16.6 Valvular heart disease 3436 Michael Henein

16.6 Valvular heart disease 3436 Michael Henein

ESSENTIALS Rheumatic valve disease remains prevalent in developing countries, but over the last 50 years there has been a decline in the incidence of rheumatic valve disease and an increase in the prevalence of de- generative valve pathology in northern Europe and North America. In all forms of valve disease, the most appropriate initial diagnostic investigation is almost always the echocardiogram. Mitral stenosis The most common cause is rheumatic valve disease. Other causes include mitral annular calcification, congenital mitral stenosis, in- fective endocarditis (very rarely), and systemic lupus erythematosus (Liebman–​Sachs endocarditis). The important consequences of mitral stenosis are its effect on left atrial pressure, size, and the pulmonary vasculature; it com- monly causes atrial fibrillation. Presenting symptoms are typically exertional fatigue and breathlessness; systemic embolism can occur. Characteristic physical signs are irregular pulse, tapping apex beat, loud first heart sound, opening snap, and an apical low-​pitched rum- bling mid-​diastolic murmur. Management—​the only medical treatments in mitral stenosis are (1) prophylactic measures against rheumatic fever and endocarditis; (2)  anticoagulation to prevent systemic thrombo-​embolism; and (3) diuretics for raised left atrial pressure. Patients who are symp- tomatic need intervention by either surgical valvotomy or catheter balloon valvuloplasty, whether or not they have pulmonary hyper- tension. Early intervention—​before the development of atrial fib- rillation and an enlarged left atrium—​is recommended, provided a conservative operation is possible. Mitral valve replacement is re- served for cases where the mitral valve cannot be repaired. Mitral regurgitation The most common causes are ischaemic myocardial dysfunction, mi- tral valve prolapse, and dilated cardiomyopathy. Other causes include congenital valve disease, infective endocarditis, endomyocardial fi- brosis, and connective tissue diseases (including Marfan syndrome). Mitral regurgitation is an isolated volume overload on the left ven- tricle, providing the physiological equivalent of afterload reduction so that a normal forward cardiac output is maintained by the com- bination of increased ejection fraction and higher preload. Patients with mild regurgitation may not have any symptoms: those with se- vere regurgitation are likely to present with dyspnoea. Characteristic physical signs are an apex beat that may be prominent and dis- placed, an apical pansystolic murmur, and a third heart sound (in severe cases). The loudness of the murmur generally correlates with severity of regurgitation. The cardinal signs of mitral prolapse are a mid-​systolic click followed by a murmur. Endocarditis prophylaxis may be recommended to high-​risk pa- tients with regurgitation. Patients in atrial fibrillation should be given anticoagulants. The development of symptoms suggests the need for surgical correction to avoid development of irreversible left ventricular dysfunction. Assessment during routine follow-​up should identify those likely to need surgical intervention even in the absence of symp- toms, with an effective regurgitant orifice of over 40 mm2 being one proposed indication. It is generally considered that a left ventricular end-​systolic dimension more than 50 mm indicates a poor prognosis and that surgical intervention is unlikely to be of benefit. If technically possible, mitral valve repair results in a much better clinical outcome than does valve replacement, but mitral replacement by a mechanical valve or bioprosthesis is the only option for irreparable valves. Aortic stenosis Aortic stenosis may be at subvalvar, valvar, or supravalvar level, the commonest being valvar stenosis. Age-​related degenerative calcific disease is the commonest cause in western Europe and the United States of America. Other causes include congenital bicuspid aortic valve and rheumatic disease (always associated with aortic regurgi- tation, ‘mixed aortic valve disease’, and usually with rheumatic mitral disease). With the increase in outflow tract resistance in aortic stenosis, left ventricular wall stress increases and hypertrophy develops, preserving overall ventricular systolic function, but potentially at the expense of subendocardial ischaemia. Patients with mild disease may be asymp- tomatic, and even severe stenosis may be silent, but breathlessness, angina, and syncope are typical. Characteristic physical signs are a slowly rising, low-​amplitude pulse, a narrow pulse pressure, a sus- tained apex beat, and a long and harsh ejection systolic murmur that is loudest at the base (second right intercostal space, also known as the aortic area) of the heart, and in most cases radiates to the carotids (where a thrill may be palpable). 16.6 Valvular heart disease Michael Henein

16.6  Valvular heart disease 3437 Management—​patients with moderate or severe disease should be advised to avoid strenuous exercise. Prophylaxis against endocar- ditis may be recommended to high-​risk patients. Asymptomatic pa- tients with mild or moderate aortic stenosis require follow-​up; those with severe disease (pressure gradient >70 mm Hg) need aortic valve replacement. Aortic regurgitation Aortic regurgitation is caused by leaflet disease or aortic root dilata- tion, the commonest causes being isolated medionecrosis, rheum- atic disease, infective endocarditis, and Marfan syndrome. The left ventricular stroke volume is significantly increased, which is accommodated by an increase in left ventricular cavity size. As dis- ease progresses, end-​systolic volume increases out of proportion to stroke volume, and eventually these changes lead to irreversible damage. The onset of symptoms, particularly breathlessness, coin- cides with the onset of left ventricular disease. Characteristic phys- ical signs of chronic severe aortic regurgitation are a large amplitude ‘collapsing’ pulse (which when severe can induce pulsations in many parts of the body), a low diastolic blood pressure (<50 mm Hg) and/​ or a high pulse pressure (>80 mm Hg), an apex beat that is sustained and/​or displaced, and an early diastolic, decrescendo murmur, loudest at the left sternal border. Acute aortic regurgitation causes the patient to be cold and shut down, with tachycardia, hypotension, and a short early diastolic murmur that is easily missed. Management—​medical treatment of chronic aortic regurgita- tion includes angiotensin converting enzyme (ACE) inhibitors and/​ or calcium channel blockers to reduce afterload. Patients with a di- lated aortic root should be given β-​blockade with ACE inhibition/​ angiotensin receptor blockers. Prophylaxis against endocarditis may be recommended to high-​risk patients. Although patients with se- vere chronic aortic regurgitation may remain asymptomatic, valve replacement should be offered when there is progressive increase in left ventricular end-​systolic dimension, which should not be allowed to reach more than 40 mm. Right heart valve disease Many of the conditions that cause right-​sided valve diseases are congenital, and are excluded from further discussion here (see Chapter 16.12). Tricuspid stenosis—​this is rare, but most often caused by rheum- atic disease that almost invariably simultaneously affects the mitral valve. Symptoms include fatigue, dyspnoea, and fluid retention. On auscultation at the left or right sternal edge, a mid-​diastolic murmur is heard and a tricuspid opening snap may be present. Diuretics can help to minimize fluid retention. Severe tricuspid stenosis needs sur- gical repair, or replacement if additional regurgitation is present. Tricuspid regurgitation—​significant disease is most commonly sec- ondary to pulmonary hypertension and/​or right heart dilatation; the commonest non​congenital primary cause is infective endocarditis. Symptoms include fluid retention and hepatic congestion. A raised venous pressure with prominent V-​wave is expected. Other signs include a pansystolic murmur at the left or right sternal edge (in one-​third of cases), expansile pulsation of the liver (in most), and peripheral oedema/​ascites. Diuretics and ACE inhibitors may reduce systemic venous pressure and right ventricular size, even restoring valve competence in some cases. Valve repair or replacement may be advised in some cases. Pulmonary stenosis—​a rare condition usually caused by rheumatic disease or carcinoid syndrome. Fatigue and dyspnoea are the main symptoms. Characteristic physical signs are a prominent venous ‘a’ wave in the neck and an ejection systolic murmur loudest at the upper left sternal edge. Balloon valvuloplasty is the procedure of choice if intervention is warranted. Pulmonary regurgitation—​significant disease is rare, but is usu- ally caused by rheumatic disease, carcinoid, and endocarditis. The characteristic physical sign is a soft early diastolic murmur in the left upper parasternal region. Arrhythmia or progressive right ventricular dilatation are indications for surgery, using homograft or conduit and valve. Introduction Over the last 50 years there has been a significant shift in the causes of heart valve disease in northern Europe and North America, with a decline in the incidence of rheumatic valve disease and an increase in the prevalence of degenerative valve pathology. Rheumatic valve disease remains prevalent in the developing countries, particularly in areas with limited clinical services. The commonest valve in- volved with rheumatic pathology is the mitral valve, but the aortic and tricuspid valves can also be involved. The apparent increase in the diagnosis of valve disease could be due either to ageing of the population or to the extensive use of echocardiography in car- diology clinics. Age affects the valves, making leaflets thicker with fibrous strands and adipose tissue deposition at the closure lines of the leaflets. Isolated myxomatous changes may also occur in the valve fibrosa. In patients with a suspected diagnosis of endocarditis these changes can add to diagnostic difficulty since they may look like small vegetations, and they also need to be distinguished from papillary muscle fibroelastoma. Medical treatment of valve disease is limited, focusing mostly on prophylaxis against endocarditis and ventricular dysfunction as well as optimizing haemodynamics. Although surgical repair is the main conventional treatment of severe valve disease, the need for this is 5 to 10 times less than that for coronary artery disease. Valve-​related mortality is more common in aortic valve disease than mitral valve disease, largely due to the frequent development of left ventricular dysfunction that causes congestive heart failure. Other causes of death in valve disease are additional pathologies such as coronary artery disease, endocarditis, or arrhythmia. The mitral valve Normal mitral valve anatomy and function Optimum function of the mitral valve depends on the intact func- tion of all its components—​leaflets, chordae, annulus, and pap- illary muscles, in addition to the left atrium and the left ventricle. A normal mitral valve does not close passively. In addition to the pressure difference between the ventricle and atrium in systole, the annular contraction and papillary muscle contraction play an important role in the competence of the mitral valve. The anterior mitral valve leaflet represents a continuation of the posterior aortic root wall. The annular fibrous ring is located mainly posteriorly; it

section 16  Cardiovascular disorders 3438 is usually D-​shaped but there is significant variability in different individuals. The normal diameter of the mitral annulus is around 3 cm with a circumference of 8–​9 cm: it is not a passive structure, so in addition to its normal movement towards the apex in systole, the contraction of the posterior myocardial muscle shortens its diam- eter by 25%, with such movement being a very important compo- nent in the mechanism of mitral valve competence. Change in the size and shape of the left atrial cavity is a cause for incompetence of the mitral valve by enlarging the annular diameter. Loss of atrial mechanical function may contribute significantly to the development of mitral regurgitation in patients with atrial fibril- lation. Likewise, atrial fibrillation itself has been shown to contribute to the enlargement of the left atrium and consequently the develop- ment of mitral regurgitation. The two leaflets of the mitral valve meet at the medial and lat- eral commissures. The area of the U-​shaped anterior leaflet is larger than that of the posterior leaflet, which is wider and shorter than the anterior leaflet. The posterior leaflet is made up of several scallops, commonly three. The two leaflets coapt at the zone of apposition, leaving an overlapping segment 5 mm long. The chordal anatomy of the mitral valve is complicated, with around 12 primary chordae rising from each papillary muscle. These divide into secondaries and numerous tertiary branches that attach themselves to the margins of the two leaflets. In addition, a number of basal chordae also attach themselves to the ventricular surface of the leaflets and to the commissures. The location of the chordae follows that of the papillary muscles anterolaterally and posteromedially. Any rupture or redundancy of the chordae or extra tissue in the leaflets results in mitral regurgitation. Mitral stenosis Causes The most common cause of mitral stenosis, which affects women more than men (2:1), is rheumatic valve disease. The rheumatic pro- cess involves not only the leaflets but may also affect the chordae and the annulus, causing fibrosis and superimposed calcification. The rheumatic leaflets become thickened and fibrosed, and the commis- sures fuse. The end result of this pathology is a reduction in mitral valve area, the rigid movement of the leaflets and the commissural fusion together contributing to the limited flow across the mitral valve orifice and hence stenosis. It is not uncommon for the fibrotic process to involve the subvalvar region in an aggressive way, thus causing flow to be limited at the level of the subvalvar apparatus. In such cases the chordae become short and the inflow tract of the left ventricle becomes tunnel-​like. Mitral annular calcification is another cause of raised filling vel- ocities; this is seen in older people with the calcification limited to the annulus and the proximal segments of the leaflets, but the leaflets themselves are normal. A very uncommon cause of mitral stenosis is congenital mitral stenosis, which may be associated with other cardiac abnormalities. Infective endocarditis with bulky vegetations may rarely cause restriction of mitral flow, and patients with sys- temic lupus erythematosus can develop fibrosis of the mitral cusps with commissural fusion following Liebman–​Sachs endocarditis. Pathophysiology and complications The important consequence of mitral stenosis is its effect on left atrial pressure and size and on the pulmonary vasculature. As the valve area falls progressively, left atrial pressure rises, its size increases, and the pulmonary venous pressure also increases. In most patients with rheumatic mitral valve disease the left ventricle is normal in size and systolic function unless the valve stenosis is severe and making the ventricle underfilled. With a mild degree of mitral stenosis, reduced orifice area is com- pensated by increased flow during atrial systole. As the valve stenosis becomes more severe, the left atrial pressure increases, the pressure difference between the atrium and the ventricle increases, and the filling occurs throughout diastole. In severe mitral stenosis the pres- sure difference may be as high as 25–​30 mm Hg. Long-​standing dis- ease may result in irreversible pulmonary hypertension secondary to the raised left atrial pressure. Atrial fibrillation also develops, with loss of mechanical atrial function. The area of a normal mitral valve area is of the order of 5 cm2, compared to less than 1 cm2 in a patient with severe mitral sten- osis. Effective mitral valve area changes very little with increase in heart rate compared to aortic valve area (which increases), the reason probably being the smaller number of commissures that as- sist opening of the mitral valve compared to the aortic valve. During exercise, particularly in atrial fibrillation, diastolic time falls and the fixed valve area causes raised left atrial pressure and pulmonary venous pressure. Left atrial dilatation Progressive reduction in mitral valve orifice area causes progres- sive increase in left atrial pressure and size and pulmonary venous pressure. Left atrial dilatation is associated with reduction in its mechanical function that slows down intra-​atrial blood circulation (swirling). With progressive disease and development of atrial fib- rillation, the circulation in the atrium becomes very sluggish and echocardiography may demonstrate spontaneous echo-​contrast, particularly on transoesophageal images. Such patients are given anticoagulants in order to avoid clot formation and hence the risk of transient ischaemic attacks or strokes. Almost one-​fifth of the patients undergoing surgery for mitral stenosis have left atrial thrombus, and in one-​third of them the thrombus is restricted to the atrial appendage. Atrial fibrillation This is the most common complication of mitral stenosis and its prevalence increases with age; it is found in 70% of patients in their thirties and in 80% of those in their fifties. The presence of pul- monary hypertension raises the prevalence of atrial fibrillation. The Framingham study estimated a 20-​fold increase in risk of stroke in patients with atrial fibrillation and mitral stenosis compared to only 5-​fold increase in those without mitral valve disease. Left atrial thrombus may also form in patients with a dilated left atrium with spontaneous echo-​contrast who are in sinus rhythm. The loss of left atrial appendage mechanical function has been proposed as a possible mechanism behind blood stagnation and thrombus formation. Left ventricular dysfunction Although in most cases of mitral stenosis the left ventricle is normal in size and systolic function, in some patients diastolic function may be impaired and end-​diastolic pressure raised. This could be related to additional pathology (e.g. systemic hypertension and

16.6  Valvular heart disease 3439 diabetes). The left ventricle is dilated only in the presence of add- itional coronary artery disease. Primary rheumatic myocardial dis- ease was proposed years ago, but no convincing evidence has ever come to light. Pulmonary hypertension With the increase in left atrial pressure, the pulmonary venous pres- sure increases and hence pulmonary arterial pressure also rises. Although pulmonary artery pressure corresponds to the degree of increase in left atrial pressure, a discrepancy between the two may reflect a raised pulmonary vascular resistance. A normal pressure drop across the pulmonary bed is of the order of 10–​15 mm Hg. The pulmonary hypertension is not always reversible after valve surgery. For any degree of mitral stenosis patients can display a variety of pulmonary pressures, but it is very rare for secondary pulmonary hypertension to develop with left atrial pressure less than 20 mm Hg in the setting of isolated mitral stenosis. Right heart disease With the development of pulmonary hypertension, the right ven- tricle becomes hypertrophied and its cavity dilates. This is also reflected in right atrial size. Patients with rheumatic mitral valve dis- ease may have additional tricuspid valve involvement; in particular, with the annulus dilating and causing significant tricuspid regur- gitation. Patients with severe tricuspid regurgitation may complain of fluid retention that needs careful management in order to main- tain the left-​sided cardiac output and obtain tissue perfusion. Long-​ standing significant tricuspid regurgitation and raised right atrial pressure may cause further deterioration of right ventricular func- tion and congestive heart failure. By that stage, the damage is usually irreversible despite any successful mitral valve surgery. Clinical presentation Symptoms Patients may remain asymptomatic with mild mitral stenosis. As the disease progresses, early symptoms are exertional fatigue and breathlessness. With severe mitral stenosis shortness of breath is accompanied by orthopnoea and paroxysmal nocturnal dyspnoea. With the development of pulmonary hypertension, right ventricular dysfunction, and tricuspid regurgitation, patients may present with fluid retention as well as recurrent chest infection. Atrial fibrillation may be an early symptom in patients with mitral stenosis, particu- larly palpitations on exercise. Major systemic embolus can also be a presenting symptom, and the condition may be detected for the first time during pregnancy as patients complain of disproportionate dyspnoea. Physical examination Long-​standing mitral stenosis characteristically causes weight loss and a malar flush. The pulse character is normal, but pulse volume may be reduced and atrial fibrillation is likely. The jugular venous pressure is usually normal unless there is tricuspid regurgitation and/​or pulmonary hypertension. The apex is not displaced, but the first heart sound is sometimes palpable (‘tapping apex’), and less fre- quently the opening snap is also. The characteristic auscultatory features of rheumatic mitral sten- osis are an opening snap in early diastole, a mid-​diastolic murmur, and a loud first heart sound. The opening snap is caused by the abrupt tension that develops in the fibrosed leaflets at the termination of the opening movement. It is best heard at the lower left sternal edge or apex, becoming closer to the second heart sound as left atrial pres- sure rises, and it is absent with leaflet calcification. The diastolic murmur is low pitched and maximal at the apex. It is caused by in- creased blood flow velocity between the left atrium and left ventricle and is accentuated in late diastole by atrial contraction in patients in sinus rhythm. The loud first heart sound is associated with fibrosis of the anterior leaflet and is lost with leaflet calcification. Many patients with mitral stenosis have some degree of mitral regurgitation, which is not significant in the presence of severe stenosis. In the presence of pulmonary hypertension the jugular venous pressure is raised, there may be a palpable right ventricular heave, and the second heart sound is usually loud. In patients with sig- nificant tricuspid regurgitation, whether secondary to pulmonary hypertension or due to rheumatic tricuspid valve, there is a clear V-​ wave and deep Y descent in the jugular venous pulse, and expansile pulsation of the liver. The murmur of tricuspid regurgitation is not usually prominent. Investigations Chest radiograph and electrocardiogram Early in the disease a chest radiograph may show a completely normal cardiac silhouette. Later, as the disease progresses, left atrial enlargement appears and a prominent left atrial appendage contour becomes very evident (Fig. 16.6.1). Left atrial double-​density and elevation of left main bronchus may also be evident. In patients with Fig. 16.6.1  Chest radiograph from a patient with pure mitral stenosis. The heart size is normal, but the left atrial appendage is enlarged. The upper lobe vessels are dilated and there are Kerley lines at both bases.

section 16  Cardiovascular disorders 3440 raised left atrial pressure, pulmonary vascular redistribution mani- fest as ‘dilated upper lobe veins’ and interstitial pulmonary oedema (‘Kerley B lines’) may be seen. The central pulmonary arteries be- come prominent as pulmonary hypertension develops, and upper lobe deviation is also seen. Finally, right-​sided dilatation may also be seen as tricuspid regurgitation develops. The electrocardiogram can show a broad and notched P-​wave due to left atrial hypertrophy and enlargement (‘P mitrale’) as a classical finding in mitral stenosis, and its progressive broadening predicts the occurrence of atrial fibrillation, which is common in mitral stenosis. Echocardiography Echocardiography is the investigation of choice in mitral valve dis- ease. A typical picture of rheumatic valve disease is a short, fibrosed, and stiff posterior leaflet; a fibrosed anterior leaflet that bows down towards the ventricle in diastole; and narrow valve area (Fig. 16.6.2). Short-​axis images clearly demonstrate the fused commissures and two-​dimensional images show the extent of chordal fibrosis. Planimetry of the mitral valve area in diastole gives an estimate of the degree of stenosis. Continuous-​wave Doppler assesses the blood flow velocity across the valve. In mild stenosis, transmitral Doppler demonstrates a peak velocity in late diastole compared to in early diastole in severe stenosis. With atrial fibrillation there is a single early diastolic filling component to the left ventricle. A transmitral mean pressure gradient of more than 4 mm Hg suggests a moderate degree of stenosis (Fig. 16.6.3), and a mean pressure gradient of more than 8 mm Hg suggests severe stenosis. Colour-​flow Doppler can provide a quantitative approach for assessing mitral stenosis se- verity using the proximal isovelocity surface area (PISA) method or the vena contracta method (the vena contracta being the narrowest region of the stenotic jet, just downstream of the valve orifice and reflecting the size of that orifice). Although the latter is easy to use, it has its limitations since it varies more with deformation of the mitral orifice area and shape. Colour-​flow Doppler will also show any mi- tral regurgitation jet and give some indication of its severity. Echocardiography also assesses any involvement of the aortic valve or the tricuspid valve by the same or other pathologies. It is now common practice that most patients with mitral valve dis- ease are studied by transoesophageal echo because this provides more detailed assessment of the mitral valve, the subvalvar ap- paratus, and the presence of left atrial spontaneous contrast and appendage clots. Cardiac catheterization Echocardiography has replaced cardiac catheterization in making the diagnosis of mitral stenosis. Catheterization may provide add- itional information on pulmonary vascular resistance and coronary artery disease before surgery. Differential diagnosis The diagnosis of mitral stenosis is usually straightforward on the basis of clinical findings supported by echocardiography, which should distinguish the presence of an Austin–​Flint murmur caused by aortic regurgitation and the rare conditions of left atrial myxoma (see Chapter 16.10) and cor triatriatum (see Chapter 16.12). Management There is a significant time lag between the acute event of rheumatic fever and the presentation of mitral stenosis with mild symptoms, which could be up to 15 years. Patients may need another 10 years to develop signs and symptoms of severe stenosis. The likely reason behind this delay is the time needed for rheumatic leaflet fibrosis and calcification to develop and cause raised left atrial pressure. This time lag between acute rheumatic fever and clinical presentation varies significantly between developed and developing countries. In Europe and North America patients need valve surgery for mitral stenosis in their fifties, whereas those in developing countries need it in their thirties. The clinical outcome of patients with unoperated rheumatic mitral stenosis has changed significantly over time, with 20-​year follow-​up mortality dropping from historically 85% to re- cently 44% in those who refuse surgery. Fig. 16.6.2  Transoesophageal echocardiogram from a patient with severe rheumatic mitral stenosis showing a dilated left atrium (LA) with spontaneous echo-​contrast. 1 m/s Fig. 16.6.3  Continuous-​wave Doppler of left ventricular filling from a patient with mitral stenosis, showing raised velocities (>2 m/​s, arrowed) across the mitral valve as the ventricle fills in diastole. A mean velocity of more than 1.3 m/​s at the mitral valve leaflet tips is abnormal.

16.6  Valvular heart disease 3441 Medical The only medical treatments in mitral stenosis are the prophy- lactic measures against rheumatic fever (penicillin prophylaxis, see Chapter 16.9.1) and endocarditis (considered for high-​risk cases, see Chapter 16.9.2), anticoagulation to prevent systemic embolism, and diuretics for raised left atrial pressure. There is no medication that has a direct effect on slowing disease progress. Patients with mitral stenosis should be followed up clinically using non​invasive investigations, particularly Doppler echocardiography. The frequency of follow-​up should be tailored according to indi- vidual patient’s clinical condition and the severity of disease: this could be every 2 years in a patient with mild stenosis and regur- gitation, but closer attention is required for the patient with severe stenosis and evidence of pulmonary hypertension. Particularly close follow-​up is advised for pregnant women who have mitral stenosis. In patients who develop atrial fibrillation, attempts to restore sinus rhythm are usually unsuccessful unless associated with surgery. To maintain sinus rhythm the organic mitral lesion should be dealt with either interventionally or surgically. In addition to heart rate con- trol, digoxin may keep a patient with a modestly dilated left atrium in sinus rhythm. However, once atrial fibrillation is established, at- tention should be diverted to rate control with digoxin, β-​blockers, or calcium channel blockers. With persistent atrial fibrillation anticoagulation is essential and INR level should be monitored and maintained at 2.5–​3.5. Patients recommended for percutaneous mitral valvuloplasty should receive stable anticoagulation therapy for at least 3 months before the procedure and transoesophageal echo should exclude left atrial clot. Those who need surgical inter- vention may receive a maze procedure as a means for restoring the sinus rhythm, which involves surgically creating a single electrical pathway from the sinus node to the atrioventricular node, while isolating the abnormal electrical activity of the left and right atrial tissue. Recently, electrophysiological mapping with isolation of pul- monary veins has offered an alternative procedure. The success of the maze procedure varies considerably, ranging between 25% and 80% even after an initially successful procedure. See Chapter 16.4 for further discussion. Patients who are symptomatic need intervention by either surgical valvotomy or catheter balloon valvuloplasty, whether or not they have pulmonary hypertension. Early intervention is highly recom- mended before the development of atrial fibrillation and an enlarged left atrium, provided a conservative operation is possible. The percu- taneous mitral valvuloplasty procedure involves inserting an Inoue balloon into the mitral valve orifice and inflating it until an increase in mitral valve area is achieved (Fig. 16.6.4). Contraindications to this procedure are left atrial appendage thrombus, calcified subvalvar apparatus, and/​or mitral regurgitation. Early results of this technique are satisfactory, particularly if patients are well selected (e.g. those with relatively mobile, non​calcified leaflets that are not greatly thickened, and without subvalvular thickening). Mitral sten- osis may recur following this procedure after the healing period of the split of the fused commissures. Surgical Closed mitral valvotomy has been replaced by percutaneous mitral valvuloplasty, but its results are not optimal in low-​workload centres in developed countries. There is thus still room for surgical repair of the mitral valve. This is better suited to patients with minimal calcifi- cation and those with short chordae. The technique offers the advan- tage of avoiding replacement of the mitral valve, which has effects on left ventricular function. However, in a patient with an irreparable mitral valve, the only remaining option is mitral valve replacement. Closed mitral commissurotomy This historic procedure aimed at opening the mitral valve by ap- plying a dilator through the ventricular apex, with the surgeon using a finger to feel the valve leaflets and orifice to judge when the desired valve area was achieved. The first successful operations were carried out in 1948. It has been intensively used in the United Kingdom and other countries, with an average mortality of 3–​4%. Open mitral valvotomy This operation requires the use of an extracorporeal circulation and aims at direct visualization of the mitral valve through a medial sternotomy, with careful dissection of the fused commis- sures under direct vision. In contrast to the closed operation, the surgeon is able to deal with the subvalvar apparatus and the fused chordae, and correct chordal shortening if required. The left atrial appendage can also be visualized, and if there is thrombus pre- sent it can be removed. With appropriate patient selection and preoperative evaluation open commissurotomy is feasible in most patients, with an operative mortality of approximately 1%; how- ever, most cases not suitable for balloon valvotomy require mitral valve replacement. Mitral valve repair Lack of access to anticoagulation medications and monitoring in low income countries, also the religious cultural bias regarding type of prosthetic valve in some countries, necessitates an increase in the proportion of patients undergoing repairs of rheumatic mi- tral valves. Fig. 16.6.4  Inoue balloon catheter, as used for mitral valvuloplasty, partially (left) and completely (right) inflated.

section 16  Cardiovascular disorders 3442 Mitral valve replacement Mitral valve replacement involves either a mechanical or a tissue valve substitute. Surgical mortality varies according to other comorbidities: it is of the order of 3% in patients with isolated mitral valve stenosis but can be as high as 12% in patients with additional pulmonary hypertension. The life of biological mitral valve substi- tutes, particularly porcine xenografts, is limited to less than 10 years in most adults, hence their use tends to be restricted to very elderly patients. Cryopreserved mitral homografts have been proposed re- cently as a better option, as has the use of a pulmonary autograft in a Dacron tube, but experience is limited. Mitral regurgitation Causes The most common causes of mitral regurgitation are ischaemic myocardial dysfunction, mitral valve prolapse, and dilated cardio- myopathy. Other causes are given in Table 16.6.1. Ischaemic mitral regurgitation The posteromedial papillary muscle is predisposed to ischaemic dysfunction and infarction because it is supplied by a single branch of the posterior descending artery and tends to have only a few collaterals. The anterolateral papillary muscle receives blood from branches of both the left anterior descending artery and the cir- cumflex artery, so it is less susceptible to ischaemia. Ischaemic dis- turbances of left ventricular function contribute to the development of mitral regurgitation through several mechanisms: (1) regional wall motion abnormalities with adverse ventricular remodelling and systolic tenting of the valve leaflets; (2) left ventricular dilata- tion and shape change that alters normal alignment of the papillary muscles and results in leaflet tethering and inadequate closure; and (3) annular dilatation leading to inadequate annular contraction. These mechanisms may contribute to further enlargement of the left ventricle and deterioration of its function, which itself would add to the severity of mitral regurgitation. Four clinical presentations are seen in ischaemic mitral regurgitation: acute myocardial infarction; papillary muscle rupture; reversible ischaemic myocardial dysfunc- tion in the presence of preserved left ventricular systolic function; and end-​stage ischaemic cardiomyopathy with reduced function. Acute myocardial infarction Significant mitral regurgitation complicates 3–​16% of acute myo- cardial infarctions. Most present within the obvious context of acute myocardial infarction, but some with pulmonary oedema from the acute development of mitral regurgitation. Most patients presenting with myocardial infarction complicated by mitral re- gurgitation have right and circumflex coronary artery disease that causes inferior wall dysfunction. Mitral regurgitation does not therefore seem to be related to infarct size, but to the extent of is- chaemic dysfunction and involvement of the posteromedial pap- illary muscle. The resulting poor support to the posterior leaflet, referred to as tethering, causes lack of leaflet coaption and valve incompetence. When severe mitral regurgitation develops it carries a poor prognosis, with mortality rising to 25% at 30 days and over 50% at 1 year. The effect of reperfusion on mitral regurgitation re- mains controversial. Papillary muscle rupture Complete papillary muscle rupture causes severe mitral regurgita- tion and cardiogenic shock that is usually fatal (70% within 24 h without emergency surgery). Surgical repair of the papillary muscle is not feasible in most cases because tissues are necrotic: valve re- placement is necessary, with risk influenced by other factors including the severe left ventricular disease that is usually present. Ischaemic mitral regurgitation in a normal left ventricle Patients with long-​standing ischaemic myocardial dysfunction usu- ally have exertional reversible ischaemia. If this affects the posterior wall of the left ventricle it leads to further deterioration of pos- terior wall function and consequently the posterior leaflet function with the development of mitral regurgitation. Exertional breath- lessness in these patients does not always have to be due to raised end-​diastolic pressure and may be caused by a sudden increase in left atrial pressure through the development of mitral regurgitation with exercise, particularly in those with a dilated left atrium. Stress echocardiography is ideal for demonstrating the stress-​induced is- chaemic ventricular dysfunction and the development of mitral re- gurgitation and raised left atrial pressure, when antianginal therapy and afterload reduction may be beneficial. Patients who develop sig- nificant mitral regurgitation with stress and who are accepted for coronary artery bypass surgery should receive mitral valve repair and a ring insertion at the time of surgical revascularization. Ischaemic mitral regurgitation in ventricular dysfunction Mitral regurgitation is very common in patients with long-​standing ischaemic left ventricular dysfunction and/​or end-​stage ventricular disease. Since the valve leaflets appear morphologically normal, the mitral regurgitation is described as ‘functional’. However, three-​ dimensional echocardiographic assessment of the mitral valve Table 16.6.1  Common causes of mitral regurgitation Structure primarily affected Anatomical defect Cause Valve cusps Congenital cleft Primary atrial septal defect Isolated Redundant cusp Mitral valve prolapse Marfan syndrome Perforation Infective endocarditis Scarring Rheumatic fever Ergot-​derived dopamine receptor agonists Chordae Redundant Mitral valve prolapse Marfan syndrome Other connective tissue disease Rupture Acute myocardial infarction Mitral valve prolapse Marfan syndrome Other connective tissue disease Infective endocarditis Rheumatic fever Shortening Rheumatic fever Endomyocardial fibrosis Papillary muscle Dysfunction Ischaemia Valve annulus Dilatation Severe left ventricular disease of any cause—​‘dilated cardiomyopathy’

16.6  Valvular heart disease 3443 proves that it is not entirely normal, with long-​standing progres- sive changes in the interleaflet relations and subvalvar apparatus. Reducing ventricular pressures may improve left ventricular geom- etry, and lowering blood pressure may reduce mitral regurgitation severity. Mitral valve prolapse Mitral valve prolapse is a genetic connective tissue disorder that affects the mitral leaflets, chordae, and annulus, with an auto- somal dominant pattern of inheritance and variable penetrance. Histologically the leaflets show thickening of the spongiosa and dis- ruption of the fibrosa with fragmentation. Collagen is also abnormal with high rate of synthesis, deficiency in type III collagen, and split- ting of collagen with fibre disarray. The cause has not yet been iden- tified: defects in a collagen gene or in a gene encoding a component of microfibrils, similar to that involved in Marfan syndrome, have obviously been considered. The condition is common: 1.5–​6% of adults have mitral prolapse, depending on definition, and screening of first-​degree family members demonstrates prolapse in approxi- mately 30% of cases. Mitral prolapse can be classified into two types: a benign condi- tion seen in young people, commonly women, that does not always progress; and the ‘myxomatous mitral valve disease’ seen in older people, often causing significant mitral regurgitation that needs sur- gical repair. Overall survival in patients with mitral prolapse is 97% at 6 years and 88% at 8 years, but those with myxomatous mitral valve disease and a flail leaflet have a 10-​year survival much less. With posterior leaflet myxomatous prolapse, progressive chronic mitral regurgitation is associated with progressive dilatation of the left atrium and left ventricle. The commonest site for posterior mitral prolapse is the middle scallop (P2). Significant mitral regurgitation occurs in less than 10% of patients with posterior prolapse compared to 25% of those with anterior leaflet prolapse. In contrast, the incidence of atrial fibril- lation and heart failure is significantly higher in posterior leaflet prolapse than in anterior leaflet prolapse. In general, severe mitral regurgitation is associated with redundant leaflets, a longer pos- terior leaflet, and a larger annulus. Chordal distribution may also be abnormal, and there may be a relative scarcity of chordae to the central scallop of the posterior leaflet, increased chordal division, or a higher incidence of chordal rupture. There is a clear relationship between mitral valve prolapse, ar- rhythmia, and sudden death. The annual rate of sudden death in mitral prolapse is approximately 2%, which significantly falls after surgical repair. The risk of endocarditis is estimated at three to eight times that of the general population, the substrate being that leaflet prolapse causes significant turbulence of the blood flow across the valve orifice, disrupting platelet and fibrin deposition on the valve surface, and subsequently resulting in vulnerability to infection. There is controversy regarding the relationship between mitral pro- lapse and embolic events. Dilated cardiomyopathy Mitral regurgitation is common in dilated non​ischaemic cardiomy- opathy. Dilatation of the left ventricle disturbs the normal closure of the mitral valve, the leaflets fail to coapt, and hence mitral regurgi- tation occurs. Pathophysiology and complications Regurgitant orifice and jet The regurgitant volume of mitral regurgitation is calculated as the regurgitant flow over the regurgitant area. The flow velocity through the orifice is related to the ventricular–​atrial systolic pres- sure difference. A high left ventricular systolic pressure (e.g. sys- temic hypertension) increases mitral regurgitation volume, and low left ventricular pressure reduces it. Left atrial pressure in acute mitral regurgitation is raised, with a V-​wave in late systole due to the increased volume and the velocity of blood entering it (al- though the absence of such a wave on the left atrial or pulmonary wedge pressure trace does not exclude the diagnosis of severe mi- tral regurgitation). Mitral regurgitation is often a dynamic lesion, with the size of the regurgitant orifice and regurgitant volume varying with the pressure gradient across the valve and with changes in left ventricular volume and geometry. The use of medical therapy to reduce left ventricular volume and improve its systolic function may therefore assist in re- ducing the severity of mitral regurgitation. Left atrium Left atrial volume increases in patients with mitral regurgitation in response to the increase in its pressure, to the transmission of the mitral regurgitation kinetic energy to the left atrial wall, and also to the development (in some cases) of atrial fibrillation. These ef- fects balance those of the mitral regurgitation jet on left atrial pres- sure, which is normal in compensated patients. In contrast to mitral stenosis, the fast regurgitant jet in the left atrium reduces the risk of thrombus formation. Afterload Mitral regurgitation is an isolated volume overload on the left ven- tricle, providing the physiological equivalent of afterload reduc- tion so that a normal forward cardiac output is maintained by the combination of increased ejection fraction and higher preload. Therefore, unlike the situation with pressure overload, the coronary blood flow is normal and the increase in myocardial oxygen con- sumption in mitral regurgitation is only mild. Left ventricular dys- function, manifest by increased end-​systolic diameter, is one of the most important determinants of outcome. Right heart The risk of right heart disease and dysfunction in mitral regurgita- tion is very similar to that in mitral stenosis. The raised left atrial pressure and pulmonary venous pressure are directly reflected on right ventricular systolic pressure. Right ventricular dysfunction as a complication of pulmonary hypertension is an important deter- minant of outcome. Clinical presentation Symptoms Patients with mild mitral regurgitation may not have any symp- toms:  those with severe regurgitation are likely to present with dyspnoea. It is sometimes reported that mitral valve prolapse may be associated with non​specific symptoms such as chest pain and fa- tigue, but this is debatable.

section 16  Cardiovascular disorders 3444 Physical examination The patient with non​rheumatic mitral regurgitation is usually in sinus rhythm; but with severe mitral regurgitation of any cause, pa- tients may present in atrial fibrillation. The pulse is likely to be of normal character, but is sometimes reported as ‘jerky’, meaning of normal amplitude but rapid upstroke. The venous pressure is normal unless there is significant pulmonary hypertension or associated tri- cuspid disease. The apex beat may be prominent and displaced, it may be double due to a palpable third heart sound, and there may be a palpable sys- tolic thrill in severe cases. A palpable left parasternal heave may be due to systolic expansion of the left atrium and/​or right ventricular hypertrophy. The first heart sound is normal or soft, the most prominent find- ings on auscultation being an apical pansystolic murmur and a third heart sound. The loudness of the murmur generally correlates with severity of regurgitation, a murmur of less than grade 2/​6 (meaning that it can be heard only with special effort) indicating mild disease, with the notable exception that no murmur may be audible with acute mitral regurgitation (when the mitral valve may effectively be absent). The cardinal signs of mitral prolapse are the mid-​systolic click, due to the backward movement of the mitral leaflet into the left atrium, and the late systolic mitral regurgitation that occurs after the click. The murmur extends throughout systole as mitral regurgi- tation becomes severe. The radiation of a mitral regurgitant murmur depends on the direction of the regurgitant jet. A  posterolateral jet—​seen in is- chaemic mitral regurgitation, anterior leaflet disease, and dilated cardiomyopathy—​radiates from the apex to the axilla, and even to the back. An anterosuperior jet due to posterior leaflet prolapse is heard better at the lower left sternal edge or cardiac base (second right intercostal space, also known as the aortic area), and even on the carotids. Other physical signs depend on the severity of mitral regurgita- tion and possible complications (e.g. pulmonary hypertension). Investigations Chest radiography and electrocardiogram The chest radiograph reflects the haemodynamic disturbance (Fig. 16.6.5). The overall heart size is often normal or only moderately enlarged, with selective enlargement of the left atrium, although not to the same extent as with mitral stenosis (see Fig. 16.6.1). However, considerable cardiac enlargement develops due to secondary left ven- tricular disease if mitral regurgitation is severe and long-​standing. The electrocardiograph (ECG) usually shows sinus rhythm. There may also be evidence of left atrial hypertrophy, left ventricular hypertrophy, and frequent ventricular ectopic beats. Echocardiography Two-​dimensional echocardiography provides a thorough assess- ment of the anatomy and function of the mitral valve apparatus, including the leaflets and annular diameter, as well as left ventricular size and function, left atrial size, and pulmonary artery pressure. The echocardiographic criterion for mitral prolapse is the presence of at least 2 mm of late systolic posterior displacement of the leaflets across the mitral annular plane (Fig. 16.6.6). Severe myxomatous degeneration is associated with thickening of the leaflets and the appearance of extensive folding or redundancy of the leaflets in dia- stole, chordal elongation, and systolic anterior motion of the leaflets. Secondary mitral prolapse can easily be distinguished from primary prolapse in patients such as those with Marfan syndrome, where the leaflets (particularly the anterior) are thin and long, and also in hypertrophic cardiomyopathy, with long leaflets and anterior mo- tion of the mitral valve. Transthoracic echocardiography is perfectly adequate, but transoesophageal echocardiography is recommended if images are limited in quality. Because it is non​invasive, echocardiography is an ideal tool for the follow-​up of patients to allow early identification of worsening of regurgitation or deterioration in ventricular function. Many Fig. 16.6.5  Chest radiograph showing acute pulmonary oedema due to acute mitral regurgitation resulting from ruptured chordae tendineae. Fig. 16.6.6  Transoesophageal echocardiogram from a patient with posterior mitral leaflet prolapse (arrow). LA, left atrium.

16.6  Valvular heart disease 3445 echocardiographic methods for determining the severity of re- gurgitation have been described (Fig. 16.6.7), three-​dimensional reconstruction of the mitral regurgitation jet being a very prom- ising tool for obtaining accurate regurgitant volume assessment since it avoids the conventional cross-​sectional limitations. The extent of left ventricular cavity activity directly reflects the se- verity of volume overload, thus limiting the accuracy of using ejection fraction as a measure of ventricular function in such patients, hence changes in left ventricular end-​systolic volume or dimensions should be taken as a marker of ventricular dys- function. Patients recommended for surgical repair need detailed transthoracic and transoesophageal echocardiographic assess- ment of the anatomy of the valve and subvalvular apparatus to assist surgeons in planning. Findings that support pulmonary hypertension, in particular en- largement of the right side of the heart and increase in the retrograde pressure drop across the tricuspid valve, are easily obtained from a conventional Doppler echocardiographic study. Tricuspid leaflet prolapse is seen in 20% of patients with mitral valve prolapse, but aortic involvement is much less frequent. Cardiac catheterization This is not indicated for diagnostic purposes but may be required for preoperative assessment of the coronary arteries. Differential diagnosis Mitral regurgitation needs to be distinguished from ventricular septal defect (VSD), aortic valve disease, and tricuspid regurgitation. Congenital VSDs are discussed in Chapter 16.12, but the com- monest scenario in adult practice where distinction between mitral regurgitation and VSD needs to be made is the patient who deteri- orates shortly after a myocardial infarction and is found to have a pansystolic murmur. It is impossible to distinguish reliably between the two by physical examination, although if the murmur is heard over the back VSD is most likely. Echocardiography and/​or right heart catheterization with measurement of oxygen tension in the various cardiac chambers are required (see Chapter 16.3.4). The systolic murmur of aortic valve disease can radiate to the apex, and sometimes be louder there than at the base (aortic area). The latter can lead to misdiagnosis of mitral valve disease, and the former can lead to confusion as to whether both aortic and mi- tral valves are diseased. Aside from looking for other evidence of aortic valve disease, the key thing is to establish the precise timing of the murmur. Mitral valve disease should only be diagnosed if the murmur is pansystolic, extending right up to and even obliterating the second heart sound (or right up to the onset of the early diastolic murmur of aortic regurgitation). The murmur of tricuspid regurgitation is typically loudest at the lower left sternal border, is loudest during inspiration, and is associ- ated with elevation of the venous pressure with systolic waves. Management Patients with chronic mitral regurgitation may survive for a long time with no limiting symptoms. Once symptoms develop they suggest the need for surgical correction of valve regurgitation to avoid development of irreversible left ventricular dysfunction. Assessment during routine follow-​up identifies those likely to need surgical intervention even in the absence of symptoms, with an effective regurgitant orifice of over 40 mm2 being the cut-​off recommended value. Although patients with acute regurgitation secondary to papillary muscle rupture need emergency surgery, this does not necessarily apply to those with ruptured chordae or chronic ischaemic regurgitation. Such patients need to be stabilized and other risk factors and comorbidities identified and optimally managed. Medical There is no medical therapy that cures mitral regurgitation or mitral valve prolapse. Endocarditis prophylaxis is recommended for high-​ risk patients with regurgitation, although isolated mitral prolapse in Fig. 16.6.7  Apical four-​chamber views from a patient with coronary artery disease and ischaemic mitral regurgitation at rest (left) and stress (right). Note the significant increase in mitral regurgitation severity with stress as the ventricle became ischaemic.

section 16  Cardiovascular disorders 3446 the absence of regurgitation might not be counted as a definite indi- cation. Symptomatic supraventricular arrhythmia needs optimum therapy, usually with β-​blockers, and patients with ventricular tachycardia and syncope should be evaluated for implantable defib- rillator (see Chapter 16.4). Those in atrial fibrillation should be given anticoagulants and INR adjusted at 2.5 to 3.5. Appropriate pacing for dilated cardiomyopathy has been reported as reducing the severity of mitral regurgitation. Vasodilators im- prove prognosis and also reduce preload and the venous return, which improves leaflet coaption and reduces mitral regurgitation. Their effect on the afterload improves the forward flow and also reduces the retrograde flow across the mitral valve. Carvedilol has been shown to reduce long-​axis length over diameter ratio (‘car- diac index’) and reduce mitral regurgitation severity. Similar find- ings have been documented in patients receiving ACE inhibitors or angiotensin receptor antagonists. Surgical Certain factors predict surgical outcome after correction of mitral regurgitation. As might be expected, the more complex the sur- gical procedure the higher the surgical risk. Age-​related opera- tive mortality is of the order of 12% in patients over 75 years of age and 1% in younger patients. Symptoms related to mitral re- gurgitation are important predictors: patients in New York Heart Association (NYHA) classes I and II carry a mortality of 0.5%, but for those in classes III and IV it is 10% or more. The aetiology of mitral regurgitation is another determinant, with 1–​3% mortality in rheumatic mitral valve disease, compared to 9% in ischaemic mitral regurgitation. Ventricular dysfunction adds to the surgical risk, in par- ticular having an end-​systolic dimension greater than 45–​50 mm. However, recent data suggest that even significant left ventricular dysfunction should not be used as an exclusion criterion for cor- rection of mitral regurgitation, although the general belief re- mains that a systolic dimension of more than 50 mm indicates a poor prognosis and that surgical intervention is unlikely to be of benefit. Pulmonary hypertension is another important predictor of outcome that carries a poor prognosis: correction of mitral regur- gitation does not always guarantee normalization of pulmonary artery pressure, particularly if long-​standing, which indicates that surgical intervention should be considered before development of this complication. Mitral valve prolapse accounts for approximately 25% of mitral valve surgical procedures. The benefit of surgical intervention and ring insertion into patients with dilated cardiomyopathy remains controversial. Mitral valve repair The intention of mitral valve repair is to preserve the integrity of the valve, which—​if successful—​results in a much better clinical out- come for patients with mitral regurgitation than does valve replace- ment. Preservation of the chordal attachment is crucial, keeping the continuity between the mitral leaflets and the papillary muscles which control the long-​axis function of the left ventricle. This itself also affects the sphericity of the left ventricle and hence overall per- formance of the cavity. Mitral valve repair avoids the use of anticoagulants that are needed for life in patients with mechanical prostheses, and even those who develop atrial fibrillation from mitral valve repair might not need the higher dose of anticoagulants necessary for those who receive a mechanical valve. The risk of endocarditis is much lower from mitral valve repair compared to replacement. As for any operation, patient selection for mitral valve repair is important. Although historical results of mitral valve repair for rheumatic regurgitation showed a success rate of 50%, better re- sults have been reported recently, with a reoperation in approxi- mately 20% of patients at 10 years. Surgical repair for rheumatic mitral valve disease is also affected by rheumatic aortic and tri- cuspid valve disease. The most common procedure is the quadrilateral resection of the posterior leaflet, removing excess valve tissue, reapproximating the scallops, and reducing the annulus, with or without mitral annuloplasty. The success rate of this technique is of the order of 90%. Although historically anterior leaflet repair was not so easy as that of the posterior leaflet, recent advances have made it as suc- cessful. An alternative approach (not widely accepted in the surgical community) is the Alfieri repair, which involves suturing the pos- terior and anterior leaflets together in the central section and cre- ating a double-​orifice mitral valve. Non​surgical mitral-​clip insertion has emerged as a replacement for repair procedures where the surgical risk is high. This procedure involves transcatheter implantation of a clip that hooks the tips of the anterior and posterior leaflets, thus creating a double-​orifice mitral valve and reducing the extent of regurgitation. Early post-​ procedure results are satisfactory, but patients may continue to com- plain of breathlessness secondary to left ventricular stiffness rather than mitral regurgitation. It is now routine practice to use intraoperative transoesophageal echocardiography to provide detailed assessment and detect signs of valve dysfunction immediately on completion of surgery on the valve:  residual regurgitation can be dealt with before closure of the chest. In addition to mitral repair, patients with atrial fibrillation may be considered for arrhythmia ablation—​surgically or by radiofrequency—​to restore sinus rhythm. Results of the combined procedure have been satisfactory, even with chronic atrial fibrilla- tion before surgery. Mitral valve replacement Mitral valve replacement has a higher operative mortality than aortic valve replacement for aortic stenosis or regurgitation, or con- servative operation for mitral stenosis. Although survival from mi- tral valve replacement surgery has improved significantly over the years, probably because of the better selection, improved myocardial preservation, and surgical techniques, it remains of concern, par- ticularly in patients with ischaemic mitral regurgitation, where 5-​ year survival is 75%. The ideal valve would be a homograft in the mitral position, but this can only be achieved by use of a composite including the mitral valve and related structures and placing it attached to the annulus, which avoids cutting the papillary muscle heads and the chordae and preserves the continuity between the mitral valve apparatus and the left ventricle. However, such attempts have proved uniformly un- successful. Pulmonary autograft has been used in the mitral position with satisfactory results, but in only a small group of patients in one or two centres.

16.6  Valvular heart disease 3447 Mitral replacement by a mechanical valve or bioprosthesis is the only option for irreparable valves. It has a very satisfactory success rate, particularly when papillary muscles and chordae are preserved. Bileaflet or tilting disc are currently the most commonly used mech- anical valves. Mixed mitral valve disease Mixed mitral disease is nearly always due to rheumatic valve disease. In general, it occurs in older patients than pure mitral stenosis, and the valve is more likely to be calcified with limited cusp mobility and scarred subvalve apparatus. The mitral regurgitation is not usually severe, but the increased stroke volume increases the diastolic pres- sure drop across the valve. Symptoms are the same as for mitral stenosis or regurgitation. On examination the first heart sound is not palpable or loud, the pansystolic murmur is usually loudest towards the axilla, and there is a mid-​diastolic murmur. The chest radiograph (Fig. 16.6.8) may show more advanced changes than in pure mitral stenosis (see Fig. 16.6.1):  the left atrium can be extremely large. Echocardiography is likely to show thickened cusps with reduced motion in addition to mitral re- gurgitation. When symptoms merit, valve replacement is usually required. Aortic valve disease Aortic stenosis Causes Aortic stenosis is caused by congenital, rheumatic, or senile disease. It may be at subvalvar, valvar, or supravalvar level, the commonest being valvar stenosis. Age-​related degenerative calcific disease is now the commonest cause of aortic stenosis in western Europe and the United States of America. The commonest congenital valvar aortic disease is the bi- cuspid aortic valve, which may remain completely silent for years, but as age advances the leaflets become thickened and calcified re- sulting in significant reduction in valve area, raised transvalvar vel- ocities, and pressure drop (gradient) across the valve. Rheumatic aortic stenosis is nearly always associated with aortic regurgitation (‘mixed aortic valve disease’) and with rheumatic mitral disease. Symptomatic valvar aortic stenosis is more prevalent in men. Subvalvar aortic stenosis is caused by a membrane (shelf) or a hypertrophied upper septal segment bulging into the outflow tract. Subaortic membrane is a congenital anomaly that commonly pro- gresses with age. Hypertrophy of the upper septum is an acquired syndrome that affects older people, particularly those with long-​ standing hypertension. Supravalvar aortic stenosis is rare:  when found it is commonly part of Williams’ syndrome (OMIM 194050; ‘elfin’ facies with low nasal bridge, unusual behaviours and mental retardation, transient hypercalcaemia; supravalvar aortic stenosis). Pathophysiology and complications In addition to the anatomical narrowing of the aortic valve, left ventricular function plays an important role in determining the transvalvar velocities. Patients with severe aortic stenosis and poor left ventricular function may have underestimated velocities and pressure drop. By contrast, those with mild valve narrowing but a hyperactive ventricle (e.g. hyperdynamic circulation) may present with overestimated velocities across the valve; in particular, signifi- cant aortic regurgitation can lead to overestimation of the degree of valve stenosis because of increased stroke volume. Despite various attempts to determine the most sensitive marker of aortic sten- osis, valve gradient (pressure drop) remains the most appropriate measure in clinical practice. Left ventricular response With the increase in outflow tract resistance in aortic stenosis, left ventricular wall stress increases and hypertrophy develops. This compensatory mechanism preserves overall ventricular systolic function. Most patients develop concentric left ventricular hyper- trophy and increased mass, which regresses after removal of the stenosis. Patients with untreated aortic stenosis may present very late with left ventricular cavity dilatation, reduced ejection fraction, and dyssynchrony. Left ventricular subendocardial ischaemia may result from long-​standing ventricular hypertrophy and outflow tract obstruction, and diastolic left ventricular function also become im- paired, resulting in increased end-​diastolic pressure and left atrial pressure. Most patients with aortic stenosis who are allowed to reach this degree of ventricular dysfunction complain of progressive breathlessness and finally pulmonary oedema. Fig. 16.6.8  Chest radiograph of a patient with mixed mitral valve disease, showing gross cardiac enlargement, mainly due to dilatation
of the left atrium.

section 16  Cardiovascular disorders 3448 Coronary circulation Even in the absence of significant coronary artery disease (ath- erosclerosis), the coronary circulation plays an important role in the pathophysiology and clinical presentation of aortic stenosis. Proximal coronary artery size is often increased, probably as a com- pensatory mechanism for the increased myocardial oxygen demand because of left ventricular hypertrophy, but coronary flow reserve re- mains suboptimal. This limited coronary flow reserve is manifested in the subendocardium, which may become irreversibly damaged, and the more severe the aortic stenosis, the greater the impairment of subendocardial function. Furthermore, left ventricular relaxation is usually prolonged in left ventricular hypertrophy, which further reduces coronary flow. The combination of hypertrophy-​related altered coronary flow and increased myocardial work probably contributes to the angina-​like symptoms, even in the absence of epi- cardial coronary disease. Regression of left ventricular hypertrophy after aortic valve replacement improves coronary flow reserve. Clinical presentation Symptoms Mild aortic stenosis does not give any symptoms, and even severe stenosis may be silent. Breathlessness or exercise intolerance is the most common symptom. Progressive deterioration of left ven- tricular function and increased end-​diastolic pressure leads to acute pulmonary oedema and florid heart failure. Angina is the second most frequent symptom, but less common than breathlessness. When it happens, it represents a significant mismatch between myo- cardial oxygen supply and demand, and it may be exercise limiting even in the absence of epicardial coronary artery disease. The third symptom is syncope, which in some patients is clearly related to ex- ertion. This can be caused by reduced cardiac output due to out- flow tract obstruction, or by arrhythmia (transient atrioventricular block, ventricular arrhythmia, and carotid sinus hypersensitivity have all been described), with exercise-​induced peripheral vasodila- tation in the face of a fixed cardiac output the likely explanation for those who collapse when exercising. Physical examination The physical signs of significant aortic stenosis are very character- istic. Proper examination of the character of the pulse is crucial: a slowly rising, low-​amplitude carotid (or brachial) pulse has high specificity for diagnosing severe aortic stenosis, and there may be a carotid thrill. Arterial pulse pressure is narrow. The venous pressure is usually normal until late in the disease, but a small ‘a’ wave is often present. This is known as a Bernheim ‘a’ wave and appears to be related in some poorly understood way to the presence of left ventricular hypertrophy and atrial cross- talk: it should not be taken in isolation as evidence of pulmonary hypertension. The apex beat is often sustained and may be double, due to an add- itional left atrial impulse. On palpation of the precordium there may be a systolic thrill over the aortic area in severe cases. On auscultation the first heart sound is normal or soft, and may be preceded by a fourth heart sound. The characteristic long and harsh ejection systolic murmur is loudest at the base (second right intercostal space, also known as the aortic area) of the heart, and in most cases it radiates to the carotids. The murmur is often heard at the lower left sternal border, and in a minority the ejection sys- tolic murmur may also be referred to the apex. A systolic ejection click may be heard, typically in patients with an uncalcified bicuspid valve. The second heart sound in aortic stenosis is typically single because of the limited cusp movement in a heavily calcified valve, but in young patients with severe aortic stenosis and mobile leaf- lets the splitting of the second sound is reversed. A normal split-​ second heart sound is a reliable sign for mild aortic stenosis. A third heart sound may be heard when left ventricular cavity dilatation and raised left atrial pressure have developed. A soft early diastolic murmur is often present, which does not necessarily imply haemo- dynamically significant aortic regurgitation. It is important to note that these physical signs are modified as ventricular disease progresses and stroke volume falls. Pulse volume drops and the pulse loses its slow rising quality, the systolic murmur becomes shorter and softer and may even disappear, and a func- tional mitral regurgitant murmur can appear along with a third heart sound. Such ‘silent’ but critical aortic stenosis cannot be diagnosed reliably on the basis of physical signs: a high index of suspicion and a good-​quality echocardiogram are required to prevent misdiagnosis of ‘congestive cardiomyopathy, cause unknown’. Investigations Chest radiograph and electrocardiogram The chest radiograph may be completely normal in patients with uncomplicated aortic stenosis. Post-​stenotic dilatation of the as- cending aorta may be seen. Associated left ventricular disease leads to pulmonary venous congestion. In most patients the ECG shows evidence of left ventricular hypertrophy based on voltage criteria, but in some cases it can be completely normal. Advanced hypertrophy may be associated with non​specific T-​wave changes. With progressive left ventricular dys- function, QRS duration broadens and left bundle branch block may develop. Inverted U wave may be seen in patients with severe left ventricular disease. Echocardiography Echocardiography is the investigation of choice for patients with aortic stenosis, providing comprehensive information on valve anatomy and function and left ventricular size and function, as well as other associated cardiac abnormalities that may contribute to patient’s symptoms (e.g. mitral valve regurgitation). Transthoracic echocardiography is mandatory in all patients with suspected aortic stenosis. Transoesophageal echocardiography may assist in exam- ining the aortic root and the proximal ascending aorta. The most clinically valuable measure of severity of aortic sten- osis is transvalvular velocity using continuous-​wave Doppler. The blood flow sounds under two-​dimensional echocardiographic guid- ance assist in deciding on the optimum positioning of the probe for velocity recordings, with the beam as parallel as possible to the jet direction. Peak velocities across the aortic valve are converted into a pressure drop (pressure gradient) using the modified Bernoulli equation, P = 4V2. Timing of peak velocity across the valve is a good indicator of the degree of aortic stenosis: in mild stenosis velocities peak in early sys- tole, but in severe stenosis velocities peak in mid-​systole, in parallel with the rise in aortic pressure.

16.6  Valvular heart disease 3449 Aortic stenosis can be quantified as valve area, which can be cal- culated from Doppler velocity data using the continuity equation based on the fact that the flow rate across the stenotic valve and the normal subvalvar area are equal. Valve area is therefore calculated from the relative increase in blood velocity across the aortic valve with respect to the subvalvar region, in conjunction with an estimate of the subvalvar cross-​sectional area. Thus, an increase in peak vel- ocity across the aortic valve by five times that of subvalvar velocity, with a pressure gradient of at least 35 mm Hg, is consistent with a fivefold drop in aortic valve area and suggests severe aortic stenosis (Fig. 16.6.9). An important application of this principle is seen in patients who have a moderate aortic pressure drop and in whom it is not clear whether this is simply because stenosis is not severe, or because stroke volume is low due to impaired left ventricular function. Stress echocardiography is a useful investigation in these circumstances (Fig. 16.6.10). With increase in heart rate, the increased blood flow across the valve differentiates between severe valve narrowing and severe left ventricular disease. A significant increase in transvalvular velocities and pressure gradient reflects fixed valve area and hence the diagnosis of severe aortic stenosis. By contrast, failure of aortic velocities to increase significantly with stress suggests impaired left ventricular function as the cause of the low cardiac output and symptoms rather than aortic stenosis. Colour-​flow Doppler will reveal the presence of mild aortic re- gurgitation in most patients with aortic stenosis, and in those with 0.2m/s 1 m/s Fig. 16.6.9  Parasternal long-​axis views from a patient with severe calcific aortic stenosis (arrow) and poor left ventricular function showing a dilated cavity with increased end-​systolic dimension (LV). Transvalvar peak velocity of 3.0 m/​s (upper right panel) and subvalvar velocity of 0.6 m/​s (lower right panel). 1 m/s 55 mm Hg 120 mm Hg Fig. 16.6.10  Continuous-​wave Doppler of transaortic valve velocities at rest (left panel) and peak stress (right panel) showing significant increase in velocities and consequently gradient from 55 to 120 mm Hg.

section 16  Cardiovascular disorders 3450 impaired left ventricular function and raised end-​diastolic pressure Doppler recordings of aortic regurgitation should be assessed care- fully to avoid overestimating the degree of regurgitation because of raised left ventricular end-​diastolic pressure. Echocardiography can also provide accurate measurements of left ventricular dimensions and systolic function, as well as left ventricular hypertrophy and mass, from which mass index can be calculated. Left ventricular filling pattern guides the assessment of left atrial pressure. Most patients with aortic stenosis and left ventricular hypertrophy have a small early diastolic filling com- ponent and a dominant late-​diastolic one. With progressive left ventricular disease and increase in end-​diastolic pressure, the left atrial pressure increases and ventricular filling becomes of the re- strictive pattern, with a dominant early diastolic filling component with short deceleration time and a very small late-​diastolic filling component with flow reversal in the pulmonary veins. Most pa- tients presenting with this pattern of physiology have a dilated left atrium and some may even present with atrial arrhythmia. The ex- tent of the commonly found mitral regurgitation can also be as- sessed, and other parameters enable estimation of the presence and degree of pulmonary hypertension. Mitral annular calcification is a very common finding in patients with severe aortic stenosis but rarely contributes to any increase in atrial pressure or results in mitral stenosis. Cardiac catheterization High-​standard echocardiographic estimation of the severity of aortic stenosis is clinically very reliable and does not need to be reconfirmed by catheterization. The traditionally measured aortic pressure gradient during cardiac catheterization, using a pull-​back technique to record the difference between peak left ventricular and aortic pressure, is a less satisfactory measure than that possible echocardiographically because the two peaks do not occur simul- taneously. A further problem with estimation of aortic gradient by cardiac catheterization occurs because left ventricular pressure may not be uniform, hence the measured pressure difference depends on the location of catheter tip in the ventricle, particularly in the pres- ence of significant hypertrophy as in most cases of aortic stenosis. The difficulty increases since aortic pressure also depends on its dis- tance from the valve leaflets and the aortic wall, as well as the pres- sure recovery process in the aortic root. Such estimates should thus be regarded as semiquantitative. Cardiac catheterization is needed only to assess possible coronary artery disease, which frequently accompanies aortic stenosis. CT coronary angiography can now provide similar information. Differential diagnosis The commonest differential diagnosis that needs to be considered is aortic sclerosis, when examination of an elderly patient reveals an ejection systolic murmur at the cardiac base or left sternal edge. Other features of aortic stenosis—​slow rising pulse, narrow pulse pressure, radiation of the murmur to the carotids, presence of a thrill—​are not present. Most often in a younger patient the possibility of hypertrophic cardiomyopathy needs to be considered, but here the carotid pulse is normal or jerky rather than slow rising (see Chapter 16.7.2). Fixed subaortic stenosis also needs to be considered in children and young adults (see Chapter 16.12). All of these differential diagnoses can be distinguished from aortic stenosis by echocardiography. Management Progression of aortic stenosis is generally slow. Symptoms are vari- able but overall reflect left ventricular disease. Patients with a con- genital bicuspid aortic valve tend to develop symptoms at an average age of 50 years, whereas those with senile valve disease do so at the age of 70–​80 years. Patients with significant congenital aortic valve stenosis may develop symptoms earlier in life. Some 50% of patients with severe aortic stenosis die suddenly. Raised aortic velocities and gradient, and the rate of increase in velocities over time, are the most accurate predictors of outcome, the rate of deterioration being faster in senile disease than rheum- atic aortic stenosis. Once symptoms develop the outcome is poor without surgical intervention, with 5-​year survival less than 50%. Autopsy series showed that the average time from symptom de- velopment to death is 2 years in patients with exertional syncope, 3 years in those with dyspnoea, and 5 years in those with angina. It should be highlighted that prognosis is much better in patients with a high valve gradient rather than those with low gradient due to severe left ventricular disease. Recent data suggests that patients presenting with an ejection fraction below 20% fail to thrive even after successful aortic valve replacement surgery. Approximately 50% of adults with aortic stenosis who need sur- gery have additional coronary artery disease. Patients with angina-​ like symptoms who have only mild aortic stenosis are likely to have significant epicardial coronary disease, but a new onset of angina in patients with severe aortic stenosis may reflect a further deterior- ation of the degree of aortic stenosis and subendocardial ischaemia. A particularly difficult group of patients to manage is those with moderate aortic stenosis and angina-​like symptoms. Medical There is no medical treatment for aortic stenosis that will stop dis- ease progression. Asymptomatic patients with mild or moderate aortic stenosis require follow-​up; those with severe aortic stenosis need aortic valve replacement. It is prudent to advise those with moderate or severe disease to avoid strenuous exercise. A pressure gradient of more than 70 mm Hg across the aortic valve is a good indication for surgery, particularly in those who are symptomatic. Patients with severe aortic stenosis and left ventricular disease who present with heart failure should be stabilized before referral for sur- gery: diuretics are important, as well as β-​blockers for controlling the heart rate; vasodilators, including ACE inhibitors, are contra- indicated. Once a patient develops raised left atrial pressure and pulmonary hypertension the outcome is less than satisfactory, even with surgery. Instructions on endocarditis prophylaxis and the use of antibiotics before dental and surgical procedures should be given to high-​risk patients. Patients with other comorbidities and risks, in particular hyperlipidaemia, should have these addressed. The effect of statins on the rate of progression of aortic stenosis seems to be negligible. Surgical Recent advances in aortic valve surgery—​earlier intervention, changes in the procedures used, improved methods of myocardial preservation—​have resulted in a significant fall in surgical mortality,

16.6  Valvular heart disease 3451 to 2.0% in adults under 70 years of age. Concurrent coronary artery disease, ventricular dysfunction, and pulmonary hypertension are important surgical risks. Older patients with aortic stenosis, particu- larly those over the age of 80 years, tend to have a higher mortality, but age is not a contraindication to surgery. Surgical intervention in octogenarians has been shown to provide improvement in quality of life, with a 5-​year postoperative survival compared to only 1 year for the unoperated. Aortic valve repair  In young people aortic valvotomy is an ac- ceptable procedure, but the option of valve repair in adults remains uncertain. It may provide a medium-​term solution for a clinical problem, but further surgical intervention will definitely be required in the long term. Aortic valve replacement  • Tissue valves Tissue valves do not need anticoagulants in the absence of atrial fib- rillation. Although their durability is significantly lower than that of mechanical valves, indications for their use are clear: older people, young pregnant women, and patients with limited access to anti- coagulant therapy. Over the years the durability of tissue valves has significantly improved: for patients over the age of 60, modern, third-​generation, glutaraldehyde-​preserved valves provide 90% survival at 15 years. Stentless tissue valves have better durability and are associated with faster recovery of ventricular function, but they are more difficult to implant. • Homografts The best option to replace a native valve is a human valve (homo- graft), but availability is limited. An aortic valve homograft replace- ment is particularly indicated in patients with endocarditis that involves the aortic root and is associated with abscess formation, be- cause a mechanical valve replacement in this scenario compromises eradication of the infection. Aortic homograft implantation tech- niques have evolved from a two-​layer subcoronary implantation to conduit implantation, which involves replacing the valve and sinus of Valsalva by a full root and valve. This still is considered more chal- lenging than mechanical or tissue valve implantation. Under the age of 30 years aortic homografts tend to fail within 10 years: in older patients the mean survival of the valve is 15 to 18 years. • Pulmonary autograft An alternative procedure is the pulmonary autograft or ‘Ross pro- cedure’. This goes back to 1967 when Donald Ross transferred a patient’s own living pulmonary valve to the aortic position and inserted a homograft in the pulmonary position. In children these autograft valves, unlike any other valve substitute, are capable of growth. A pulmonary homograft is placed in the right ventricular outflow tract, where because of the lower pressures on the right side of the circulation the mean survival of the valve is 20 years. • Mechanical valves Over the years, technical improvement in valve design has been remarkable, providing larger orifice area and greater resistance to thrombosis. In the long term the commonest problem, affecting less than 5% of patients with mechanical prostheses, is paravalvular dehiscence. While this may not always be haemodynamically significant, it may be responsible for haemolytic anaemia due to shear stress on red blood cells, and it is a focus for infective endocar- ditis. Valve dysfunction due to subvalvar tissue ingrowth that influ- ences valve opening and closure remains a problem. • Transcutaneous aortic valve implantation A transcatheter stent-​mounted bioprosthesis is an alternative to surgical aortic valve replacement in patients with impaired left ven- tricular function, prior coronary artery bypass surgery, or other comorbidities (e.g. renal impairment or chronic obstructive pul- monary disease). The procedure has proved a great success in pa- tients with heavily calcified aortic root and valve. Long-​term clinical results of the transcatheter aortic valve implantation (TAVI) pro- cedure are similar to those of surgical aortic valve replacement, des- pite a slightly higher prevalence of stroke. Aortic regurgitation Causes Aortic regurgitation is caused by either leaflet disease or aortic root dilatation (Table 16.6.2), the commonest causes being iso- lated medionecrosis, rheumatic disease, infective endocarditis, and Marfan syndrome. Pathophysiology and complications The left ventricular stroke volume, which equals the forward stroke volume plus the regurgitant volume, is significantly increased in aortic regurgitation. This is accommodated by an increase in left ven- tricular cavity size, a process that is progressive in a similar fashion to mitral regurgitation, although the degree of ventricular dilata- tion is greater. Another difference between the two conditions is the peripheral vascular resistance, which is significantly raised only in patients with aortic regurgitation. This combination of volume over- load and raised peripheral resistance results in a progressive increase in left ventricular wall thickness and mass. In uncomplicated aortic regurgitation, the left ventricular ejection fraction is maintained, but as the disease progresses end-​systolic volume increases out of pro- portion to stroke volume, and eventually these changes lead to irre- versible damage which persists even after surgical correction of the aortic regurgitation. Table 16.6.2  Causes of aortic regurgitation Structure primarily affected Anatomical defect Cause Cusp Distortion Rheumatic Rheumatoid Ergot-​derived dopamine receptor agonists—​ pergolide, cabergoline (treatments for Parkinson’s disease) Fenfluramine, phentermine (appetite suppressants) Perforation Infective endocarditis Root disease Dilatation Isolated medionecrosis Marfan syndrome Syphilis Ankylosing spondylitis or other connective tissue disease Loss of support Dissecting aneurysm of aortic root Subaortic ventricular septal defect

section 16  Cardiovascular disorders 3452 Whether or not aortic regurgitation is accompanied by some degree of aortic stenosis due to intrinsic valve leaflet disease, the increase in stroke volume causes high systolic velocities across the aortic valve. Pressure relations between the aorta and the left ventricle in diastole are of great importance, in particular the end-​ diastolic pressure difference that depends not only on aortic but also on left ventricular end-​diastolic pressure: the higher the left ventricular end-​diastolic pressure, the lower the pressure difference across the valve. In mild aortic regurgitation the pressure drop between the aorta and the left ventricle is maintained throughout diastole. By contrast, with acute aortic regurgitation the pressure difference between the aorta and the left ventricle falls to 15 mm Hg or even less before end of diastole, either because of the very low resistance at the valve level or because the left ventricle is stiff, hence a relatively small regurgitant volume causes a disproportionate rise in left ventricular diastolic pressure. This disturbed physiology has major implications because the aortic–​left ventricular diastolic pressure gradient is the pressure head supporting the coronary flow. Coronary autoregulation stops at a perfusion pressure difference between the aorta and the left ven- tricle of 40 mm Hg, and with acute aortic regurgitation—​or even severe chronic aortic regurgitation—​the gradient is less than this, resulting in significant myocardial ischaemia and progressive ven- tricular dysfunction. This disturbed physiology may be tolerated in chronic severe aortic regurgitation, but in acute severe aortic regur- gitation it may contribute to rapid clinical deterioration. The limitation of coronary flow by a raised ventricular end-​ diastolic pressure is further exacerbated by the increased oxygen demand of the myocardium as a result of the hyperdynamic ven- tricular state, as well as (in chronic regurgitation) the hypertrophy resulting from the volume overload. This causes subendocardial is- chaemia, particularly with stress. Clinical presentation Symptoms Patients with aortic regurgitation may remain asymptomatic for a long time. The onset of symptoms, particularly breathlessness, co- incides with the onset of left ventricular disease, a significant rise in end-​diastolic pressure, and development of pulmonary venous hypertension. Angina is an uncommon symptom in chronic aortic regurgitation, but when it occurs it should suggest significant subendocardial ischaemia as a result of the mismatch between the coronary artery flow and myocardial mass. It is more common in those with acute aortic regurgitation. Any sudden worsening of symptoms may reflect acute deterioration of the degree of aortic re- gurgitation or impairment of left ventricular function. Physical examination The physical signs of significant chronic aortic regurgitation are characteristic. The pulse has large amplitude and is ‘collapsing’ in nature (‘water hammer’, Corrigan’s pulse) due to the increased stroke volume and rapid fall-​off in aortic pressure during diastole. When severe, this can induce pulsations in many parts of the body, generating many eponyms that describe what is effectively a single physical finding. Among the better known of these are Quincke’s ca- pillary pulsations (best demonstrated by blanching a portion of a fingernail by applying gentle pressure and observing the pulsating border between the white and the red segments), de Musset’s sign (bobbing of the head in time with the arterial pulse, named after the French poet who had the condition), and pulsations of various organs or their parts (uvula—​Muller’s sign, retinal arteries—​Becker’s sign). The same pathophysiology underlies two peripheral arterial signs. Pistol shot sounds are short, loud sounds that can be heard over large peripheral arteries if the stethoscope is lightly applied: they occur because of sudden expansion and tensing of the walls during sys- tole. Duroziez’s sign is a double to-​and-​fro (systolic and diastolic) murmur heard over the brachial or femoral artery if the stethoscope is firmly applied: the diastolic component results from reversal of flow in the artery during diastole. A diastolic blood pressure of less than 50 mm Hg and/​or a pulse pressure of 80 mm Hg or more suggest moderate or severe regurgi- tation in patients who have a characteristic murmur (but are of no significance with regard to the aortic valve if no murmur is present). The venous pressure is normal until late in the course of disease, although a dominant Bernheim ‘a’ wave may be seen. The apex beat is sustained and/​or displaced because of the left ventricular hyper- trophy and/​or dilatation. On auscultation the classical murmur of aortic regurgitation is diastolic, starting immediately after the second heart sound, de- crescendo in nature, and loudest at the left sternal border. It may be short, or extend throughout diastole. It may radiate to the right sternal border if it is caused by aortic root dilatation, and rarely it is loudest at the apex or even in the left axilla. The louder the murmur, the more severe is the regurgitation. The heart sounds may not dem- onstrate any specific change in aortic regurgitation, or—​as with aortic stenosis—​the aortic component of the second heart sound may be absent. An ejection systolic murmur due to increased stroke volume is nearly always present. At the apex, a low-​pitched mid-​ diastolic murmur (Austin–​Flint murmur) mimicking that of mitral stenosis may be heard: it is usually assumed that this is due to the aortic regurgitant jet striking the anterior leaflet of the mitral valve, but other hypotheses have been advanced. In acute aortic regurgitation—​usually caused by infective endo- carditis, thoracic aortic dissection, or disintegration of a tissue valve replacement—​the physical signs are quite different, based on the fact that the stroke volume in acute regurgitation does not increase by the same magnitude as in chronic regurgitation. The patient is cold and shut down due to a low cardiac output, with tachycardia, a low systolic blood pressure and low pulse pressure, and a short early dia- stolic murmur that is easily missed. The apex is not displaced and peripheral signs are absent. There may be a loud third heart sound. Investigations Chest radiograph and electrocardiogram The chest radiograph may show increased cardiothoracic ratio and dilatation of the aortic root (Fig. 16.6.11). In isolation these appear- ances cannot be taken as diagnostic, but they are very useful for follow-​up of a known case. The 12-​lead ECG may demonstrate increased voltage and a ‘strain’ pattern that correlates with increase in left ventricular cavity dimen- sions, hypertrophy, and wall stress. The voltage pattern may fall sig- nificantly after correction of the aortic regurgitation and regression of left ventricular mass. Non​specific T-​wave changes may occur with exercise, reflecting either the development of subendocardial

16.6  Valvular heart disease 3453 ischaemia or increase in systolic left ventricular volume. Increased QRS duration is a marker of left ventricular disease. A  long PR interval may indicate aortic root abscess, particularly in those with other clinical suspicion of endocarditis. Echocardiography Doppler echocardiography is an invaluable investigation in the assessment of patients with aortic regurgitation (Fig. 16.6.12). Two-​dimensional images can identify the exact cause of regurgi- tation, revealing the valve anatomy, leaflet number, calcification, or evidence of infection. The diameter of the aortic root and prox- imal ascending aorta can also be measured. Transoesophageal examination is always recommended if this is not achievable on transthoracic images, particularly in patients with Marfan syn- drome or those presenting with suspected dissection. Left ven- tricular size, dimensions, wall thickness, and ejection fraction can easily be measured, and muscle mass calculated using simple for- mulae. Colour Doppler detects the presence of aortic regurgita- tion and gives some idea of its severity: the finding of large vena contracta, a large regurgitant orifice area, and jet diameter more than 50% of the aortic root diameter are all consistent with signifi- cant regurgitation. Continuous-​wave Doppler is ideal for assessing regurgitation severity as well as pressure differences between the aorta and the left ventricle (Fig. 16.6.13): in general, the faster the pressure decline on the aortic regurgitation trace, the more severe is the regurgitation likely to be, although this does not apply in patients with raised end-​diastolic pressure. Doppler can also con- firm severity of aortic regurgitation by demonstrating flow re- versal in the descending aorta or femoral arteries. In patients with symptoms disproportionate to the degree of aortic regurgitation, a diagnosis of left ventricular disease should be considered (e.g. hypertension or coronary heart disease). In acute aortic regurgitation echocardiography clearly demon- strates the cause of the disease; endocarditis with its complications or disintegrating homograft or bioprosthesis. M-​mode echocardi- ography shows premature mitral valve closure which, together with the left ventricular activity, support the diagnosis of acute aortic regurgitation. Fig. 16.6.11  Chest radiograph of a patient with chronic aortic regurgitation showing cardiac enlargement and dilatation of the ascending aorta. Fig. 16.6.12  Transoesophageal echocardiogram from a patient with aortic regurgitation on colour-​flow Doppler. Fig. 16.6.13  Continuous-​wave Doppler from the same patient as shown in Fig. 16.6.12, showing significant regurgitation based on the rate of transvalvar pressure decline in diastole (between the arrows).

section 16  Cardiovascular disorders 3454 Cardiac catheterization Cardiac catheterization is not needed to assess the severity of aortic regurgitation: it is only needed to confirm the presence of additional coronary artery disease, particularly before surgical intervention. Differential diagnosis It can sometimes be difficult to distinguish the early diastolic murmur of aortic regurgitation from that caused by pulmonary re- gurgitation (Graham Steell murmur). In this circumstance no other features of aortic regurgitation are expected, and pulmonary regur- gitation is usually associated with other signs indicating the presence of significant pulmonary hypertension (including a large pulmonary artery on the chest radiograph). Other causes of aortic run-​off, including persistent ductus arteriosus, ruptured sinus of Valsalva aneurysm, and coronary ar- teriovenous fistula, can also produce auscultatory findings that can be confused with aortic incompetence. However, they all cause a continuous murmur, rather than one confined to diastole. Management It is uncommon for mild aortic regurgitation to progress rapidly to severe regurgitation, hence the importance of Doppler echocardi- ography in the follow-​up of patients. Identification of the cause of aortic regurgitation helps in determining how often patients should be reviewed: those with mild aortic regurgitation due to aortic root or ascending aorta disease should be followed up more closely than those with stable valve disease. Patients with moderate or severe aortic regurgitation may have no symptoms for years. As symptoms always reflect ventricular dysfunction, a progressive increase in end-​systolic dimension/​volume should be taken as an indication for serious consideration of surgery, even in the absence of symptoms. Ejection fraction cannot be taken as a marker of ventricular function in aortic regurgitation because of the volume overload and overesti- mation of the ejection performance: an end-​systolic dimension up to 40 mm carries a good prognosis, whereas a dimension more than 50 mm is associated with 20% possibility of developing ventricular dysfunction, symptoms, or even death over a course of 5 years. In the same way that patients with aortic regurgitation secondary to aortic valve disease are managed, those with aortic regurgitation associated with or causing aortic root dilatation should be followed up to assess the aortic root dimensions, with the aim of preventing progressive dilatation and the potential risk thereof. Some patients with a bicuspid aortic valve develop progressive dilatation of the aortic root and ascending aorta because of the eccentric jet, as well as the accompanying aortopathy. Another group of patients who need regular follow-​up and careful aortic root assessment are those with Marfan syndrome, in whom aortic root aneurysmal dilatation and dissection are the major causes of morbidity and mortality. In addition to using conventional Doppler echocardiography, CT scan- ning and MRI can play a useful role in the follow-​up of patients with aortic root or ascending aorta disease, and three-​dimensional echo- cardiography for assessment of left ventricular size and function (see Chapters 16.3.2 and 16.3.3 for further discussion). Medical Medical management in aortic regurgitation aims at slowing down its progression, supporting the left ventricle, and determining the optimal time of surgical intervention. The increased afterload in patients with aortic regurgitation should be managed medically to reduce the wall stress and the diastolic driving pressure across the valve. Doing so decreases the pressure and the volume overload on the left ventricle and prevents progressive left ventricular dilatation and systolic dysfunction, and can delay the need for surgery. This effect has been demonstrated using ACE inhibitors and calcium channel blockers, the choice of the pharmacological agent for left ven- tricular afterload reduction depending on the other comorbidities (e.g. coronary artery disease), as well as patient tolerance. Patients with aortic root dilatation should not be treated with vasodilators alone. In this instance β-​blockers are recommended because they decrease aortic wall stress, blood pressure, and the rate of pressure increase in systole. Although patients with Marfan syn- drome may remain completely asymptomatic, the rate of aortic root dilatation is the most important risk factor. It may be that the com- bination of β-​blockade with ACE inhibition/​angiotensin receptor blockers (possibly acting through inhibition of TGF​β signalling) may prove effective in retarding or even preventing dilatation. However, when dilatation does occur, previous guidelines have suggested that aortic root dimension larger than 55 mm is a good indication for surgical intervention, although recent recommenda- tions have advocated an earlier surgical approach, particularly in the presence of family history of dissection. See Chapter 16.11 for further discussion. As is the case with all valve disease, oral hygiene should be en- couraged in patients with aortic regurgitation and prophylactic antibiotics prescribed to cover dental, proctological, urological, and gynaecological surgeries for patients at risk. Surgical Although patients with severe chronic aortic regurgitation may re- main asymptomatic, surgical intervention should be offered when there is progressive increase in systolic dimension. A left ventricular end-​systolic dimension of 40 mm is a cut-​off value for preserved left ventricular systolic function, particularly for an active ventricle. Predictors of outcome after valve surgery are severe aortic regur- gitation, age, severe symptoms, exercise intolerance, and evidence for left ventricular hypertrophy on echocardiography. Raised left ventricular end-​diastolic pressure and the ratio of wall thickness to chamber dimension have also been identified as potential predictors of outcome. An additional risk is the presence of coronary artery disease. These patients should be carefully evaluated by preoperative cardiac catheterization and receive myocardial revascularization surgery and coronary grafting at the same setting with aortic valve replacement surgery. There is evidence to suggest that patients with aortic regurgitation and ventricular dysfunction develop faster re- verse remodelling and fall of left ventricular mass index following successful valve replacement if they receive a stentless rather than a stented valve. Details of surgical procedures for aortic regurgitation are as described in the preceding section on aortic stenosis. Acute aortic regurgitation, irrespective of its aetiology, should be managed as an emergency with surgical intervention. While diag- nostic evaluation is in progress, the patient should be treated with afterload reduction. Aortic balloon counterpulsation is contra- indicated because it increases afterload. Cases caused by infective endocarditis should receive optimal antibiotic therapy following blood culture and emergency valve replacement, which could be life-​saving.

16.6  Valvular heart disease 3455 Mixed aortic disease Mild to moderate aortic regurgitation often accompanies aortic stenosis but does little to alter the overall clinical picture. The com- bination can result from a bicuspid aortic valve or chronic rheum- atic heart disease, or be the result of endocarditis or conservative surgery on a stenosed valve. The main haemodynamic disturbance is increased resistance to ejection, but the superimposition of even a moderately increased stroke volume due to regurgitation on the small, stiff left ventricle of pure aortic stenosis can lead to high filling pressures, left atrial enlargement, and even pulmonary hyperten- sion. Breathlessness and chest pain are the most prominent symp- toms. The arterial pulse is bisferiens, and typical ejection systolic and early diastolic murmurs are expected. Patients with symptoms are likely to require valve replacement. Right heart valve disease Many of the conditions that affect right-​sided valves are congenital: these are discussed in detail in Chapter 16.12. Particularly pulmonary and tricuspid valve diseases that develop later in life are discussed here, after general discussion of effects of abnormal right-​sided haemodynamics on right heart function and diagnostic techniques. Pathophysiology and complications Right ventricular response to valve disease The right ventricle responds to chronic pressure overload (e.g. caused by pulmonary stenosis or pulmonary hypertension) by hypertrophy and early dilatation. With increased afterload and right ventricular dilatation the ventricle adapts by making the intraventricular septum function as part of the right heart. This can be identified by studying septal movement during various phases of the cardiac cycle using M-​mode echocardiography, revealing that it becomes reversed in systole and in diastole. Right ventricle dilatation includes the tri- cuspid annulus and results in tricuspid regurgitation. Eventually right ventricular systolic function deteriorates, and this may become irreversible even after correcting the volume or pressure overload. With right ventricular volume overload the ventricle is very active, readily apparent on recording its free-​wall movement at the level of the tricuspid ring. However, assessing right ventricular ejection frac- tion and overall systolic function is difficult because of its complex anatomy, being made up of an inlet portion and an outlet portion that are at a significant angle to each other, and a trabecular portion at the apex. Assessment of right ventricular size and function A three-​dimensional approach to the assessment of right ven- tricular systolic function is the ideal method, but other cross-​ sectional echocardiographic and MRI techniques have developed over the years and proved sensitive in assessing right ventricular ejection fraction. Right ventricular inlet diameter can be used as a marker of cavity dilatation. Free-​wall long-​axis movement studied by M-​mode and tissue Doppler imaging from the lateral angle of the tricuspid annulus is an easy measure of systolic function and correlates closely with right ventricular ejection fraction. Likewise, right ventricular outflow tract diameter has been shown a sensi- tive measure of systolic function. In patients with reversed septal movement, it is crucial to exclude any shunt as a cause for volume overload on the right ventricle. Estimation of pulmonary artery pressure is an essential compo- nent in the evaluation of patients with right-​sided valve disease. The retrograde flow velocity across the tricuspid valve gives an indica- tion of systolic right ventricular pressure by use of the simplified Bernoulli equation. In all patients systolic pulmonary artery pres- sure equals the retrograde peak pressure drop across the tricuspid valve added to the estimated right atrial pressure, according to the collapsibility of the inferior vena cava. These measurements are clin- ically useful in patients without pulmonary stenosis. Investigation of valve stenosis and regurgitation The methods used in clinical practice for investigating possible tri- cuspid and pulmonary valve stenosis and regurgitation are the same as those used in assessment of conditions affecting the left side of the heart. Colour Doppler detects the level at which there are increased velocities as a sign of valve narrowing, which can be confirmed by continuous-​wave Doppler. In patients with valve regurgitation, colour Doppler assesses the jet diameter, direction, and area which, with respect to the right atrial area in cases of tricuspid regurgita- tion, gives some indication of the severity of tricuspid regurgitation. Transoesophageal echo images, particularly in tricuspid valve dis- ease, provide detailed assessment of valve pathology. Transthoracic images of the pulmonary valve can be somewhat limited technically, but in most cases Doppler studies can exclude significant valve disease based on forward and backward velocities and pressure drop. Transoesophageal echo provides a clearer image of the pulmonary valve and so is best suited for determining the level of valve stenosis. The degree of pulmonary stenosis and regurgita- tion severity is assessed by continuous-​wave Doppler, with timing of reversal of regurgitant pulmonary flow being another confirmation of its severity. Mild pulmonary regurgitation occupies the whole of diastole, while in severe regurgitation there is early pressure equal- ization between the two chambers. A jet diameter of 7 mm or more also supports the diagnosis of severe pulmonary regurgitation. MRI is another good non​invasive technique for assessment of right-​sided chamber size and valve function, in particular the pul- monary valve. The level of narrowing can easily be determined, the degree of stenosis by velocity mapping, and severity of regurgitation by estimating the regurgitant volume. Tricuspid stenosis Tricuspid stenosis is a rare condition, most often caused by rheum- atic disease, which almost invariably simultaneously affects the mitral valve. Other (even rarer) causes are carcinoid disease, in- fective endocarditis, and Whipple’s disease. A right atrial myxoma or extension of hypernephroma into the inferior vena cava and right atrium can in very rare instances present with signs and symptoms of right ventricular inflow tract obstruction, similar to tricuspid stenosis. Symptoms include fatigue, dyspnoea, and fluid retention. In pa- tients with chronic rheumatic heart disease the problem is to rec- ognize that the tricuspid valve has been affected in addition to the mitral valve (and perhaps the aortic valve as well). If the patient is in sinus rhythm, there may be an ‘a’ wave in the venous pulse, which would be unusual in the presence of pulmonary hyperten- sion and mitral stenosis alone (when the patient is very likely to be in atrial fibrillation). On auscultation at the left or right sternal edge a mid-​diastolic murmur (usually higher in pitch than the murmur

section 16  Cardiovascular disorders 3456 of mitral stenosis) is heard, and a tricuspid opening snap may be present (later in the cardiac cycle than a mitral opening snap, and varying in timing in relation to P2 with respiration), although it is not possible to differentiate this reliably from the mitral opening snap that is likely to coexist. The chest radiograph shows a large right atrium with normal pul- monary artery size and clear lung fields. Echocardiography shows a dilated right atrium and demonstrates clearly the valve anatomy and function, as well as other intracardiac pathologies. The echo- cardiographic signs of rheumatic tricuspid disease are similar to those of the mitral valve, including commissural fusion, fibrosed leaflets that dome in diastole, short and fibrosed chordae, and raised transtricuspid forward flow velocities. Tricuspid valve disease progresses very slowly and needs careful follow-​up. Medical treatments are not satisfactory:  diuretics can help to minimize fluid retention, but at the expense of reduced car- diac output if pushed too hard. Mild and moderate tricuspid stenosis is generally tolerated; severe tricuspid stenosis needs surgical repair, or replacement if additional regurgitation is present. Tricuspid regurgitation Mild tricuspid regurgitation is found in 50% of normal individ- uals. Causes of significant tricuspid regurgitation are shown in Table 16.6.3, the commonest being secondary to either pulmonary hypertension or right heart dilatation. Endocarditis is commonly caused by intravenous access, either in those who abuse drugs intravenously, or in patients who required prolonged right heart catheters for medical therapy. Endomyocardial fibrosis, which is prevalent in tropical Africa, causes fibrosis of the papillary muscle tips and thickening and shortening of tricuspid valve leaflets and chordae. Permanent pacemaker wires across the tricuspid valve may rarely cause leaflet adhesions and dysfunction. Blunt trauma to the chest may be complicated by tricuspid regurgita- tion through the papillary muscle or chordal lacerations. Metastatic carcinoid tricuspid valve disease is rare, but echocardiographic find- ings of carcinoid involvement of the tricuspid valve are very charac- teristic, showing short, fibrosed, and thickened leaflets resulting in larger areas of incomplete coaption and severe tricuspid regurgita- tion. Tricuspid valve prolapse is occasionally seen in patients with mitral valve prolapse. The symptoms of tricuspid regurgitation are usually non​specific. When it develops in a patient with mitral stenosis it is often associ- ated with increased fatigue rather than breathlessness. Some patients will present with increasing peripheral oedema, and hepatic conges- tion may cause nausea or upper abdominal pain exacerbated by ex- ercise. Diarrhoea caused by a protein-​losing enteropathy (thought to be secondary to venous congestion of the gut) has been reported. The main physical sign is a raised venous pressure with prom- inent V-​wave, without which the diagnosis of significant tricuspid regurgitation is very difficult to sustain. In about one-​third of cases a pansystolic tricuspid regurgitation murmur can be heard at the left or right sternal edge: this tends to increase in intensity with in- spiration as the venous return increases, and it can radiate into the epigastrium. Expansile pulsation of the liver is present in most cases, but hepatic fibrosis (and jaundice) can occur if regurgitation is long-​ standing and this physical sign then disappears. Most patients with severe regurgitation have peripheral oedema, ascites, or both. The findings on a chest radiograph depend mainly on whether or not the patient has any other cardiac disease, but there may be enlargement of the heart shadow towards the right. The ECG may show right atrial hypertrophy. Echocardiography is the best way to make the diagnosis (Fig. 16.6.14). Cardiac catheterization is not re- quired for assessment of tricuspid regurgitation but may be indi- cated for diagnosis or assessment of other concurrent heart disease. Many patients tolerate tricuspid regurgitation for a long time, but some present with symptoms that significantly limit their exercise Table 16.6.3  Causes of tricuspid regurgitation Cause Type of condition Disease Primary Congenital Ebstein’s anomaly Atrioventricular defect Prolapsing cusp Acquired Rheumatic fever Infective endocarditis Permanent pacemaker wires Endomyocardial fibrosis Blunt trauma to the chest Carcinoid syndrome Ergot-​derived dopamine receptor agonists Following radiotherapy to the chest Secondary Functional Pulmonary hypertension or right heart dilatation Ischaemic right ventricular disease Fig. 16.6.14  Apical four-​chamber view from a patient with tricuspid regurgitation secondary to left-​sided dilated cardiomyopathy and mitral regurgitation: regurgitation into both left atrium (LA) and right atrium (RA) can be seen.

16.6  Valvular heart disease 3457 capacity and lifestyle. Medical treatment with diuretics and ACE in- hibitors may reduce systemic venous pressure and right ventricular size, even restoring competence to the tricuspid valve in some cases. Attempts should be made to treat pulmonary hypertension if this is the primary cause of right ventricular dilatation and tricuspid regur- gitation. If fluid retention is severe and refractory to medical treat- ment, careful consideration should be given to surgical correction of tricuspid regurgitation before the patient develops irreversible right ventricular damage. Repair and replacement of the tricuspid valve are problematic operations, with the former sometimes failing to prevent regurgitation and the latter leading to a significant dia- stolic pressure drop between the right atrium and ventricle, creating a problem of iatrogenic tricuspid stenosis, but in specialist centres the current approach is less conservative than it used to be. Tricuspid valvuloplasty is often performed at the time of mitral valve surgery for rheumatic disease. Annuloplasty involves a full ring, incomplete ring, or suture plication of the annulus. A semicir- cular ring has the advantage of maintaining annular flexibility and avoiding conduction disturbances, but residual tricuspid regurgi- tation occurs less often with a circular angioplasty ring than with a semicircular one. Tricuspid valve replacement by a mechanical prosthesis has a potential risk for endocarditis, particularly in drug abusers. Bioprostheses have a much lower thrombogenicity and re- sistance to flow in the tricuspid position and are therefore the pre- ferred choice. The surgical mortality of tricuspid valve surgery depends par- ticularly on the degree of preoperative hepatic congestion. Survival following tricuspid valve replacement is not purely related to the surgical procedure itself or to valve function, but is significantly af- fected by right ventricular dysfunction that is almost always masked by the volume overload before surgery. Pulmonary stenosis Pulmonary stenosis is congenital in 95% of cases (see Chapter 16.12): rarely it is caused by rheumatic valve disease or carcinoid syn- drome. Patients can tolerate moderate pulmonary stenosis (gra- dient <50 mm Hg) for years, fatigue and dyspnoea due to reduced cardiac output being the main symptoms in those with severe dis- ease. Physical examination reveals a prominent venous ‘a’ wave in the neck and an ejection systolic murmur at the upper left sternal edge that radiates to the suprasternal notch and left side of the neck. With severe pulmonary stenosis the pulmonary component of the second sound may be delayed, but it is often inaudible. An ejection click may be heard at the upper left sternal edge. Echocardiography and MRI show the level of stenosis. Doming leaflets are consistent with congenital valve disease. MRI imaging is particularly good for demonstrating supravalvar stenosis. Event-​free survival is related to the pressure gradient across the pulmonary valve. Balloon valvuloplasty is the procedure of choice for chil- dren and adults with significant pulmonary stenosis. On average transpulmonary gradient drops by two-​thirds of the baseline value without development of significant pulmonary regurgita- tion. Additional subvalvar stenosis may underestimate the success of the procedure. Surgical valvotomy may be considered if balloon valvuloplasty fails, and valve replacement may be needed for those with iatrogenic significant pulmonary regurgitation, especially after repair of tetralogy of Fallot. Homograft replacements might be ad- vantageous to avoid anticoagulation and thrombogenicity. Pulmonary regurgitation A small amount of pulmonary regurgitation is common. Significant pulmonary regurgitation is very rare and most commonly preceded by intervention to the pulmonary valve during childhood. Although the outcome of repair of tetralogy of Fallot is excellent in most cases, many of its complications are related to pulmonary regurgitation. Rare causes of pulmonary regurgitation are rheumatic disease, car- cinoid, and endocarditis. Many patients with pulmonary hyper- tension and dilatation of the right ventricular outflow tract will demonstrate some degree of pulmonary regurgitation. The typical murmur of pulmonary regurgitation is a soft early dia- stolic murmur that is best heard in the left upper parasternal region. It begins after the pulmonary component of the second sound and may be accompanied by an ejection systolic murmur caused by in- creased stroke volume. Most patients have enlarged neck veins and other evidence of pulmonary hypertension. Most patients with mild pulmonary regurgitation remain com- pletely asymptomatic for years. Although those with severe regurgi- tation may remain asymptomatic, correction of valve incompetence may save them irreversible damage of the right ventricle. Arrhythmia or progressive right ventricular dilatation are indications for sur- gery, using homograft or conduit and valve. Normalization of right ventricular size and function following pulmonary homograft inser- tion occurs in some but not all patients, probably depending on pre- operative ventricular dysfunction that could be masked by volume overload. FURTHER READING Henein MY (2009). Valvular heart disease in clinical practice. Springer, London. Henein MY (2012). Clinical echocardiography, 2nd edition. Springer, London. Mitral valve disease Alpert JS (1999). Mitral stenosis. In: Alpert JS, Dalen JE, Rahimtoola SH (eds) Valvular heart disease. Lippincott Williams & Wilkins, Philadelphia, PA. Baumgartner H, et al. (2017). 2017 ESC/​EATS guidelines for the man- agement of valvular heart disease. Eur Heart J, 21, 2739–​91. Breithardt OA, et al. (2003). Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol, 41, 765–​70. Devereux RB (1995). Recent developments in the diagnosis and man- agement of mitral valve prolapse. Curr Opin Cardiol, 10, 107–​16. Devereux RB, Kramer-​Fox R, Kligfield P (1989). Mitral valve pro- lapse: causes, clinical manifestations, and management. Ann Intern Med, 111, 305–​17. Dudek D, et al. (2017). Current trends in structural heart interventions: an overview of the EAPCI registries. EuroIntervention, 13, Z11–​13. Duren DR, Becker AE, Dunning AJ (1988). Long-​term follow-​up of idiopathic mitral valve prolapse in 300 patients: a prospective study. J Am Coll Cardiol, 11, 42–​7. Enriquez-​Sarano M, et al. (2005). Quantitative determinants of outcome in asymptomatic mitral regurgitation. N Engl J Med, 352, 875–​83. Gilard G, et al. (2016). 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