (target international normalized ratio [INR] 2.0 to 3.0, with at least monthly monitoring). The mean subject age was 50.5 years, and 72 percent were female. The mean duration of follow-up was 3.1 years.

The mortality rate was higher with rivaroxaban than with VKA (7.95 versus 6.35 percent per year; hazard ratio [HR] 1.23, 95% CI 1.09 to 1.40), largely due to a higher rate of cardiac death.

The rate of stroke was higher with rivaroxaban than with VKA (1.32 versus 0.94 percent per year; HR 1.37, 95% CI 1.00 to 1.89), due to a higher rate of ischemic stroke.

The rate of major bleeding was similar with rivaroxaban and VKA (0.67 versus 0.83 percent per year; HR 0.76, 95% CI 0.51-1.15).

It is unclear why the stroke rate and mortality rate with rivaroxaban therapy were higher than with VKA in this population, in contrast to trials in patients with AF without rheumatic heart disease, in which these rates were lower with DOAC than with VKA (see "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'). A cointervention that might have impacted outcomes is the greater physician interaction for patients in the VKA group (because of INR monitoring) than the rivaroxaban group.

MANAGEMENT OF NONCARDIAC SURGERY

Preoperative evaluation and management — The presence of MS has potentially important implications for the perioperative management and prognosis of the patient undergoing noncardiac surgery. The prognosis is poor in patients with untreated symptomatic MS, while asymptomatic patients with MS without PH or AF may not incur excess risk with noncardiac surgical procedures.

Standard indications for intervention for rheumatic MS apply prior to elective noncardiac surgery [1,2]. (See 'Indications for intervention' below.)

The risks and benefits of proceeding with elective noncardiac surgery should be considered in asymptomatic patients with severe MS who are not candidates for PMBC (due to unfavorable valve anatomy or other contraindication). Though evidence is limited, in some cases it may be reasonable to proceed with moderate-risk elective noncardiac surgery with appropriate intraoperative and postoperative hemodynamic monitoring and management in this setting.

Perioperative management — Perioperative management of patients with unoperated MS undergoing noncardiac surgery should include attention to the following key concerns [1] (see "Anesthesia for noncardiac surgery in patients with aortic or mitral valve disease", section on 'Mitral stenosis'):

Adequate heart rate control – Tachycardia should be avoided since it shortens diastolic left ventricular filling time across the stenotic mitral valve and can result in reduced cardiac output, exacerbation of the transmitral gradient, and, potentially, pulmonary congestion. Anesthetic agents and muscle relaxants associated with decreased heart rates are preferred. Among patients with AF, the ventricular rate should be well controlled prior to elective surgery.

Careful management of central blood volume – Pulmonary venous pressure (ie, pulmonary artery balloon occlusion pressure) should be monitored and maintained high enough to allow adequate cardiac output but low enough to avoid pulmonary edema. Because of the obstruction to flow from left atrium to left ventricle, any situation that increases venous return and central blood volume will lead to a rise in pulmonary pressures and congestion. As an example, the Trendelenburg position dramatically increases pulmonary blood flow and can cause overt pulmonary edema. Right heart pressure monitoring during surgery is essential to manage the volume status.

Maintenance of systemic vascular resistance – MS impairs the normal compensatory response associated with a fall in blood pressure, since the stroke volume cannot be substantially increased. As a result, maintenance of systemic vascular resistance is important, since sudden drug-induced reductions in systemic vascular resistance can lead to hypotension.

Avoidance of marked changes in pulmonary vascular resistance – Patients with MS have some degree of PH. However, an acute increase in PH (eg, from arterial hypoxemia) may produce frank right ventricular decompensation.

Cardiovascular risk reducation — General recommendations for cardiovascular disease risk modification apply to patients with rheumatic MS. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

The value of statins as therapy for rheumatic MS is uncertain. A preliminary retrospective observational study found an association between treatment with statins and slower progression of rheumatic MS [38].

INDICATIONS FOR INTERVENTION — Since MS is a mechanical disorder once valve obstruction is present, only intervention (with percutaneous mitral balloon commissurotomy [PMBC] or surgery [surgical repair, commissurotomy, or valve replacement]) provides sustained symptom control and improved survival [1,2,39,40]. This section will discuss indications for intervention for MS.

Indications for intervention in pregnant patients with MS and additional discussion of PMBC and mitral valve surgery in patients with MS are presented separately. (See "Pregnancy in women with mitral stenosis" and "Percutaneous mitral balloon commissurotomy in adults" and "Surgical and investigational approaches to management of mitral stenosis".)

Our approach — Decisions on whether and how to intervene are largely based upon the following criteria:

The stage of MS, which is largely determined by the mitral valve area (MVA) and presence of symptoms (table 1).

The feasibility and risk of intervention (PMBC or mitral surgery) – Criteria for PMBC are discussed below (see 'Criteria for PMBC' below). Risk assessment for mitral valve surgery is discussed separately. (See "Estimating the risk of valvular procedures".)

Whether the patient is undergoing cardiac surgery for a concurrent condition (eg, coronary artery disease).

The following recommendations are grouped according to stage of MS (table 1):

Severe MS (MVA ≤1.5 cm2) (algorithm 1)

Symptomatic patients (stage D) – For most symptomatic patients (New York Heart Association [NYHA] class II, III, or IV) with severe rheumatic MS (stage D) (table 1), we recommend PMBC rather than either mitral valve surgery or no valve intervention, provided the patient meets criteria for PMBC (see 'Criteria for PMBC' below). For those who do not meet criteria for PMBC and are not at high surgical risk, we recommend mitral valve surgery (repair, commissurotomy, or valve replacement).

For patients with severe symptomatic rheumatic MS who do not have favorable valve morphology for PMBC (see 'Criteria for PMBC' below) and have high surgical risk, management decisions are individualized. For patients in this category with severe symptoms (NYHA class III or IV), no left atrial thrombus, and less than moderate mitral regurgitation (MR), we suggest attempting PMBC despite unfavorable valve morphology. Medical management or high-risk mitral valve surgery are reasonable alternatives.

Asymptomatic patients (stage C) – For asymptomatic patients with severe MS (stage C) (table 1) who have elevated pulmonary artery systolic pressure (PASP; >50 mmHg) or AF and are appropriate candidates for PMBC (see 'Criteria for PMBC' below), we suggest PMBC. (See "Surgical and investigational approaches to management of mitral stenosis", section on 'Risk assessment'.)

Patients without elevated PASP or AF and those who do not meet criteria for PMBC are managed medically. An exception is patients undergoing cardiac surgery for a concurrent condition (eg, coronary artery disease). In such patients, we suggest concomitant mitral valve surgery.

Nonsevere ("progressive") MS (MVA >1.5 cm2, stage B) (algorithm 2)

Isolated nonsevere MS – Most patients with isolated MS with MVA >1.5 cm2 are asymptomatic, do not require mitral valve intervention, and should continue to be monitored. However, for patients with exertional symptoms and evidence of hemodynamically significant MS with exercise (ie, pulmonary artery wedge pressure >25 mmHg or mean mitral valve gradient >15 mmHg) who are appropriate candidates for PMBC (see 'Criteria for PMBC' below), we suggest PMBC. (See "Rheumatic mitral stenosis: Clinical manifestations and diagnosis", section on 'Exercise testing'.)

Mixed nonsevere MS and moderate MR – Patients with nonsevere MS and MR should be monitored for development of symptoms. For symptomatic patients with MS with MVA >1.5 cm2 and moderate or greater MR, we suggest surgical mitral valve replacement. (See "Management and prevention of rheumatic heart disease", section on 'Management of mixed mitral disease'.)

Criteria for PMBC — Appropriate candidates for PMBC should optimally meet all of the following criteria (see "Percutaneous mitral balloon commissurotomy in adults", section on 'Evaluation of candidates for PMBC'):

Favorable valve morphology – This refers to features of the mitral valve complex (valve and subvalvular apparatus) associated with effective PMBC with low risk of induction of MR. Criteria for favorable valve morphology include the Wilkins score and the pattern of commissural calcification. (See "Percutaneous mitral balloon commissurotomy in adults", section on 'Evaluation of candidates for PMBC'.)

Less than moderate (2+) MR – Transesophageal echocardiography may be helpful is assessing the degree of MR since imaging of the left atrium on transthoracic echocardiography may be suboptimal. (See "Percutaneous mitral balloon commissurotomy in adults", section on 'Valve anatomy and function'.)

No left atrial thrombus.

No prior failed appropriately performed PMBC.

The above approach is in broad agreement with recommendations for rheumatic MS in the 2020 American College of Cardiology/American Heart Association valve guideline [1], which is similar to the approach in the 2021 European Society of Cardiology valve guidelines [2].

Evidence

Timing of intervention — Recommendations for timing of intervention for rheumatic MS are based largely upon observational data on outcomes for PMBC and mitral valve surgery (commissurotomy, repair, or replacement) and observational studies showing that MS is progressive (at variable rates) with inadequate symptom control and poor prognosis in symptomatic patients with MS managed medically [1,2]. (See "Percutaneous mitral balloon commissurotomy in adults" and "Surgical and investigational approaches to management of mitral stenosis" and "Pathophysiology and natural history of mitral stenosis".)

Symptomatic severe MS – Most patients with symptomatic MS have severe MS (MVA ≤1.5 cm2).

Symptomatic nonsevere MS

Symptomatic isolated MS – Some symptomatic patients with isolated MS have MVA >1.5 cm2 and are evaluated by exercise testing to identify parameters during exercise consistent with hemodynamically significant MS (pulmonary artery wedge pressure >25 mmHg or a mean mitral valve gradient <15 mmHg). (See "Rheumatic mitral stenosis: Clinical manifestations and diagnosis", section on 'Exercise testing'.)

Symptomatic mixed mitral disease – Symptomatic patients with mixed moderate MS and moderate MR have outcomes similar to those for symptomatic patients with severe isolated MS or severe isolated MR. (See "Management and prevention of rheumatic heart disease", section on 'Management of mixed mitral disease'.)

Asymptomatic severe MS – A rationale for intervention in patients with asymptomatic severe MS with pulmonary hypertension (PH) is to reduce the risks of progressive PH and combined pre- and postcapillary PH). Patients with severe MS and PH (including those with severe PH or combined pre- and postcapillary PH) generally show early clinical and hemodynamic improvement following mitral valve intervention [41,42]. However, moderate or severe PH is a predictor of adverse long-term outcomes in patients with severe MS undergoing intervention [43,44]. Isolated postcapillary PH generally resolves after successful mitral valve intervention, but precapillary PH may persist [45].

PMBC versus surgical commissurotomy — Evidence from randomized trials suggests that the clinical and hemodynamic results of PMBC are generally comparable with open and closed surgical mitral commissurotomy (OMC and CMC), and PMBC is associated with less procedural morbidity than mitral valve surgery. (See "Percutaneous mitral balloon commissurotomy in adults" and "Surgical and investigational approaches to management of mitral stenosis".)

A meta-analysis included seven randomized controlled trials (n = 553 patients) comparing PMBC with surgical OMC or CMC [46]. Pooled estimates showed similar immediate postprocedure MVA with PMBC compared with surgery (weighted mean difference 0.15, 95% CI -0.18 to +0.48), rates of restenosis or reintervention (15 percent fewer with PMBC, 95% CI -20 to +8 percent), and MVA at 30 months. The incidence of postprocedural severe MR was only nominally higher with PMBC (3 percent more with PTMC, 95% CI -1 to +10 percent).

PMBC versus mitral valve replacement — Limited data are available comparing outcomes following PMBC versus surgical mitral valve replacement. An observational study compared outcomes in 276 patients who underwent PMBC (mean follow-up 4.7 years) with those in 251 patients who underwent surgical mitral valve replacement (mean follow-up 5.45 years) in Turkey [47]. Duration of hospital stay was shorter with PMBC that with mitral valve replacement (2.02 versus 10.62 days). The in-hospital mortality rate was also lower with PMBC (0 versus 2 percent). In the PMBC group, the early postprocedural success rate was 92.1 percent. While there was a higher rate of reintervention after PMBC (16.3 versus 2.4 percent), the mortality rate was higher with mitral valve replacement (0 versus 4 percent). Functional status at follow-up was similar in the two groups (NYHA class I or II in 94.5 versus 95.2 percent).

Concomitant indication for cardiac surgery — The rationale for performing concomitant mitral valve surgery in patients with severe rheumatic MS (MVA ≤1.5 cm2, stage C or stage D) undergoing cardiac surgery for a concurrent condition (eg, coronary artery disease) is to avoid the risk associated with multiple cardiac interventions, particularly if required within a short period of time. The additional risk of concomitant mitral valve surgery at the time of another cardiac surgery is generally estimated to be lower than the risk of multiple separate interventions.

One example may be performing concomitant mitral and tricuspid surgery in patients with severe MS and severe secondary tricuspid regurgitation (TR). Improvement in associated secondary TR occurs in some but not all patients following successful PMBC. For patients with severe MS and severe TR, mitral valve surgery combined with tricuspid valve repair is more likely to reduce TR than PMBC alone. A retrospective study from Korea in patients with severe MS and severe TR suggested that mitral valve replacement combined with tricuspid valve repair may yield better outcomes in patients with severe MS and severe TR than PMBC [48]. The study compared outcomes in 48 patients undergoing PMBC versus 44 patients undergoing mitral valve replacement combined with tricuspid valve repair. During 57 months of follow-up, two deaths occurred in each group, there were no other clinical events in the surgical group, and there were seven cases of heart failure requiring surgical intervention in the PMBC group (event rate difference was borderline significant, p = 0.05). Severe TR was improved to mild or absent TR in 98 percent of the surgery group and in 46 percent of the PMBC group.

Some patients with severe rheumatic MS have concomitant rheumatic tricuspid valve disease (characterized by thickened retracted leaflets) causing moderate or severe TR. In such patients, PMBC will not improve TR, which is a rationale for concomitant mitral and tricuspid valve surgery in this setting.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Mitral stenosis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition and cause – Mitral stenosis (MS) is a progressive condition characterized by obstruction of blood flow across the mitral valve. The most common cause is rheumatic heart disease. (See 'Introduction' above and "Pathophysiology and natural history of mitral stenosis".)

Role of valve centers – Comprehensive Valve Centers or Heart Valve Centres serve as referral centers for concentration of expertise and experience for management of rheumatic MS, particularly percutaneous mitral balloon commissurotomy (PMBC). (See 'Role of heart team and experienced valve centers' above.)

General management – Management of rheumatic MS includes patient education regarding the need for ongoing care, periodic monitoring, rheumatic fever prophylaxis, management of heart failure, management of atrial fibrillation (AF), prevention of thromboembolism, endocarditis prophylaxis, counseling on physical activity, management of risk associated with pregnancy, management of risk of noncardiac surgery, and cardiovascular risk reduction. (See 'General management' above and "Pregnancy in women with mitral stenosis".)

Heart failure management – Medical management is not a substitute for valve intervention in patients with MS and is only appropriate for stabilization purposes prior to intervention, to treat hemodynamic decompensation due to an intercurrent illness, or for persistent symptoms after intervention. (See 'Medical management of heart failure' above.)

Anticoagulation – Patients with rheumatic MS with left atrial thrombus or prior embolic event require anticoagulation. In addition, for patients with rheumatic MS with paroxysmal, persistent, or permanent AF, we recommend long-term oral anticoagulation (Grade 1B).

For patients with rheumatic MS requiring anticoagulation (for AF, left atrial thrombus, or a prior embolic event), we recommend chronic anticoagulation with a vitamin K antagonist (VKA: eg, warfarin) rather than with a direct oral anticoagulant (DOAC) (Grade 1B). The target international normalized ratio (INR) is 2.5 (range 2.0 to 3.0). (See 'Choice of anticoagulant' above and "Warfarin and other VKAs: Dosing and adverse effects".)

Indications for intervention – Decisions on whether and how to intervene are based upon the stage of MS (which is largely determined by the mitral valve area [MVA] and presence of symptoms (table 1)), the feasibility and risk of intervention, and whether the patient is undergoing cardiac surgery for a concurrent condition (algorithm 2 and algorithm 1). (See 'Indications for intervention' above.)

Severe MS (MVA ≤1.5 cm2) (algorithm 1)

-Symptomatic severe MS (stage D) – For most symptomatic patients (New York Heart Association [NYHA] class II, III, or IV) with severe rheumatic MS (stage D) (table 1), we recommend PMBC rather than either mitral valve surgery or no valve intervention (Grade 1B), provided the patient meets criteria for PMBC (as summarized below). For those who do not meet criteria for PMBC and are not at high surgical risk, we recommend mitral valve surgery (repair, commissurotomy, or valve replacement) (Grade 1B).

For patients with severe symptomatic rheumatic MS who do not meet criteria for PMBC and have high surgical risk, management decisions are individualized. For patients in this category with severe symptoms (NYHA class III or IV) and less than moderate mitral regurgitation (MR) and no left atrial thrombus, we suggest attempting PMBC despite unfavorable valve morphology (Grade 2C). Medical management or high-risk mitral valve surgery are reasonable alternatives.

-Asymptomatic severe MS (stage C) – For asymptomatic patients with severe MS (stage C) (table 1) who have elevated pulmonary artery systolic pressure (PASP; >50 mm Hg) or AF and are appropriate candidates for PMBC (criteria summarized below), we suggest PMBC (Grade 2C). Patients without elevated PASP or AF and those who do not meet criteria for PMBC are managed medically. An exception is patients undergoing cardiac surgery for a concurrent condition (eg, coronary artery disease). In such patients, we suggest concomitant mitral valve surgery (Grade 2C).

Nonsevere ("progressive") MS (MVA >1.5 cm2, stage B) (algorithm 2)

-Isolated nonsevere MS – Most patients in this stage are asymptomatic, do not require mitral valve intervention, and should continue to be monitored. However, for patients with exertional symptoms and evidence of hemodynamically significant MS with exercise (ie, pulmonary artery wedge pressure >25 mmHg or mean mitral valve gradient >15 mmHg) who are appropriate candidates for PMBC (criteria summarized below), we suggest PMBC (Grade 2C). (See "Rheumatic mitral stenosis: Clinical manifestations and diagnosis", section on 'Exercise testing'.)

-Mixed MS and MR – Patients with nonsevere MS and MR should be monitored for development of symptoms. For symptomatic patients with MS with MVA >1.5 cm2 and moderate and greater MR, we suggest surgical mitral valve replacement (Grade 2C). (See "Management and prevention of rheumatic heart disease".)

Criteria for PMBC – Appropriate candidates for PMBC should optimally meet all of the following criteria (see 'Criteria for PMBC' above and "Percutaneous mitral balloon commissurotomy in adults", section on 'Evaluation of candidates for PMBC'):

Favorable valve morphology – This refers to features of the mitral valve complex (valve and subvalvular apparatus) associated with effective PMBC with low risk of induction of MR.

Less than moderate (2+) MR.

No left atrial thrombus.

No prior failed appropriately performed PMBC.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William H Gaasch, MD (deceased), who contributed to earlier versions of this topic review.

  1. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72.
  2. Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2022; 43:561.
  3. Carroll JD, Feldman T. Percutaneous mitral balloon valvotomy and the new demographics of mitral stenosis. JAMA 1993; 270:1731.
  4. Nishimura RA, O'Gara PT, Bavaria JE, et al. 2019 AATS/ACC/ASE/SCAI/STS Expert Consensus Systems of Care Document: A Proposal to Optimize Care for Patients With Valvular Heart Disease: A Joint Report of the American Association for Thoracic Surgery, American College of Cardiology, American Society of Echocardiography, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2019; 73:2609.
  5. Chandrashekhar Y, Westaby S, Narula J. Mitral stenosis. Lancet 2009; 374:1271.
  6. Horstkotte D, Niehues R, Strauer BE. Pathomorphological aspects, aetiology and natural history of acquired mitral valve stenosis. Eur Heart J 1991; 12 Suppl B:55.
  7. Stapleton JF. Natural history of chronic valvular disease. In: Cardiovascular Clinics. Valvular heart disease: comprehensive evaluation and management, Frankl WS, Brest AN (Eds), FA Davis, Philadelphia 1986. p.128.
  8. Edwards WD, Peterson K, Edwards JE. Active valvulitis associated with chronic rheumatic valvular disease and active myocarditis. Circulation 1978; 57:181.
  9. Clawson, BJ. Rheumatic heart disease. An analysis of 796 cases. Am Heart J 1940; 20:454.
  10. Dickinson GM, Bisno AL. Antimicrobial prophylaxis of infection. Infect Dis Clin North Am 1995; 9:783.
  11. Wilson W, Taubert KA, Gewitz M, et al. Prevention of Infective Endocarditis. Guidelines From the American Heart Association. A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 115 published online April 19, 2007. www.circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.106.183095v1 (Accessed on May 04, 2007).
  12. Mitchell JH, Haskell W, Snell P, Van Camp SP. Task Force 8: classification of sports. J Am Coll Cardiol 2005; 45:1364.
  13. Bonow RO, Nishimura RA, Thompson PD, et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 5: Valvular Heart Disease: A Scientific Statement From the American Heart Association and American College of Cardiology. Circulation 2015; 132:e292.
  14. Russell EA, Walsh WF, Costello B, et al. Medical Management of Rheumatic Heart Disease: A Systematic Review of the Evidence. Cardiol Rev 2018; 26:187.
  15. Austin SM, Schreiner BF, Kramer DH, et al. The acute hemodynamic effects of ethacrynic acid and furosemide in patients with chronic postcapillary pulmonary hypertension. Circulation 1976; 53:364.
  16. Boon NA, Bloomfield P. The medical management of valvar heart disease. Heart 2002; 87:395.
  17. Meister SG, Engel TR, Feitosa GS, et al. Propranolol in mitral stenosis during sinus rhythm. Am Heart J 1977; 94:685.
  18. Stoll BC, Ashcom TL, Johns JP, et al. Effects of atenolol on rest and exercise hemodynamics in patients with mitral stenosis. Am J Cardiol 1995; 75:482.
  19. Klein HO, Sareli P, Schamroth CL, et al. Effects of atenolol on exercise capacity in patients with mitral stenosis with sinus rhythm. Am J Cardiol 1985; 56:598.
  20. Ramos JDA, Cunanan EL, Abrahan LL 4th, et al. Ivabradine Versus Beta-Blockers in Mitral Stenosis in Sinus Rhythm: An Updated Meta-Analysis of Randomized Controlled Trials. Cardiol Res 2018; 9:224.
  21. Toutouzas P. Left ventricular function in mitral valve disease. Herz 1984; 9:297.
  22. Gaasch WH, Folland ED. Left ventricular function in rheumatic mitral stenosis. Eur Heart J 1991; 12 Suppl B:66.
  23. Demirkan B, Guray Y, Guray U, et al. The acute effect of percutaneous mitral balloon valvuloplasty on atrial electromechanical delay and P-wave dispersion in patients with mitral stenosis. Herz 2013; 38:210.
  24. Nair M, Shah P, Batra R, et al. Chronic atrial fibrillation in patients with rheumatic heart disease: mapping and radiofrequency ablation of flutter circuits seen at initiation after cardioversion. Circulation 2001; 104:802.
  25. Chiang CW, Lo SK, Ko YS, et al. Predictors of systemic embolism in patients with mitral stenosis. A prospective study. Ann Intern Med 1998; 128:885.
  26. Iung B, Leenhardt A, Extramiana F. Management of atrial fibrillation in patients with rheumatic mitral stenosis. Heart 2018; 104:1062.
  27. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:104.
  28. Karthikeyan G. Stroke risk in rheumatic heart disease. Heart 2021; 107:694.
  29. Vasconcelos M, Vasconcelos L, Ribeiro V, et al. Incidence and predictors of stroke in patients with rheumatic heart disease. Heart 2021; 107:748.
  30. SZEKELY P. SYSTEMIC EMBOLISM AND ANTICOAGULANT PROPHYLAXIS IN RHEUMATIC HEART DISEASE. Br Med J 1964; 1:1209.
  31. Karthikeyan G, Ananthakrishnan R, Devasenapathy N, et al. Transient, subclinical atrial fibrillation and risk of systemic embolism in patients with rheumatic mitral stenosis in sinus rhythm. Am J Cardiol 2014; 114:869.
  32. Boonyasirinant T, Phankinthongkum R, Komoltri C. Clinical and echocardiographic parameters and score for the left atrial thrombus formation prediction in the patients with mitral stenosis. J Med Assoc Thai 2007; 90 Suppl 2:9.
  33. Acartürk E, Usal A, Demir M, et al. Thromboembolism risk in patients with mitral stenosis. Jpn Heart J 1997; 38:669.
  34. Rittoo D, Sutherland GR, Currie P, et al. A prospective study of left atrial spontaneous echo contrast and thrombus in 100 consecutive patients referred for balloon dilation of the mitral valve. J Am Soc Echocardiogr 1994; 7:516.
  35. Goswami KC, Yadav R, Bahl VK. Predictors of left atrial appendage clot: a transesophageal echocardiographic study of left atrial appendage function in patients with severe mitral stenosis. Indian Heart J 2004; 56:628.
  36. Manjunath CN, Srinivasa KH, Panneerselvam A, et al. Incidence and predictors of left atrial thrombus in patients with rheumatic mitral stenosis and sinus rhythm: a transesophageal echocardiographic study. Echocardiography 2011; 28:457.
  37. Connolly SJ, Karthikeyan G, Ntsekhe M, et al. Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation. N Engl J Med 2022; 387:978.
  38. Antonini-Canterin F, Moura LM, Enache R, et al. Effect of hydroxymethylglutaryl coenzyme-a reductase inhibitors on the long-term progression of rheumatic mitral valve disease. Circulation 2010; 121:2130.
  39. Ellis LB, Singh JB, Morales DD, Harken DE. Fifteen-to twenty-year study of one thousand patients undergoing closed mitral valvuloplasty. Circulation 1973; 48:357.
  40. Orrange SE, Kawanishi DT, Lopez BM, et al. Actuarial outcome after catheter balloon commissurotomy in patients with mitral stenosis. Circulation 1997; 95:382.
  41. Hart SA, Krasuski RA, Wang A, et al. Pulmonary hypertension and elevated transpulmonary gradient in patients with mitral stenosis. J Heart Valve Dis 2010; 19:708.
  42. Fawzy ME, Hassan W, Stefadouros M, et al. Prevalence and fate of severe pulmonary hypertension in 559 consecutive patients with severe rheumatic mitral stenosis undergoing mitral balloon valvotomy. J Heart Valve Dis 2004; 13:942.
  43. Fawzy ME, Osman A, Nambiar V, et al. Immediate and long-term results of mitral balloon valvuloplasty in patients with severe pulmonary hypertension. J Heart Valve Dis 2008; 17:485.
  44. Yang B, DeBenedictus C, Watt T, et al. The impact of concomitant pulmonary hypertension on early and late outcomes following surgery for mitral stenosis. J Thorac Cardiovasc Surg 2016; 152:394.
  45. Maeder MT, Weber L, Buser M, et al. Pulmonary Hypertension in Aortic and Mitral Valve Disease. Front Cardiovasc Med 2018; 5:40.
  46. Singh AD, Mian A, Devasenapathy N, et al. Percutaneous mitral commissurotomy versus surgical commissurotomy for rheumatic mitral stenosis: a systematic review and meta-analysis of randomised controlled trials. Heart 2020; 106:1094.
  47. Usta E, Erdim R, Görmez S, et al. Comparison of early and long-term follow-up results of percutaneous mitral balloon valvuloplasty and mitral valve replacement. Rev Assoc Med Bras (1992) 2021; 67:58.
  48. Song H, Kang DH, Kim JH, et al. Percutaneous mitral valvuloplasty versus surgical treatment in mitral stenosis with severe tricuspid regurgitation. Circulation 2007; 116:I246.
Topic 8139 Version 33.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟