Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

Abstract

Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under “reloaded” conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients.

Sarcolemmal Alterations in Unloaded Rat Heart after Heterotopic Transplantation

“…It should be noted that heterotropic rat heart transplantation has been considered to be a relevant model to mimic unloading-induced changes in the failing heart, especially for investigating molecular mechanisms of myocardial remodelling. 1 Our data regarding the increased activities of sarcolemmal Ca 2þ pump and Na þ -Ca þ exchange activities can thus be seen to serve as an adaptive mechanism for the maintenance of intracellular Ca 2þ concentration in heterotopic transplanted heart and support the view that unloading of the failing left ventricle plays a critical role for the improvement of heart function. It is also likely that the reversal of cardiac remodeling and improved heart function in failing hearts due to myocardial infarction upon treatments with diverse interventions, such as losartan, prazosin, and metoprolol may be occurring through unloading of the left ventricle and subsequent reduction is the ventricular wall tension.…”

Isovolumic loading of the failing heart by intraventricular placement of a spring expander attenuates cardiac atrophy after heterotopic heart transplantation

“…First, they support our main thesis that cardiac atrophy is the most serious harmful effect of prolonged mechanical unloading which, even in the face of the sound evidence on molecular and structural ‘reverse remodeling’ after LVAD application [ 4 , 6 , 11 , 15 , 30 ], could limit successful outcomes of such treatment in terms of functional cardiac recovery and possible weaning from LVAD treatment.…”

“…Using an array of imaging and functional assessment techniques these workers showed that despite considerable atrophy, the intrinsic contractile properties of the myocardium apparently remained normal [ 4 , 14 , 15 , 17 , 19 , 20 , 25 , 30 , 35 , 51 ]. In addition, quantitative histologic studies showed that cardiac atrophy after HT x is due to the loss of volume of existing myocytes without any significant change in their number [ 15 , 29 , 35 , 42 , 50 ]; therefore cardiac atrophy is considered the most detrimental effect of prolonged heart unloading [ 4 , 9 , 11 , 14 , 15 , 22 , 30 , 51 ]. Since a close relationship between the decrease in the myocyte volume and of the heart mass has been clearly shown [ 15 , 29 , 47 , 50 ], it is commonly accepted that ‘unsophisticated’ markers such as whole heart, LV and RV weights, when compared with the respective values in the recipient, are reliable indices of the function of the heart exposed to long-term unloading after HT x [ 11 , 30 , 51 ].…”

“…In the absence of studies performed with failing hearts, the process of cardiac atrophy and the potential anti-atrophic mechanisms would remain virtually unknown [ 11 , 14–30 ]. Recent analyses of experimental studies of the process of unloading-induced cardiac atrophy pointed to the merits of implanting into the LV a device that would provide sufficient isovolumic loading [ 9 , 30 ]. However, the approach used previously, involving placement in the LV of an inflated balloon, cannot be applied in patients treated with LVAD [ 23 ].…”

“…Since it is believed that in the failing heart the return to the ‘ fetal cardiac genes ’ (cardiac gene expression of contractile proteins and of the genes controlling substrate uptake and substrate oxidation) is detrimental and contributes to the development of unloading-induced cardiac atrophy [ 30–32 ], the second aim of our study was to elucidate the effects of isovolumic loading on the expression of the ‘fetal cardiac gene program’.…”