Mitral Stenosis, Acquired

 

INTRODUCTION

Background: Acquired mitral valve stenosis (MS) is virtually synonymous with rheumatic heart disease. Rheumatic fever occurs, in genetically susceptible individuals, as a complication of group A streptococcal infection. Other rare causes of acquired MS include carcinoid causes, systemic lupus erythematosus, rheumatoid arthritis, and some mucopolysaccharidoses. The underlying pathological process is a diffuse inflammation of connective tissue. All group A streptococcal infections do not lead to rheumatic fever. Studies demonstrate that rheumatic fever follows infection of the upper respiratory tract and rarely, if ever, follows skin infection. Similarly, not all cases of streptococcal pharyngitis lead to rheumatic fever. In fact, only 2-3% of patients with untreated group A streptococcal pharyngitis develop this complication. Appropriate treatment of streptococcal pharyngitis prevents rheumatic fever.

Rheumatic heart disease primarily affects the mitral valve with mitral valve regurgitation (MR) as the initial hemodynamic consequence. Lesions of the mitral valve begin as deposits of fibrin and red blood cells that form small verrucae along the borders of the mitral valve leaflets. When the inflammation subsides, the verrucae are replaced by fibrous tissue. Over at least several years, the individual may then develop fibrosis of the mitral ring; contracture of the mitral leaflets, chordae tendineae, and papillary muscles; and commisural adhesions resulting in valve stenosis. Rheumatic heart disease, therefore, is a lifelong, and sometimes progressive, disease.

Definition

Mitral valve stenosis results from a pathologic process that narrows the effective mitral valve orifice. Proper function of the mitral valve requires an intact mitral valve apparatus and satisfactory left ventricle (LV) function.

Anatomy

The mitral valve is the inlet valve to the LV. The normal mitral valve is a complex apparatus composed of an annulus and two leaflets that are attached by chordae tendineae to two papillary muscles. The papillary muscles arise from the walls of the left ventricle and secure the chordae and mitral leaflets, preventing prolapse of the valve during ventricular systole.

Anatomy of subtypes

Mitral valve stenosis, such as in rheumatic fever, occurs because of fibrous scarring of the valve leaflets with subsequent calcification thereby decreasing size of the effective valve orifice. Subvalvular and supravalvular MS are congenital anomalies (see Mitral Stenosis, Congenital).

 

Pathophysiology: The normal adult mitral valve orifice cross-sectional area is 4-6 cm2. When reduced to 2 cm2, hemodynamically significant MS occurs. At 1 cm2 obstruction to blood flow into the LV becomes critical because a left atrial mean pressure of 25 mm Hg is necessary to maintain normal cardiac output. Elevated left atrial pressure is transmitted to the pulmonary veins and pulmonary capillaries. Congested bronchial veins encroach on small bronchioles and cause subsequent increase in airway resistance. In addition, elevated hydrostatic pressure in the capillaries forces fluid into the alveoli and interstitial space, producing pulmonary congestion.

As a compensating mechanism, pulmonary vasoconstriction develops, causing pulmonary hypertension. At this stage, the right ventricle (RV) faces an increased afterload, leading to RV hypertrophy. Over time, fixed pulmonary arterial hypertension may develop from medial hypertrophy and intimal thickening of the pulmonary arterioles. RV myocardial dysfunction may develop, resulting in tricuspid valve regurgitation. Severe MS results in decreased cardiac output. If reduction in cardiac output is critical, end organ failure with renal and/or hepatic insufficiency, shock, and metabolic acidosis can occur. In addition, RV failure provokes systemic venous congestion with development of hepatomegaly, ascites, and pedal edema.

Natural history

Patients may remain asymptomatic for many years as long as MS is mild and not accompanied by more than mild mitral regurgitation. These patients, of course, are susceptible to further damage to the mitral valve with repeated group A streptococcal pharyngitis. For this reason, ongoing antibiotic prophylaxis is recommended.

By the second or third decade of life, calcium deposits further constrict the effective mitral orifice of the already damaged mitral valve. Once the effective valvular orifice decreases significantly, symptoms occur.

In developing countries, rheumatic MS manifests 10-30 years after the initial rheumatic insult to the mitral valve. In developed countries, this latent period may be as long as 50 years.

 

Frequency:

  • In the US: Acquired MS is exceedingly rare in the pediatric population in the United States. Acquired MS secondary to rheumatic fever remains the most common cause of MS that occurs in adulthood. Current estimates indicate that the incidence of rheumatic fever in the United States is less than 1 per 100,000 population. A steady decline has been observed in the incidence of rheumatic fever and, thus, in acquired MS.
  • Internationally: In some developing countries, such as India, the incidence of rheumatic fever is 100-150 per 100,000 population. Following development of rheumatic heart disease, evidence of MS may develop as early as the teenage years, presumably because of a more aggressive initial attack and/or recurrent bouts of rheumatic fever (consequences of suboptimal or absent antibiotic prophylaxis). In some developing countries, the prevalence of rheumatic heart disease in children is 5-15 per 1000 population.

Mortality/Morbidity: If symptoms are absent or minimal, the overall 10-year survival rate of untreated patients with MS is 80%.

  • Once symptoms develop, the mortality risk and disease progression increase substantially. In an unselected group of patients with MS of varying severity, 60% were alive after 10 years.
  • A significant risk of arterial embolization exists in patients with atrial fibrillation.
  • If congestive heart failure (CHF) develops, the prognosis is grim, with a 10-year survival rate of 15%.

Race: Genetic predisposition plays a significant role in occurrence of rheumatic fever after group A streptococcal infection. Family studies suggest that susceptibility to the disease involves a single recessive gene.

Sex: Rheumatic fever affects both sexes equally. However, in those who acquire rheumatic heart disease, MS is more common in women. Reasons for this are unknown.

Age: Rheumatic fever is a disease of childhood, its incidence paralleling that of streptococcal pharyngitis. MS usually arises in persons older than 15-20 years because the disease progresses to that stage over many years. This time interval is significantly shorter in developing countries.

CLINICAL

History: Patients with mild MS may deny all symptoms. They may provide a history consistent with acute rheumatic fever, although in a given patient an inverse relationship between the severity of rheumatic heart disease and the severity of rheumatic arthritis tends to exist.

The most prominent symptom of severe MS is dyspnea. This results from pulmonary congestion. Such patients may also experience orthopnea as well as significant exercise limitation.

MS due to rheumatic heart disease rarely occurs in childhood in the United States. When it does occur, the history generally reveals the insidious onset of exercise limitation. These patients may present with the following signs:

  • Pulmonary congestion is evidenced by increasing severity of dyspnea (depending on degree of MS) ranging from dyspnea only during exercise to paroxysmal nocturnal dyspnea, orthopnea, or even symptoms related to frank pulmonary edema.
  • Dyspnea may be precipitated or worsened by an increase in blood flow across the stenotic mitral valve (eg, pregnancy, exercise) or a reduction in diastolic filling time because of increased heart rate (eg, emotional stress, fever, respiratory infection, atrial fibrillation with rapid ventricular rate).
  • Signs of right heart failure, including peripheral edema and fatigue, may appear late.
  • Approximately 30-40% of patients with MS eventually develop atrial fibrillation. This occurs rarely in the pediatric age group. Atrial fibrillation may cause the following:
    • Loss of the atrial kick to LV filling may further diminish cardiac output.
    • Thromboembolic events occur in 10-20% of patients with MS. Approximately 75% of these emboli cause stroke.
    • Infective endocarditis should be suspected if embolization occurs during sinus rhythm.
  • Hemoptysis may be caused by rupture of dilated bronchial veins, and pink frothy sputum may be a manifestation of pulmonary edema. Both are associated with endstage and severe MS.
  • Chest pain, possibly related to RV hypertension, occurs in approximately 15% of patients with MS.
  • Rarely, dysphagia may occur from compression of the esophagus by an enlarged left atrium. Hoarseness may occur if the enlarged left atrium impinges on the recurrent laryngeal nerve.

Physical: Physical examination findings vary according to the severity of MS.

  • Mild-to-moderate MS
    • Normal peripheral pulses and good perfusion
    • Loud S1 because of abrupt closure of a stenotic, but still pliable, mitral valve
    • Long A2 to opening snap interval: In mild MS, left atrial pressure is mildly increased. As a result, the mitral valve opens at a more normal interval after closure of the aortic valve (A2).
    • Diastolic murmur: The diastolic murmur of MS begins at the time of mitral valve opening and accentuates following atrial contraction (presystolic accentuation) as long as the patient is in sinus rhythm. The murmur is low frequency and rumbling in quality. In mild MS, the mid diastolic murmur may be difficult to hear. As MS becomes more severe, murmur duration increases and, to some extent, intensity increases also.
    • No third heart sound
    • Pulmonic component of S2: The pulmonic component of the second heart sound increases in intensity in direct proportion to elevation of left atrial (and consequently pulmonary artery) pressure. Similarly, the A2-P2 splitting interval narrows as pulmonary artery pressure increases.
  • Severe MS
    • Diminished peripheral perfusion and pulses because of decreased cardiac output
    • Palpation of an RV impulse (enlarged RV) because of pulmonary hypertension
    • Soft S1 because of decreased mobility of the mitral leaflets as they become more thickened and/or calcified: Decreased cardiac output with severe stenosis also decreases intensity of the S1, particularly with faster heart rate.
    • Shorter A2 to opening snap interval: As left atrial pressure increases, the mitral valve opens earlier in relation to aortic valve closure (S2).
    • Diastolic rumble: A long low-frequency diastolic rumble with presystolic accentuation is best heard at the apex. Murmur intensity decreases as cardiac output decreases.
    • Increased intensity of pulmonic component of S2 (P2) secondary to pulmonary hypertension
    • RV S3 or RV S4: RV S3 or RV S4 may occur; however, an RV S3 is rare in the presence of tricuspid valve regurgitation.
    • Systolic murmur: A systolic murmur of tricuspid regurgitation may occur as right ventricular function deteriorates. This murmur is best heard at the lower left sternal edge. It accentuates with inspiration.
    • Diastolic murmur: A high-frequency early diastolic murmur of pulmonic valve regurgitation may be heard immediately following an accentuated P2. Eponymously called the Graham Steell murmur, this finding reflects severe pulmonary hypertension.

Causes:

  • Epidemiology: Acute rheumatic fever is an immunologic disease occurring in 0.3-3% of patients as a complication of group A streptococcal infection of the pharynx. It is very rarely observed after group A streptococcal infection of the skin.
  • Inheritance: A distinct genetic susceptibility to rheumatic fever exists, with studies suggesting a single recessive gene. Other studies identified an allotypic marker on B lymphocytes, present in almost all patients with rheumatic fever but only a small proportion of healthy controls. Investigations also revealed a significantly higher percentage of certain human leukocyte antigens (HLA) in patients with rheumatic fever than in controls.
  • Risk factors: Family history of rheumatic fever is a risk factor and is consistent with genetic factors. Poverty, poor hygiene, and medical deprivation are predisposing factors for rheumatic fever, probably because they identify a population less likely to obtain proper treatment of streptococcal pharyngitis.
  • Acquired MS: Acquired MS results from long-term damage to the mitral valve and its supporting structures.
    • In rheumatic heart disease, autoimmune responses occur secondary to beta-hemolytic streptococci group A antigens. Damage to the heart is postulated to result from antiheart antibodies (eg, gamma-globulins, complement C3). An initial pancarditis, which involves the pericardium, epicardium, myocardium, and endocardium, may result in long-term changes with damage along the free edges of a heart valve with deposition of platelets that result in inflammation with subsequent fibrosis and, finally, contracture of the valve leaflets. If inflammation is severe, cusps are damaged and valvar insufficiency ensues. The mitral and aortic valves are the most commonly affected.
    • Systemic lupus erythematosus may induce pericarditis, myocarditis, and endocarditis (ie, Libman-Sacks endocarditis), which consists of verrucous vegetations on the valves composed of proliferating and degenerating cells, fibrin, and occasional hematoxylin body deposits. The most commonly affected valve is the mitral valve, but these lesions rarely cause either insufficiency or stenosis.
    • Amyloidosis, rare in childhood, is secondary to an underlying inflammatory process. Extracellular deposits of insoluble proteins (amyloid) in the myocardium, pericardium, and conducting tissue produce a restrictive or hypertrophic cardiomyopathy. When amyloid deposits in the valves, insufficiency and/or stenosis can ensue.
    • Postsurgical acquired MS, such as MS occurring after mitral valve annuloplasty for severe mitral valve regurgitation, is caused by fibrosis along the annulus. These patients may require mitral valve replacement with a prosthetic mitral valve if MS is severe enough to cause symptoms (eg, pulmonary edema). Improper repair of the cleft mitral valve in an endocardial cushion defect can also result in mitral stenosis.

DIFFERENTIALS

Cor Triatriatum
Mitral Stenosis, Congenital
Mitral Stenosis, Supravalvular Ring
Pulmonary Hypertension, Primary


Other Problems to be Considered:

Atrial myxoma


WORKUP

Lab Studies:

  • Rheumatic heart disease - Nonspecific, unless the patient is experiencing an acute attack of recurrent rheumatic fever, in which case, C-reactive protein, sedimentation rate, and antistreptolysin O (ASLO) antibodies are evident.
  • Chronic rheumatic mitral valve disease - Persistence of elevated levels of antibody to the streptococcal group A carbohydrate has been found in the majority of patients with chronic rheumatic mitral valve disease.
  • Systemic lupus erythematosus - Antinuclear antibodies, antibodies to double stranded DNA, and lupus erythematosus (LE) cells
  • Amyloidosis - Amyloid deposits in affected tissues

Imaging Studies:

  • Chest radiography
    • Left atrial enlargement
    • Pulmonic trunk and right ventricular and right atrial enlargement
    • Pulmonary venous congestion results in redistribution of pulmonary blood flow with greater flow to the upper lobes. Interstitial edema is manifested by Kerley B lines
  • Echocardiography, both transthoracic and transesophageal, are the most important diagnostic tools for evaluating patients with MS. Echocardiography provides the following:
    • Direct anatomic data including visualization of valve leaflet morphology and motility and measurement of valve orifice dimensions, as well as the degree of left atrial dilation
    • Hemodynamic and physiologic data including the pressure gradient across the stenotic mitral valve, the presence and severity of mitral regurgitation, and the degree of pulmonary hypertension
    • Transesophageal echocardiography is recommended when transthoracic examination is incomplete, especially if left atrial thrombus is suspected. It is also used in the operating room and catheterization laboratory to assess the effectiveness of intervention.
  • Magnetic resonance imaging is used infrequently. However, experience with this imaging modality is much less than with echocardiography.

Other Tests:

  • The findings on electrocardiogram (ECG) are often normal in patients with mild MS. In those with moderate-to-severe MS, it demonstrates left atrial enlargement, right ventricular hypertrophy, and, often, right atrial enlargement. It also identifies atrial dysrhythmia.

Procedures:

  • Cardiac catheterization can be used to obtain direct measurement of the pressure gradient across the mitral valve as well as pulmonary artery pressure and pulmonary vascular resistance. The mitral valve area can be calculated using the Gorlin formula. Currently, the diagnosis and hemodynamic assessment of patients with MS is performed noninvasively with echocardiography. Cardiac catheterization may be needed to supplement the information obtained noninvasively. More commonly, it is undertaken to perform percutaneous balloon valvuloplasty.
    • Possible complications of cardiac catheterization include tachyarrhythmias, bradyarrhythmias, and vascular occlusion. Balloon valvuloplasty may result in significant mitral regurgitation.
    • Postcatheterization complications include hemorrhage, pain, nausea and vomiting, and arterial or venous obstruction from thrombosis or spasm.
Histologic Findings: Cardiac involvement in rheumatic fever is characterized by inflammation of the endocardium and myocardium. Histologic changes are not observed during the early stage of myocarditis but become evident at later stages of the inflammatory process. The changes include edema of the tissue and a cellular infiltrate consisting of lymphocytes and plasma cells but few polymorphonuclear white blood cells.

Endocardial inflammation of the mitral valve produces essentially the same histologic changes observed in myocarditis.

 

TREATMENT

Medical Care:

  • Asymptomatic patients with mild MS require yearly follow-up care to monitor for disease progression. Yearly evaluation should include physical examination, chest radiography, and echocardiography.
  • For the patient with signs or symptoms of CHF, diuretics may provide benefit.
  • Tachyarrhythmias, such as atrial flutter and atrial fibrillation, usually require medical treatment aimed at restoration and maintenance of sinus rhythm. If this is not possible, therapy may be aimed at decreasing ventricular response and maintaining an acceptable heart rate.
    • Digoxin, beta-blockers, and calcium channel blockers have all been used to slow atrioventricular (AV) node conduction and decrease ventricular rate response.

       

    • Antiarrhythmics from class I (eg, procainamide, flecainide, propafenone) and class III (eg, sotalol, amiodarone) have been used with variable success in converting to and maintaining sinus rhythm.

       

    • Thromboembolic complication from chronic atrial arrhythmia can be reduced with anticoagulation using warfarin.
  • Electrophysiologic ablation of atrial fibrillation or flutter circuits may be performed in the catheterization laboratory.
  • Percutaneous mitral balloon valvuloplasty for acquired MS was first described in 1984 and approved by the US Food and Drug Administration in 1994. Indications for this procedure are similar to those for surgery, including CHF unresponsive to medical management and in asymptomatic patients with a pulmonary artery (PA) systolic pressure of 50 mm Hg or greater. In some centers, the procedure is successful in 80-90% of selected cases. The procedural mortality rate is 1-2%.

Surgical Care: Surgical intervention is necessary when intervention is indicated and the valve is not amenable to balloon valvuloplasty.

  • Mitral valvotomy
    • Commissurotomy consists of an incision of fused mitral valve commissures and shaving of thickened mitral valve leaflets.
    • Fused chordae tendineae and papillary muscles can be divided to relieve subvalvular stenosis.
    • Supravalvular tissue contributing to the MS should be resected.
  • Mitral valve replacement with mechanical valve or bioprosthesis
    • This is reserved for patients in whom mitral valvotomy is considered unlikely to achieve a satisfactory result. Mechanical mitral valve replacement is performed frequently in adolescents and adults in whom anticoagulation with warfarin (Coumadin) is not contraindicated. In older patients in whom warfarin therapy may be relatively contraindicated or in patients who have other contraindications to warfarin therapy, mitral valve replacement can be performed using a bioprosthesis, although these are less durable than a mechanical prosthesis.
    • Weigh the risk of warfarin therapy against that of bioprosthetic valve deterioration resulting in the need for reoperation. Warfarin is contraindicated during pregnancy.
    • Complications after mitral valve replacement include anticoagulation-related complications, valve thrombosis, valve dehiscence, infective endocarditis, valve malfunction, and embolic events.

Consultations: Consult a cardiologist and a cardiothoracic surgeon.

Diet: Salt intake should be restricted and excessive fluid intake minimized to avoid exacerbating signs and symptoms of CHF.

Activity: Patients with more than mild MS should avoid strenuous exertion. Increased heart rate may result in decreased diastolic filling, thereby decreasing cardiac output. Coexistent atrial arrhythmias result in loss of atrial augmentation of LV filling and may further impair cardiac output.

MEDICATION

Medical therapy is directed at alleviating symptoms, treating rhythm abnormalities, and preventing thromboembolic complications.

Drug Category: Diuretics -- Promote excretion of water and electrolytes by the kidneys. Diuretics are administered to decrease fluid overload and pulmonary congestion.
Drug Name
 Furosemide (Lasix) -- Acts by inhibiting absorption of sodium and chloride in proximal and distal tubules and in the loop of Henle, thereby promoting excretion of sodium chloride and water. Acts as a diuretic and antihypertensive.
Adult Dose 20-80 mg/d PO/IV divided q6-12h; not to exceed 600 mg/d
Pediatric Dose 0.5-2 mg/kg per dose PO/IV/IM q8-24h; not to exceed 6 mg/kg/d
Contraindications Documented hypersensitivity; hepatic coma; anuria; severe electrolyte depletion
Interactions May increase ototoxicity of aminoglycosides; may be ototoxic if used with ethacrynic acid; salicylate toxicity in patients receiving high doses of these concomitantly; decreases lithium renal clearance with subsequent increase in lithium toxicity; potentiation of antihypertensive drugs (eg, ganglionic or peripheral adrenergic blockers); simultaneous sucralfate or indomethacin administration may reduce natriuretic and antihypertensive effects of furosemide
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Severely oliguric patients may be ototoxic; may precipitate gout (rare); excessive diuresis in MS may compromise cardiac output by reducing preload; also may precipitate circulatory collapse with thromboembolism; may cause electrolyte imbalance (hypokalemic-hypochloremic metabolic alkalosis, hyponatremia, hypomagnesemia, hypocalcemia); caution in hepatic disease; prolonged use in premature infants may result in nephrocalcinosis; alterations in glucose tolerance test results and precipitation of diabetes mellitus (rare) have occurred
Drug Category: Potassium-sparing diuretics -- Used to prevent potassium depletion induced by more potent loop-diuretics (eg, furosemide).
Drug Name
 Spironolactone (Aldactone) -- Used to decrease edema resulting from excessive aldosterone excretion. Inhibits aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule, thereby retaining potassium and excreting sodium and water. Serves as a diuretic and antihypertensive agent.
Adult Dose 25-100 mg/d PO divided bid/qid; not to exceed 200 mg/d
Pediatric Dose 1-3.3 mg/kg/d PO divided bid/qid; not to exceed 200 mg/d
Contraindications Documented hypersensitivity; anuria; renal failure; hyperkalemia
Interactions May potentiate ganglionic-blocking agents; may potentiate antihypertensive drugs; may induce severe hyperkalemia when administered with ACE inhibitors or indomethacin; increases digoxin half-life, increasing risk of developing digitalis toxicity; potassium and potassium-sparing diuretics may increase toxicity of spironolactone; may decrease effect of anticoagulants
Pregnancy D - Unsafe in pregnancy
Precautions Caution in renal and hepatic impairment; may cause hyperkalemia, especially when administered with ACE inhibitors; GI distress, rash, and gynecomastia have been reported with its use; may cause transient elevation of BUN, especially if preexisting renal impairment; may cause mild metabolic acidosis; few cases of agranulocytosis have been reported; tumorigenic in rats when administered in excess
Drug Category: Inotropic-antiarrhythmic agents -- Mainly used in MS in atrial flutter or fibrillation because of its antiarrhythmic properties. Digoxin is not expected to improve overall cardiac function because, in MS patients, heart failure is from mechanical obstruction causing elevated left atrial pressure, with subsequent transmission to RV and, ultimately, failure. Theoretically, digoxin could aid in improving RV dysfunction.
Drug Name
 Digoxin (Lanoxin) -- Digitalis glycoside that inhibits sodium-potassium ATPase (enzyme that extrudes sodium and brings potassium into myocyte). Resulting increase in intracellular sodium stimulates sodium-calcium exchange, extruding sodium and bringing in calcium with consequent increase in myocyte contractility. It exerts vagomimetic action on sinus and AV nodes (slowing heart rate and conduction). Also, decreases degree of activation of sympathetic nervous system and renin-angiotensin system, which is referred to as the deactivating effect. Therapeutic serum level range is 0.8-2 ng/mL.
Adult Dose Digitalizing dose:
10-15 mcg/kg/d (approximately 0.75-1.5 mg/d) PO
8-12 mcg/kg/d (approximately 0.5-1 mg/d) IV/IM
Maintenance dose:
2.5-5 mcg/kg/d (approximately 0.125-0.5 mg/d PO) PO
2-3 mcg/kg/d (approximately 0.1-0.4 mg/d) IV/IM qd
May accomplish digitalization by administering one half of total digitalizing dose (TDD) in first dose, followed by 2 doses that are one fourth TDD administered at 8- to 12-h intervals
Pediatric Dose Infants:
Digitalizing dose: 30 mcg/kg/d PO; 20 mcg/kg/d IV/IM
Maintenance dose: 8-10 mcg/kg/d PO; 6-8 mcg/kg/d IV/IM divided bid
<2 years:
Digitalizing dose: 40-50 mcg/kg/d PO; 30-40 mcg/kg/d IV/IM
Maintenance dose: 10-12 mcg/kg/d PO; 7.5-9 mcg/kg/d IV/IM divided bid
2-10 years:
Digitalizing dose: 30-40 mcg/kg/d PO; 20-30 mcg/kg/d IV/IM
Maintenance dose: 8-10 mcg/kg/d PO; 6-8 mcg/kg/d IV/IM divided bid
May accomplish digitalization by administering one half of TDD in first dose, followed by 2 doses that are one fourth TDD administered at 8- to 12-h intervals
Contraindications Documented hypersensitivity; ventricular fibrillation; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome
Interactions Potassium-depleting diuretics predispose to digitalis toxicity; calcium IV administered rapidly predisposes to serious arrhythmias; serum levels of digoxin are raised by quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, spironolactone, erythromycin, clarithromycin, and tetracyclines; serum levels of digoxin are decreased by rifampin
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May cause anorexia, nausea, emesis, and diarrhea; may cause blurred vision, headaches, dizziness, confusion, anxiety, depression, and hallucinations; gynecomastia occasionally occurs after prolonged use; in case of sinus node disease and in AV block, may cause severe bradycardia, sinoatrial block, or complete heart block; in WPW during atrial fibrillation or flutter, may cause ventricular fibrillation by increasing antegrade conduction through accessory pathway (bypassing AV node); may provoke ventricular fibrillation in patients treated with digoxin, cardioversion, or calcium infusion (prevented by pretreatment with lidocaine); may reach toxic levels in patients with impaired renal function because digoxin is excreted through kidneys; hypokalemia, hypomagnesemia, or hypercalcemia may increase risk of toxicity (despite levels <2 ng/mL) because of hypersensitization of myocardium to digoxin
Drug Category: Class II antiarrhythmic agents (beta-blockers) -- Used for atrial flutter or fibrillation. Beta-adrenergic receptor blocking agents are used as a second option when digoxin does not stop atrial flutter or fibrillation.
Drug Name
 Propranolol (Inderal) -- By blocking the beta-adrenergic receptor, these compounds blunt chronotropic, inotropic, and vasodilator responses of any beta-adrenergic stimulation. Beta-blockers lower ventricular rate; therefore, they are used in patients with atrial flutter or fibrillation.
Adult Dose Emergent control: 1 mg per dose IV; may repeat q5min; not to exceed a cumulative dose of 5 mg
Maintenance: 40-320 mg/d PO divided tid/qid
Pediatric Dose Emergent control: 0.01-0.15 mg/kg per dose IV infused over 10 min; not to exceed 1 mg per dose
Maintenance: 2-4 mg/kg/d PO divided tid/qid; not to exceed 16 mg/kg/d
Contraindications Documented hypersensitivity; uncompensated congestive heart failure; bradycardia; cardiogenic shock; AV conduction abnormalities
Interactions Increases effects of reserpine and calcium channel blockers; NSAIDs may blunt effects; aluminum hydroxide gel reduces intestinal absorption; ethanol slows rate of absorption; phenytoin and rifampin accelerate clearance
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in impaired hepatic or renal function; not indicated to treat hypertensive emergencies; risk of anaphylactic reaction unresponsive to usual doses of epinephrine in susceptible individuals; in IDDM, may prevent appearance of certain premonitory signs and symptoms of hypoglycemia (eg, increased heart rate and pressure changes); in thyrotoxicosis, may mask certain signs of hyperthyroidism, with exacerbation of symptoms of hyperthyroidism after withdrawal of propranolol; may produce hypotension, syncope, bronchospasm, nausea, emesis, hypoglycemia, lethargy or depression, or heart block
Drug Name
 Esmolol (Brevibloc) -- Selective beta1 (cardioselective)–adrenergic receptor blocking agent; may be used with class I antiarrhythmics if digoxin therapy does not abort atrial arrhythmia. Administer in patients needing prompt slowing of ventricular rate in response to atrial flutter or fibrillation and who are most likely to become hemodynamically unstable if left without treatment or in those waiting for the start of the therapeutic effects of digoxin (average, 10 h).
Has rapid onset and short duration of action. Administered IV to stop atrial arrhythmia; afterward, patient is placed on class I antiarrhythmics for maintenance.
Adult Dose Loading dose: 100-500 mcg/kg IV infused over 1 min
Maintenance dose: 25-200 mcg/kg/min IV continuous infusion (gradually titrated upward in increments of 25-50 mcg/kg/min q5-10min); not to exceed 300 mg/kg/min because safety of higher dosages is unknown
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; uncompensated CHF; bradycardia; cardiogenic shock; AV conduction abnormalities; second- or third-degree heart block
Interactions Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effect; cardiotoxicity may increase when administered concurrently with sparfloxacin, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; toxicity increases when administered concurrently with flecainide, acetaminophen, clonidine, epinephrine, nifedipine, prazosin, haloperidol, phenothiazines, and catecholamine-depleting agents; may increase digoxin level by 10-20%; morphine may increase level by 45%
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Beta-adrenergic blockers may mask signs and symptoms of acute hypoglycemia and clinical signs of hyperthyroidism; symptoms of hyperthyroidism, including thyroid storm may worsen when medication is abruptly withdrawn; withdraw drug slowly and monitor patient closely; administer only in monitored settings; may cause bronchospasm, wheezing, dyspnea, CHF, marked hypotension, bradycardia, nausea, emesis, dizziness, confusion, somnolence, seizures (occur in >1% of patients), asthenia, and depression
Drug Category: Class IA antiarrhythmics -- Used to stop atrial fibrillation and convert it into sinus rhythm. Also, can decrease myocardial excitability.
Drug Name
 Procainamide (Pronestyl) -- Increases effective refractory period by reducing conduction velocity of fibers of the atria and, to a lesser extent, the ERP of His-Purkinje and ventricles. Thus, decreases myocardial excitability and may speed AV node conduction (vagolytic effect). Therapeutic serum level range is 4-10 mg/L.
Adult Dose Loading dose:
50-100 mg per dose IV
250-500 mg (immediate release) per dose PO q3-6h; not to exceed 1000 mg per dose
Maintenance dose:
1-6 mg/min IV continuous infusion
2-4 g/d PO
Pediatric Dose Loading dose: 2-6 mg/kg per dose IV over 5 min; not to exceed 100 mg per dose
Maintenance dose:
20-80 mcg/kg/min IV continuous infusion; not to exceed 2 g/d
20-30 mg/kg/d IM divided q4-6h; not to exceed 4 g/d
Contraindications Documented hypersensitivity; SLE (may aggravate symptoms in myasthenia gravis, ie, worsening of symptoms); first-degree heart block; complete heart block (may cause asystole in torsade de pointes); decreasing cardiac contractility (may worsen CHF); renal failure
Interactions Can expect increased levels of procainamide metabolite NAPA in patients taking cimetidine, ranitidine, beta-blockers, amiodarone, trimethoprim, and quinidine; procainamide may increase effect of skeletal muscle relaxants, quinidine, lidocaine, and neuromuscular blockers; ofloxacin inhibits tubular secretion of procainamide and may increase bioavailability; when taken concurrently with sparfloxacin, may increase risk of cardiotoxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May cause hypotension, lupuslike syndrome, hemolytic anemia, thrombocytopenia, neutropenia, arrhythmias, anorexia, nausea, emesis, confusion, dizziness, depression, psychosis, and elevated liver enzymes; QRS widening >0.02 seconds (20 ms) suggests toxicity
Drug Category: Class IC antiarrhythmics -- Used after digoxin and/or beta-blockers that have not converted atrial arrhythmia.
Drug Name
 Propafenone (Rythmol) -- Class IC antiarrhythmic drug that exerts local anesthetic effects and has direct stabilizing action on myocardial cell membrane. Reduces upstroke velocity (phase 0) of action potential by reducing rapid inward current carried by sodium ions. It prolongs effective refractory period and reduces spontaneous automaticity. Prolongs AV node conduction and does not affect sinus node.
Adult Dose Initial: 150 mg PO tid; not to exceed 450 mg/d
Maintenance: May increase q3-4d to 225 mg PO tid; not to exceed 675 mg/d; if necessary, may increase up to 300 mg PO tid; not to exceed 900 mg/d
Pediatric Dose Not established (limited data exist); 200-300 mg/m2/d PO divided tid/qid; may increase q2-3d; not to exceed 600 mg/m2/d
Contraindications Documented hypersensitivity; bronchospastic disorders; conduction disorders; bradycardia; uncontrolled heart failure
Interactions Rifampin may decrease plasma levels; quinidine may increase pharmacologic effects; propafenone may increase plasma levels of beta-blockers, cyclosporine, warfarin, and digoxin; CYP4502D6 inhibitors (ritonavir, cimetidine, quinidine, beta-blockers, amiodarone) may increase serum levels and cardiotoxicity of propafenone
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May provoke new arrhythmias or may worsen existing arrhythmias (from increased frequency of PVCs to ventricular fibrillation); may cause bronchospasm; may worsen CHF; may alter sensing and pacing thresholds of artificial pacemakers; agranulocytosis; may impair spermatogenesis; may exacerbate myasthenia gravis
Drug Category: Class III antiarrhythmics -- Decrease rate of sinus node and relax vascular smooth muscle, with concomitant reduction in peripheral vascular resistance (afterload). Also, may exert a mild negative inotropic effect.
Drug Name
 Amiodarone (Cordarone) -- Prolongs duration of myocyte action potential, prolongs myocyte refractory period, and exerts alpha- and beta-adrenergic inhibition. Therapeutic serum level ranges from 0.5-2.5 mg/L.
Adult Dose Loading dose: 800-1600 mg PO qd for 1-3 wk
Maintenance dose: 600-800 mg PO qd for 1 mo, then 200-400 mg PO qd
Pediatric Dose <1 year: 600-800 mg/1.73 m2/d PO divided q12-24h for 7-14 d, then 200-400 mg/1.73 m2/d
>1 year: 10-15 mg/kg/d PO for 7-14 d, then 5 mg/kg/d PO qd or divided bid
Contraindications Documented hypersensitivity; complete AV block; intraventricular conduction defects; concurrent use of ritonavir or sparfloxacin
Interactions Increases effect and blood levels of theophylline, quinidine, procainamide, phenytoin, methotrexate, flecainide, digoxin, cyclosporine, beta-blockers, and anticoagulants; cardiotoxicity of amiodarone is increased by ritonavir, sparfloxacin, and disopyramide; coadministration with calcium channel blockers may cause additive effect and decrease myocardial contractility further; cimetidine may increase levels
Pregnancy D - Unsafe in pregnancy
Precautions Long elimination half-life (40-55 d); asymptomatic corneal microdeposits leading to loss of vision from optic neuritis; alters liver enzymes; inhibits peripheral conversion of T4 to T3; may cause hypothyroidism or hyperthyroidism; pulmonary fibrosis has been reported in adults; may worsen preexisting arrhythmias with bradycardia and AV block; may cause anorexia, nausea, vomiting, dizziness, paresthesias, ataxia, and tremor
Drug Category: Anticoagulants -- Used to prevent clot formation secondary to blood stasis because of an enlarged (left) atrium and (left) atrial fibrillation.
Drug Name
 Warfarin (Coumadin) -- Inhibits vitamin K–dependent clotting factors II, VII, IX, and X and anticoagulant proteins C and S. Anticoagulation effect occurs 24 h after drug administration, but peak effect may happen 72-96 h later. Antidotes are vitamin K and FFP.
Adult Dose 5-15 mg PO qd for 2-5 d, adjust to desired INR or PT; 2-10 mg/d PO qd maintenance
Pediatric Dose 0.1 mg/kg/d PO qd, adjust to desired INR or PT; 0.05-0.34 mg/kg/d PO qd maintenance
Adjust dose to maintain INR of 2.5-3.5 or PT of 1.5-2 times baseline
Contraindications Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers; pregnancy (passes through the placental barrier and may cause fatal hemorrhage to fetus); malignant hypertension because of increased risk of intracranial hemorrhage; before invasive procedures (eg, spinal tap)
Interactions Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate; medications that may increase anticoagulant effects of warfarin include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac
Pregnancy X - Contraindicated in pregnancy
Precautions Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis; requires periodic determinations of PT/INR

FOLLOW-UP

Further Inpatient Care:

  • Intravenous diuretics may be used in patients with severe or refractory symptoms.
  • Oxygen administration or endotracheal intubation and mechanical ventilation may be necessary in patients with respiratory compromise due to pulmonary edema.
  • Patients with unstable tachyarrhythmias should undergo DC cardioversion. Medical cardioversion can be attempted in patients who are hemodynamically stable. Echocardiography must be accomplished prior to cardioversion in order to assess the left atrium and its appendage for thrombi.

Further Outpatient Care:

  • Follow-up visits to the pediatrician and/or generalist are needed to monitor general health status.
  • Follow-up clinical visits to the pediatric cardiologist are needed to monitor antiarrhythmic drug levels and anticoagulation drug effectiveness by measuring prothrombin time (PT) and/or international normalization ratio (INR).
  • Serial echocardiograms are indicated to monitor progression of MS. Frequency of these studies varies according to the patient's general health status and according to the cardiologist's criteria. Stress echocardiography may provide additional hemodynamic information.

In/Out Patient Meds:

  • Critically ill inpatients or those unable to receive oral medications may be treated intravenously.

Transfer:

  • Transfer patients to an intensive care unit when general status is unstable because of CHF with pulmonary edema or serious cardiac dysrhythmia. Once medically stabilized, surgical or transcatheter intervention should be considered.

Deterrence/Prevention:

  • Prophylactic antibiotics to reduce the risk of infective endocarditis in accordance with recommendations of the American Heart Association.
    • In children, administer amoxicillin 50 mg/kg PO 1 hour before the procedure (not to exceed 3 g). In adults, administer amoxicillin 2 g PO 1 hour before the procedure.
    • In high-risk patients (eg, prosthetic heart valves, previous history of endocarditis), administer ampicillin 50 mg/kg IV/IM in children and 2 g IV/IM in adults (not to exceed 2 g) plus gentamicin 1.5 mg/kg IV/IM for children and adults (not to exceed 120 mg) within 30 minutes before starting the procedure. This is followed 6 h later by amoxicillin 25 mg/kg PO in children and 1 g PO in adults (not to exceed 1.5 g) or ampicillin 25 mg/kg IV/IM in children and 1 g IV/IM in adults. High-risk patients allergic to ampicillin/amoxicillin should receive vancomycin 20 mg/kg IV in children (not to exceed 1 g) and 1 g IV in adults over 1-2 hours plus gentamicin 1.5 mg/kg IV/IM for children and adults (not to exceed 120 mg).
    • For penicillin-allergic patients, use erythromycin 20 mg/kg PO (not to exceed erythromycin ethylsuccinate 800 mg; stearate 1 g) 2 hours before the procedure, then 10 mg/kg 6 hours later. Other treatment options are clindamycin 20 mg/kg PO (not to exceed 300 mg) in children and 600 mg PO in adults 1 hour before the procedure, cephalexin or cefadroxil 50 mg/kg PO in children and 2 g PO in adults 1 hour before the procedure, and azithromycin or clarithromycin 15 mg/kg PO in children and 500 mg PO in adults 1 hour before the procedure.
  • For patients with acquired MS due to rheumatic fever, prophylaxis should be administered to prevent rheumatic fever recurrence. Penicillin G benzathine is administered at a dose of 1.2 million U IM every 3-4 weeks. Alternate regimens include penicillin V 250 mg PO bid. For penicillin-allergic patients, administer erythromycin stearate 250 mg PO bid.

Complications:

  • If MS is left untreated, the following complications may arise:
    • Pulmonary edema

       

    • Right ventricular failure

       

    • Renal insufficiency (caused by low cardiac output)

       

    • Progression to pulmonary hypertension

       

    • Atrial arrhythmias such as fibrillation or flutter

       

    • Thromboembolic complications

       

    • Dysphagia from compression of esophagus by the enlarged left atrium
  • Complications of medical treatment include the following:
    • Diuretics may provoke dehydration (decreased preload) with subsequent compromise in cardiac output. These drugs may also predispose patients to arrhythmias when administered with digoxin or class I or III antiarrhythmics because of electrolyte derangements.
    • Antiarrhythmic medications or electrolyte derangements precipitate fatal arrhythmias.
    • Warfarin may cause hemorrhagic complications.
  • Complications of surgery include the following:
    • Mitral commissurotomy may cause significant mitral regurgitation that may necessitate mitral valve replacement.

       

    • Complications of mitral valve replacement include valve thrombosis, valve dehiscence, infective endocarditis, valve malfunction, embolic events, and anticoagulation-related complications.
  • Percutaneous balloon valvuloplasty may result in significant mitral regurgitation (especially if the mitral valve is already calcified). Approximately 3% of patients require mitral valve replacement after balloon valvuloplasty. Fatality occurs in 1-2% of patients. Perforation of the ventricle occurs in 0.5-4%. Embolic events occur in 1-3%. Myocardial infarction occurs in 0.3-0.5% of patients.

Prognosis:

  • Untreated acquired MS due to rheumatic heart disease demonstrates a slowly progressive course with the patient remaining asymptomatic for years before dyspnea or sudden deterioration from atrial fibrillation ensues. The overall 10-year survival rate of untreated patients who have acquired MS is 50-60%, but the 10-year survival rate reaches 80% if the patient is asymptomatic. Once symptoms develop, prognosis worsens significantly. If the patient presents with dyspnea, the 1-year survival rate is less than 15%.
  • After percutaneous balloon valvotomy or surgical commissurotomy, the 5- to 7-year survival rate is 50-90%.
  • After surgical commissurotomy, the reoperation rate is 5-7% and the 5-year complication-free survival rate is 80-90%.
  • Mitral valve replacement entails a 5% mortality risk in young healthy patients.

Patient Education:

  • Patients and their families should be counseled regarding the appearance and/or worsening of symptoms.
  • Patients must follow American Heart Association infective endocarditis prophylaxis guidelines.
  • Monitor PT and INR if the patient is taking anticoagulation medication.
  • Patients should refrain from strenuous exercise.
  • Women should avoid taking warfarin during pregnancy. If MS is more than mild, strenuous activity and excessive salt intake are also contraindicated during pregnancy.

MISCELLANEOUS

Medical/Legal Pitfalls:

  • Failure to diagnose the primary problem
  • Failure to recognize worsening symptoms
  • Failure to recommend prophylaxis to prevent recurrent rheumatic heart disease

Special Concerns:

  • Pregnancy
    • Acquired MS, the most common valvular disease in pregnant women in developing countries, has begun to appear in the United States as a result of immigration. It often manifests for the first time during pregnancy with orthopnea, paroxysmal nocturnal dyspnea, pulmonary edema, and hemoptysis.
    • Asymptomatic or minimally symptomatic patients may only require close observation, but severely symptomatic patients may require balloon valvuloplasty or surgical commissurotomy before delivery.
    • Pregnant women requiring anticoagulation for a prosthetic mechanical mitral valve should receive heparin. Warfarin should be avoided, especially during the first and third trimesters.
    • In the event of atrial fibrillation, beta-blockers may be used. Cardioversion can be administered if necessary because it has been proven safe during pregnancy. Echocardiography must be accomplished prior to cardioversion in order to evaluate the left atrium and its appendage for thrombi.
    • Cesarean delivery or uncomplicated abdominal delivery is not an indication for antibiotic prophylaxis.