Abstract
Mechanical unloading (MU) by implantation of left ventricular assist devices (LVAD) has become clinical routine. This procedure has been shown to reverse cardiac pathological remodeling, with the underlying molecular mechanisms incompletely understood. Most studies thus far were performed in non-standardized human specimens or MU of healthy animal hearts. Our study investigates cardiac remodeling processes in sham-operated healthy rat hearts and in hearts subjected to standardized pathological pressure overload by transverse aortic constriction (TAC) prior to MU by heterotopic heart transplantation (hHTx/MU). Rats underwent sham or TAC surgery. Disease progression was monitored by echocardiography prior to MU by hHTx/MU. Hearts after TAC or TAC combined with hHTx/MU were removed and analyzed by histology, western immunoblot and gene expression analysis. TAC surgery resulted in cardiac hypertrophy and impaired cardiac function. TAC hearts revealed significantly increased cardiac myocyte diameter and mild fibrosis. Expression of hypertrophy associated genes after TAC was higher compared to hearts after hHTx/MU. While cardiac myocyte cell diameter regressed to the level of sham-operated controls in all hearts subjected to hHTx/MU, fibrotic remodeling was significantly exacerbated. Transcription of pro-fibrotic and apoptosis-related genes was markedly augmented in all hearts after hHTx/MU. Sarcomeric proteins involved in excitation-contraction coupling displayed significantly lower phosphorylation levels after TAC and significantly reduced total protein levels after hHTx/MU. Development of myocardial fibrosis, cardiac myocyte atrophy and loss of sarcomeric proteins was observed in all hearts that underwent hHTX/MU regardless of the disease state. These results may help to explain the clinical experience with low rates of LVAD removal due to lack of myocardial recovery.
Highlights
Due to limited availability of donor organs for heart transplantation, implantation of intracorporal miniaturized left ventricular assist devices (LVAD) became clinical daily routine, with the number of procedures increasing annually[1,2]
Prior investigation of Mechanical unloading (MU) in a genetic model of dilated cardiomyopathy showed an association of prolonged left ventricle (LV) unloading with impaired myocardial relaxation induced by myocardial atrophy, fibrosis development and apoptosis[18]
Similar effects of MU on the extracellular matrix of the LV were demonstrated for human hearts subjected to LVAD therapy[26,27,28,29]
Summary
Due to limited availability of donor organs for heart transplantation, implantation of intracorporal miniaturized left ventricular assist devices (LVAD) became clinical daily routine, with the number of procedures increasing annually[1,2]. To better reflect the clinical situation, previous studies have assessed the outcome of MU in volume-overloaded hearts[18] or in a genetic model of dilated cardiomyopathy[19] To further complement these studies with a clinically relevant model, we set out to investigate the molecular mechanisms of MU-mediated pathological remodeling in pressure-overloaded hearts. To this end, we subjected rat hearts to 3 or 6 weeks of thoracic aortic constriction (TAC) prior to heterotopic heart transplantation and investigated alterations in intracellular signaling mechanisms. We aimed to use our standardized protocol for pressure overload/MU to establish a possible relationship between pre-MU disease-severity and outcome after MU
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