Mitral regurgitation. Diagnosis, echocardiography and management. / A clinical case (VIDEO)

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A case of a  65- years- old man with effort dyspnea and nocturnal dyspnea, atrial fibrillation and an apical systolic murmur. Echo showed severe mitral regurgitation A discussion of the ECG, chest X-ray, echocardiogram and indications for surgical treatment. Analysis of how to assess the severity of mitral regurgitation with echocardiography and of the indications for surgery and the therapeutic desicion on the type of surgery.

Mitral Regurgitation (MR) -Important Notes

 The role of the mitral valve (MV) is to permit unidirectional flow from the left atrium (LA) to the left ventricle (LV).
The mitral apparatus is composed of an annulus, two leaflets, chordae tendinae and two papillary muscles (anterolateral and posteromedial). The mitral subvalvular apparatus is a term, that includes the chordae tendinae and the two papillary muscles.
For adequate function of the mitral valve, proper function and  interaction between these parts, together with the LV and the LA, is necessary. Abnormal function of any one of these components can lead to mitral regurgitation (MR).
MR is the presence of backward flow of blood  from the left ventricle (LV) into the left atrium (LA) during systole, caused by inadequate coaptation of the valve leaflets.

Mechanisms and causes of mitral regurgitation

There are three basic mechanisms of mitral regurgitation (MR): 1) Alteration of mitral leaflets, commissures, or annulus 
2) Defective subvalvular (tensor) apparatus and
 3) Alterations of left ventricular and left atrial size and function (i.e dilatation of the LV or the LA can cause MR).
Organic (primary) MR is caused primarily by abnormalities of the valve leaflets and/or chordae tendinae. 
Causes of primary MR  
Myxomatous degeneration (mitral valve prolapse is caused by myxomatous degeneration and it is also the most common cause of isolated severe mitral regurgitation),
 Infective endocarditis (it may cause valve leaflet perforation or a vegetation interfering with leaflet coaptation),
Rheumatic valve disease,(it is caused by rheumatic fever and gradually deforms the valve over many years, with thickening of the leaflet tips, chordal shortening, and calcification of the valve. Usually, in rheumatic valve disease, the regurgitation is in combination with stenosis, but pure MR can also occasionally occur. 
A congenital cleft of the anterior mitral leaflet (associated with a primum atrial septal defect or an atrioventricular canal defect, but it can also occur in isolation). 
Ruptured chordae tendinae are responsible for a considerable percentage of cases of mitral regurgitation.Rupture of chordae can be a result of myxomatous degeneration in the setting of mitral valve prolapse, a complication of endocarditis, a complication of a blunt or penetrating thoracic trauma, or idiopathic (not attributed to a specific cause). 
Degenerative MR is caused by myxomatous degeneration of the valve (myxomatous proliferation can occur in the leaflets, chordae tendineae, and/or annulus). This is the cause of the mitral valve prolapse syndrome. It usually occurs as a primary condition-the most common form (Barlow's disease or fibroelastic deficiency) which can be familial or non familial. However, it has also been associated with genetic syndromes affecting the connective tissue, including Marfan syndrome, Ehlers–Danlos syndrome, osteogenesis imperfecta, etc.
A paravalvular prosthetic leak (PVL) is another cause of MR, in cases of prosthetic valves, where blood flows through a gap between the structure of the implanted valve and the mitral annulus. It can be related to disruption of sewing ring sutures caused by infectious endocarditis, accompanied by an abscess formation. Another cause is calcification and fibrosis of the annulus or even technical factors of the surgical procedure (incomplete apposition of the valvular structure against the annulus). In most cases, paravalvular leaks are mild and cause no symptoms but sometimes they are large. A significant PVL can cause heart failure, or hemolytic anemia.
Carpentier’s classification is used to classify MR according to its mechanism, specifically relying on the pattern of leaflet motion. It categorizes MR into:
 Type I: MR with normal leaflet motion (i.e. annular dilatation, or leaflet perforation), 
Type II: MR due to excessive leaflet motion (mitral valve prolapse or a flail mitral leaflet), 
type III: MR due to a restricted motion of its leaflets, with the following subtypes:
 IIIa systolic and diastolic restrictive leaflet motion (such as in rheumatic MR) and
 IIIb  leaflet motion is restrictive only in systole (such as in secondary MR).

Causes of Secondary (functional) mitral regurgitation

Functional MR is caused primarily by ventricular dysfunction usually accompanied by annular dilatation (e.g., in dilated cardiomyopathy and ischemic MR). Ischemia can cause either dysfunction or rupture of a papillary muscle. Rupture can occur in acute myocardial infarction (either transmural, or subendocardial). The posteromedial papillary muscle is most often affected by ischemic dysfunction or rupture because it has a single-arterial blood supply. 
Global or regional left ventricular dysfunction and enlargement can alter the position of the papillary muscles and can also cause dilatation of the mitral ring. These are changes that often result in mitral regurgitation (MR).
In hypertrophic obstructive cardiomyopathy, MR results from distortion of the mitral valve apparatus due to the systolic anterior motion of the mitral valve.

Physical examination findings in mitral regurgitation

In clinical examination,  the hallmark of chronic mitral regurgitation (MR) is a  holosystolic murmur heard with maximum intensity at the position of the heart apex (fifth intercostal space at the midclavicular line). The murmur frequently radiates to the axilla. Occasionally (if the regurgitant jet is directed anteriorly, in a primary posterior leaflet abnormality) the radiation can be toward the anterior chest wall or toward the aortic area.
  The intensity of the murmur does not correlate reliably with the severity of MR. In significant MR a third heart sound (S3) that does not necessarily indicate left ventricular dysfunction and/or an early diastolic flow rumble may be present. These are due to an increased antegrade flow through the mitral valve in early diastole. This happens because not only blood returning from the pulmonary circulation to the left atrium (LA) passes through the mitral orifice in diastole, but also blood, that has regurgitated into the LA during the previous systole. 
In severe chronic mitral regurgitation the apical impulse is usually brief (of small duration), laterally displaced and enlarged. (If ventricular systolic function gradually deteriorates, then the duration of the apical impulse increases). 
 The presence of an apical thrill indicates severe MR.
In mitral valve prolapse, the murmur is endsystolic and a midsystolic click is heard before the murmur. 
 It is important to know that in acute severe mitral regurgitation the systolic apical murmur may be short (not holosystolic), or soft, or even completely absent, because of the low left ventricular-to-atrial pressure gradient. This lower pressure gradient is due to the markedly elevated left atrial (LA) pressure, since the LA in acute MR, does not have the time to dilate, in order to accommodate the regurgitant volume without a marked pressure elevation. Because of the markedly raised LA pressure, if acute MR is severe, it promptly results in severe pulmonary congestion. A third or fourth heart sound (S3, S4) may also be present due to the elevated atrial and ventricular diastolic pressures. Acute MR usually results from infective endocarditis, myocardial infarction, chordal rupture (rupture of chordae tendinae), or trauma.

Echocardiographic assessment of the etiology of mitral regurgitation

In degenerative mitral valve disease, the leaflets are thick and redundant (with excessive, unnecessary tissue) and the chordae are elongated. In some cases, there is a rupture of one or more chordae tendinae.  Ruptured chordae appear echocardiographically as flail segments. To diagnose mitral valve prolapse, the following echocardiographic criteria should be fulfilled: Movement of any part of either leaflet more than 2 mm behind the annular plane (towards the left atrium) in systole, in the parasternal long axis view and the point of leaflet coaptation being located behind the annular plane in apical 4 chamber view.
In rheumatic mitral regurgitation, echocardiographic findings include thickening of the tips of the mitral leaflets and some degree of commissural fusion. The movement of the valve leaflets is restricted. 
 Secondary or functional MR results from local or global left ventricular remodeling (a pathologic change in the shape of the left ventricle). This leads to the displacement of the papillary muscles resulting in tethering of mitral leaflets. Tethering means that the leaflets are pulled and their closing motion is restricted. This causes a failure of coaptation of the mitral valve leaflets. An echocardiographic parameter which reflects tethering is the coaptation distance or coaptation height. This is the end-systolic distance between the center of the mitral annular plane and the coaptation point of the leaflets. It can be evaluated in transthoracic parasternal long axis view or transoesophageal a long axis view at 135°. Normal coaptation height or distance is ≤ 10 mm. When it exceeds this value, it is an indication of tethering of the mitral valve leaflets.  Another parameter which reflects tethering is the tenting area. This is the triangular zone comprised between the mitral annulus, both leaflets and the coaptation point.

Echocardiographic criteria of severe MR 

Vena contracta, which is the narrowest portion ("the neck") of the regurgitant jet-at the level of the valve: with width ≥ 7 mm.
Color jet area >8.0 cm2 (the color jet area is not a very accurate index and it can underestimate MR when the jet is eccentric. The color doppler gain must be properly set and color doppler aliasing velocity should be at about 55-60 cm/s).
An effective regurgitant orifice area ERO >0.4 cm2 in primary (organic) MR.  or > 0.2 cmin functional MR. ERO area is usually calculated with the PISA method (see the video on the top of the page for details about the assessment of mitral regurgitation severity with echocardiography and for a simple and complete description of the PISA-proximal isovelocity area- method).
CW Doppler signal intensity: A dense CW Doppler signal of MR is suggestive of severe MR.
Transmitral PW peak early diastolic flow velocity E >1.5 m/s (for a native mitral valve) / E > 2 m/s (for a prosthetic valve), are suggestive of severe MR, if there is no indication of concomitant valve stenosis (PHT of the E wave of the early diastolic transmitral flow is normal).
Regurgitant volume  in primary MR >60 ml / in secondary (functional) MR > 30 ml.
Magnetic resonance imaging (MRI) is the most accurate method for the assessment of the regurgitant volume and can also provide an accurate assessment of the left ventricular end diastolic and end systolic volume.

Cardiac catheterization findings in mitral regurgitation

The pulmonary capillary wedge pressure (PCWP) tracing or the left atrial pressure tracing show an increased amplitude of the v wave and y descent is particularly rapid. Severe mitral regurgitation is suggested by an amplitude of the v wave > 2-3 times the mean PCWP. However, occasionally in slow developing MR, the amplitude of the v wave is not markedly elevated. 
With left ventriculography (infusion of contrast into the left ventricle with a pig-tail angiographic catheter) the severity of MR can be visually assessed, using Seller's criteria: There are four grades of MR (1+/4+, 2+/4+, 3+/4+, 4+/4+). In moderately severe MR (3+) contrast opacifies (makes visible) the entire left atrium (LA) with the same intensity of opacification as the left ventricle (LV), in 2-3 beats after its infusion in the LV. 
In severe MR (4+) contrast completely opacifies the LA in one beat and there is also contrast reflux into the pulmonary veins. (In mild to moderate MR of 2+ , the entire LA is fairly opacified but the intensity of opacification of the LA is less than of the LV, and in mild MR of 1+ contrast does not opacify the entire LA and clears from the LA in one heartbeat.)

Generally in severe valve disease with an indication for surgery coronary angiography is performed before surgery in patients >40 years old, or with multiple risk factors or suspicion for coronary artery disease.

Treatment of chronic mitral regurgitation

Drugs such as ACE inhibitors, diuretics, beta blockers and/or digoxin are given in cases of symptomatic patients due to left ventricular dysfunction. However definitive treatment is surgery.
Valve repair, when feasible, is preferable to valve replacement (with a prosthetic valve) because it is associated with less morbidity and mortality.

Indications for surgery in chronic severe MR

Patients with symptoms NYHA II-IV
Asymptomatic patients with evidence of left ventricular (LV) dysfunction : LV ejection fraction (EF) 30-60 % and/or LV end systolic dimension  ≥ 45 mm ( in cases, where valve repair is feasible with low surgical risk, the decision for surgery can be made with LV end systolic dimension > 40 mm).
Asymptomatic patients with new onset atrial fibrillation.
Asymptomatic patients with pulmonary hypertension (pulmonary artery systolic pressure at rest >50 mmHg, or with exercise >60 mmHg.)

Acute mitral regurgitation

It is characterized by a left atrium (LA) of normal or almost normal size, but with acute rise of LA pressure, because in acute MR the LA does not have the time to dilate, in order to accommodate an increased volume load. For this reason acute MR often leads to pulmonary edema and pulmonary hypertension. 
In contrast to chronic MR, in acute MR the systolic murmur is decrescendo, softer in intensity and not holosystolic (it does not last in all the period of systole and ends well before the aortic component of the second heart sound-A2). This happens because the increased LA pressure results in a lower pressure gradient between the left ventricle (LV) and LA in systole. A fourth heart sound (S4) is frequently audible in acute MR. Echocardiography in acute MR shows no (or only little) dilation of the LA and the LV and a hyperkinetic (with increased systolic motion) LV.
Treatment of acute MR
Afterload reduction with intravenous nitroprusside and if there is hypotension an inotrope (eg dobutamine) is administered. Afterload reduction is beneficial because it helps to increase forward flow of blood into the aorta in systole and thus it decreases regurgitant flow through the mitral valve. Intraortic balloon counterpulsation can help stabilize the patient. Surgery (this the definitive and absolutely necessary treatment) is generally performed promptly, after initial patient stabilization.

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Useful links

2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease

ESC Guidelines on the management of valvular heart disease (version 2012)

2015 ESC Guidelines for the management of infective endocarditis