I. Mitral Regurgitation: What every physician needs to know.
Primary mitral regurgitation
The mitral valve is composed of its leaflets, the chordae tendineae, the mitral annulus, and the papillary muscles that link the chordae to the left ventricle (LV). Primary mitral regurgitation (PMR) may occur from pathology of any of these valve components. In developed countries the most common cause of MR is myxomatous valve degeneration associated with mitral valve prolapse. Other causes include infective endocarditis, rheumatic heart disease, and collagen vascular disease.
Primary MR is a distinct entity from functional or secondary MR (Please see the chapter on Functional Mitral Regurgitation) wherein the mitral valve itself is normal but regurgitation results from ventricular disease caused by either myocardial infarction or cardiomyopathy.
Mitral regurgitation exerts a volume overload on the LV, compensated by eccentric hypertrophy and remodeling (Figure 1, Figure 2). The pure volume overload of MR is nearly unique in Cardiology. In most other forms of volume overload (aortic regurgitation, anemia, heart block, etc.), the extra volume is pumped into the aorta where increased stroke volume increases systolic blood pressure. Thus, most LV volume overloads are in fact combined pressure and volume overloads.
In MR the extra volume is delivered into the left atrium (LA) and systolic pressure tends to be lower than normal. This pattern of overload causes the LV to remodel as a thin-walled enlarged chamber that permits supernormal diastolic function, allowing the LV in chronic compensated MR to fill at a normal filling pressure. Increased preload in concert with normal afterload allows the enlarged LV to deliver increased total stroke volume and a normal forward stroke volume.
A common misconception is that afterload in MR is reduced. A reasonable measure of afterload is systolic wall stress (σ), where σ = P × r/2h and P = LV pressure, r = radius and h = thickness. While the extra pathway for LV ejection into the LA does unload the ventricle, the remodeling pattern of a large LV radius and a thin LV wall offset the extra ejection pathway for unloading and return stress (afterload) to normal. Mild to moderate MR may be tolerated indefinitely provided the magnitude of MR does not increase. Severe MR may also be compensated by the mechanisms noted above, but eventually the overload damages the LV and heart failure ensues.
II. Diagnostic Confirmation: Are you sure your patient has Mitral Regurgitation?
A. History, Part 1: Pattern Recognition.
Mitral regurgitation is usually first identified when the patient’s provider hears a systolic murmur. In compensated MR, the patient may be asymptomatic. In acute MR, before compensation from remodeling has occurred or in chronic severe decompensated MR, typical symptoms of left heart failure arise. These include progressive dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea. When pulmonary hypertension complicates decompensated MR, the symptoms of right heart failure, including fatigue, ascites and edema, may develop.
B. History, Part 2: Prevalence.
It is estimated that 4 million Americans have some degree of MR. Most are asymptomatic and unaware of the disease. A history of rheumatic fever, collagen vascular disease or of infective endocarditis may raise the suspicion that MR might be present.
C. History, Part 3: Competing diagnoses that can mimic Mitral Regurgitation.
Heart diseases that cause a systolic murmur are those most likely to be confused with MR. Conversely, in acute MR the rapid rise in LA pressure due to the filling of that chamber from both the pulmonary veins and from the regurgitant flow limits the gradient for LV to LA transfer of blood. In such cases, the MR murmur may be short and unimpressive and the diagnosis missed.
D. Physical Examination Findings.
Mitral valve prolapse
As noted above, mitral valve prolapse due to myxomatous valve degeneration is the most common cause of primary MR in developed countries. Mitral prolapse has often been termed the “click-murmur” syndrome because of the physical findings it produces, i.e., a mid-systolic click followed by a late systolic murmur. The click arises from the tightening of the redundant chordae tendineae as the valve closes. The murmur commences when the leaflets move past their point of coaptation. Maneuvers that reduce LV volume, such as standing or the Valsalva maneuver, lengthen the valve apparatus and cause the click to occur earlier and the murmur to become louder and more holosystolic. The opposite is true of conditions that increase LV volume, such as lying down or squatting.
Chronic severe MR
As valve degeneration proceeds, prolapse becomes more severe and the MR worsens until it eventually becomes pan-systolic. In chronic severe MR, LV to LA flow begins when LV pressure exceeds LA pressure, hemodynamics that occur almost immediately at the onset of systole. Thus, the murmur of MR is holosystolic. It usually radiates to the axilla, but may also radiate to the top of the head or to the elbow.
Murmur intensity does not vary very much with changes in cycle length because while longer R-R intervals allow for increased LV filling and thus greater stroke volume, aortic pressure is lower after a long pause. In turn, lower aortic pressure preferentially increases aortic flow so that regurgitant flow does not change and murmur intensity does not increase.
The high volume of blood stored in the LA during systole often causes an S3 when it is discharged into the LV during early diastole. An S3 in severe primary MR is more likely a sign of volume overload than of heart failure, but it might signal the presence of both. In chronic severe MR, LV enlargement moves the apical beat downward and to the left of its normal position. If pulmonary hypertension develops, a right ventricular impulse may be felt over the sternum, and the pulmonic component of the second heart sound (P2) may become accentuated.
E. What Diagnostic Tests Should Be Performed?
Because atrial fibrillation often accompanies MR, an EKG should be obtained to establish baseline cardiac rhythm. The EKG may also demonstrate evidence of left ventricular hypertrophy and left atrial enlargement, but both conditions are much more accurately assessed during echocardiography. Increasing levels of natriuretic peptides may presage worsening of MR, but specific levels that should be used in management decisions are not yet established. However, increasing levels from baseline are worrisome and can be viewed as a supportive evidence for moving toward valve intervention.
What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Echocardiography forms the mainstay of diagnosis. Transthoracic imaging is usually adequate to completely assess the heart in MR. Echocardiography can establish the mechanism of MR, its severity, its effect on LA and LV size and function, all of which provide data that determine management.
Criteria for assessing severity are given in Table I. Quantification of MR is often performed using the proximal isovelocity surface area (PISA) method. As the regurgitant flow approaches the mitral valve from the ventricular side, the MR jet often assumes a hemispheric shape (Figure 3). The area (a) of a hemisphere = 2π r2 where r is the radius of the hemisphere. Multiplying area × jet velocity (v) (determined by the echo machine settings) yields flow (f). In turn f/v = regurgitant orifice area. However, in general it is unwise to grade the severity of MR on a single parameter, and most experienced echocardiographers use an integrated approach incorporating several parameters into severity assessment. It is especially important to consider chamber volume in assessing MR severity.
In severe MR the LV must enlarge to compensate for stroke volume lost to regurgitation. The LA must also enlarge to accommodate the volume overload at a tolerable filling pressure. Failure of the LA and LV to enlarge indicates that either the MR is not severe or it is acute (in which case the patient should be symptomatic). LV ejection fraction, volumes and dimensions should be measured carefully as these will be used to help time surgical intervention (see below).
Most patients experience symptoms during exercise; yet, echocardiography is usually performed at rest. If symptoms seem out of proportion to the less severe findings of the resting echocardiogram, exercise echo may demonstrate worsened MR with exercise and/or exercise-induced pulmonary hypertension that help explain the clinical picture.
As LV and LA filling pressure increase, the pulmonary pressure and right ventricular must also increase to provide the force needed to fill the left heart. However, pulmonary hypertension adversely affects prognosis. If any tricuspid regurgitation is present, the tricuspid jet velocity (v) can be used to calculate RV pressure. The gradient (g) across the tricuspid valve is calculated using the modified Bernoulli equation, where g = 4v2. By adding an estimated right atrial pressure to the tricuspid gradient, peak RV pressure, and thus peak pulmonary artery pressure, can be estimated.
In some cases, transthoracic echocardiography yields images that are inadequate to assess the MR patient fully. If patient characteristics such as size, chest configuration, etc., preclude diagnostic quality images from being obtained, transesophageal echocardiography almost always provides high quality diagnostic cardiac images. On the other hand, it should not be assumed that 2-D echo will automatically add to overall assessment of valve anatomy. Three-dimensional echocardiography can also be useful because it replicates the “surgeon’s view,” i.e., the view the surgeon will see when he/she opens the LA and looks down on the valve. Cardiac magnetic resonance imaging may be utilized to precisely measure LA and LV volume and ejection fraction if those data are needed in clinical decision-making.
If, after non-invasive imaging, discordance remains between symptom severity and the apparent MR severity, invasive hemodynamic data should help resolve the issues. Direct measurement of LV filling pressure at rest or during exercise confirms or refutes a hemodynamic basis for symptoms. Left ventriculography that images LV to LA flow (instead of flow velocity visualized during echocardiography) adds another way of assessing MR severity. If surgical correction of MR is contemplated and the patient has risk factors for coronary artery disease, coronary arteriography is performed during catheterization.
In acute severe MR, as might be encountered after a ruptured chorda tendineae, there has been no time for compensatory enlargement of the LV; thus, forward stroke volume and cardiac output are reduced. The increased volume filling the small unprepared LA causes high left atrial pressure that is referred to the lungs, causing pulmonary congestion. As noted above, the rapid systolic rise in LA pressure limits the pressure gradient from LV to LA; thus, the murmur of acute MR may be short and unimpressive.
A high index of suspicion raised by unexplained heart failure and a new murmur leads to an echocardiogram, confirming the diagnosis. Diuretics may be used to lower LA pressure, but reduced cardiac output with reduced renal perfusion may limit their use.
Arterial vasodilators such as sodium nitroprusside may be administered to reduce aortic impedance in an effort to preferentially increase aortic outflow while decreasing the amount of regurgitation. However, reduced cardiac output and hypotension may limit the use of vasodilators. In such cases, aortic balloon counterpulsation is used to reduce afterload and regurgitant flow while augmenting mean arterial blood pressure. In most cases, urgent surgery for mitral valve repair is necessary to restore normal circulation.
Laboratory Tests to Monitor Response to, and Adjustments in, Management.
Implicit in the strategy for timing of surgery noted above is the need to conduct surveillance for changes in symptom status or in LV function that would then trigger the need for surgery. Patients with severe asymptomatic MR should have an office visit that includes an echocardiogram at least yearly. If the LV is approaching the “trigger” benchmarks, the frequency should be increased to every-6-month intervals.
Following surgery, an echo should be performed to establish the baseline function of the repair or of the inserted valve prosthesis. Some clinicians perform this exam to take place prior to discharge, while other clinicians wait for the first post-operative office visit. Afterwards, the echo need not be repeated unless there is change in symptoms or in the physical examination.
Chronic Severe MR
Primary mitral regurgitation is a mechanical problem wherein an anatomic abnormality of the mitral valve permits backflow into the LA. The only effective management for MR is its mechanical correction.
There is no evidence from large trials to support the use of afterload reducing agents to treat chronic MR, and most of the data that do exist are disappointing. Conversely, patients with hypertension should receive standard therapy for that condition.
Mild to moderate MR is usually tolerated indefinitely as long as it does not worsen. However, because MR causes ventricular enlargement, in turn placing additional stress on the valve, MR tends to cause worsening of MR. Severe MR may be tolerated for several years, but most patients reach a “trigger” for surgery within about 6 years of initial diagnosis. These triggers are demarcations in the disease which, if left unattended, lead to worsened prognosis and include: the onset of symptoms, evidence of LV dysfunction, and evidence of pulmonary hypertension.
Because the increased preload of MR increases ejection fraction (EF), “normal” EF in MR is probably about 70%. When EF declines to less than 60% or when the LV becomes unable to contract to an end systolic dimension of 40 mm, prognosis following corrective surgery worsens. This suggests that these benchmarks are a sign that LV dysfunction has ensued. If the patient is seen for the first time when symptoms or LV dysfunction have occurred, a short course (3-6 months) of standard heart failure therapy that includes the administration of ACE inhibitors and beta blockers is probably advisable before proceeding to mitral valve surgery. However, even if the patient improves clinically after this therapy, the indications for surgery have been met and there is no evidence that surgery should be delayed any further.
Mitral Valve Repair versus Mitral Valve Replacement
Preventing systolic regurgitation of blood from the LV to the LA is only one of the mitral valve’s functions. The mitral valve is an integral part of the LV; the mitral apparatus aids in LV contraction and helps maintain the efficient prolate ellipsoid shape of the LV.
Destruction of the mitral valve apparatus and concomitant mitral valve replacement cause increased operative mortality, poorer postoperative LV function, and decreased postoperative survival when compared with mitral valve repair.
Thus, in the treatment of MR, when possible, the mitral valve should be conserved and repaired instead of replaced. Reparability depends upon valve pathology and surgical skill. In general, rheumatic valves are difficult to repair and the durability of the repair is undependable. Simple posterior leaflet prolapse is the easiest to repair and most durable; bileaflet myxomatous disease is in the middle between the two.
It must be noted that surgical expertise varies widely, with some surgeons able to repair most non-rheumatic MR, while others have never performed a mitral valve repair. However some valves ultimately will require replacement. Preservation of the natural connections between the native valve and the papillary muscles can be maintained even when the valve is replaced, and this procedure helps preserve LV function.
In cases of severe MR where the anatomy is consistent with almost certain valve repair, many would argue for early surgery before symptoms or evidence of LV dysfunction develop. This strategy can be carried out in experienced centers, with < 1% operative mortality and the high likelihood of a durable repair, thereby obviating the need for repetitive follow-up visits and echocardiographic observation. This strategy only works if a successful repair is carried out. If an unwanted mitral valve replacement ensues, with its higher risk of both operative mortality and long-term prosthetic valve complications, the strategy fails.
Common Pitfalls and Side Effects of Management
Many providers remain unaware of the nuances of therapy. Common mistakes in management include:
Treating symptoms medically. Despite evidence that the presence of even mild symptoms worsens prognosis, many providers add diuretics or other therapies to improve symptoms. However, there is no evidence that medical therapy improves prognosis even if symptoms improve.
Assessing MR severity “by eyeball”. In some cases, it is entirely obvious that the patient has severe MR from all aspects of the clinical presentation. However, in other cases visualizing, only the MR jet at color-flow Doppler examination may overestimate or underestimate MR severity because all the clues available are not considered.
Under-appreciation of the importance of mitral repair. Many practitioners are willing to accept mitral replacement when repair could be performed by surgeons more skilled in the technique.
IV. Management with Co-Morbidities
As noted above, the only effective management of MR is mechanical correction. However, very elderly patients or those with advanced liver, lung or renal disease may be at unacceptable risk for mitral surgery.
Recently, experimental approaches using transcatheter, percutaneous, or transapical methods for mitral repair or replacement have been attempted. One, the MitraClip, is now approved in the United States for mitral repair in inoperable patients with severe primary symptomatic MR. The technique employs trans-septal deployment of a device that clips the midportions of the two mitral leaflets together, reducing MR from severe to moderate or mild in most cases. The technique is less effective than surgery in eliminating MR but safer in this group of patients and has provided excellent relief of symptoms for up to 5 years. While currently the indications for use are limited as described above, in Europe it is most often used to treat secondary MR and trials for that use are currently underway in the United States.
What's the Evidence for Specific Management and Treatment Recommendations?
Carabello, BA. “Mitral Regurgitation: Basic pathophysiologic principles”. Part Mod Concepts Cardiovasc Dis. vol. 57. 1988. pp. 53-8. (Summarizes the pathophysiology of MR.)
Wisenbaugh, T, Spann, JF, Carabello, BA. “Differences in myocardial performance and load between patients with similar amounts of chronic aortic versus chronic mitral regurgitation”. J Am Coll Cardiol. vol. 3. 1984. pp. 916-23. (Emphasizes the “pure” nature of the volume overload in MR.)
Corin, WJ, Murakami, T, Monrad, ES, Hess, OM, Krayenbuehl, HP. “Left ventricular passive diastolic properties in chronic mitral regurgitation”. Circulation. vol. 83. 1991. pp. 797-807. (Demonstrates that diastolic function in MR is super-normal.)
Corin, WJ, Monrad, ES, Murakami, T, Nonogi, H, Hess, OM, Krayenbuehl, HP. “The relationship of afterload to ejection performance in chronic mitral regurgitation”. Circulation. vol. 76. 1987. pp. 59-67. (Dispels the misconception that MR unloads the LV.)
Rozich, JD, Carabello, BA, Usher, BW, Kratz, JM, Bell, AE, Zile, MR. “Mitral valve replacement with and without chordal preservation in patients with chronic mitral regurgitation: mechanisms for differences in postoperative ejection performance”. Circulation. vol. 86. 1992. pp. 1718-26. (Demonstrates the importance of the mitral apparatus in aiding LV function.)
Ghoreishi, M, Evans, CF, DeFillippi, CR, Young, CA, Griffith, BP, Gammie, JS. “Pulmonary hypertension adversely affects short-and long-term survival after mitral valve operation for mitral regurgitation: implications for timing of surgery”. J Thorac Cardiovasc Surg. vol. 142. 2011. pp. 1439-52. (Demonstrates the risks of pulmonary hypertension in MR.)
Enriquez-Sarano, M, Tajik, AJ, Schaff, HV, Orszulak, TA, Bailey, KR, Frye, RL. “Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation”. Circulation. vol. 90. 1994. pp. 830-7. (One of the sources for using an EF falling toward 60% as a trigger for mitral surgery.)
Tribouilloy, C, Grigioni, F, Avierinos, JF, Barbieri, A, Rusinaru, D, Szymanski, C. “MIDA Investigators. Survival implication of left ventricular end-systolic diameter in mitral regurgitation due to fall leaflets: a long-term follow-up multicenter study”. J Am Coll Cardiol. vol. 54. 2009. pp. 1961-8. (Cements LV systolic dimension as a predictor of outcome in MR.)
Gillinov, AM, Mihaljevic, T, Blackstone, EH, George, K, Svensson, LG, Nowichi, ER. “Should patients with severe degenerative mitral regurgitation delay surgery until symptoms develop”. Ann Thorac Surg. vol. 90. 2010. pp. 481-8. (Shows that even mild preoperative symptoms in MR effect post-operative outcome negatively.)
Enriquez-Sarano, M, Schaff, HV, Orszulak, TA. “Valve repair improves the outcome of surgery for mitral regurgitation: a multivariate analysis”. Circulation. vol. 91. 1995. pp. 1022-8. (Demonstrates the survival benefit of mitral repair compared to replacement.)
Bolling, SF, Li, S, O’Brien, SM, Brennan, JM, Prager, RL, Gammie, JS. “Predictors of mitral valve repair: clinical and surgeon factors”. Ann Thorac Surg. vol. 90. 2010. pp. 1904-12. (Reveals the importance of repair volume in predicting the likelihood of a successful repair.)
Glower, DD, Kar, S, Trento, A, Lim, DS, Bajwa, T, Quesada, R, Whitlow, PL, Rinaldi, MJ, Grayburn, P, Mack, MJ, Mauri, L, McCarthy, PM, Feldman, T. “Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study”. J Am Coll Cardiol. vol. 64. 2014. pp. 172-81.
Feldman, T, Kar, S, Elmariah, S. “Randomized comparison of percutaneous repair and surgery for mitral regurgitation: 5-year results of EVEREST II”. J Am Coll Cardiol. vol. 66. 2015. pp. 2844-54. (Five-year follow-up of the EVEREST trial that randomized MR patients to surgical vs MitraClip repair.)
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- I. Mitral Regurgitation: What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Mitral Regurgitation?
- A. History, Part 1: Pattern Recognition.
- B. History, Part 2: Prevalence.
- C. History, Part 3: Competing diagnoses that can mimic Mitral Regurgitation.
- D. Physical Examination Findings.
- E. What Diagnostic Tests Should Be Performed?
- What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- III. Management.
- Immediate Management.
- Laboratory Tests to Monitor Response to, and Adjustments in, Management.
- Long-Term Management.
- Common Pitfalls and Side Effects of Management
- IV. Management with Co-Morbidities