Dynamic Regulation of the Extracellular Matrix After Mechanical Unloading of the Failing Human Heart

One of the most exciting scientific challenges that faces investigators in the field of heart failure today is to unravel the mechanisms that are responsible for preventing and/or reversing the process of left ventricular (LV) remodeling (dilation) in the failing heart. Given that LV remodeling may contribute to disease progression in heart failure1 and that all drugs that have been shown to exert beneficial effects on mortality in patients with heart failure also favorably impact the remodeling process,2–4 it is likely that the quest to identify the mechanisms responsible for reversing LV remodeling will lead to the identification of novel therapeutic targets for the treatment of heart failure. Thus far, clinical studies with β-blockers and left ventricular assist devices (LVADs) have consistently shown that these 2 treatment modalities allow the heart to become smaller and to assume a more normal prolate ellipsoid geometry,2,5 thus increasing the mechanical efficiency of the heart.2 However, it is not at all intuitively obvious how or why this occurs. Moreover, although considerable research time and effort has (justifiably) been expended on understanding the basic mechanisms that promote LV dilation, it is not clear that a simple reversal of these same mechanisms will allow the heart to revert back to its normal size and shape. Thus, our understanding of the mechanisms that are responsible for the regression of LV remodeling remains far from complete.See p 1147 The clinical experience with LVADs has yielded a number of unique insights into the mechanisms of the LV remodeling, the most notable of which have clustered around the important changes that occur in the biology of the failing human cardiac myocyte. Studies performed with clinical material obtained before and after LVAD support have demonstrated favorable changes in myocyte structure (decreased size, decreased myocytolysis) and function …