In our pilot study, the left ventricular diastolic and systolic dimensions increased with heart failure and decreased after LVAD support, although baseline levels were not regained after 11 weeks of LVAD support. The cardiac index and left ventricular mass were elevated during heart failure and returned to near baseline levels after 11 weeks of LVAD support. Together, these results indicated the successful development of heart failure in sheep after chordal disruption, followed by recovery after LVAD support, as determined by physical measurements and hemodynamic data.
We used an adult sheep model, primarily because of the ease with which heart failure can be induced and subsequent LVAD therapy can be applied in this model. Other fundamental advantages of the sheep are the animal's size (which allows placement of a human-sized LVAD), minimal growth rate, ease of management, and hemodynamic similarities to humans. Moreover, the ability to perform sequential biopsies allowed us to monitor the progress of heart failure and to correlate the extent of remodeling and its reversal with ANP, ET-1, BAR, and dystrophin levels. Because our volume-overload heart failure ovine model was not a previously established one, biopsies to detect heart failure creation (remodeling) and postimplant recovery timing (reverse remodeling) were scheduled and performed according to the guiding results of the echocardiographic follow-up data. The echocardiographic findings of volume-overload heart failure (such as ejection fraction, left atrial diameter, left ventricular end-systolic and end-diastolic dimensions, ventricular mass and thickness, etc.) and LVAD recovery correlated well with the animal's clinical picture and hemodynamics, so we also scheduled LVAD implantation and support times according to these echocardiographic results.
The changes in dystrophin expression in our pilot study were consistent with the development of heart failure and subsequent recovery after LVAD placement in humans [14
]. Because dystrophin has been demonstrated to play a key role in linking the actin cytoskeletal networks and the sarcolemmal dystrophin-associated protein complex, the lack of dystrophin is associated with altered structure and mechanical adherence of costameres to the underlying cytoskeletal actin network, resulting in cardiomyopathy [15
]. Therefore, the possible fragility (disruption) of the dystrophin-actin bonds may be important for tracking early myocardial structural changes in remodeling and reverse remodeling and for developing a more precise animal model of heart failure to test the efficacy of short- or long-term LVAD support.
One of our study's limitations was the lack of plasma profiles of dystrophin levels, which may be used as a predictive/clinical biomarker for left ventricular remodeling related to LVAD use. Such plasma profiles will be a main focus of our future studies involving a larger number of animals. Moreover, the location of the outflow-graft anastomosis may be considered another study limitation, as it may not be the anastomotic site currently preferred for most fully implantable LVAD outflow grafts.