**3.2.2.1 CPC activation as an adjuvant to VAD "resting" of ventricle**

It has been reported that pharmacological therapy in conjunction with VAD support may enhance myocyte population expansion. Recent studies by Soppa used therapy with the beta-2 agonist clenbuterol (Soppa et al., 2008) in a murine heterotopic abdominal transplant of failing hearts. Testing the effects of clenbuterol on mechanical unloading, they were able to show that it improves LV function. Bhavsar demonstrated that clenbuterol positively affects cardiac physiology through myocyte hypertrophy, concluding that the effect was mediated by a paracrine action of fibroblast-derived IGF-1 (Bhavsar et al., 2010). At the present time, we can find no reports of an effect of clenbuterol on CPC recruitment/activation. It is conceivable that such combined pharmacological plus mechanical therapy approaches could provide a markedly re-strengthened ventricle capable of many more years of function if not for the rest of the patient's life. CPC recruitment could be combined with VAD-mediated myocardial unloading to augment myocardial tissue while "resting" the ventricle, whether left or right sided. Another possible use of therapies designed to expand the population of CPC is in the area of "ventricular training" a potential approach to prepare the LV of, e.g., delayed repair TGA patients for greater force production once the arterial switch operation has been performed. If VAD use can augment cardiomyocyte populations in otherwise normal ventricles, this could potentially help prepare the TGA patient for the switch operation by enhancing ventricular adaptation to increased loads.

#### **3.2.2.2 Cardiomyopathy**

Is it realistic to expect the manipulation of resident CPC populations to achieve a reversal in the decline in myocardial function in the setting of cardiomyopathy? Given the genetic nature of known lesions in sarcomeric proteins in this disease (Frazier et al., 2011), one may anticipate that the progenitor cell population may also harbor the same mutant alleles and therefore the expansion of that population may provide no benefit. However, for cardiomyopathy induced by chemical injury such as doxorubicin/adriamycin therapy (Shi et al., 2011), strategies to promote expansion of the resident CPC population could be considered an adjuvant or co-therapy used to mitigate cardiotoxicity. It is important to consider that, although the resident CPC may have an advantage in already being present within the muscular wall of the heart, therapies designed to help recruit bone marrowderived CPC (and EPC) (see section 3.1.3.1) are certainly worthy of exploration while investigators try to understand the possibly different significance of resident versus bone marrow-derived CPC. Indeed, given the mismatch between patients in need of transplantation and the availability of transplantable hearts there would seem to be little reason not to emphasize the exploration of multiple approaches designed to utilize endogenous progenitor cells whether they be resident in the tissue or delivered to the tissue from sites such as the bone marrow.

#### **3.2.2.3 Summary: Potential therapeutic opportunities**

At present, investigators have only begun to exploit the potentials of using small molecule (drugs, growth factors) based therapies to expand desirable cell populations. We know of no examples of demonstrated CPC-based therapies for congenital cardiac disease at this time. Since CPC likely undergo senescence and their number as a percentage of total cells declines with expansion of the myocardial cell population, conceivably the benefits of such therapy may be far greater for the pediatric population than the adult.
