Can we mend a broken heart?


By José M Pérez-Pomares

Myocardial infarction is a common, severe manifestation of the altered status of the heart muscle after oxygen deprivation that is characterised by a significant loss of cardiac muscle. Ventricular remodelling of the heart, involving and the formation and expansion of a fibrotic scar, follows myocardial infarction. Such remodelling is associated with chronic myocardial infarction and the progressive impairment of cardiac function, a condition that frequently results in heart failure.

The human heart, as with other mammals, is unable to compensate for the death of an important part of heart muscle. For a long time, this sharp restriction of myocardial regenerative abilities was thought to be a direct consequence of the post-mitotic nature of the adult heart. However during the last decade, a number of studies have challenged this dogma by reporting the existence of a low proportion of immature cardiomyocytes, cardiomyocyte progenitors and cardiac resident stem cells that are able to mature or differentiate into functional myocytes. Despite the extreme importance of all these findings, the clinical challenge remains as none of these cell populations has been shown to effectively drive a massive de novo myocardial formation after a myocardial infarction.

The restricted regenerative potential of the adult mammalian heart is in contrast with the impressive regenerative ability of the adult heart of some non-mammalian vertebrates, such as fishes and amphibians. In these animals, various organs or structures can regenerate, being the regeneration process heavily dependent on somatic cell (mature cell) de-differentiation or re-entry into the cell cycle (mitosis), two mechanisms that are characteristic of morphogenesis during embryonic development. Interestingly, the inflammatory and fibrotic responses elicited by the hearts of mammalian and non-mammalian species after myocardial cell death are quite different too, supporting the idea that certain forms of scarring can hamper myocardial regeneration.

At the 2012 annual meeting of the ESC (25–29 August, Munich, Germany), a session entitled “Repairing a Broken Heart” reviewed the differences and similarities that exist between mammals (including humans) and mammalian vertebrate animal heart regeneration. This session included talks from Michael Schneider (Imperial College, London, UK), Robert Kelly (IBDM-CNRS-AMU, Marseille, France), Nadia Mercader (CNIC, Madrid, Spain) and me (José M. Pérez-Pomares, University of Málaga, Spain).

Several essential points were raised during this session. For example, it was emphasised that a deep understanding of the genes and molecules involved in the regulation of cardiac progenitor/stem cell differentiation into cardiomyocytes is needed to instruct and promote de novo differentiation of heart muscle after myocardial infarction and, also, that an extensive analysis of the divers adult heart cells that may have potential to differentiate into functional myocardium is required. In fact, the session highlighted that identifying optimal sources of new cardiac muscle was a key factor in the design of cell therapies aiming at the endogenous repair of the diseased myocardium from resident cardiac progenitor/stem cells. The identification of the optimal cardiomyocyte precursor candidate was found to be determined by the real number of that cell type in the adult heart, the genetic heterogeneity of this cell population (as related to its embryonic origin and a defined genetic background), its ability to expand in vitro and to differentiate in mature and functional cardiac muscle efficiently.

Also at the session, the importance of understanding the response of non-muscular cells to myocardial death was underlined. Furthermore, it was noted that improvement of myocardial performance in chronic myocardial infarction necessarily requires the reduction of scar tissue by restricting the fibrotic response and optimising scar reabsorption. Both of these goals could be achieved by both modulating post-myocardial infarction immune response and targeting fibroblast progenitors of different origins, as they are likely to respond differently to heart damage. The aim of restricting myocardial remodelling after myocardial infarction was also discussed as a strategy to enhance endogenous regenerative responses that might be interfered by fibrous scar formation.



In summary, further research is therefore required to develop successful therapies to repair and/or regenerate the damaged heart. Combined actions targeting at understanding the response of a great variety of cardiac cell types to myocardial infarction are needed to treat this ailment. We still cannot mend a broken heart, but we are on the right research track.

José M Pérez-Pomares is associate professor at the Department of Animal Biology, University of Málaga, Málaga, Spain, visiting scientist at the Spanish National Centre for Cardiovascular Research-CNIC, Madrid, Spain, and treasurer of the European Society of Cardiology Working Group on Development, Anatomy and Pathology