Role of chymase in matrix and myocardial remodeling due to mitral regurgitation: Implications for therapy

The pure volume overload of mitral régurgitation (MR) has many unique features including matrix metalloproteinase (MMP) activation, increased bradykinin, extracellular matrix loss, disruption of the focal adhesion complex, and cardiomyocyte myofibrillar loss-all of which either directly or indirectly are beneficially affected by inhibition of chymase. Cardiomyocyte myofibrillar loss and cytoskeletal disruption may be related to intracellular oxidative stress and/or increased chymase production within the cardiomyocyte. Increased adrenergic drive is also an important underlying pathophysiologic feature, which, like chymase activation, is present both early and late in course of MR. There is now both dog and human data demonstrating the benefit of ß₁-receptor blockade in isolated MR. However, neither chymase inhibition nor ß₁-receptor blockade alone attenuates left ventricular (LV) dilatation. These data raise the intriguing question whether the combination of a chymase inhibitor and ß₁-receptor blocker would have a synergistic effect in preventing LV remodeling, especially if started early in the course of isolated MR.