br Conclusions and future perspectives

Conclusions and future perspectives It has been suggested that developmental mechanisms are prisoners of their own phylogenetic histories (Goss, 1991). On the basis of recent studies of cardiac regeneration in fetal/neonatal mammals, it would appear that regenerative mechanisms are also prisoners of their developmental histories. These findings raise the following question — what is the evolutionary advantage of shutting down cardiac regenerative pathways after birth? It appears that in the absence of any selective pressure to maintain regenerative capacity in organisms that typically don\'t succumb to cardiovascular disease until well after reproductive maturity, there may not have been a strong evolutionary drive to maintain regenerative potential after birth in mammals. So, what could be the advantage of arresting cardiomyocyte proliferation after birth? In mammals, the heart undergoes a number of physiological adaptations during the immediate postnatal period to cope with the increased loading and oxygen demands associated with the pulmonary circulation, and the rapid growth demands of postnatal life (Gao and Raj, 2010). These environmental and physiological stressors are matched by marked structural and metabolic adaptations in the cardiomyocyte, including a switch from glycolyis to fatty calpain inhibitor oxidation and sarcomere reorganization, both of which are suited to the high-energy demands of the postnatal heart (Pohjoismaki et al., 2012). Given the requirement to disassemble sarcomeres during cell division (Ahuja et al., 2004), cardiomyocyte proliferation may not be particularly advantageous during postnatal life in mammals and this adaptation may have come at the expense of cardiac regeneration. An important aspect of future studies that attempt to recapitulate early developmental regenerative mechanisms, including cardiomyocyte cell cycle re-entry, will be to establish whether these approaches have any detrimental effects on adult cardiac physiology. It is our belief that understanding the detailed physiological and molecular mechanisms that drive cardiomyocyte maturation and regenerative arrest during neonatal life will be imperative for establishing the biological basis and clinical utility of future cardiac regenerative therapies. Much work remains to be done in order to identify the molecular and cellular basis for neonatal heart regeneration. However, recent studies suggest that re-activation of neonatal cardiac regenerative pathways to drive cardiomyocyte proliferation in the adult heart may be possible (Porrello et al., 2013; Xin et al., 2013; Mahmoud et al., 2013). Given the ever-expanding molecular genetic and pharmacological toolkit for studies in mammals and lower vertebrates, it is likely that many more natural cardiac regenerative mechanisms will be identified in the near future. If successful, these studies may indeed uncover a developmental blueprint for cardiac regeneration.
Introduction Myocardial infarction (MI) is a leading cause of mortality and morbidity. Although surgical and medical advances over the past several decades have greatly improved survival after acute MI (Dargie, 2005), the long term prognosis of these patients remains poor. A major reason is the heart has limited regenerative capacity. Because of the refractoriness of adult cardiomyocytes to re-enter the cell cycle, the billions of cardiomyocytes lost during acute myocardial infarction cannot be restored, being replaced instead by fibrotic myocardial tissue with little contractile function, poor diastolic compliance, and a propensity to arrhythmia. As an adaptive response, the surviving cardiomyocytes undergo pathological hypertrophic growth through activation of neurohumoral signaling pathways. Over the long term, this adverse remodeling following MI has a deleterious effect on cardiomyocyte function and survival, and ultimately leads to congestive heart failure. Current post-MI pharmacological management suppresses neurohumoral activation that drives pathological cardiomyocyte hypertrophy. Although this strategy has been successful for heart failure management, clinical trial evidence with new neurohormonal targets did not show greater salutary effects (Mehra et al., 2003), suggesting that we are reaching a ceiling for this approach and pinpointing the need to develop new therapeutic targets.