The shifting paradigm in mitral regurgitation

BY RALPH M. LEVY, MD, FACC

The mitral valve (MV) is a complex organ. Anatomically, it consists of two leaflets (anterior and posterior) attaching via tendinous cords and two major papillary muscles (anterolateral and posteromedial) to the left ventricular wall. It is supported by connective tissue (the annulus, which is part of the cardiac fibrous skeleton) and has close relationships to the aortic valve and the left atrium. The failure of the MV to close in its appropriate anatomical plane leads to valvular insufficiency.

Mitral regurgitation (MR), when significant, causes a series of hormonal and hemodynamic events, which rapidly or slowly (depending on the etiology of the MR) lead to left ventricular failure, congestive heart failure, and death. New insights into the pathophysiology and natural history of MR have led to a sea of change in the way in which physicians approach the treatment of the disease. For instance, it is now known that patients with MR have a 20% survival rate at four years when severely symptomatic (class III-IV of the New York Heart Association [NYHA]) and a 65% survival rate at 10 years when asymptomatic or minimally symptomatic (this is in excess of expected mortality for age). Once symptomatic, patients with MR also have a significant rate of sudden cardiac death.

Medications Do Not Suffice

	The mitral valve consists of two leaflets attached via tendinous cords (mitral chordae) and two major papillary muscles to the left ventricular wall (myocardium), supported by connective tissue (mitral annulus).

Conventional wisdom indicates that surgery is too risky and the outcomes too poor to justify intervention, thereby mandating medical therapy. Unfortunately, medical therapy, as far as the evidence goes, is ineffective in delaying the progression of MR. Once MR occurs and becomes at least moderate, compensatory mechanisms using Frank-Starling Law develop, resulting in left ventricular (LV) hypertrophy and neurohormonal activation. It is also now known that the degree of MR depends on the effective regurgitant orifice (ERO), the degree of left atrium compliance, the gradient for the MR, and the closing force effected on the leaflets. Eliminating or decreasing MR is not enough to alter the disease progression. It is also necessary to reverse ventricular remodeling, attenuate the neurohormonal activation, and improve hemodynamics.

Remarkably, afterload is not particularly increased in MR, which likely explains why a recent study of angiotensin-converting enzyme inhibitors in patients with chronic MR did not show any benefit (including delaying progression to surgery) at seven years. There is some recent evidence that beta-blockers may improve survival but only in patients after MV repair. With the advent of MV repair and improved operative techniques, surgery is now the therapy of choice for patients with significant MR. MV repair is now performed for prolapse of the anterior or posterior leaflets with similar results and has proven to be of low risk and durable.

For NYHA class I or II patients, the expected surgical mortality is zero percent for patients 75 years of age and younger and 3.6% for patients 75 years of age and older. The most important insight gained by cardiologists recently is that we should identify and operate on patients earlier in their diseases, as the operative mortality rises to 2.5% in NYHA class III-IV patients 75 years of age and younger and 12.7% in patients 75 years of age and older. The obvious lesson is to operate before it is too late.

Evaluating the Severity

The current evaluation of MR depends on the usual culprits, such as the history and physical exam, but MR is not always detectable this way. For example, there are patients with ischemic MR whose murmurs are barely auscultable. Another group of patients with functional, usually ischemic, MR is detectable only during stress echocardiography.

For most patients, however, the quantification of MR is performed by echocardiography. MR was quantified as mild, moderate, or severe by estimating the area of regurgitation into the left atrium as visualized by color flow mapping. This approach was generally unreliable. Major changes here include the fact that color Doppler is now utilized for actual quantification of severity, including the quantification of the ERO and regurgitant volume based on the principle of proximal isosystolic area. Based on prospective and retrospective data, some recommendations for stratification of therapy are now given:

• In asymptomatic patients, if the LV ejection fraction is more than 60%, there is normal exercise tolerance (VO2 or oxygen consumption per unit of time), there is normal brain natriuretic peptide (insensitive but reasonably specific), and the ERO is more than 40 mm2, observation is suggested.
• In asymptomatic patients with an ERO of more than 40 mm2 and BNP activation, early surgery is considered.
• In patients with ischemic MR, intervention is suggested if the ERO is more than 20 mm2.

Surgery is also suggested in symptomatic patients with severe MR (probably moderate MR as well, if LV dysfunction is present). If the ejection fraction is less than 60%, the LV is already dysfunctional in the setting of severe MR (remember that the LV ejection fraction is falsely elevated by the fact that the LV is emptying in part into a low-resistance chamber, the left atrium) and surgery should be considered.

A Complex Medical Issue

Of course, many other considerations are included in the decision-making process — the age of the patient (particularly 75 years of age and older), comorbidities (diabetes, chronic kidney disease, arteriosclerotic heart disease, chronic obstructive pulmonary disease, etc.), level of activity, severity of LV dysfunction (MV surgery in patients with severe LV dysfunction is controversial and beyond the scope of this review), the quality and experience of the surgical team, and, most important, the mechanism of MR. Patients whose MR is due to heavy mitral annular calcification (MAC), MV endocarditis, or ischemia benefit from different types of intervention. They include preferential repair for MAC-induced MR, mostly MV replacement for infectious endocarditis (30% rate of repair in healed endocarditis) and only after full debridement is accomplished, and a multiplicity of techniques for ischemic MR (from restrictive and remodeling annuloplasty to stented tissue prostheses).

A Promising Procedure

A very interesting technique — one Raul D. Mitrani, MD, and John Cogan, MD, have used in conjunction with the clinicians at Cardio Consultants of South Florida — is the use of biventricular pacing in patients with MR in the setting of ventricular dysynchrony (i.e., left bundle branch block). Although this has been studied in patients with dilated cardiomyopathies (EF less than 35%, QRS more than 130 ms, NYHA class III-IV on optimal medical treatment), the results so far are encouraging, with evidence of reverse remodeling, decreased MR, significant improvement in symptoms, and decreased mortality. The rate of responders is about 70%, although the data on patients with ischemic MR are sketchy.

As one can see, MR is a complex medical issue. The approach to treatment depends on careful evaluation of the etiology, clinical consequences, and prognosis. It requires close coordination with the surgeons and relies on accurate estimation of severity, for which a variety of advanced echocardiographic and transesophageal echocardiography techniques are required. It is always evolving and exciting, and the future of therapy will include the development of percutaneous techniques for valve repair, which are currently undergoing clinical trial evaluation. Proof of efficacy is always required, and on this point, the cardiology literature is sorely lacking. As of this year, of more than 3,500 major randomized studies in clinical cardiology, only 16 are properly conducted studies for valvular therapy.