Mitral Valve Diseases

Transcription

1 1 7 Mitral Valve Diseases Maurice L. Enriquez-Sarano and Robert L. Frye The Normal Mitral Valve Mitral Valve Prolapse Mitral Regurgitation Key Points The predominant cause of mitral stenosis is rheumatic heart disease. The most frequent ECG abnormality with mitral stenosis is atrial fibrillation. The occurrence of atrial fibrillation (or atrial flutter) in the patient with atrial fibrillation requires anticoagulation initially by heparin followed by coumadin and often of treatment aiming at control of rapid ventricular response using digoxin, beta-blockade, and calciumchannel blockade. Guidance by transesophageal echocardiography (TEE) is useful to rule out atrial thrombus before cardioversion. Prolapse of the mitral valve is a fall below its normal position, and billowing (bulge beyond its normal place) of the mitral valve is an abnormal movement of the mitral valve during systole beyond its normal position and into the left atrium. Often mitral valve prolapse is a progressive disease with flail leaflets and chordal rupture being found in older patients. Mitral insufficiency is an organic mechanism if there is intrinsic mitral valve disease or a functional mechanism if the valve is structurally normal but regurgitates due to an extravalvular abnormality. Surgical correction of mitral regurgitation (MR) is indicated in patients with severe MR and symptoms or with reduced LV systolic function. Prevention of infective endocarditis using the appropriate antibiotic prophylaxis is necessary in patients with MR. The most frequent cause of mortality after surgical correction of MR is left ventricle dysfunction due to chronic irreversible myocardial damage. The Normal Mitral Valve The mitral valve has two leaflets (Fig. 17.1) attached at their bases to a fibrous annulus and by their free edges to their chordae tendineae. 1 Each leaflet has a rough zone toward the free edge and a central clear zone toward the base. The anterior leaflet occupies only one third of the circumference of the annulus but is longer than the posterior leaflet so that the leaflet apposition (coaptation) is along an upward concave curve resembling a smile. The anterior leaflet is attached by a fibrous connection to the aortic annulus (intervalvular fibrosa). The posterior leaflet is attached to the mitral annulus above which the valve tissue is a continuation of left atrial endocardium. The separations between leaflets (the commissures) are anterolaterally and posteromedially positioned. 2 The posterior leaflet is composed of three scallops, anterolateral (P 1 ), medial (P 2 ), and posteromedial (P 3 ). The anterior leaflet has no scallops but the zones coapting with the posterior scallops are similarly called A 1 to A 3. The leaflets are thin, pliable, and have no inertia so that full opening is obtained immediately in diastole. The leaflets are attached to chordae tendineae by their tip (primary) or their body (secondary). The chordae are attached to the two papillary muscles (anterolateral and posteromedial), which provide chordae to both leaflets at and around each commissure. 3 The papillary muscles are attached to the left ventricle (LV) wall. The mechanisms ensuring competence of the mitral valve are the preclosure following atrial contraction, which allows the leaflets to approximate before the ventricular contraction; the orientation of the anterior leaflet, parallel to the flow, which slides on its ventricular surface in systole; and the coaptation on rough zones of the atrial surface, creating strong but passive friction resistance when the leaflets are apposed. The leaflets are composed of four layers: auricularis, spongiosa, fibrosa, and ventricularis. The auricularis is composed of collagen and elastic tissue and is continuous with the endocardium of the left atrium. The spongiosa is situated between the auricularis and fibrosa layers and is formed by a loose connective tissue. The fibrosa constitutes the basic support for the leaflet and is composed of thick collagen. This layer is continuous at its base with the mitral annulus and the intervalvular fibrosa and at its free edge with the chordae tendineae. The ventricularis is a thin layer of collagen and elastic tissue that covers the ventricular aspect of the fibrosa and is continuous beyond the 397

2 398 chapter 17 FIGURE Anatomic ventricular view of a normal mitral valve. The commissures (C) are closed by a narrow band of valvular tissue. Ant Leaf, the anterior leaflet, the longest and narrowest; Post Leaf, the scallops of the short but widest posterior leaflet; PM, the two papillary muscles situated in regard to the commissures and distributing chordae to the corresponding parts of both leaflets. Chordae are indicated by arrows. posterior leaflet with the left ventricular endocardium and is part of the fibrosa. 4 Mitral Stenosis Pathophysiology The predominant cause of mitral stenosis (MS) is rheumatic heart disease. The valvular lesions produced by the rheumatic process in patients with MS are characterized by commissural fusion, which directly cause the stenosis. 5 There is also tissue retraction of leaflets and chordae tendineae, fusion of chordae, and ultimately postinflammatory calcification, which combined determine the feasibility of interventional or surgical treatment. 5 The commissural fusion is responsible for the reduction of mitral orifice size during diastole and also for the loss of physiologic valvular reserve (larger opening with larger flow) characterized by fixed mitral orifice irrespective of blood flow. 6,7 The major hemodynamic consequence of MS is left atrial (LA) pressure elevation, which when greater than 25 to 30 mm Hg is responsible for transudation of fluid into the pulmonary interstitial space. Left atrial pressure is determined by the transmitral diastolic pressure gradient, governed mostly by the orifice area and also by duration of diastole and stroke volume transported through the orifice. 8,9 Tachycardia decreases diastolic time and for a given stroke volume augments transmitral diastolic flow rate, pressure gradient, and LA pressure. 10 Increased stroke volume for any given diastolic filling period (such as with pregnancy or anemia) increases transvalvular velocity linearly with flow, but as pressure gradient is a square function of velocity, may lead to marked LA pressure elevation. 11 When the mitral orifice (normally 4 to 6 cm 2 ) is reduced to 2 to 2.5 cm 2 (mild MS), LA pressure is normal under resting conditions, but may increase abnormally with excess blood flow or heart rate changes. With orifices of 1.5 to 2.0 cm 2 (moderate MS), LA pressure, mildly elevated at rest, may increase markedly with sustained exercise. When the mitral orifice is <1.5 cm 2 (moderately severe to severe MS), LA pressure is augmented at rest, and pressure gradients of more than 10 mm Hg can be observed. Such patients have often reduced cardiac output and dyspnea during mild exercise or even at rest. For any given orifice area, previously asymptomatic patients may suddenly become symptomatic if they become pregnant, infected, or anemic or develop atrial fibrillation with rapid ventricular response. Left atrial response to MS with chronic elevation of LA pressure is characterized by LA dilatation, which in turn is a compensatory mechanism normalizing LA compliance 12 and activating natriuretic peptides. 13 However, LA dilatation may also have deleterious consequences with reduced blood flow and increased local coagulability, 14,15 which may lead to thrombus formation and with reduced electrical stability which may lead to atrial fibrillation. Also, increased LA transport function plays an important hemodynamic role in MS. Left atrial contraction augments end-diastolic mitral blood flow and maintains stroke volume despite reduced orifice area. Occurrence of atrial fibrillation, even with acceptable ventricular response, is responsible for approximately a 20% decrease in cardiac output. Therefore, maintenance of sinus rhythm is important for the well-being of patients with MS. Conversely, left ventricular dysfunction is not a major concern in MS. Although ejection fraction may be reduced, it is mostly an unloading phenomenon, is usually not progressive, and has modest effects on outcome. 16 Pulmonary vascular response to chronically elevated LA pressure leads to increased pulmonary vascular resistance and excessively elevated pulmonary pressure, which in turn may lead to right ventricular dilatation, tricuspid annular dilatation, and functional tricuspid regurgitation, and ultimately may lead to global heart failure. 17 Mitral stenosis is a progressive disease with progressive commissural fusion leading to a reduced valve area, which is amplified by periorificial calcifications and by subvalvular obstruction to flow due to chordal fusion and retraction. 18 Natural History The natural history from the initial rheumatic fever episode to the development of MS is reputed to be slow, taking a decade or much longer in developed countries, whereas in developing countries 19 the disease may progress more rapidly, 20,21 and severe MS may already be present in early adolescence. 22 This difference may be due to differences in utilization of antibiotics, recurrent carditis, virulence of bacterial strains, or genetic factors, but is attested to by differences in age at intervention in various world regions. This reduced MS development in developed countries has resulted in a major decline in the prevalence of MS requiring medical attention. The natural history of patients with established MS and medically managed has been defined by retrospective studies conducted in the 1950s and 1960s. 23,24 Mitral stenosis is a progressive disease with a slow, lifelong course that is initially asymptomatic and subsequently punctuated by acute complications or evolving into symptoms development. Once mitral stenosis has become symptomatic, it takes approximately 5 to 10 years for most patients to progress

3 mitral valve diseases 399 from mild to severe disability. In these natural history studies, survival has been analyzed according to the development of symptoms, but information regarding the influence of mitral valve area, LA size, or pulmonary pressure is lacking. Ten years after diagnosis in asymptomatic or minimally symptomatic patients, rates of mortality and of new symptoms are 20% and 40%, respectively. In the presurgical era, 5-year mortality rates were 38% in mildly symptomatic patients and 85% in severely symptomatic patients. The cause of death in these series was heart failure in 60% to 70% and thromboembolism in 20% to 30%. Clinical Evaluation The diagnosis of MS may be based on abnormal physical examination or Doppler echocardiography with symptoms either absent or nonspecific, such as fatigue or chest pain. Most patients are diagnosed with MS because of exertional dyspnea and more rarely because of complications such as pulmonary edema, hemoptysis, global heart failure, atrial fibrillation, or an embolic event (Table 17.1). The general appearance of patients with critical MS, the facies mitralis with malar cyanosis, is now exceptionally observed. Inspection of jugular veins may show prominent A waves in patients with pulmonary hypertension and in sinus rhythm or large V waves in patients with severe functional tricuspid regurgitation. Jugular vein distention, peripheral edema, and liver enlargement appear in patients with heart failure. Precordial palpation may reveal a right ventricular heave in patients with right ventricular dilatation, a palpable S 2 with severe pulmonary hypertension, and at the apex a palpable S 1 and rarely a diastolic thrill found while the patient lies on the left side. Auscultation reveals 25,26 a characteristically S 1 accentuated (due to the mitral thickening and wide closure movement with elevated LA pressure), but which may be normal or reduced with decreased leaflet mobility. S 2 is usually normal, but with pulmonary hypertension accentuation of the pulmonary component may be noted. An opening snap follows S 2, is best heard at the apex, and is usually highpitched but may be attenuated when valve excursion is limited by thickening or calcification. However, it rarely disappears and it may be the only auscultatory finding in patients with markedly reduced cardiac output. The time interval between A 2 and the opening snap is an indicator of LA pressure and is most often 0.08 second with mildly elevated LA pressure. Intervals <0.06 and >0.10 second suggest respectively severe and minimal LA pressure elevation. Thus, the A 2 opening snap interval, best measured by phonocardiography (or estimated at the bedside on physical examination), is an indirect measure of MS severity. A diastolic rumble can be best heard while the patient lies on the left side; it follows the opening snap and decrescendo, and displays presystolic accentuation in sinus rhythm. With a smaller mitral valve area the rumble is more holodiastolic, and with a higher gradient it is more intense. However, a holodiastolic rumble may be present in mild mitral stenosis and tachycardia. The diastolic rumble may be difficult to hear with increased heart-skin distance (obesity or emphysema) but may be of low intensity with low cardiac outputlow gradient. With markedly reduced output in patients with calcified leaflets of reduced mobility, MS may be silent, and the only clue to the presence of MS may be a faint opening snap. Systole is usually silent, but a systolic murmur (apical, early systolic with mild mitral regurgitation or xiphoid with inspiratory accentuation with tricuspid regurgitation) may be heard. An associated diastolic murmur may be heard along the left sternal border either due to pulmonary insufficiency (Graham Steell s murmur) with severe pulmonary hypertension or due to the frequently associated aortic regurgitation. Thus, it is usually possible to obtain a strong clinical impression of severe MS with loud and holodiastolic rumble with a thrill, short A 2 -opening snap interval, loud S 2, and tricuspid regurgitant murmur, but all these signs can be observed with moderate stenosis and increased cardiac output due to pregnancy, infection, or anemia. The most frequent ECG abnormality is atrial fibrillation. In sinus rhythm a prolonged P wave is due to LA enlargement. With pulmonary hypertension, a P pulmonale (tall P 2, P 2 > P 3 > P 1 ), a right axis deviation of QRS, and a tall R wave in V 1 with negative T s in V 1 to V 3 may be observed. The chest radiography may show LA dilatation, creating a double contour, widening of the carina, and LA appendage dilatation along the left sternal border. While the heart size is usually normal, marked LA, right atrial, and ventricular dilatation may result in frank cardiomegaly. With TABLE Clinical syndromes of mitral stenosis (MS) presentation Edematous MS Fibrotic MS Silent advanced MS Presentation year-old; no symptoms year-old; mild dyspnea year-old until pulmonary edema with exertion Class IV CHF Physical examination Loud S 1 and OS Audible S 1 and OS Soft OS Loud rumble Moderate rumble No rumble, decreased S 1 Pulsatile liver ECG Sinus; LA enlargement Atrial fibrillation Atrial fibrillation Chest x-ray Small heart; LA enlarged Marked LA and RA enlargement Marked cardiomegaly Echo-Doppler Small MVA, large gradient; Small MVA, modest gradient at Critical MS with massive calcification no MR; no calcification rest, MR present; commissural Severe pulmonary hypertension and TR calcifications Follow-up Balloon mitral valvuloplasty PBMV or surgery depending on MVR MR and calcification LA, left atrium; MR, mitral regurgitation; MS, mitral stenosis; MVA, mitral valve area; OS, opening snap; PBMV, percutaneous mitral balloon valvuloplasty; RA, right atrium; TR, tricuspid regurgitation.

4 400 chapter 17 FIGURE Echocardiographic long-axis view of the mitral valve in a patient with mitral stenosis. The large arrows indicate the leaflet tip thickening, typical of rheumatic mitral involvement and the small arrows indicate the diastolic hockey-stick deformation due to the restriction of movement of the anterior leaflet due to commissural fusion. Left atrium (LA) is markedly enlarged with normal left ventricular (LV) size suggestive of severe stenosis. Ao, aorta. Note the associated thickening of the aortic valve, suggestive of rheumatic disease. pulmonary hypertension, pulmonary trunk and branch dilatation and cephalization of the pulmonary circulation are present and often associated with interstitial markings of pulmonary edema and pleural effusion. Doppler echocardiography is the core test allowing positive diagnosis and assessing the severity and morphology of MS. Imaging shows the features of rheumatic disease (Fig. 17.2) with valvular thickening (predominant early on leaflet tips), retraction, and reduced mobility (particularly of posterior leaflet). Mitral stenosis diagnosis is based on doming of the anterior leaflet, direct planimetry of the stenotic mitral orifice, and increased diastolic velocity (and gradient) through the mitral valve. 27 Assessing MS severity can rely on several methods. First, mitral orifice planimetry (Fig. 17.3) in the FIGURE Doppler measurement of mitral transvalvular gradient in a patient with severe mitral stenosis in sinus rhythm. The transvalvular velocity is in excess of 2 m/sec and the mean gradient is calculated at 13.8 mm Hg. short axis view is simple but requires delicate positioning at the tip of the mitral funnel The value of three-dimensional echocardiography is currently being evaluated, 31 and may improve with enhanced image quality. Second, Doppler allows measurement of the transvalvular gradient (Fig. 17.4) and the pressure half-time method of measurement of the mitral valve area (Fig. 17.5) uses the velocity decay in early diastole and is most frequently used, 32 but may be affected by associated aortic regurgitation 33 or alterations of LV and LA compliance, particularly after balloon valvuloplasty. 34 Third, the continuity equation measures the orifice area as the ratio of the aortic stroke volume to the mitral stenotic jet time velocity integral by Doppler. It may be affected by underestimation of stroke volumes or by frequent presence of aortic regurgitation. Fourth, the proximal isovelocity Scale RV Area = 1.5 cm 2 LV Planimetered mitral orifice FIGURE Echocardiographic short-axis parasternal view in a patient with mitral stenosis. The image is obtained at the leaflet tip to allow planimetry of the mitral orifice. RV and LV, right and left ventricle. FIGURE Doppler measurement of the mitral valve area by the pressure half-time method. The slope of deceleration of the transmitral velocity indicates a pressure half-time of 223 ms, which calculates a mitral valve area of 1.0 cm 2.

5 mitral valve diseases 401 surface area (PISA) method uses color flow imaging of the flow convergence proximal to the mitral orifice to measure transvalvular flow (Fig. 17.6), the ratio of which to transvalvular velocity provides the orifice area. 35,36 Complex angular correction tends to limit its accuracy and reproducibility. Because all of these methods have a notable range of error, it is prudent to use two or more methods and average them to estimate the mitral diastolic valve area. An important measure of MS severity is the mean transvalvular gradient, measured by continuous-wave Doppler (Fig. 17.4) as the average of multiple beats. The mean gradient should be interpreted carefully depending on cardiac output (lower gradient with reduced output) and heart rate (increased gradient with higher rate). If necessary, assessment of mean gradient with exercise (using a graded recumbent bike protocol) 37 or dobutamine stress 38 shows rapid and marked gradient increase related to the heart rate and output increase in severe MS. Assessing MS morphology relies on the complete description of leaflets, commissures, chordae, and papillary muscle. 39 The valve score is a number between 4 and 16 (from lightest to most severe alteration) obtained by summing the scores between 1 and 4 for the leaflets thickening, lack of mobility, and calcification, and for subvalvular alteration. 40 Scores above 8 to 10 are usually considered as precluding balloon valvuloplasty. 41 Calcification location and severity assessment is crucial, because minor or unicommissural calcifications do not limit valvuloplasty, while bicommissural, diffuse, or severe calcifications usually preclude good results of valvuloplasty. 42,43 Presence and severity of mitral regurgitation (MR) are assessed by color flow imaging, if necessary using transesophageal echocardiography (TEE) in patients with uncertain transthoracic assessment. The presence of LA thrombus, particularly in the appendage, is assessed by TEE before valvuloplasty and in patients with recent thromboembolic complications. 44,45 Echocardiography should also differentiate true MS with commissural fusion from mitral obstruction due to protrusive mitral annular calcification, FIGURE Doppler echocardiographic measurement of the mitral valve area using the proximal flow convergence (proximal isovelocity surface area, PISA) method in a patient with mitral stenosis. The color flow image (left) is obtained with an upward shift of the baseline allowing the measurement of the radius of the flow convergence (double-head arrow), which allows calculation of the diastolic transvalvular flow. Measurement of the transvalvular velocity using continuous-wave Doppler (right) facilitates calculating the mitral valve area as the ratio of flow to velocity. C(17) D(9) 50 0 which is degenerative without commissural fusion and cannot be treated by balloon valvuloplasty. Cardiac catheterization, which was the first method to measure mitral valve area, 46,47 is now rarely necessary for the diagnosis or for severity assessment of MS. 48 It is usually part of pre balloon-valvuloplasty assessment. It allows direct verification of mitral gradient between LA and LV (Fig. 17.7) of pulmonary pressures and resistance and of MR severity by LV angiography. Coronary angiography may be performed depending on the patient s age and symptoms, particularly if surgery is considered. Management PCWP LV C(9) D(8) Mitral stenosis is a mechanical obstruction to mitral inflow, which should be relieved by a mechanical intervention (balloon valvuloplasty, commissurotomy, or valve replacement), indicated when the MS is severe and the patient presents with overt clinical consequences of the MS. As LV dysfunction is not a major outcome issue in MS, interventions in asymptomatic patients are rarely needed. Medical management aims at avoiding symptoms and complications. Appropriate rheumatic fever and infective endocarditis prophylaxis are needed. Limitation of physical activity and of salt intake, combined with low-dose diuretic administration, allows maintenance in a minimally symptomatic status sometimes for years. Patients with symptoms associated with marked tachycardia 10 with activity can benefit from beta-blockade. 49,50 The occurrence of atrial fibrillation (or flutter) requires administration of anticoagulation initially by heparin followed by Coumadin 51 and often of treatment aiming at control of rapid ventricular response using a combination of digoxin, beta-blockade, and calciumchannel blockade. Cardioversion covered by anticoagulation may be required urgently in patients with poor tolerance and is otherwise considered in patients with recent (<3 months) arrhythmia and without major atrial dilatation. Guidance by TEE is useful to rule out atrial thrombus before cardioversion. As atrial arrhythmias are markers of disease m/s FIGURE Pressure curve tracing obtained by catheterization with simultaneous continuous-wave Doppler recording. The left curves show a gradient measured simultaneously between the pulmonary capillary wedge pressure (PCWP) and left ventricular (LV) pressure. The gradient by catheterization (C), overestimates the Doppler (D) gradient. The right curves show a gradient obtained between the left atrial (LA) and LV pressures. The gradient by catheterization and Doppler are identical. LA LV

6 402 chapter 17 FIGURE Echocardiographic examination post balloon valvuloplasty in short axis view. RV, right ventricle: mv, mitral valve. Note the large mitral orifice with the large commissural opening of the medial commissure indicated by the arrow. The cross indicates the orientation (A, anterior; P, posterior; L, left; R, right). progression, recurrence should lead to the consideration of mechanical intervention rather than repeated cardioversion. Atrial fibrillation, even paroxysmal or a history of embolic events, requires permanent anticoagulation. Interventional treatment using percutaneous valvuloplasty with Inoue balloon (Fig. 17.8), or more rarely commissurotomy, 52 opens the commissural fusion mostly unilaterally and is the mainstay of mechanical obstruction relief currently. The most frequent approach is through transseptal catheterization with preprocedural TEE to rule out the presence of atrial thrombus, and echo guidance to progressively open the mitral orifice (Fig. 17.9) without inducing new mitral regurgitation. 53 Procedural mortality is <1% in high volume centers, and good results (orifice area >1.5 cm 2 with MR <2+) are obtained in 85% of patients, and these results are identical to those of surgical commissurotomy Postprocedural MR is often the result of valvular tears 60 and may require urgent surgical intervention. 54,61 The procedure is indicated in patients with MS with a valve area <1.5 cm 2, with class III or IV symptoms, or transient heart failure without atrial thrombus and with acceptable valvular anatomy (valve score 8, no bicommissural calcification, and MR <2+). Symptoms or severe exertional limitations may be unveiled by exercise testing in patients with asymptomatic MS 62 but with notable pulmonary hypertension. Patients who complain of no dyspnea but who present with embolic events and severe MS are also candidates for intervention after anticoagulation. The quality of the immediate result is mostly dependent on valvular anatomy, 54,63,64 while that of long-term result depends on age, heart failure at presentation, baseline anatomic characteristics, and the quality of the immediate result. 19,65 Patients with advanced valve score may have short-term benefit but incur a high rate of secondary degradation. 66 Long-term restenosis following surgical or percutaneous commissurotomy may benefit from repeated percutaneous intervention if the anatomic characteristics remain adequate. 55 Percutaneous valvuloplasty may be performed during pregnancy with minimal irradiation and with good maternal and fetal clinical results. 67,68 At 10 years the event-free survival after percutaneous valvuloplasty is 56%, implying that after the procedure continued careful followup is necessary. 19 Surgical treatment, which has been lifesaving in the initial phase of commissurotomy development, is rarely indicated currently and is reserved for patients in whom percutaneous intervention is considered contraindicated. Open-heart commissurotomy may be performed in patients with MS with severe subvalvular alterations requiring papillary muscle splitting or with MR that may require associated repair. However, most patients with advanced anatomic alterations or MR 2+ require mitral valve replacement. Because of the small but definite risk of interventional or surgical treatment, patients with asymptomatic MS and without embolic complications, even those with severe MS, are rarely considered candidates for preventive interventions. Asymptomatic patients with pulmonary hypertension should be carefully evaluated, particularly with exercise testing, to avoid underestimation of the functional limitations. Therefore, indications for interventions are based on comprehensive evaluation integrating clinical symptoms, history of embolism, comorbidity, functional capacity, hemodynamics, severity, and morphology of MS. FIGURE Percutaneous balloon valvuloplasty using the Inoue balloon and the transseptal approach. The sequence is as follows: upper left, the positioning of the balloon through the mitral orifice; lower left: inflation and pull back of the distal component of the balloon; upper right: partial inflation showing the marking of the mitral orifice on the balloon; lower right: complete inflation for commissural opening. Mitral Valve Prolapse The prolapse (fall below its normal position) or billowing (bulge beyond its normal place) of the mitral valve is an abnormal movement of the mitral valve during systole, beyond its normal position and into the LA. 72 Confusion has

7 mitral valve diseases 403 surrounded mitral valve prolapse (MVP) because of terminology (the use of the word prolapse to describe the movement and its cause) and because of diagnostic criteria (the saddle shape of the mitral annulus led to a false appearance of prolapse and to excessive diagnoses of MVP in the 1980s). An ensemble of etiologies causes this abnormal mitral movement by a variety of mechanisms, with a variable extent and variable consequences, so that MVP is a highly heterogeneous condition. 73 Etiology and Mechanisms FIGURE Anatomic posterior view of a heart showing the mitral, tricuspid aortic and pulmonary valves, and extensive mitral valve prolapse. Note the extensive billowing with hooding and thickening involving both leaflets. A mitral prolapse movement requires, isolated or grouped, any of the following mechanisms: excessive leaflet tissue, chordal elongation or rupture, or papillary muscle elongation or rupture. 74 The etiology can be primary or secondary. Primary MVPs have in common myxomatous degeneration, which is diffuse or localized and is characterized by leaflet redundancy and thickening due to an increase in spongiosa thickness with increased hydric content, 75 accumulation of proteoglycans, and collagen alterations. 74,76 The detailed mechanisms of myxomatous degeneration are uncertain, but alterations of matrix metalloproteinase expression in the spongiosa suggest that the process of degradation-regeneration of the matrix support tissue is dysfunctional. 77 Primary MVPs (also called floppy mitral valve) present in two forms: (1) diffuse myxomatous degeneration (also called Barlow s disease), in addition to the prolapse present with extensive valvular hooding, chordal elongation, and annular dilatation (Fig ), and (2) localized myxomatous degeneration, which is observed in older patients with chordal rupture causing flail leaflets. Whether the myxomatous degeneration causes the chordal rupture or is the consequence of the tension on the flail leaflet is unknown, but the tissue in patients with flail leaflets is characterized by chordae of lower stiffness and failing at lower stress. 78 However, chordal rupture may also complicate the diffuse form of myxomatous valve disease. Primary MVP has a prevalence between 0.6% and 3.5% in various echocardiographic populationbased studies, and is usually sporadic but may be familial; linkage analysis mapped loci on chromosome 11, 16, or X associated with MVP Secondary prolapse of mitral leaflets can be seen with diseases, such as rheumatic disease, with the initial rheumatic insult or later after rupture of chordae; endocarditis complicated by ruptured chordae; coronary disease complicated by elongation or rupture of the papillary muscles; hypertrophic cardiomyopathy, with ruptured mitral chordae; posttraumatic chordal or papillary muscle rupture; and connective tissue disorders (e.g., Marfan s disease). Pathophysiology Mitral valve prolapse, although due to permanent valve lesions, is a dynamic condition. Because the length of the mitral apparatus is constant, the MVP often does not occur in early systole while LV volume is close to the end-diastolic volume. With ventricular emptying, the papillary muscles move toward the heart s base and center, and at a specific LV volume the length of valve and chordae allows one or two leaflets to billow into the LA. 86 The occurrence of the prolapse causes a sudden tension of chordae, producing a sound (click) and may be followed by MR (end-systolic murmur). 87,88 Even for MVPs with sufficient chordal elongation (or rupture) to produce holosystolic regurgitation, LV emptying causes an aggravation of the prolapse and the MR increases throughout systole (Fig ) to culminate with the largest regurgitant orifice at end-systole. 89,90 Thus maneuvers that increase LV volume (recumbent position, increased afterload) tend to delay the occurrence of the prolapse, while maneuvers that decrease LV volume (standing, vasodilators) lead to an earlier prolapse in systole. Thus, the consequence of MVP, regarding MR severity in individual patients, is variable during the cardiac cycle and under the influence of changes in loading conditions due to the magnitude of the loss of coaptation owing to the prolapse. Similarly, MR complicating MVP is widely different between patients due to differences in the coaptation abnormality. 73 Mitral valve prolapse is a progressive disease. The lesions of simple MVP without flail leaflets are encountered mostly in young patients, 73 whereas flail leaflets and chordal rupture are diagnosed mostly in older patients. 91 The mechanism of anatomic progression of MVP is unknown but it leads to progressive MR, in particular because of the occurrence of new ruptured chords and also because of progression of annular dilatation. 92 The overload due to MR induces LA and LV overload and dysfunction. Natural History Mitral valve prolapse has been reported as carrying a high risk of complications in hospital-based studies. More recently, population and community studies provided a more balanced view of the clinical outcome of MVP. 73 The lifetime progression and complication rates of affected patients have not been defined, but outcome according to initial presentation at diagnosis is now better defined. Patients younger than 50 with MVP but no other complication display an excellent outcome (no excess mortality and low morbidity), showing that myxomatous degeneration of the mitral valve, in and of

8 404 chapter 17 FIGURE Sequential measurement of the regurgitant orifice throughout systole in a patient with mitral valve prolapse showing the progressively increasing mitral regurgitation. The upper images show the flow convergence diameter measurement while the lower images show the corresponding continuous-wave velocity, from early systole (left) to middle systole, to mid-late systole, to late systole (right). From early to late systole, the effective regurgitant orifice increased from 0.52 to 0.58 to 0.78 to 1.27 cm 2. itself, is a generally benign condition. 73,81,93 The major primary risk factors and determinants of outcome are severe degree of MR or of LV dysfunction. Risk factors of lesser severity (secondary risk factors) are age 50, slight MR, LA enlargement >40 mm, atrial fibrillation, and the presence of a flail leaflet (Fig ). Patients without major risk factors but with two or more minor risk factors incur no excess risk of mortality but a high risk of cardiovascular morbid events (6.2% per year) and of MVP-related events (1.7% per year), whereas those with major risk factors incur excess mortality and high rates of morbidity (18.5% per year) and MVP-related events (15% per year) even if they are asymptomatic at diagnosis (Fig ). 73 Thus, MVP is a highly heterogeneous condition spanning from a benign finding to a severe disease. The role of valve thickness in outcome is controversial. Thickened valves have been considered as a marker of poor outcome in the pre-doppler era, 94 probably related to the Survival (%) Overall survival p (exp) = ± 2 p (exp) =.20 Cardiac survival ± ± 5 No or 1 secondary RF 2 secondary RF 60 p (exp) =.01 Primary RF 66 ± 10 p (dif) < ± 2 p (dif) < Years after diagnosis FIGURE Survival after diagnosis of asymptomatic mitral valve prolapse in the community according to the presence of primary and secondary risk factors at baseline. The left graph represents the overall survival; the right graph represents survival free of cardiovascular death; p(dif), p value for comparison of the three curves; p(exp), p value for comparison of overall survival to the expected survival. Note the excess mortality in patients with primary risk factors, essentially mitral regurgitation, moderate or severe, and note the very low mortality of patients with no or one secondary risk factor. CV morbidity (%) Cardiovascular morbidity No or 1 secondary RF 2 secondary RF Primary RF 84 ± 5 40 ± ± Years after diagnosis FIGURE Cardiovascular morbid events after diagnosis of asymptomatic mitral valve prolapse in the community according to the presence of primary and secondary risk factors at baseline. Note the wide difference in morbidity according to this classification, with the group with no or one secondary risk factor incurring little morbid events, where those with two or more secondary risk factors incur frequent morbidity and those with primary risk factors incur almost inescapable morbidity.

9 mitral valve diseases 405 Stroke rate (%) p <.001 Lifetime risk Expected Observed 3 ± ± 1 Medical management p = ± 1 5 ± Years Years FIGURE Cerebral ischemic event rates after diagnosis of mitral valve prolapse in sinus rhythm in the community. The left graph represents the event-rate throughout follow-up including after cardiac surgery. The right graph indicates the event rate under conservative management only. The solid line represents the expected rate of ischemic stroke in patients in sinus rhythm of same age and sex in the same community. The dashed line represents the observed rate of events. Both graphs show the modest but significant excess risk of ischemic stroke in patients with mitral valve prolapse. severity of MR. More recently, it was shown that mitral thickening ( 5 mm) is not independently linked to mortality or cardiac morbid events. 73 However, mitral thickening is associated with a small but significant excess risk of cerebral ischemic events. 95 The contribution of MVP to the occurrence of stroke is controversial. Case-control studies reported discordant findings. 96,97 However, in the community-dwelling population, MVP is associated with a small but definite lifetime risk of stroke or transient ischemic attack (Fig ). 95 The major determinants of strokes in patients with MVP are linked to the MR complicating the MVP, that is, the need for cardiac surgery and the occurrence of atrial fibrillation. 95 The link between the occurrence of stroke and mitral thickening, irrespective of the need for surgery, is consistent with the reported observation of clots on thickened myxomatous leaflets. 98 Other morphologic characteristics (location of MVP or flail segment) do not appear to determine stroke incidence. However, the risk of stroke is only notable in patients older than 50, and thus MVP is not a significant contributor to strokes in young patients. 97 A risk of sudden death associated with MVP has been suggested by autopsy studies 99 and has been a concern because of arrhythmias associated with MVP. However, these arrhythmias are most prevalent with severe MR, 100 and longitudinal studies showed that young patients with no or minimal MR exhibit no excess risk of mortality, 73 whereas older patients with severe MR display excess mortality and notable risk of sudden death especially in patients with symptoms or LV dysfunction. 101 Bacterial endocarditis is rare but may complicate MVP and it justifies prophylaxis, particularly in patients with MR. Clinical Evaluation Presentation is rarely motivated by symptoms related to MR, such as dyspnea, arrhythmia, or heart failure (Table 17.2). Most often presentation is for nonspecific symptoms, fatigue, atypical chest pain, or palpitation, or diagnosis is made after discovery of auscultatory abnormalities during a general medical examination. Abnormal autonomic function leading to clinical presentation in patients with MVP has received attention but is controversial. 102 Increased catecholergic activity and reduced vagal response have not been confirmed consistently. 103 Physical examination may find marfanoid characteristics with arched palate, pectus excavatum, and rarely kyphoscoliosis. Examination may reveal signs of mild or more severe MR, and the radiation of the murmur suggests specific leaflet involvement. Radiation from the apex to the base suggests a prolapse predominant or isolated from the posterior leaflet, whereas in patients with anterior or bileaflet prolapse, the murmur tends to radiate to the axilla and sometimes the back. The typical findings of MVP are the midsystolic click and end-systolic murmur. 87 The click is a high-pitched sound occurring in midsystole, and is well separated from S 1 and S 2. As a result, these clicks are classified as nonejectional and are quite different from ejectional clicks, which mimic a split S 1. Mitral clicks are best heard between the apex and left sternal border as superficial sounds. Not infrequently, there are multiple systolic clicks. Maneuvers that increase ventricular volume, such as squatting, phenylephrine administration, and leg raising, shift the click later in systole, whereas maneuvers that decrease LV volume, such as standing, amyl nitrate inhalation, or Valsalva maneuver, shift the click earlier in systole. These changes explain the day-to-day TABLE Clinical syndromes of mitral valve prolapse (MVP) presentation Incidental MVP Barlow s syndrome Flail leaflet Symptoms None; incidental finding by echo Chest pain Sudden dyspnea Physical examination Normal Midsystolic click Loud murmur with basal radiation End-systolic murmur Pectus excavatum ECG Normal ST-T change LA enlargement LVH Chest x-ray Normal Cardiomegaly Enlarged LA Echo-Doppler MVP of 2-mm depth with no or Bileaflet MVP Flail posterior leaflet; large ERO trivial MR Moderate late systolic MR Follow-up In 5 years In 1 2 years Consider valve repair ERO, effective regurgitant orifice; LA, left atrium; LVH, left ventricular hypertrophy; M, mitral regurgitation; MVP, mitral valve prolapse.

10 406 chapter 17 variability in the detection and timing of the click. The murmur in late systolic, immediately follows the click, and changes in duration with the maneuvers that change the timing of the click. The intensity and character of the murmur are variable, but it is usually soft, blowing, and best heard at the apex. The murmur may be confused with that of hypertrophic cardiomyopathy because both murmurs increase with standing and decrease with squatting. However, the murmur of hypertrophic cardiomyopathy becomes louder after amyl nitrate inhalation, whereas that of MR does not. Postextrasystolic potentiation in murmur intensity in hypertrophic cardiomyopathy contrasts with the lack of change in MVP. Also, in patients with MVP and notable MR the murmur will tend to predominate at end-systole, a recognizable feature different from the rectangular shape of the murmur in other forms of MR (e.g., rheumatic MR). The electrocardiogram (ECG) is usually normal but may show flattening or inversion of the T waves in leads II, III, and avf, which may mimic ischemia in the inferior territory. Premature ventricular contractions are frequently observed, are sometimes bigeminal, and have been attributed to the traction of the chordae on the papillary muscle. Atrial fibrillation is rare and is more frequent in patients with larger degrees of MR and atrial dilatation. Chest radiography shows no specific feature of MVP. Doppler echocardiography is the mainstay of diagnosis, and of assessment of the MVP s extent and of the severity of MR and of LV and LA overload and function. The diagnosis of MVP has been a source of confusion, 88 as normal mitral valves may appear to billow in certain views, particularly the four-chamber apical view because of the saddle shape of the mitral annulus Therefore, the current criteria require a systolic movement beyond the plane of the annulus of at least 2 mm of the body or the tips of one or both mitral leaflets detected in long-axis views (Fig ). 105 With this criterion, the detected prevalence of MVP is considerably lower than initially reported, and false-positive diagnoses were eliminated. Thickening of mitral leaflets beyond 5 mm is noted to FIGURE Echocardiographic long axis parasternal imaging in systole showing a posterior leaflet prolapse. A solid line marks the annulus plane from which the depth of the prolapse is measured. LV, left ventricle; LA, left atrium; Ao, ascending aorta. define the classic MVP but is not indispensable to the diagnosis. 81 It is important to note the uni- or bileaflet nature of the MVP and the leaflet s segments affected (using the A 1 A 3, P 1 P 3 classification). Timing of the prolapse (holosystolic vs. midsystolic) may be noted on 2D or M-mode echocardiography. 88 The presence of a flail leaflet or ruptured chords can be detected by transthoracic echocardiography (Fig ), but sensitivity is higher by TEE, which is indicated in a minority of cases depending on the therapeutic implications of these findings. 107 Mitral regurgitation severity is assessed using the criterion of the American Society of Echocardiography. 108 The size of the LA and LV is measured using 2D-directed M-mode diameters or better using LA and LV volumes measurements. The associations of tricuspid valve or more rarely aortic valve prolapse are also examined. Cardiac catheterization is used only as a preoperative test. It may contribute to the assessment of MR and hemodynamics and to defining the coronary anatomy. Left ventricle angiogram may also observe large mitral prolapse. Management LV LA RV RA FIGURE Echocardiographic four-chamber view of a patient with a flail posterior mitral leaflet. The arrow indicates the flail segment with a ruptured chordae attached. LV, left ventricle; LA, left atrium; RV, right ventricle; RA, right atrium. Mitral valve prolapse is a heterogeneous condition and management should be guided by the individualized risk stratification, in which the degree of MR plays a central role. Although the risk is low, endocarditis prophylaxis is recommended for all patients. There is no medical treatment that affects the course of the mitral tissue myxomatous degeneration, and treatment focuses on the consequences of the MVP. Low-risk patients do not require close follow-up and may be reevaluated at 5-year intervals unless new symptoms or

11 mitral valve diseases 407 Survival (%) AL-MVP 100 PL-MVP 87% ± 2% 85% ± 2% 74% ± 4% p =.003 Repair 63% ± 5% 49% ± 4% Replacement Replacement Years after surgery Years after surgery FIGURE Survival after surgical correction of mitral valve prolapse (MVP) with severe mitral regurgitation, and with exclusive posterior leaflet (PL) prolapse (right graph, PL-MVP) or anterior leaflet (AL) involvement (left graph, AL-MVP). Survival of patients who underwent valve repair is indicated with a dashed line, whereas that of patients who underwent valve replacement is indicated with a solid line. Note that irrespective of the location of the mitral valve prolapse, valve repair provides an improved survival as compared to valve replacement and should be the preferred mode of correction of mitral valve prolapse with mitral regurgitation. events develop. Patients with palpitations may benefit from beta-blockade for symptom s relief. The role of aspirin in preventing embolic complications in patients with thickened leaflets is not established. 109 Medium-risk patients, in particular with mild or moderate MR, require more frequent follow-up as the degree of MR tends to progress. Vasodilators, particularly with angiotensin blockade, are not yet confirmed in stabilizing the degree of MR but are justified in treating hypertensive patients. 110 Atrial fibrillation should lead to reevaluation of the degree of MR and requires anticoagulation. 111 A limited number of patients with atrial fibrillation with uncontrolled ventricular response and moderate MR benefit from surgical treatment combining a Maze procedure and mitral repair. 112,113 Patients with severe MR are at high risk. These patients are immediate candidates for surgery if they are symptomatic or have LV dysfunction. For asymptomatic patients there is no agreement on the need for early surgery, but in the hands of surgeons skilled in reparative procedures these patients can benefit from valve repair in 85% to 90% of cases, which implies a low operative risk and excellent long-term outcome (Fig ). Therefore, delaying surgery until severe symptoms or congestive heart failure occurs compromises survival and should be avoided, justifying a trend for proceeding with valve repair without waiting for the occurrence of these severe complications. 114, % ± 5% p =.0004 Repair 70% ± 3% 49% ± 5% approaches. With improved understanding of the natural history of MR, and most importantly with major advances in conservative surgery, the management of MR has become far more proactive. Etiology and Mechanism Mitral regurgitation is an organic mechanism if there is an intrinsic valve disease or a functional mechanism if the valve is structurally normal but regurgitates due to an extravalvular abnormality. Mitral regurgitation of ischemic etiology may be organic (ruptured papillary muscle) or functional (LV dysfunction). Nonischemic MR may be organic (e.g., rheumatic) or functional (e.g., cardiomyopathy). The Carpentier classification of MR mechanisms is as follows: type I, normal valvular movement (such as that seen with annular dilatation); type II, excessive movement (such as that due to MVP or flail leaflets); type III, restrictive motion; type IIIa, diastolic restriction (such as in rheumatic diseases); and type IIIb, systolic restriction (such as ischemic functional MR). Rheumatic MR is rarely pure, and in most cases is associated with stenosis and fusion of the commissures. Severe rheumatic MR requiring surgical correction is still frequent in developing countries but is now rare in developed countries. 116 The underlying lesion is retractile fibrosis of leaflets and chordae causing loss of coaptation (Fig ). Secondary dilatation of the mitral annulus tends to further decrease the contact between leaflets. Elongated or ruptured chords are infrequent. Degenerative MR is often associated with MVP and represent the most frequent cause leading to surgery for severe MR. 116 Degenerative MR can be categorized as follows: Primary MVP with diffuse myxomatous infiltration Degenerative primary ruptured chordae, which involve more often the posterior than the anterior leaflet and occur more often in men than in women (Fig ). There is usually no excessive tissue, but enlargement of the annulus may occur as in any MR. The involved leaflet Mitral Regurgitation Mitral regurgitation is characterized by an abnormal, reversed blood flow from the LV to the LA. The etiologic profile of MR is now dominated by degenerative and ischemic causes in developed countries. The development of noninvasive assessment with Doppler echocardiographic methods, particularly for quantitation of MR, has transformed diagnostic FIGURE Anatomic posterior view of the left atrium and mitral valve in a case of rheumatic mitral regurgitation. Note the wide orifice despite the presence of limited commissural fusion and note the tissue retraction leaving a wide-open orifice.

12 408 chapter 17 FIGURE Anatomic long-axis view of the heart (left panel) and mitral valve (right panel) in a case of degenerative mitral regurgitation with flail posterior leaflet and ruptured chordae. Note the thickening of the flail segment of the posterior leaflet, whereas the anterior leaflet is of normal thickness. shows myxomatous infiltration, 117 but the other leaflet usually remains normal. Calcification of the mitral annulus or systemic hypertension may precede the occurrence of the ruptured chordae. Isolated ruptured chord may occasionally be due to blunt thoracic trauma and endocarditis (secondary forms). Degenerative MR without prolapse, which is usually mild and due to valve sclerosis or isolated annular calcification, in which regurgitation is secondary to deformation of the valves or annulus. Infective endocarditis accounts for about 5% of cases of severe MR. Vegetations may produce mild MR by interposition between leaflets. Severe endocarditic MR is usually related to ruptured chords and less frequently to destruction of mitral tissue involving either the leaflet s edges or a perforation (Fig ). Ischemic and functional MR, that is, due to LV wall dysfunction secondary to ischemia, scarring, aneurysm, cardiomyopathy, or myocarditis, have in common the same mechanism. The coaptation of intrinsically normal leaflets is incomplete (Fig ). 118 Rupture of papillary muscle produces MR because of the flail leaflet and involves in 80% of cases the posteromedial papillary muscle and is most often associated with infarction of the adjacent ventricular wall. 119 It is the rarest form of heart rupture and of ischemic MR. Complete rupture is rapidly fatal without surgery, and partial or single-head rupture of the papillary muscle more often allows emergency surgery. 119 There are numerous other causes of MR. It is observed frequently with color flow imaging, even in patients without FIGURE Anatomic ventricular view of the mitral valve in a case of endocarditic mitral regurgitation with perforation of the anterior leaflet. Note the large perforation with inflammatory borders. FIGURE Anatomic view of the heart and mitral valve in a case of functional mitral regurgitation due to ischemic heart disease (with septal and anterior wall thinning and scarring). The mitral valve is structurally normal. Traction by the papillary muscle and chordae tether the leaflets within the LV cavity. Note the enlarged and spherical LV and LA.

13 mitral valve diseases 409 cardiac disease. Clinically significant MR may be found in (1) connective tissue disorder: Marfan syndrome, Ehlers- Danlos syndrome, pseudoxanthoma elasticum, osteogenesis imperfecta, Hurler s disease, systemic lupus erythematosus, and anticardiolipin syndrome; (2) penetrating or nonpenetrating cardiac trauma; (3) myocardial disease: hypertrophic cardiomyopathy or sarcoidosis; (4) endocardial lesions due to eosinophilic syndrome, endocardial fibroelastosis, carcinoid tumors, ergot toxicity, radiation toxicity, 120 and diet or drug toxicity 121 ; (5) congenital lesions, such as cleft mitral valve isolated or associated with persistent atrioventricular canal; corrected transposition with or without Ebstein abnormality of the left atrioventricular valve may also cause MR; and (6) cardiac tumors. Pathophysiology The abnormal coaptation of the mitral leaflets creates a regurgitant orifice during systole and is measured as the effective regurgitant orifice (ERO), which represents the lesion severity. The systolic pressure gradient between the LV and LA is the driving force of the regurgitant flow, which accumulates into a regurgitant volume (RVol). The RVol is responsible for the volume overload, by entering the LA in systole and the LV in diastole, modifying LV loading and function. Chronology of Regurgitation The pressure gradient between the LV and atrium begins with mitral closure (simultaneous to S 1 ) and persists after closure of the aortic valve (S 2 ) until the mitral valve opens. 122 Thus, timing of regurgitant flow is determined by that of the regurgitant orifice and is most often holosystolic. Various dynamic changes in regurgitant orifice can be observed depending on its cause. 90 With small regurgitant orifices, the regurgitant orifice declines, with the ventricular volume tending to limit regurgitation to early systole. 122 Conversely, in valve prolapse the regurgitant orifice appears or increases late in systole, and variations of regurgitant flow throughout systole are the complex results of combined effects of changes of regurgitant orifice and gradient. 89,90 Degree and Consequences of Regurgitation The degree of volume overload depends on three factors: the area of the regurgitant orifice, 123 the regurgitant gradient, and the regurgitant duration. The volume overload is usually less severe in mitral than in aortic regurgitation, despite the usually larger regurgitant gradient and orifice. 123 Such differences are related to a shorter duration of MR during the cardiac cycle in mitral than in aortic regurgitation. 123 The degree of MR is not fixed and may vary with interventions. Vasodilators improve the clinical status of patients with acute regurgitation, 124 and the mechanism of improvement is a decline in ERO area rather than that of the ventriculoatrial gradient. In functional 125 and organic MR, 126 the ERO increases with increased afterload or ventricular volume and decreases with decreased afterload or improved contractility, but is not influenced by changes in heart rate. 126 The regurgitant energy is produced by the LV and is transformed in two components: the kinetic energy (regurgitant volume) and the potential energy (elevation of atrial pressure). The typical LA pressure change is the V wave, 127 which is also determined by LA compliance. 127 In acute MR, the LA is smaller and less compliant than in chronic MR, and a similar RVol produces a higher V wave and LA pressure, which in turn minimizes the LV-LA gradient. Thus, for any ERO, 123 acute MR translates into more potential energy (LA pressure) with smaller RVol (and murmur) than chronic MR. When MR becomes chronic, the LA dilates, and the V wave is less prominent and does not limit the regurgitant volume, and the LA pressure may be normal even with severe MR. 128 At that stage, usually the cardiac output is decreased but the pulmonary pressures are often normal. Pulmonary hypertension in MR is poorly understood, and observed mostly in elderly patients. Left Ventricle Function With MR the LV is dilated but less so than in aortic regurgitation of comparable degree. 129 End-diastolic LV volume and wall stress are increased, 129 and its shape becomes spherical. End systolic volume is increased in chronic MR, but end systolic wall stress is usually normal. 130 The myocardial mass is increased proportionately to LV dilatation. 131 Left ventricle function is difficult to characterize because of the changes in preload and afterload. It has been suggested that normalization of ejection fraction to the preload would provide an appropriate assessment of LV function. Afterload is more difficult to assess because the MR may decrease the instantaneous impedance to ejection, but the measure of afterload provided by end systolic wall stress is within the normal range. 130 However, the usual inverse correlation between end systolic wall stress and ejection fraction is also observed in MR. 132 Complex indices using the afterload such as the end systolic wall stress, 133 or maximum elastance, 130 normalized to the LV volume, have been proposed and may be sensitive to subtle changes in function. Left ventricle dysfunction is a frequent and dismal complication of MR. 134,135 The mechanism of LV hypertrophy is a reduction in protein degradation, but the mechanisms leading to interstitial fibrosis and LV dysfunction remain mysterious. Experimentally, LV dysfunction is not due to changes in coronary blood flow. The changes in myofiber contractility parallel those in LV function 136 and are associated with reduced myofiber content, 137 but the cause of the myofiber dysfunction and the explanation of its high incidence have not been clarified. During diastole LV relaxation is prolonged, but chamber stiffness is reduced. 138 Age and decreased systolic function 138 are associated with increased chamber stiffness. The significance of the diastolic abnormalities is unclear. Ischemic and Functional Mitral Regurgitation The pathophysiology of ruptured papillary muscles is poorly known but it represents the most typical form of acute MR with large ERO, low RVol, and often inaudible murmur but severe clinical consequences due to the LA pressure elevation. In chronic ischemic MR (IMR) or functional MR (FMR), the primary disease involves the LV, which is often poorly contracting while the mitral valve is intrinsically normal. The classically invoked mechanisms of MR, that is, papillary muscle dysfunction and annular dilatation, have been shown

14 410 chapter 17 LV T Ao LA the predominance of IMR after inferior myocardial infarction. 142 Therefore, similar degrees of LV enlargement or dysfunction may be associated with quite variable degrees of IMR due to the variability in the local remodeling. The importance of chordal tethering in generating tenting and FMR or IMR has been demonstrated experimentally, by inducing papillary muscle repositioning 143 or by secondary chordae cutting, 144,145 which resulted in disappearance of the MR. Cardiomyopathic versus ischemic LV dysfunction shows slight differences in the distribution of chordal tethering and tenting that are often predominant on the medial commissure in IMR due to the frequent association with inferior myocardial infarction. In functional versus organic MR, RVol is usually smaller, 146 and LV and LA dilatation are in excess to the degree of MR. 123 Nevertheless, MR is associated with elevated LA pressure, 123 poor outcome, 147 and is a marker of sensitivity to vasodilators. FIGURE Echocardiographic long-axis view of the mitral valve in a patient with ischemic mitral regurgitation (MR). The LV is enlarged and demonstrates thinning of the inferolateral wall consistent with an inferior myocardial infarction. The mitral valve is protruding forward and the tenting area (T) under the mitral valve up to the annulus (solid line) is large, preventing coaptation of the mitral leaflet although they are structurally normal. The LA is enlarged. to contribute little to functional MR. The occurrence of MR is due mostly to mitral valve tenting. 139 Tenting is a systolic deformation of the leaflets, which protrude forward in the LV and thus cannot appose their rough zone on each other (Fig ). Other valvular contributors to the lack of coaptation are the loss of annular contraction and the low ventricular pressure pressing on mitral leaflets. 139 Tenting as the main determinant of IMR and FMR is in turn the consequence of tethering by excessive traction on the secondary chordae due to localized LV deformation (Fig ) with apical and inferior displacement of papillary muscles, which explains Hormonal Activation in Organic Mitral Regurgitation Natriuretic peptides are activated in experimental 148 and clinical 149 studies. The main determinant of elevation of A-type natriuretic peptide is the elevation of atrial pressures, 149 but also atrial arrhythmias, which result in disproportionate elevation of this natriuretic peptide. Thus, B-type natriuretic peptide (BNP) has been the focus of increasing interest. Pilot studies suggested that BNP reflected the severity of symptoms. Its activation is weakly linked to the degree of MR and is more notably determined by the consequences of MR, LA enlargement, LV dysfunction, and the degree of heart failure associated with the MR in particular. In that, it appears as a promising marker of outcome. The catecholamine activity is increased in MR with norepinephrine release rates increased compared to controls, even in asymptomatic patients 150 and similar to those measured in cardiomyopathy. 151 Alterations in adrenergic activity and receptor density are strongly correlated to the degree of LV overload 152,153 and dysfunction 154,155 and to hormonal activation. 156 Importantly, in long-term experiments with MR due to ruptured chords, similar to the most frequent human form of FIGURE Echocardiographic apical longaxis view with two-dimensional imaging of papillary muscles (left) and with color flow imaging of the left atrium (right). Left, the vertical arrows show the tips of the papillary muscles tensing the secondary chordae inserted on the body of the leaflet (horizontal arrows) and pulling the leaflets apically, away from the annulus (arrowheads), resulting in tenting. Right, the tenting results in a large jet of mitral regurgitation.

15 mitral valve diseases 411 MR, bradycardia induced by beta-blockers provides recovery of LV function. 157 Activation of the renin-angiotensin system is also noted. In dogs with organic MR, systemic activation of the renin-angiotensin system is rare, 158 but tissue levels of angiotensin II are markedly elevated. 159,160 The role of tissue angiotensin activation in the development of hypertrophy and fibrosis is not fully clarified. Beta-1-blockade prevents angiotensin-ii mediated tissue catecholamine release, 161 but the therapeutic role of hormonal modulation in human MR is not yet defined. Survival (%) Class III-IV 21% ± 11% Class I-II p < % ± 7% Natural History Because organic and functional MR occur in very different contexts, it is important to analyze their natural history separately. Organic From the presurgical era to the 1980s, assessment of the degree of MR has remained qualitative and imprecise, so that the natural history of MR was ill-defined. Patients with mild rheumatic MR appeared to have a good prognosis, 162 whereas in those with more severe MR higher mortality has been noted. 91,163 In patients with unoperated and clinically significant MR, long-term survival was reported as high as 60% at 10 years 164 or as low as 46% 165 or even 27% 166 at 5 years. In our experience with flail mitral leaflets, at 10 years, survival was 57%, which represents an excess mortality as compared to the expected survival (Fig ). 91 A notable component of sudden death has been noted. Such a devastating complication occurs more often if the ventricular function is decreased 167 but may also occur in patients with normal ejection fraction who are asymptomatic. 163 In our experience, sudden death in patients with MR due to flail leaflets occurs at a rate of 1.8% per year. 101 The rates are higher in patients with symptoms (Fig ) or reduced ejection fraction (<60%; Fig ), but even in the absence of these risk factors sudden death rate is 0.8% per year, 101 or approximately the double of the expected rate of sudden death in the general Years FIGURE Natural history of mitral regurgitation due to flail leaflets: survival after diagnosis under medical management according to symptomatic status at baseline. The patients presenting in New York Heart Association class III or IV incur considerable mortality under medical management (solid line). Those presenting in New York Heart Association class I or II display a better survival, but note that one third die within 10 years under medical management (dotted line). population. These combined data suggested that survival under medical management is determined by the degree of MR. This hypothesis was supported by the study of MVP in the community, which showed that the degree of MR due to MVP was the strongest determinant of survival after diagnosis, even in asymptomatic patients. 73 This hypothesis was confirmed in a prospective study of organic MR with degree of MR quantified using modern Doppler echocardiographic methods and stratified according to guidelines of the American Society of Echocardiography. 168 The ERO area proved to be the strongest predictor of survival after diagnosis (Fig ) and patients with ERO 40 mm 2 incurred excess mortality as compared to expected mortality. Importantly, the 100 Survival (%) Expected Observed p = % 57% Years FIGURE Natural history of mitral regurgitation due to flail leaflets: survival after diagnosis under medical management. The expected survival for age and sex is indicated by a dashed line. The observed survival indicated by a solid line is significantly lower. Survival (%) p =.001 EF 60% EF < 60% 61% ± 8% 40% ± 12% Years FIGURE Natural history of mitral regurgitation due to flail leaflets: survival after diagnosis under medical management according to echocardiographic ejection fraction at baseline. The patients presenting with ejection fraction (EF) <60% incur considerable mortality under medical management (solid line). Those presenting with EF 60% display a better survival but note that almost 40% die within 10 years under medical management (dotted line).

16 412 chapter 17 patients with moderate MR (ERO mm 2 ) displayed mortality that was initially low but increased markedly after 3 years. Morbidity in patients with severe MR is also high. In patients who were initially asymptomatic, approximately 10% per year develop symptoms, 169 which may be hastened by atrial fibrillation. In patients with flail leaflets, heart failure occurred in 63% within 10 years of diagnosis. 91 Atrial fibrillation occurred at a rate of 5% per year in patients diagnosed in sinus rhythm and was associated after its occurrence with increased mortality under conservative management. 111 Left atrium enlargement is a strong predictor of occurrence of atrial fibrillation. 111 Quantitation of MR provides important predictors of outcome, and cardiac events (cardiac death, heart failure, new atrial fibrillation) occur at a rate almost six times higher in patients with ERO 40 mm 2 than in those with ERO <20 mm 2 (Fig ). 168 Finally, surgery is almost unavoidable in patients with severe MR. Indeed, 10 years after diagnosis of MR due to flail leaflets, 90% of patients underwent surgery or died before surgery could be performed, 91 whereas in patients with any etiology of MR and ERO 40 mm 2 the rate of death or surgery is 86% at 5 years. 168 The predictors of poor outcome in patients medically treated are (1) severe symptoms [New York Heart Association (NYHA) class III IV], 165 even if the symptoms are transient 91 ; (2) pulmonary hypertension; (3) markedly increased LV enddiastolic volume or arteriovenous difference in O ; (4) reduced ejection fraction 91 ; (5) marked LA enlargement; and (6) ERO area 40 mm Comparison of prognosis in medically and surgically treated patients shows a trend in favor of the surgical treatment, 163 especially early surgery, 91 with definite improvement of outcome of patients with decreased systolic LV function. 170 Asymptomatic patients who undergo Survival (%) ERO <20 mm 2 ERO mm 2 ERO 40 mm 2 p <.01 91% ± 3% 66% ± 6% 58% ± 9% Years FIGURE Natural history of mitral regurgitation quantitatively defined: survival after diagnosis under medical management according to Doppler-echocardiographic effective regurgitant orifice (ERO) at baseline. The patients presenting with ERO <20 mm 2 incur minimal mortality, not different from the expected mortality (solid line). Those presenting with ERO 40 mm 2 display a considerable mortality, higher than the expected mortality (dashed line). The patients with ERO 20 mm 2 and <40 mm 2, or the moderate MR as per the American Society of Echocardiography classification (dotted line) show initially little mortality but after 3 years mortality markedly increases. Cardiac events rate (%) Years FIGURE Natural history of mitral regurgitation quantitatively defined: cardiac events (cardiac death, heart failure, or new atrial fibrillation) after diagnosis under medical management according to Doppler-echocardiographic effective regurgitant orifice (ERO) at baseline. The patients presenting with ERO <20 mm 2 incur minimal morbidity (solid line). Those presenting with ERO 40 mm 2 display a considerable mortality, higher than the expected mortality (dashed line). The patients with ERO 20 mm 2 and <40 mm 2, or the moderate MR as per the American Society of Echocardiography classification (dotted line) show initially little morbidity but after 3 years the event rate markedly increases. valve repair display a considerable reduction of mortality with restoration of life expectancy. 168 The progression of LV dysfunction in patients with organic MR medically treated is not well defined. Progression of the degree of MR is usually slow, with progression of regurgitant volume of 7 to 8 ml per year, but it reaches 20 ml per year in patients with new flail leaflets. 92 The mechanism of progression of MR is an increase in ERO without change in gradient. The major determinant of regression of MR is a reduction in afterload, whereas increase in annular size and new flail are major determinant of progression of MR. 92 The progression of the degree of MR is the probable mechanism by which patients with moderate MR (ERO mm 2 ) experience a marked increase in risk within a few years after diagnosis. Functional ERO 1 19 mm 2 ERO mm 2 ERO 40 mm 2 p <.01 62% ± 8% 40% ± 7% 15% ± 4% Data on the natural history of functional MR are limited. Functional MR complicating cardiomyopathy appears to contribute to the poor outcome of this disease. 171,172 Recently, more compelling information has been gathered on IMR, which is noted in approximately one patient in five post myocardial infarction, 147,173 irrespective of the presence of ST elevation. 173 The presence of IMR is associated with more severe clinical presentation 167,173,174 and severity of LV remodeling. 175 During follow-up, IMR (Fig ) is associated with increased mortality (approximately doubling of the mortality risk) even after adjustment or matching for the associated LV alterations, 147,173,174 and revascularization by surgery 176 or interventional procedures. 177 Furthermore, IMR is linked to subsequent occurrence of heart failure, 173 even in patients

17 mitral valve diseases Survival p < % ± 6% 38% ± 5% Controls Years FIGURE Natural history of ischemic mitral regurgitation: survival after diagnosis in patients with Q-wave myocardial infarction matched for age, sex, and EF with (solid line) and without (dashed line) ischemic mitral regurgitation. Note that patients with ischemic MR incur a considerably higher mortality despite similar ejection fraction. who were asymptomatic at baseline. 178 Importantly, it appears that even a degree of IMR that would be labeled as mild or moderate is associated with adverse outcomes. Indeed, in the SAVE study in which severe MR was an exclusion criterion, IMR severely affected the outcome. 147 This concept of lower thresholds for severe IMR has been confirmed in quantitative studies, which showed that patients with ERO 20 mm 2 incur a considerable risk of mortality (Fig ), 174,179 and heart failure (Fig ). 178 Thus, it is essential to evaluate IMR with specific criteria of severity. Ischemic MR is more dynamic than organic MR, and an exercise-induced increase in IMR degree 180 may portend a high risk of subsequent mortality 179 and heart failure. 181 Therefore, current information suggests that IMR has a poor outcome. Survival (%) ERO p <.0001 MR 61% ± 6% 47% ± 8% 29% ± 9% Years FIGURE Natural history of ischemic mitral regurgitation: survival after diagnosis in patients with Q-wave myocardial infarction and quantified MR, matched for age, sex, and EF between those without MR (dashed line) and with MR and effective regurgitant orifice (ERO) 1 to 19 mm 2 (dotted line) or 20 mm 2 (solid line). Note that patients with larger ERO due to ischemic MR incur a considerably higher mortality despite similar ejection fraction. Incidence of CHF (%) ERO, mm p < FIGURE Natural history of ischemic mitral regurgitation: occurrence of congestive heart failure after diagnosis in initially asymptomatic patients with Q-wave myocardial infarction and quantified MR, matched for age, sex, and EF between those without MR (dashed line) and with MR and effective regurgitant orifice (ERO) 1 to 19 mm 2 (dotted line) or 20 mm 2 (solid line). Note that patients with larger ERO due to ischemic MR incur a considerably higher rate of congestive heart failure despite asymptomatic status and similar ejection fraction at baseline. Clinical Evaluation 68% ± 12% 46% ± 9% 18% ± 5% Sex distribution of disease has changed in parallel to the changes in etiology of MR. With the decrease in rheumatic heart disease, severe MR is now predominantly seen in males (65 75%). Prevalence of MR increases with older age, 182 and therefore, patients with severe MR most often present in the sixth decade of life. 91 Clinical presentation is determined by the degree, rapidity of development, and cause of MR. Patients with mild MR usually have no symptoms. Severe MR is diagnosed most often because of the murmur when no or minimal symptoms are present. 91 Fatigue and mild dyspnea on exertion are the most usual symptoms and are rapidly improved by rest. The administration of diuretics and progressive self-limitation of physical activity may prevent the occurrence of more severe symptoms. Severe dyspnea on exertion or, more rarely, paroxysmal nocturnal dyspnea, frank pulmonary edema, or even hemoptysis, may be observed later in the course of the disease. Such severe symptoms may be triggered by new onset of atrial fibrillation, an increase in the degree of MR, the occurrence of endocarditis or ruptured chord, or a change in ventricular compliance or function. With severe MR of acute onset, symptoms are usually more dramatic, such as pulmonary edema and congestive heart failure, which may subside with administration of diuretic and increased LA compliance, an improvement that should not falsely reassure, as such patients remain at high risk even after symptoms have improved. 91 A syndrome of sudden onset of atypical chest pain and dyspnea may occur with abrupt chordal rupture. Rupture of papillary muscle usually has a dramatic presentation with cardiogenic shock or a severe pulmonary edema. Pulmonary edema may be also observed in transient severe papillary muscle dysfunction. Sudden death as the initial presentation of MR is rare. 167

18 414 chapter 17 FIGURE Electrocardiogram in a patient with mitral regurgitation and sinus rhythm. The prolonged duration and morphology of the P wave is consistent with LA enlargement. The deep S wave in V 2 is consistent with borderline left ventricular hypertrophy. FIGURE Chest radiography in a patient with mitral regurgitation. There is mild cardiomegaly with LA enlargement. Physical examination usually finds a normal blood pressure and brisk carotid upstroke. Cardiac palpation may show laterally displaced, diffuse, and brief apical impulse. An apical systolic thrill is characteristic of severe MR. A right ventricular heave (left sternal border lift) is observed with right ventricular dilatation and may be difficult to distinguish from a LA lift due to the dilated, expansive LA, which is usually lower. S 1 is included in the murmur and usually normal but may be increased in rheumatic disease. S 2 is usually normal but may be paradoxically split if the LV ejection time is markedly shortened. The presence of a third heart sound is directly related to the volume of the regurgitation in patients with organic MR. 183 It is often associated with an early diastolic rumble due to the increased mitral flow in diastole even without mitral stenosis. The S 3 and diastolic rumble are low-pitched sounds and may be difficult to detect without careful auscultation in the left lateral decubitus position. The S 3 increases with expiration. In ischemic-functional MR, S 3 corresponds more often to restrictive LV filling. An atrial gallop is heard mainly in MR of recent onset and in ischemic/functional MR in sinus rhythm. Midsystolic clicks are markers of valve prolapse. The hallmark of MR is the systolic murmur, most often holosystolic and including first and second heart sounds. If an opening snap or S 3 are mistakenly interpreted as S 2, the murmur may appear midsystolic. A careful examination beginning at the base of the heart to identify S 2 and progressing toward the apex will facilitate recognizing the origin of the murmur. The murmur is blowing but may be harsh, especially in valve prolapse. Maximum intensity is usually apical with radiation to the axilla in rheumatic or anterior leaflet prolapse MR. In posterior leaflet prolapse, the jet is usually superiorly and medially directed and the murmur radiates toward the base of the heart. 184 The murmur may be heard in the back, in the neck, and sometimes on the skull. When the murmur radiates to the base, it may be difficult to distinguish from that of aortic stenosis or obstructive cardiomyopathy, and pharmacologic maneuvers showing that the murmur decreases with amyl nitrite and increases with methoxamine, strongly suggest MR. Murmur intensity does not increase with postextrasystolic beats and usually parallels the degree of MR. 185 Murmurs of shorter duration usually correspond to mild MR; they may be mid-late systolic in MVP or early systolic in FMR. However, with myocardial infarction and in general in functional MR, severe MR may be totally silent. 186 Indeed, the intensity of murmur is usually low and does not parallel MR severity, 185 so that the presence and intensity of murmur is a poor detector of FMR or IMR. 147,173 The ECG s most frequent feature is atrial fibrillation, found in approximately 60% to 75% of earlier series and now present in approximately 30% to 50% of surgically corrected MR. 187 Patients in sinus rhythm may present with signs of left atrial enlargement (Fig ). Left ventricle hypertrophy is more rarely seen and may be associated with secondary ST-T abnormalities. 188 Right ventricular hypertrophy is uncommon. The ECG, especially in acute MR, may be entirely normal. In ischemic MR, Q waves in the inferior leads or left bundle branch block are often noted. Chest roentgenogram often shows cardiomegaly in chronic organic MR or in ischemic/functional MR. Left atrium body and appendage dilatation is frequent, but giant LA is rare and usually seen in severe mixed valve disease (Fig ). Although valvular calcifications are rare, annular calcification is seen as a C-shaped density below the posterior leaflet and is frequent. Because LA pressure is frequently normal, even with severe MR, signs of pulmonary hypertension or pulmonary edema are rarely observed. The clinical, ECG, and radiographic signs are often grouped into specific clinical syndromes suggestive of the diagnosis and are schematically separated in four syndromes summarized in Table 17.3.

19 TABLE Clinical syndromes of mitral regurgitation (MR) presentation mitral valve diseases 415 Sclerotic MR Chronic MR Acute MR Ischemic/functional MR Symptoms None; incidental diagnosis Fatigue Pulmonary edema CHF Physical examination Early systolic murmur Loud murmur S 3 Loud murmur S 4 Soft Murmur S 4, S 3 ECG Normal Atrial fibrillation Normal Q waves, LBBB Chest x-ray Normal Cardiomegaly Normal heart size Cardiomegaly, pulmonary Pulmonary edema edema Echo-Doppler Jet may be large but is Enlarged LA Jet eccentric and thin Severe LV dysfunction purely early systolic Incipient LV Normal mitral structure dysfunction Clinical pitfall Overestimate MR on the Ignore the LV Underestimate MR Ignore the silent but jet basis alterations clinically important MR CHF, congestive heart failure; LA, left atrium; LBBB, left bundle branch block; LV, left ventricle; MR, mitral regurgitation. Doppler echocardiography is the mainstay of the diagnosis of MR, of the morphologic assessment to determine the etiology and mechanism of MR, and of the quantitation of MR and of its consequences. The morphologic features of the most common causes are discussed below. Rheumatic MR is characterized by thickening of the leaflets and chordae. The posterior leaflet has reduced mobility, whereas the anterior leaflet may be doming if commissural fusion is associated. A valvular prolapse is usually not present unless a ruptured chordae or active rheumatic carditis is present. Similar lesions are observed in lupus or anticardiolipin syndrome in which transesophageal echocardiography may also show small vegetations. In degenerative MR, prolapse is observed with the passage of valvular tissue beyond the annulus plane in long-axis view (as indicated in the MVP section). Localization of the leaflet involved (most often the posterior) is confirmed by the initial direction of the jet. A large mitral annular calcification may represent a limitation for conservative surgery if extensive and severe. Flail segments appear as a complete eversion of the segment with or without the small floating echo of ruptured chordae (Fig ). 107 The mechanism of MR due to bacterial endocarditis is most often flail leaflets (due to the ruptured infected chordae), which are relatively easy to diagnose. 107 Perforations are more difficult to diagnose. Mitral annular abscesses are rare and are best detected by transesophageal echocardiography. Vegetations can be seen on leaflets or on ruptured chords with superior sensitivity by transesophageal echocardiography. 189 To diagnose IMR or FMR, a dilated annulus, 118,190 is nonspecific, 146 but annular contraction is reduced. The features of ischemic heart disease may be observed as regional wall motion abnormalities (Fig ). 118 The leaflet tissue is normal. The mitral tenting is due to the abnormal traction by the secondary chordae on the leaflets, 139 which deforms the leaflets with a typical mid-leaflet tethering and the jet of MR is central (Fig ). 118,190 Rarely, the tethering predominates on one leaflet and the other leaflet overshoots in systole beyond the tethered leaflet (but without prolapse) and the jet is eccentric. Short axis views may reveal the origin of MR on the medial commissure in IMR due to inferior myocardial infarction. 191 With papillary muscle rupture, 119 MR is due to the flail leaflet. The diagnosis is based on visualization (if necessary by TEE) of a small mass of muscle attached to chordae and floating freely during the cardiac cycle. 192 The assessment of severity of MR is based on the criteria defined by the American Society of Echocardiography. The guiding concepts are that the entire Doppler echocardiographic information is gathered (lesion, color-flow, pulsed and continuous wave Doppler) but that specific signs for each grade of MR are preferred, and that in the analysis of colorflow imaging vena contracta measurements are preferred to jet analysis, and that overall, as often as possible, quantitative methods should be preferred. 108 The methods facilitating collecting these specific signs and the gradation scheme for MR are delineated below. Color-flow imaging defines the origin and direction of the jet, related to etiology (Figs and 17.36). Jet length, jet to left atrial area ratio, or more simply jet area 193 shows rough correlations to MR severity. Small jets consistently correspond to mild MR. 146 However, color-flow imaging has significant limitations intrinsically related to the nature of regurgitant jets. The extent of a jet is determined by its momentum, and thus as much by regurgitant velocity as by regurgitant flow. Also jets are constrained by the LA and expand more in a large LA. 146 The eccentric jets of valve prolapse 194 impinge on the LA wall and tend to underestimate MR. 146 Central jets of functional MR expand markedly in the enlarged LA and tends to overestimate MR. 146 FIGURE Transesophageal echocardiography showing a flail posterior leaflet (arrowheads) with ruptured chord (long arrow). Note the normal thickness of the anterior leaflet and the enlarged LA.

20 416 chapter 17 FIGURE Eccentric jet of mitral regurgitation associated with a flail posterior leaflet. (Left) An echocardiographic four-chamber view of the flail leaflet (arrow). (Right) A jet directed superiorly in the left atrium, remaining thin and wall-attached (Coanda effect) to the bottom of the LA. Transesophageal echocardiography usually shows larger jets but does not suppress these limitations of color-flow imaging. The vena contracta is the region of the regurgitant flow immediately below the flow convergence through the regurgitant orifice. 195 Therefore, direct measurement of the vena contracta width provides a surrogate of the regurgitant orifice area. The vena contracta width is simple, appears superior to jet measurements, and can be obtained either through transesophageal 195 or transthoracic echocardiography. 196 Pulsed-wave Doppler assessment of pulmonary venous velocity profile is useful to assess the degree of MR. 197 Systolic reversal in pulmonary veins is a specific sign of severe MR (Fig ) and is related not only to MR severity but also to jet direction and LA pressure. 198 Consequently, pulmonary venous reversal may be absent or asymmetric in severe MR. 198 The goal of the quantitative methods is to measure the volume overload expressed as the regurgitant volume (difference between the total and forward stroke volume) or fraction (proportion of LV ejection volume regurgitated in the LA). The lesion severity is expressed as the effective regurgitant orifice (ERO) area and calculated as follows 123,199 : ERO = regurgitant flow/regurgitant velocity, or ERO = regurgitant volume/regurgitant TVI where regurgitant TVI is the time velocity integral of the regurgitant jet. Quantitation of MR can be performed using various methods: Quantitative Doppler is based on the calculation of the mitral and aortic stroke volumes (Fig ) using pulsed wave Doppler. 200 The principle is simple and applicable.50 D n/s.50 S FIGURE Central jet of mitral regurgitation (apical long-axis view) in a patient with functional mitral regurgitation. Despite a small regurgitant volume the jet is large and fills most of the LA. FIGURE Pulsed-wave Doppler recording of pulmonary venous flow in a patient with severe mitral regurgitation. The early forward systolic flow is blunted and followed by a late systolic flow reversal (S). The diastolic flow (D) is normal.

21 mitral valve diseases 417 FIGURE Quantitative Doppler measurement of the mitral regurgitant volume. The lower images show the measurement of annular diameters and the upper tracings the measurement of pulsed-doppler velocity at the annular levels. On the left the mitral stroke volume is measured, and on the right the aortic stroke volume. The difference between these volumes is the regurgitant volume, 81 ml in this example. in most cases, but the measurement of the mitral stroke volume is technically demanding with a significant learning phase. 200 Quantitative two-dimensional echocardiography is of similar principle, but is based on measurement of LV volumes for total stroke volume calculation. 201 The proximal isovelocity surface area (PISA) method, conversely directly measures regurgitant flow by analyzing the flow convergence proximal to the regurgitant orifice and is based on the principle of conservation of mass. Because color flow mapping allows precise determination of velocity in the flow convergence region, the regurgitant flow can be calculated. Using regurgitant flow and velocity, regurgitant orifice (Fig ) and volume can be calculated. 199 This method is simple and accurate if the assumptions are respected. FIGURE Proximal flow convergence (PISA) measurement of the mitral effective regurgitant orifice. (Left) The color flow imaging of the flow convergence with down shifting of the color baseline so that the blue-yellow aliasing velocity reaches 53 cm/s. The flow convergence radius of 0.94 cm allows calculation of regurgitant flow at 294 ml/s. (Right) The continuous-wave Doppler measurement of the peak regurgitant velocity at 557 cm/s. The ratio of flow to velocity calculates the effective regurgitant orifice at 0.53 cm 2. Flow = 294 ml/sec. MR velocity = 557 cm/s ERO = flow/velocity = 0.53 cm2 or 53 mm 2

22 418 chapter 17 TABLE Signs used for MR severity assessment by Doppler-echocardiography Mild Moderate Severe Specific signs Small central jet <4 cm 2 or <20% Signs of MR > mild present, Vena contracta width 0.7 cm with of LA area but no criteria for severe MR large central MR jet (area >40% of Vena contracta width <0.3 cm LA) or with wall-impinging jet of any No or minimal flow convergence size, swirling in LA Large flow convergence Systolic reversal in pulmonary veins Prominent flail MV leaflet or ruptured papillary muscle Dense, triangular CW Doppler MR jet Supportive signs Systolic dominant flow in Intermediate signs, findings E-wave dominant mitral inflow pulmonary veins (E >1.2 m/sec) A-wave dominant mitral inflow Enlarged LV and LA size (particularly Soft density, parabolic CW when normal LV function is present) Doppler MR signal Normal LV size Quantitative parameters RVol (ml/beat) < RF (%) < ERO (cm 2 ) < The gradation schemes in mild, moderate, or severe MR for specific and supportive signs are presented in Table Importantly, RVol 60 ml and ERO area 40 mm 2 (or 0.40 cm 2 ) are thresholds representing severe organic MR, 202 and are associated with excess risk under medical management. 168 It is also important to note that smaller RVol and ERO are markers of IMR with severe clinical consequences, 174,178 and therefore that differential grading for organic and FMR should be used. Assessment of left ventricular and atrial function is most often based on guided M-mode diameters, with assessment of LV size, mass, and wall stress. 187,203,204 The LV volumes can be reliably measured by two-dimensional echocardiography. 205,206 The ejection fraction can be calculated 207 or estimated. 208 M-mode diameter or volume can assess the LA size by two-dimensional echocardiography. 209 Cardiac Catheterization Cardiac catheterization is rarely performed for the diagnosis of MR but may assess the hemodynamics, MR severity, and LV function if Doppler echocardiographic imaging is poor or ambiguous, and allows assessment of coronary anatomy preoperatively. The major hemodynamic consequences of MR are reduction of cardiac output and elevation of pulmonary artery wedge pressure. Marked pulmonary hypertension is rarely present. The large V wave of the LA or pulmonary wedge pressure (Fig ) is more frequent in acute than in chronic MR, 210 but can be observed in either disease with reduced left atrial compliance without MR. 211 The assessment of MR degree can be obtained by LV selective angiography and can be qualitatively graded in three or four grades on the basis of the degree and persistence of opacification of the LA. 212 Although time honored, this method has limitations similar to all qualitative methods. 213 Quantitation of MR can be obtained by comparing the angiographic stroke volume to the forward stroke volume FIGURE Cardiac catheterization with simultaneous recording of the LA and LV pressure and of the transmitral continuouswave Doppler. Note the large V wave on the LA pressure tracing reflected on the Doppler tracing by the triangular shape of the systolic jet signal revealing the ventriculoatrial equalization of pressure at end-systole.

23 mitral valve diseases 419 calculated by the Fick or thermodilution methods 214 to calculate RVol. The angiographic stroke volume usually overestimates the true stroke volume, and corrections have been used to minimize the overestimation of RVol. Subtraction of two stroke volumes introduces a potentially high range of error, which cannot be verified by combined methods or by repeating the measurements, and therefore this method is rarely utilized. The assessment of LV function can be performed using quantitative angiography. Left ventricle volumes correlate strongly with the regurgitant volume, duration, and etiology of MR and LV function. The most frequently utilized indices of LV function are end-systolic volume and ejection fraction, which are useful prognostic indices. 135,215 High-fidelity pressure recording with LV angiography allows calculation of more complex indices of LV distensibility in diastole, 138 and of wall stress, maximum LV elastance, and LV systolic stiffness. The additional value of these complex measurements has been investigated in small groups of patients and remains to be defined in larger populations. Selective coronary angiography allows definition of coronary anatomy. Obstructive coronary atherosclerosis continues to be frequent even in the absence of angina, 216 and coronary angiography is performed ordinarily in patients older than 40 to 50 years before surgery. 217 Management Medical Treatment Prevention of infective endocarditis using the appropriate prophylaxis is necessary in patients with MR. 218 Young patients with rheumatic MR should receive rheumatic fever prophylaxis. In patients with atrial fibrillation, rate control is achieved using Digoxin or beta-blockers. Long-term maintenance of sinus rhythm after cardioversion in patients with severe MR or enlarged LA is usually not possible in patients medically managed. However, return to sinus rhythm after surgery is possible in patients with atrial fibrillation of short duration. 219 Oral anticoagulation should be used in patients with atrial fibrillation. Diuretic treatment is useful for the control of heart failure and for the chronic control of symptoms, especially dyspnea. However, these efforts should not delay consideration of surgical repair in patients who are otherwise candidates for surgical therapy. Acute afterload reduction may decrease the degree and consequences of MR. 124 This effect is achieved by reducing the LV systolic pressure but also by decreasing the effective regurgitant orifice area. 125 Acute utilization of sodium nitroprusside in unstable patients with severe MR, especially in the context of myocardial infarction, may be lifesaving in preparation for surgery. 124 Chronic afterload reduction is more controversial. Hydralazine has positive acute effects, 220 but this drug is often poorly tolerated chronically. The effects of angiotensinconverting enzyme inhibitors have been analyzed in small series, and their long-term efficacy is not defined. Furthermore, discrepancies between series are noted regarding the effect on the degree of MR 224 and on LV remodeling. 225 In a nonrandomized open series, we observed positive results on MR severity, LV volumes, and LA enlargement of treatment with angiotensin-receptor blockade. 226 Because there are no results of long-term randomized studies, vasoactive therapy is not yet recommended for chronic treatment of MR. 110,217 Despite interesting animal data, 157,227,228 beta-blockade in chronic organic MR remains unproven in human subjects. Conversely in IMR and FMR there is a strong body of evidence suggesting that medical treatment improves the degree and consequences of MR. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers decrease afterload and remodeling and improve MR. 229 Furthermore, beta-blockade also improves LV remodeling and decreases the degree of FMR with subsequent improvement in survival Therefore, these drug therapies are considered standard in patients with ischemic and functional MR. Interventional treatment remains currently experimental. Devices that allow percutaneous suture between the mitral leaflets, 234,235 similar to the surgical Alfieri suture 236 or annular cinching, 237,238 mimicking annuloplasty, are under initial evaluation. Great hopes of new therapeutic avenues are yet to be confirmed. 239 Surgical Treatment The approach to surgery can be the traditional median sternotomy or the more recently used minimally invasive approaches, which range from port-access surgery to small sternotomy to thoracotomy. 240 These new techniques appear interesting but their long-term outcome remains uncertain. There are two main valvular surgical options: mitral valve repair and valve replacement. Mitral valve repair is possible in >85% of patients with MR, when the intervention is performed in advanced repair centers by surgeons with considerable experience with mitral surgery. 168 Nationally, valve repair is performed in approximately 50% of patients operated for mitral valve diseases. The frequency with which valve repair can be used varies with the experience of the operating team and the spectrum of the underlying valve disease; repair is more often feasible with degenerative than with rheumatic or endocarditic valve disease. 107 Valvular procedures involve plication or more often excision of a valve segment with prolapse (Fig ). 241 However, the resulting reduction in area of the leaflet could reduce coaptation and induce residual MR; therefore, annuloplasty is usually a routine part of the repair. 242 This type of repair is most successful with posterior leaflet prolapse. However, postoperative systolic anterior motion of the mitral valve and LV outflow tract obstruction may be observed. 243 This complication is due mainly to hypovolemia and excessive use of inotropes. 244 However, extensive myxomatous disease of the posterior leaflet with excessive leaflet length may lead to persistent systolic anterior motion, which can be prevented by sliding repair, which reduces the leaflet length. 245 With anterior leaflet prolapse, because of the limited width of the leaflet, the risk of residual MR is higher with plication or resection. 114,244,246 Other highly repairable leaflet abnormalities include congenital clefts and acquired perforation, which may be closed by using a patch. New procedures extended the armamentarium of valvular procedures used to correct lesions traditionally not considered repairable. In patients

24 420 chapter 17 FIGURE Schematic representation of the mitral valve repair technique in a patient with flail posterior leaflet (upper left) with triangular resection of the flail segment (upper right), reapproximation of the leaflets segments left in place and restoration of an appropriate coaptation line. with leaflets retraction, mitral leaflet augmentation with a pericardial patch may be helpful. 247,248 Similar approaches have been proposed in ischemic MR. 249 Subvalvular procedures are often necessary. In patients with elongated chordae, chordal shortening was intended to ensure appropriate coaptation of leaflets, but the durability of this procedure is limited. 114 Major recent improvements were the use of transposition of chordae or of artificial chordae, which have made anterior leaflet prolapse repair almost as feasible and as durable as posterior leaflet prolapse repair. 246 Annular dilatation, almost constantly associated with MR, is treated by reduction of mitral circumference, i.e., annuloplasty. 253 A rigid ring was originally developed by Carpentier, but flexible annuloplasty rings have been developed to preserve the normal systolic contraction of the mitral annulus, 254 and even simple bands have been proposed to support the repaired leaflet. No definitive differences have been demonstrated between the various rings. In ischemic and functional MR, restrictive annuloplasty has been advocated, 255 because standard annuloplasty leads to frequent recurrence. 256 Although early experience with this approach appears interesting, 257 the effect on survival is uncertain. 258 Intraoperative assessment of valve repair 259 is essential to assess the adequacy of mitral valve reconstruction before completion of the operation, 260 and is a significant component of improved results of mitral repair. When satisfactory repair cannot be achieved, it is preferable to replace the valve immediately. To assess the adequacy of mitral repair (residual stenosis, regurgitation, or systolic anterior motion), TEE, which does not interfere with the surgical procedure, is performed routinely. 244 Valve replacement must be performed when mitral repair is impossible or is unsuccessful. The choice is between a mechanical valve of potentially excellent durability but with a hazard of thromboembolism and a biologic valve with undefined long-term durability 261 but less tendency to cause thromboembolism. With atrial fibrillation, chronic anticoagulant therapy is necessary even with a bioprosthesis, so that avoiding anticoagulation is not relevant in choosing a prosthesis. An important component in maintaining LV function postoperatively is chordal preservation during valve replacement. 262,263 Postoperative outcome after surgery for organic MR is essential to determine the appropriate indications. Valve repair, by preserving the normal valvular tissue, is preferable to valve replacement. Compared to prosthetic replacement, valve repair has a lower operative mortality. 264,265 Direct comparison of the results of valve repair and replacement is difficult 265 because patients undergoing valve repair are usually at a less advanced stage of the disease than patients undergoing valve replacement. 264 However, survival and LV function after valve repair are better than after insertion of a prosthetic valve, 264,266,267 even in patients with anterior leaflet prolapse (Fig ). 246 Better ventricular function with valvuloplasty may be due to preservation of chordae and papillary muscles. 268 Durability of valve repair for degenerative disease is excellent if no more than mild residual MR is accepted intraoperatively, 114,246 even very long term after surgery. 269 Some centers noted, despite superior survival, higher rates of recurrent MR and lesser durability after valve repair, 270 suggesting that the results of each individual center should be analyzed in indicating mitral repair. However, valve repair has the same low rate of reoperation than valve replacement. 246,264 Mitral regurgitation postrepair is attributed in two thirds of the cases to new lesions and in one third to an inadequate primary correction. 271 Therefore, valve repair is the preferred procedure for surgical correction of organic MR. Operative mortality has been reported between 5% and 12% 261 in earlier series, but most patients had prosthetic valve replacement rather than reconstruction. The operative risk is lower in the current era, around 1% in patients younger than 75 years with organic MR whether they had valve repair or replacement, 187 and around 2% to 3% above that age. Left ventricle function is not a predictor of operative mortality, and patients with organic MR even with markedly depressed function have a reasonable chance of surviving surgery. 187 Age, symptoms, and coronary disease are the most important predictors of operative mortality. 187 The operative mortality is notably higher in ischemic MR even after valve repair. 272,273 Long-term postoperative survival has considerably improved, and survival after valve repair is close to expected survival, whereas it is reduced compared to expected survival after valve replacement. 114,246,264,269 Another important determinant of long-term postoperative outcome is the preoperative symptomatic status. Patients with severe