Active adaptation of the mitral valve to mechanical stretch

The mitral valve, which separates the left atrium from the left ventricle, is composed of two leaflets attached to papillary muscles in the left ventricle.  The left ventricle often becomes dilated (enlarged) in patients with heart failure.  This enlargement causes the papillary muscles to become displaced, thereby pulling the mitral leaflets away from each other (tethering).  As a result, blood leaks backwards between the mitral leaflets (functional mitral regurgitation).  This regurgitation reduces the efficiency of the heart’s pumping action and has important consequences, as heart failure patients with mitral regurgitation are twice as likely to die as patients without it.

It has been observed that the surface area of the mitral leaflets can be up to 35% greater in heart failure patients with left ventricular dilatation than in normal controls.  However, it is not known whether leaflets enlarge in a given patient over time, nor whether leaflets enlarge through passive stretching or active growth with increased production of cells and proteins.

Investigators from the Mitral Valve Disease: From Genetic Mechanisms to Improved Repair network sought to better understand the mitral valve changes in left ventricular dilatation.  This research, supported by the Fondation Leducq, the National Institutes of Health and the American Society of Echocardiography, was first presented at the 2008 Scientific Sessions of the American Heart Association by Dr. Jacob Dal-Bianco, a finalist in the Samuel A. Levine Young Clinical Investigator Awards competition, and later published in the July 28, 2009 issue of Circulation.

The investigators compared how the mitral leaflets changed over time among 6 sheep in which the papillary muscles were separated surgically with those in 6 sheep who underwent sham surgery.  This surgical animal model, which did not create mitral regurgitation, allowed the team to focus on the mechanical stretch effects of tethering, while excluding the additional fluid dynamic effects of mitral regurgitation.  Three-dimensional echocardiography demonstrated that, after 2 months, stretched leaflets had a surface area 17% greater and a thickness 2.8 times greater than unstretched leaflets. In addition, cells in the stretched leaflets began to express certain proteins indicating a transformation of cell type (endothelial to mesenchymal transition) and, possibly, activation of an embryonic valve development pathway.  These molecular changes were also found in 4 mitral valve surgical specimens from patients with chronic functional mitral regurgitation.

This study shows that the mechanical stresses caused by papillary muscle tethering cause active adaptation in mitral leaflets that result in increased leaflet area and thickness.  Insights into this adaptive process may lead to new therapeutic strategies for functional mitral regurgitation.

Click on the title to access the article in Circulation:  Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation.