Valvular Heart Disease February 1, 2009 Henry Green, MD, FACC, FACP Aortic stenosis Left ventricular outflow tract obstruction is most common at the valve itself, but can be subvalvular or supravalvular. Valvular aortic stenosis may be congenital, rheumatic, or degenerative. Histologically its appearance resembles that of atherosclerosis, and it even shares the same risk factors (smoking, hypertension, hyperlipidemia). Commonly these patients also have coronary artery disease. Paget‟s disease and end-stage renal disease are additional risk factors. Bicuspid aortic valve predisposes to both aortic stenosis and insufficiency. There may be aortic root dilatation, coarctation, and dissecting aneurysm, even in the absence of aortic valve dysfunction. Aortic stenosis increases the load on the left ventricle, which can lead to left ventricular hypertrophy, diastolic dysfunction and increased oxygen demand. At the same time, oxygen supply is reduced due to the stenosis. Symptoms There is usually a long latent period, before symptoms develop. The disease can progress significantly, even in elderly patients. The classic symptoms are those of heart failure, syncope and angina. Physical findings One often finds a diminished and delayed carotid upstroke. This is not as reliable a finding as it was formerly thought to be. A systolic ejection murmur is heard at the upper right sternal border and is transmitted to the neck. With severe aortic stenosis, the murmur increases in duration and peaks later in systole. There may be a thrill. An atrial gallop is common. The aortic component of the second heart sound becomes softer and eventually disappears. The second heart sound may also be paradoxically split (narrow with inspiration) with severe aortic stenosis. The electrocardiogram usually shows left atrial and left ventricular hypertrophy. The chest x-ray may be normal, even with severe aortic stenosis. There may be post-stenotic dilatation of the ascending aorta. Echocardiography permits recognition of aortic stenosis and assessment of its severity, as well as its effect on left ventricular dimension and dynamics. Mild Moderate Severe Valve area >1.5 cm2 1-1.5 cm2 <1 cm2 Mean gradient <25 mm Hg 25-40 mm Hg >40 mm Hg The normal aortic valve area is 3-4 cm2

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Stress testing can be carefully performed in asymptomatic patients with aortic stenosis. This will often elicit symptoms in patients that have adapted to their disability, and deny symptoms. Furthermore, if the blood pressure drops or fails to rise during exercise, severe aortic stenosis is likely. It is contraindicated to do an exercise test on a symptomatic patient. Prognosis without treatment: Patients with angina have a 50% 5-year survival. Patients with syncope have a 50% 3-year survival. Patients with congestive heart failure have a 50% survival < 2 years. Asymptomatic patient with severe aortic stenosis require close followup, especially if the following are present: A jet velocity of over 4 meters/second Heavily calcified valve Progression of jet velocity of over 0.3 meters/second/year Mild or moderate aortic stenosis can also worsen rapidly in some patients. This is especially true if the valve is severely calcified, or if coronary artery disease is present, and in patients over the age of 50. Medical treatment Endocarditis prophylaxis is no longer routinely advised. Life style modification should be applied as indicated. However, the uses of statins to delay progression of aortic stenosis are controversial. Diuretics should be used carefully, since hypovolemia can reduce cardiac output. Likewise, nitrites and other vasodilators should be used with caution if at all. Digoxin may be helpful. Surgery Valve replacement is the only definitive therapy for aortic stenosis. Indications include: Symptomatic aortic stenosis Moderate aortic stenosis in patients undergoing coronary bypass or other cardiac operations, or surgery on the aorta. Exercise-induced hypotension on treadmill testing. Surgery is also indicated if the left ventricular ejection fraction is under 50%. Asymptomatic patients should be advised of the warning symptoms of progression, and instructed to report them promptly. Some centers operate on asymptomatic patients with severe aortic stenosis, but to justify this, they should be able to offer a surgical risk of ≤ 1%. In patients with poor left ventricular function, decision-making is difficult. The valve gradient is underestimated because of low cardiac output. There are two possibilities: 1. The ventricle may have been weakened by severe aortic stenosis 2. The ventricular dysfunction may be due to an independent cause, such as ischemic cardiomyopathy and the gradient may not be severe. In the first instance, aortic valve replacement can be beneficial, but not in the second. Low dose dobutamine stress echocardiography can be used to increase the cardiac output. If the calculated valve area increases by ≥ 0.2 cm2 and there is little change in gradient, then the stenosis is probably not severe.

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If the gradient increases with dobutamine and the stroke volume increases, a favorable surgical result is likely. If the stroke volume fails to increase by at least 20%, the outcome is poor with either medical or surgical therapy. Balloon valvuloplasty of the aortic valve is effective in congenital noncalcific aortic stenosis, but in the adult it is only used as a bridge to surgery in patients who are very ill or unstable. Percutaneous aortic valve replacement is possible in high risk patients. This has been done transvenously (requiring crossing the interatrial septum), as a retrograde arterial procedure, or by inserting the prosthesis through the left ventricle directly. Subvalvular aortic stenosis This is a congenital condition characterized by a fibromuscular membrane below the aortic valve. Supravalvular aortic stenosis This is an uncommon congenital anomaly that may be associated with hypercalcemia, elfin facies, short stature and multiple arterial stenoses (William‟s syndrome). Aortic regurgitation Acute aortic regurgitation is usually an emergency resulting in rapid hemodynamic deterioration. It can result from trauma, endocarditis, dissecting aneurysm, or prosthetic valve dysfunction. Chronic aortic regurgitation results in volume overload of the left ventricle. There are many possible causes: rheumatic fever aortic dilatation infective endocarditis annuloaortic ectasia trauma cystic medial necrosis bicuspid aortic valve hypertension myxomatous degeneration syphilitic aortitis congenital giant cell arteritis lupus Reiter‟s syndrome ankylosing spondylitis Behcet syndrome Takayasu‟s arteritis psoriatic arthritis Whipple‟s disease osteogenesis imperfecta Crohn‟s disease relapsing polychondritis drug induced valve disease Ehlers-Danlos syndrome Symptoms Chronic aortic regurgitation may be asymptomatic for many years. Eventually there can be dyspnea, orthopnea and paroxysmal nocturnal dyspnea. Angina is uncommon. Physical findings Numerous signs related to increased pulse pressure have been described: Water hammer (Corrigan‟s) pulse DeMusset‟s sign: head bobbing with each heartbeat Muller‟s sign: pulsation of uvula Quincke‟s sign: capillary pulsations visible in lunula of nailbed

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A diastolic decrescendo murmur is characteristically heard at the left sternal border, usually best with the patient sitting, leaning forward, with the breath held in expiration. The duration of the murmur tends to correlate with the severity of the lesion. Uncommonly, the murmur radiates to the right sternal border. This is often indicative of one of the following causes: Aortic aneurysm (syphilitic, idiopathic, or cystic medionecrosis) Sinus of Valsalva aneurysm Aortic dissection Perforation or eversion of the right coronary cusp The murmur is increased by isometric handgrip, squatting, or administration of an inotrope. It is decreased by standing, during the strain phase of a Valsalva maneuver, or on inhalation of amyl nitrite. In severe aortic regurgitation, an Austin Flint murmur may be heard at the apex, resulting from vibration of the anterior mitral leaflet. It resembles the murmur of mitral stenosis, except that it is not associated with an opening snap, and the first heart sound is not accentuated. There may be a short midsystolic ejection murmur that radiates to the neck, due to increased flow across the aortic valve. The electrocardiogram typically shows left ventricular and atrial hypertrophy. The chest x-ray may show marked cardiomegaly and dilatation of the aortic root and knob. Echocardiography permits quantitation of the regurgitant leak and provides information about its etiology. It also evaluates the size and function of the left ventricle, the size of the aortic root and the pulmonary artery pressure. Assessment of severity: Regurgitant volume Regurgitant fraction

Mild <30% <30%

Moderate 30-59% 30-49%

Severe ≥ 60% ≥ 50%

Medical treatment Endocarditis is no longer advised routinely. Vasodilator therapy (hydralazine, ACE inhibitors or calcium channel blockers) has been used to slow the progression of the disease. Surgical indications Symptomatic patients with severe aortic regurgitation Asymptomatic patients with severe disease and a left ventricular ejection fraction of ≤ 50% Asymptomatic patients who are having other cardiac of aortic surgery Aortic root repair or replacement in patients with a bicuspid valve is done if the aortic root or ascending aortic is > 5 cm. or if it is expanding at 0.5 cm/year Surgery is also reasonable if there is severe left ventricular dilatation (EDD >75 mm or ESD >55 mm).

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It may be considered for patients with moderate aortic regurgitation undergoing other cardiac or aortic surgery or in asymptomatic patients with severe regurgitation if there is progressive left ventricular dilatation or other evidence of deterioration. Bicuspid aortic valves with regurgitation are now being repaired in some centers. Mitral regurgitation Mitral regurgitation can result from malfunction of either of the leaflets, the annulus, the chordae tendineae or the papillary muscles. myxomatous degeneration of leaflets rheumatic disease endocarditis congenital deformities papillary muscle misalignment chordal rupture papillary muscle rupture annular dilatation papillary muscle dysfunction It is important to distinguish primary from secondary mitral regurgitation. In primary mitral regurgitation, the leaking valve causes left ventricular volume overload, resulting in remodeling and dysfunction. Properly timed correction of the valve can reverse these abnormalities. Secondary mitral regurgitation results from a damaged left ventricle that causes papillary muscle displacement and annular dilatation. In these patients, valve repair is generally inadequate to correct the situation. Symptoms Acute severe mitral regurgitation usually causes dyspnea, orthopnea, and sometimes cardiogenic shock Chronic mitral regurgitation may be asymptomatic for years. Eventually there may be fatigue, dyspnea, orthopnea and paroxysmal nocturnal dyspnea. Atrial fibrillation commonly develops. Physical findings The apical impulse may be hyperdynamic. There can be a parasternal systolic thrust. There is often an S4, which can be loud. An S3 may be present and does not necessarily imply left ventricular dysfunction. The first heart sound is usually diminished. There is usually a pansystolic apical murmur. However, it may be midsystolic if the mitral regurgitation is due to mitral valve prolapse or papillary muscle dysfunction. It typically radiates to the axilla, but can radiate to the base if there is an anteriorly directed jet. Differential diagnosis of a pansystolic murmur: The murmur of tricuspid regurgitation is heard best at the lower left sternal border and is accentuated b inspiration. That of a ventricular septal defect usually is loudest at the left sternal border. Electrocardiography commonly shows atrial fibrillation. There may be left atrial enlargement, and left and right ventricular hypertrophy. A chest x-ray can show cardiac enlargement with left atrial and left ventricular enlargement, and evidence of pulmonary congestion. Calcification of the mitral annulus may be seen. Echocardiography permits estimation of the severity, left ventricular function, and pulmonary artery pressure. It is helpful in determining the cause of the type of mitral valve disease.

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Assessment of severity Regurgitant volume Regurgitant fraction

Mild <30% <30%

Moderate 30-59% 30-49%

Severe ≥ 60% ≥ 50%

Medical treatment Endocarditis prophylaxis is no longer advised routinely. There is no generally accepted medical treatment. Vasodilators may be helpful in acute mitral regurgitation, but they do not appear useful in chronic mitral regurgitation unless there is associated hypertension or left ventricular systolic dysfunction. In the latter case, beta-blockers (mainly carvedilol) may help. Surgical indications Acute severe mitral regurgitation Chronic mitral regurgitation If the patient has a normal ejection fraction he can be kept under observation. However, the presence of even mild symptoms is an indication for repair, even if left ventricular function is normal. Asymptomatic patients with chronic severe mitral regurgitation are offered surgery with any of the following: mild to moderate left ventricular dysfunction, significant left ventricular dilatation an ejection fraction of 30-60% probably new onset of atrial fibrillation or pulmonary hypertension Once the ejection fraction falls toward 60% or less, or when the end-systolic dimension measures 40 mm, the postoperative result is not as good. Nevertheless, mitral valve repair is reasonable even in patients with class III-IV symptoms with ejection fraction <30%. Surgical mortality is as low as 1% in experienced centers, if the patient is not elderly and has acceptable left ventricular function. It is higher in other patients. It is probably unwise to recommend surgery to elderly asymptomatic patients. Mitral valve repair is preferred over mitral valve replacement when feasible. Usually this is done as an open heart procedure. However several transcatheter approaches have been developed. Secondary mitral regurgitation Almost all these patients are in heart failure. This should be the focus of therapy. Angiotensin converting enzyme inhibitors, angiotensin receptor blocker, diuretics, aldosterone antagonists and resynchronization therapy are of potential benefit. Several surgical approaches are available. Mitral annuloplasty is a relatively simple procedure designed to reduce the mitral orifice. Another treatment consists of applying restraining mesh over the heart in order to maintain it in an ellipsoid shape. Still another is the mitral clip procedure. The clip can be placed percutaneously. It apposes the two leaflets, and reduces the degree of mitral regurgitation.

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Mitral stenosis Etiology Mitral stenosis is almost always due to rheumatic fever. Rare causes include congenital disorders, carcinoid syndrome, lupus, rheumatoid arthritis, endocarditis and mucopolysaccharidosis. Symptoms The patient may remain asymptomatic for years. As the disease progresses, the patient begins to experience fatigue, dyspnea, orthopnea and paroxysmal nocturnal dyspnea. These may be exacerbated by the onset of atrial fibrillation, or during pregnancy. Hemoptysis may result from ruptured bronchial veins. The dilated left atrium may impinge on the recurrent laryngeal nerve, causing hoarseness. Complications, such as systemic emboli and endocarditis may occur. Eventually there may develop right heart failure. Signs The classic findings consist of exaggeration of the first heart sound. The second heart sound is followed by an opening snap, unless the valve is heavily calcified. The characteristic murmur is an early diastolic murmur that begins with the opening snap and fades into diastole. If the patient is in sinus rhythm, there is a presystolic murmur coinciding with atrial contraction. The duration of the early diastolic murmur increases with the severity of stenosis. The opening snap occurs earlier in severe mitral stenosis. The neck veins show prominent „a‟ waves during sinus rhythm. If the cardiac output is low, peripheral cyanosis may be seen. Pulmonary hypertension may result in a parasternal right ventricular lift, and a palpable pulmonic second sound.

Electrocardiogram If the patient is in sinus rhythm, left atrial enlargement is seen. Right ventricular hypertrophy eventually develops. Chest x-ray Left atrial enlargement is recognizable as a double density on the PA view and by elevation of the left main stem bronchus. On the lateral view, the barium-filled esophagus is indented and displaced posteriorly. Right ventricular enlargement results in diminished retrosternal space on the lateral view Kerley B lines may be present. Mitral valve calcification may be seen. Echocardiography Rheumatic mitral stenosis has a characteristic appearance on echocardiography. This study also permits estimation of the severity of the stenosis, chamber size, the degree of calcification, the presence of other valvular abnormalities, and left atrial thrombi. Indications for surgery Patients with class 3 or 4 symptoms or with moderate to severe mitral stenosis should have surgery. If the mitral stenosis appears to be mild but the patient is symptomatic, an exercise test should be done to determine whether the symptoms are due to the mitral stenosis. A significant rise in pulmonary pressure or in mitral valve gradient suggests that the stenosis is more than mild. Treatment Balloon valvuloplasty is often feasible. This is done by inserting a catheter transvenously into the right atrium. The septum is crossed, and the mitral orifice is dilated using one or more balloons. It does not work well if the valve is significantly calcified or noncompliant. It is contraindicated if there is more than 2+ mitral regurgitation, left atrial thrombus, severe tricuspid regurgitation or severe tricuspid regurgitation. 7

Prosthetic valves Bioprosthetic valves Homografts are cryopreserved cadaveric human aortic valves Heterografts (xenografts) are made from animal tissue, such as bovine or porcine pericardium Autografts are tissue taken from the same patient. The Ross procedure consists of using the patient‟s own pulmonic valve in the aortic position, and then replacing a homograft in the right ventricular outflow tract... Bioprosthetic valves require anticoagulation for the first 3 months after implantation. Afterward, anticoagulants are only used if there are continued indications, such as atrial fibrillation, left ventricular dysfunction, a hypercoagulable state, or previous thromboembolism. In such cases, there is little if any advantage to a bioprosthetic valve. Low-dose aspirin (75-100 mg) or clopidogril in patients who cannot take aspirin, is continued for the life of the patient. Bioprostheses tend to deteriorate, particularly in younger patients, those with renal failure, or with hypercalcemia. Later re-operation is often required. This is less of a concern in patients over the age of 65, and they are usually given bioprostheses to avoid the need for anticoagulation. Tissue valves are also used when anticoagulants are contraindicated. Women of childbearing age may also be candidates, in order to avoid anticoagulation during pregnancy. The risk of a first replacement is less than the risk of anticoagulation to the mother and fetus during pregnancy. (Lytel on ACCEL 2007). Mechanical valves The types are caged-ball prostheses (which are no longer in use) and several types of tilting disk prosthesis They are more durable than bioprosthetic valves, but require anticoagulation for the lifetime of the patient. This is a drawback in patients in whom chronic anticoagulation is relatively contraindicated, and in women of childbearing age. The target INR depends on the type of valve and the valve position. Often low-dose aspirin is added to the warfarin. For mechanical prostheses in the aortic position, an INR of 2 to 3 is usually satisfactory. In the mitral position, an INR of 2.5 to 3.5 is recommended. If the patient requires surgery, it is often necessary to stop warfarin and “bridge” the patient to the time of surgery using heparin or enalapril. If the patient has had a thromboembolic episode, has a hypercoagulable condition, has left ventricular dysfunction, or is in atrial fibrillation, then the INR should be kept at 2.5-3.5. Older valves, such as the caged ball prosthesis, should also be maintained at the higher level. Low-dose aspirin (or clopidogrel) is continued, along with the warfarin in all patients. Followup of patients with prosthetic valves Patients should be examined and receive echocardiograms at least annually. All should carry a wallet card, indicating the valve type, location of the valve, model number and serial number. Physical findings Mechanical valves Bileaflet aortic valve: Closing click is normally louder than opening click Soft midsystolic ejection murmur radiates to carotids Suspect malfunction if any diastolic murmur or if closing click is softer than opening click.

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Bileaflet mitral valve The opening click follows the second heart sound and is softer than the closing click Low frequency diastolic rumble Suspect malfunction if there is a holosystolic murmur Single leaflet aortic valve Closing click is normally louder than opening click Soft midsystolic ejection murmur radiates to carotids There may be a soft diastolic murmur with a normally functioning valve. Single leaflet mitral valve The opening click follows the second heart sound and is softer than the closing click Low frequency diastolic rumble Suspect malfunction if there is a holosystolic murmur Caged ball prostheses are rarely used The opening click should be louder than the closing click (otherwise consider malfunction) Aortic valves often produce a systolic flow murmur Any diastolic murmur suggests malfunction. Bioprosthetic valves The sounds are similar to those of native heart valves. Stented aortic heterografts Systolic ejection murmur that can radiate to the carotids Stented mitral heterografts May cause an early to mid systolic ejection murmur An opening sound may follow the second heart sound Stentless valves and homografts usually sound similar to native valves. Echocardiography An initial echocardiogram should be done within two or three months after implantation. It is repeated annually if the patient is asymptomatic. A small gradient is usual. In the presence of a high cardiac output, it may be higher. Mechanical valves may show a small amount of low velocity regurgitation. Choice of prosthetic valve In general, bioprosthetic valves tend to degenerate over ten years or less. This necessitates a reoperation. Many prefer bioprosthetic valves in the very young and the elderly, to avoid the need for long-term anticoagulation. The Ross procedure is a reasonable option, although the long-term results are not as certain as with mechanical valves. . If the patient already has an indication for anticoagulation (atrial fibrillation, or a pre-existing mechanical valve), then there is no advantage to a bioprostheses. In patients that are not considered

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very high risk for anticoagulation, a mechanical valve will provide a longer-lasting repair. Usually it will last for life, but the patient is committed to long-term warfarin. Complications of prosthetic valves Atrial fibrillation is very common in patients with prosthetic valves. Conduction disturbances, sometimes requiring pacemaker implantation, may occur. Endocarditis can occur on a prosthetic valve, and carries a higher mortality than native valve endocarditis. Therefore routine endocarditis prophylaxis is for patients with prosthetic valves prior to dental and other invasive procedures. Hemolysis This may occur, particularly with caged ball prostheses. It is due to mechanical trauma to the red cells. It can result in anemia. It is recognized by finding an elevated LDH, reticulocyte count, unconjugated bilirubin and urinary haptoglobin, and finding schistocytes on the blood smear. It can be treated with iron and folic acid supplement. Sometimes beta-blockers are used to reduce the trauma. Valve surgery is sometimes required. Prosthetic valve thrombosis This is uncommon but often serious. It can manifest itself as a thromboembolic episode, or as valve malfunction with symptoms of congestive heart failure. Left-sided valve thrombosis is treated surgically if the patient is in congestive heart failure or has a large clot burden. Thrombolytic therapy carries a significant risk of cerebral embolism. Fibrinolytic therapy can be used for thrombosis of right sided valves causing congestive heart failure or with a large clot burden. It is also sometimes used for left sided valves if the clot burden is small, and the congestive heart failure is mild, or if surgery is not feasible. Intravenous heparin can be used for patients with a small clot burden and mild congestive heart failure. Valve dehiscence and paravalvular leaks Valve malfunction can often be recognized by changes in the quality of the valve sounds, or by a new or changed murmur. In the case of an aortic prosthesis, any diastolic murmur is abnormal. Decreased intensity of the closing click of the valve may signal malfunction. Decreased intensity of either the opening or closing sound of a caged-ball prosthesis signals trouble. For mitral prostheses, a high frequency holoystolic murmur spells trouble. For mechanical valves, decreased intensity of the closing click is abnormal. With caged-ball prostheses, an apical diastolic rumble would be a warning. Echocardiography is always used to monitor patients with prosthetic valves. Pannus formation This results from fibroblastic proliferation and can result in valve obstruction.

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References: 1. AHA/ACC 2006 Guidelines for the management of patients with valvular heart disease. JACC 2006 48:1 2. Carabello B. Evaluation and management of patients with aortic stenosis. Circulation 2002;105:1746 3. Stout KS et al, Quantification of aortic valvular stenosis. ACC Current Journal Review 2003; p. 254 4. Rosenhek R, Statins for aortic stenosis. N Engl J Med 2005;352:2441 5. Griffin BP and Topol EJ. Manual of cardiovascular medicine, 2nd ed. 2004 6. Bettadapur MS et al. Caring for patients with prosthetic heart valves. Cleveland Clin J Med 2002; 69:75-87 7. Reginelli JP and Griffin B. The challenge of valvular heart disease: when is it time to operate. Cleveland Clin J Med 2004; 71:464-482 8. Maurer G. Progression of aortic stenosis. ACCEL October 2006. 9. Carabello BA. The current therapy for mitral regurgitation. JACC 2008; 52:319-326

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