Unloading-Induced Remodeling in the Normal and Hypertrophic Left Ventricle
American Journal of Physiology-Heart and Circulatory Physiology
myocardial atrophy, reverse remodeling, extracellular matrix, volume overload
To date, no study has assessed the degree of similarity between left ventricular (LV) reverse remodeling and atrophic remodeling. Stable LV hypertrophy was induced by creation of an arteriovenous fistula (AVF) in Lewis rats (32 days). LV unloading was induced by heterotopic transplantation of normal (NL-HT) and/or hypertrophic (AVF-HT) hearts (7 days). We compared indexes of remodeling in AVF, NL-HT, and AVF-HT groups with those of normal controls. LV unloading induced decreases in cardiomyocyte size in NL-HT and AVF-HT hearts. NL-HT and AVF-HT LV were both characterized by relative increases in collagen concentration that were largely a reflection of decreases in myocyte volume. NL-HT and AVF-HT LV were associated with similar increases in matrix metalloproteinase (MMP-2 and -9) zymographic activity, without change in the abundance of the tissue inhibitors of the MMPs. In contrast, AVF-HT, but not NL-HT, was associated with a dramatic increase in collagen cross-linking. Our findings suggest an overall similarity in the response of the normal and hypertrophic LV to surgical unloading. However, the dramatic increase in collagen cross-linking after just 1 wk of unloading suggests a potential difference in the dynamics of collagen metabolism between the two models. Further studies will be required to determine the precise molecular mechanisms responsible for these differences in extracellular matrix regulation. However, with respect to these and related issues, heterotopic transplantation of hypertrophied hearts will be a useful small animal model for defining mechanisms of myocyte-matrix interactions during decreased loading conditions. Surgical implantation of a left ventricular (LV) assist device (LVAD) has proven to be an effective therapeutic modality for medically refractory patients with class IV heart failure awaiting transplantation. Beyond this therapeutic role, recent studies demonstrate that LVAD support alters the structure and function of the failing heart toward a less pathologic phenotype. These changes have been referred to as “reverse remodeling.” In general, remodeling of LV myocardium is associated with alterations of both cellular (7) and extracellular components (6, 31). Levin et al. (20) observed a leftward shift in the passive tension curve of the LVAD-supported heart compared with non-LVAD-supported failing hearts, thus demonstrating the structural plasticity of the failing human heart. Other work has demonstrated that LVAD support is associated with reductions in LV mass (LVM), reductions in cardiomyocyte length and volume, and alterations in myocardial remodeling enzymes (1, 6,22, 44). Function of the LVAD-supported heart may also be altered. Studies performed on isolated cardiomyocytes and cardiac trabeculae have demonstrated improved contractility, normalized electrophysiology, and improved adrenergic responsiveness in the failing heart (9, 14, 15, 34). Although the structural and functional outcomes of LVAD-induced unloading are well described, clinical success of achieving sustained recovery of the end-stage failing heart has been poor. One possible explanation for insufficient improvement in organ physiology relates to the maladaptive responses of the cardiac extracellular matrix, including fibrosis and altered patterns of collagen cross-linking (3, 25, 29, 31, 32, 39). Another argument against the clinical efficacy of LVAD-induced recovery relates to the comparison of reverse remodeling to the phenomenon of myocardial atrophy. Unfortunately, patient-based studies do not permit appropriately timed and controlled comparisons of myocardial atrophy and reverse remodeling. Therefore, the broad goal of this study was to compare the structural adaptations induced by surgical unloading of both normal and hypertrophied rat hearts. We hypothesized that hypertrophy would alter the LV response to surgical unloading with respect to remodeling of the cardiomyocyte and noncellular fractions of the myocardium.
Mcgowan, Brian & Scott, Christopher & Mu, Anbin & McCormick, Richard & Thomas, David & Margulies, Kenneth. (2003). Unloading-induced remodeling in the normal and hypertrophic left ventricle. American journal of physiology. Heart and circulatory physiology. 284. H2061-8. 10.1152/ajpheart.00873.2002.