**4. Conclusions**

284 Congenital Heart Disease – Selected Aspects

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

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

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

**3.2.2 Augmenting current therapy with CPC targeting** 

increased loads.

**3.2.2.2 Cardiomyopathy** 

from sites such as the bone marrow.

**3.2.2.3 Summary: Potential therapeutic opportunities** 

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

The presence of resident CPC in myocardium is well supported through multiple studies. There is still much independent confirmation to be completed to clarify the promise of cardiac progenitor cell-mediated repair. Importantly, the major novel discoveries in the field of CPC biology have been made by only a small group of investigators and interpretation of some data is impaired by the lack of independent corroborating studies. Controversies also continue regarding the origin of CPC: during cardiac development, e.g., Isl1+ CPC, or from bone marrow, e.g., c-Kit+ CPC. Most likely, both sources are important but their therapeutic utilization may need to be approached with different strategies. Methods for activating resident CPC to realize their potential for effecting endogenous cardiac repair are still in the early discovery period. The fundamental question of CPC role in homeostatic maintenance of the myocardium throughout life has yet to be fully clarified, although an understanding of this highly significant role appears to be limited only by a lack of detection. Nonetheless, the potential applications of CPC-focused therapies in congenital heart disease treatments are likely manifold, awaiting only further investigation and implementation.
