I. Functional Mitral Regurgitation: What every physician needs to know

Secondary (functional) Mitral Regurgitation

Secondary mitral regurgitation (SMR) occurs when coronary disease with myocardial infarction or primary dilated cardiomyopathy cause a combination of left ventricular (LV) wall motion abnormalities, mitral annular dilatation, papillary muscle displacement and reduced closing force that prevent the mitral valve from coapting normally. The valve itself is usually normal but the LV abnormalities cause tenting of the valve, preventing its closure.

While the burden of the volume overload of SMR may contribute to the pathology and poor outcome found in many SMR patients, the central problem that drives outcome is LV dysfunction, not MR. In primary MR the pathophysiology is straightforward. The volume overload caused by MR causes the symptoms, LV remodeling, LV damage, heart failure and eventually death if untreated. Correction of primary MR is “curative.” In SMR the MR itself is only part of the problem. Correction of SMR is accompanied by poor long-term survival; thus, the best therapy for SMR is much less certain than it is for primary MR.

II. Diagnostic Confirmation: Are you sure your patient has Secondary Mitral Regurgitation?

Because SMR is caused by other diseases of the LV that have already led to severe LV dysfunction, SMR is usually discovered during the work-up for heart failure. Thus, the typical SMR patient is symptomatic, complaining of dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea and if right heart failure has intervened, ascites and edema. There may be a history of recent or remote myocardial infarction. Occasionally, SMR is discovered when the patient’s provider discovers a new heart murmur or when a cause for worsening heart failure is sought.

A. History, Part 1: Prevalence

Approximately 5 million American suffer from heart failure. Roughly half of these have heart failure with reduced ejection fraction (EF), of whom at least half have some degree of SMR.

B. History, Part 2: Competing diagnoses that can mimic Functional Mitral Regurgitation

The presence of SMR should always be suspected in patients with heart failure and reduced EF. In some cases, infarct size and LV dysfunction are only modest in severity, but strategically placed wall motion abnormalities lead to SMR. Occasionally, the question of cause and effect arises as it may be uncertain if severe untreated primary MR has caused LV dysfunction or if LV dysfunction has caused SMR. The patient’s history and echocardiographic imaging can usually make the distinction. A previous history of myocardial infarction or dilated cardiomyopathy and an echocardiogram that demonstrates an anatomically normal valve, restricted from closing due to ventricular abnormalities, confirms the diagnosis of SMR.

C. Physical Examination Findings

Secondary MR is usually detected by auscultation of a holosystolic apical murmur. Because advanced LV dysfunction usually reduces developed LV pressure, the murmur of SMR may be unimpressive. It is often accompanied by a soft S₁. The apical beat may be dyskinetic and is displaced downward to the left of its normal position. An S₃is often present, but in SMR, it usually reflects heart failure rather than volume overload, the usual cause in primary MR. Because advanced heart failure is usually present, pulmonary hypertension causing a loud P₂ component of S₂ may be heard. An RV lift, neck vein distension, hepatomegaly and edema indicate right heart failure.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

An EKG should be obtained to establish baseline cardiac rhythm. Because myocardial infarction is often the remote cause of SMR, the EKG may offer evidence of this diagnosis. The presence of conduction abnormalities, especially left bundle branch block, raises the potential of cardiac resynchronization as a possible therapy for SMR. Levels of natriuretic peptides may be helpful in confirming that heart failure is present, although the specific utility of this test in SMR remains controversial.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Echocardiography

As is true with all valvular heart disease, echocardiography forms the mainstay of diagnosis. In patients with SMR the mitral valve itself is usually normal, lacking anatomical evidence for why the valve is leaking. Instead (as noted above), a combination of papillary muscle displacement, annular dilatation and wall motion abnormalities cause tenting of the valve leaflets, preventing closure.

These abnormalities should be detectable by echocardiography that also demonstrates severe LV dysfunction. When caused by previous myocardial infarction, there are usually extensive areas of akinesis; while in dilated cardiomyopathy, there is usually global LV dysfunction. Unlike in primary MR, there is no specific ejection fraction that predicts a poorer than “average” prognosis, perhaps because prognosis in SMR is inherently poor, with an average survival of just 5 years. However, an end diastolic dimension that exceeds 65 mm may indicate a worse prognosis; thus, this measurement should be made during echocardiography.

Viability Testing

Ischemic heart disease and myocardial infarction are often the cause of SMR. However, severe coronary disease (CAD) may lead to viable but non-functioning myocardium, referred to as hibernation. Revascularization may dramatically restore function and in some cases concomitantly improve SMR. Thus, assessment of myocardial viability should be made in preparation for possible coronary revascularization. Stress echo, MRI, and nuclear perfusion scanning are all satisfactory for assessing viability. Typically, institutions have greater expertise in one modality versus the others, and that modality is the one chosen for assessing viability.

Cardiac catheterization

If surgical correction of SMR is contemplated, cardiac catheterization to assess hemodynamics and coronary anatomy is performed first. Cardiac filling pressure at rest or with exercise can confirm a hemodynamic basis for the patient’s symptoms. Left ventriculography can help assess the severity of MR if it is unclear following echocardiography.

Immediate Management

Virtually all patients with SMR also have systolic heart failure and should be treated for that condition. ACE inhibitors, or angiotensin receptor blockers, beta blockers and aldosterone antagonists that are standard therapy for heart failure should be instituted. Diuretics should be adjusted to control the symptoms of pulmonary congestion when they exist. As noted above, wall motion abnormalities frequently cause or exacerbate SMR. Because conduction abnormalities, when present, may cause wall motion abnormalities, electrical resynchronization (CRT) may in some cases dramatically reduce SMR while simultaneously improving LV function. Thus, CRT should always be considered in the therapy of SMR patients that display EKG evidence of abnormal conduction.

Laboratory Tests to Monitor Response To, and Adjustments in, Management

Unlike in primary MR, where there are specific changes in cardiac size and function that dictate when mitral surgery should be undertaken, no such benchmarks exist for SMR. While one study recommended surgery prior to the LV enlarging to an end diastolic dimension of 65 mm, it is not clear that repeated echocardiograms to monitor LV size are warranted.

Long-Term Management

There is little question that when SMR complicates heart failure, prognosis worsens. Thus, it would seem logical that correction of SMR would be beneficial. Unfortunately, data regarding this concept are quite discordant, with some studies suggesting no benefit to mitral surgery, while others suggest the opposite. No randomized exist to give a definitive answer. Further, unlike in primary MR where mitral repair is of clear benefit over mitral replacement, no such agreement exists in SMR. Indeed a recent randomized trial demonstrated no benefit of valve repair over valve replacement, opposite to accepted practice for primary MR. In primary MR, the MR IS the disease, and its correction is curative. In SMR, the main disease is the LV muscle dysfunction, either from myocardial infarction or dilated cardiomyopathy; thus, correcting MR corrects only part of the problem so that its impact on outcome is reduced and mixed. No randomized trial yet demonstrates improved survival, although some indicate improved peak oxygen consumption and reduction in LV volume after surgery. A recent randomized trial found no benefit in correcting moderate SMR at the time of coronary bypass surgery. Thus, SMR mitral surgery is only recommended for patients who have severe symptoms after maximum medical therapy (including CRT when appropriate) has been applied.

Recently, percutaneous application of a device (Mitraclip) that clips the 2 mitral leaflets together in their mid-portions has been utilized in the treatment of SMR in Europe and has been used experimentally in the US. The clip substantially reduces the amount of MR without surgery and helps relieve symptoms. Its effect on survival is unknown.

Common Pitfalls and Side Effects of Management

The most common mistake in the management of SMR is equating it with primary MR and expecting similar results from therapy. While the indications for surgery in primary MR are clear, the indications in SMR are not. While it is likely that some patients benefit from mechanical correction, it remains uncertain which patients will improve, when to time surgery for SMR and even which operation to perform.

What’s the Evidence for Specific Management and Treatment Recommendations?

van Bommel, RJ, Marsan, NA, Delgado, V, Borleffs, CJ, van Rijnsoever, EP, Schalij, MJ. “Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk”. Circulation. vol. 124. 2011. pp. 912-9. (A study that demonstrates the benefit of CRT in patients with SMR.)

Trichon, BH, Felker, GM, Shaw, LK, Cabell, CH, O’Connor, CM. “Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure”. Am J Cardiol. vol. 9. 2003. pp. 538-43. (This study shows that the mortality of heart failure increases with increasing degrees of MR. but doesn’t prove cause and effect.)

Rossi, A, Dini, FL, Faggiano, P, Agricola, E, Cicoira, M, Frattini, S. “Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy”. Heart. vol. 97. 2011. pp. 1675-80. (An exhaustive study, indicating that SMR by itself has a negative impact on survival in heart failure.)

Fattouch, K, Guccione, F, Sampognaro, S, Panzarella, G, Corrado, E, Navarra, E. “Efficacy of adding mitral valve restrictive annuloplasty to coronary artery bypass grafting in patients with moderate ischemic mitral valve regurgitation: a randomized trial”. J Thorac Cardiovasc Surg. vol. 138. 2009. pp. 278-85. (A small randomized trial of mitral surgery versus bypass alone for SMR that showed no mortality benefit for mitral surgery, but did show that mitral repair led to reverse LV remodeling.)

Mihaljevic, T, Lam, BK, Rajeswaran, J, Takagaki, M, Lauer, MS, Gillinov, AM. “Impact of mitral valve annuloplasty combined with revascularization inpatients with functional ischemic mitral regurgitation”. J Am Coll Cardiol. vol. 49. 2007. pp. 2191-201. (There was no benefit to adding mitral surgery to bypass alone in this large non-randomized study from the Cleveland Clinic.)

Wu, AH, Aaronson, KD, Bolling, SF, Pagani, FD, Welch, K, Koelling, TM. “Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction”. J Am Coll Cardiol. vol. 45. 2005. pp. 381-7. (A propensity-matched comparison of medical therapy versus restrictive annuloplasty for SMR that showed no survival benefit for surgery.)

Benedetto, U, Melina, G, Roscitano, A, Florani, B, Capuano, F, Sclafani, G. “Does combined mitral valve surgery improve survival when compared to revascularization alone in patients with ischemic mitral regurgitation? A meta-analysis on 2479 patients”. J Cardiovasc Med (Hagerstown). vol. 10. 2009. pp. 109-14. (A large meta-analysis of surgery for SMR found no mortality or symptomatic benefit for surgery.)

Kang, DH, Kim, MJ, Kang, SJ, Song, JM, Song, H, Hong, MK. “Mitral valve repair versus revascularization alone in the treatment of ischemic mitral regurgitation”. Circulation. vol. 114. 2006. pp. I499-503. (An observational study suggesting benefit for adding mitral surgery to bypass in ischemic SMR.)

Deja, MA, Grayburn, PA, Sun, B, Rao, V, She, L, Krejca, M. “Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial”. Circulation. vol. 125. 2012. pp. 2639-48. (A non-randomized study suggesting survival benefit for adding mitral surgery to bypass for ischemic SMR.)

Chan, KM, Punjabi, PP, Flather, M, Wage, R, Symmonds, K, Roussin, I. “RIME Investigators. Coronary artery bypass surgery with or without mitral valve annuloplasty in moderate functional ischemic mitral regurgitation: final results of the Randomized Ischemic Mitral Evaluation (RIME) trial”. Circulation. vol. 126. 2012. pp. 2502-10.

Acker, MA, Parides, MK, Perrault, LP, et, N. “Mitral-valve repair versus replacement for severe ischemic mitral regurgitation..”. NEngl J Med. vol. 370. 2014. pp. 23-32. A randomized trial finding no benefit of valve repair compared to valve replacement in SMR primarily because repair failed in 1/3 of cases.

Smith, PK, Puskas, JD, Ascheim, DD, Voisine, P. “Surgical treatment of moderate ischemic mitral regurgitation”. N Engl J Med. vol. 371. 2014. pp. 2178-88. A randomized trial finding no benefit to repairing moderate SMR at the time of bypass surgery.

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Secondary (Functional) Mitral Regurgitation