A small percentage of cardiomyocyte’s proliferation occurs in adult human heart (Bergmann et al. 2009). This extraordinary phenomenon was demonstrated through the measurement of the amount of 14C incorporated into the DNA of cardiomyocytes of individuals born before and after the nuclear bomb tests and the comparison with the levels of atmospheric 14C. Interestingly, the detectable pool of new cardiomyocytes ranged from 1 % per year in young adults to 0.45 % in the elderly. While these renewal rates cannot support the endogenous myocardial self-regeneration in response to injury, they have nonetheless encouraged the study of any regulatory mechanism able to enhance it. Heart failure is an heterogeneous disease and recent scientific reports have demonstrated that the improvement of intercellular cross-talk is essential to foster a more effective adaptive response to injury (Tirziu et al. 2010). Less than a third of the total cell number of the adult myocardium consists of cardiomyocytes, which communicate with a broad pool of additional cell types, such as smooth muscle cells, endothelial cells, fibroblasts, mast cells, immune system-related cells and progenitor cells (Bu et al. 2009). The myocardial homeostasis implies different cell-to-cell and cell-to-matrix connections, which form a mature and self-regulated functional unit (Ausoni and Sartore 2009). These distinct cell pools also interact via a variety of soluble paracrine , autocrine and endocrine factors , which require a stable apparatus of gene expression (Lionetti et al. 2010a, b). Recent studies of developmental biology and integrative physiology have highlighted the role played by epigenetic modifications as common regulatory pathway of cell function and threshold of cell turnover in adult’s heart (Romano and Lionetti 2013). The epigenetic signals in fact activate, maintain, and change the cardiac transcriptional status underlying the tissue ability to tolerate the microenvironmental stress without losing functional coherence. All epigenetic pathways remodel chromatin and ensure the maintenance of cardiac homeostasis during several cell divisions and across generations without altering the DNA sequence. Lack of gene function and the cell death follow the failure of balancing epigenetic signals. Specific signaling pathways may drive the phenotype of cardiac resident cells at transcriptional and post-transcriptional levels in healthy and damaged hearts (Lionetti and Ventura 2013a, b). In particular, the following pathways play a key role in the self-regulation of the epigenetic state of adult cardiac cells: DNA methylation , histone modifications , and RNA-based modulation (Issa and Baylin 1996).

The epigenetic memory relies on the ability of cardiac cells to translate environmental cues in adaptive response and it remains unchanged after several cell divisions. High levels of DNA methylation lead to maintenance of cell epigenetic memory (Sanchez-Freire et al. 2014). In addition, histone modifications support epigenetic inheritance mechanisms of adult cardiac cells during transient or persistent exposure to different microenvironments (Schlingman et al. 2014). Histone modifications, which determine the structure and function of the chromatin, transmit stable epigenetic information between proliferating cells. Finally, pool of regulatory small noncoding RNAs (ncRNAs) regulate the expression of factors leading to histone modifications, such as the Polycomb-group proteins (Mathiyalagan et al. 2014).

Epigenetic modifications are emerging as endogenous mechanisms sustaining cardiac self-renewing properties and are therapeutic candidates for regeneration of heart failure.

Studies conducted so far have provided convincing experimental evidences that different epigenetic mechanisms underlie the changes of the cardiac physiological traits during myocardial regeneration. The pleiotropic non-invasive modulation of the epigenetic threshold of resident cardiac cells by drugs or diet is a frontier of investigation that should be encouraged in order to overcome the limitations that hinder an efficient structural and functional recovery of the adult heart in an epigenetic manner. In fact, emerging scientific evidences have shown that it is possible to modulate the cardiac epigenome and to induce cardiac benefits by the regular intake of lower doses of active plant compounds, such as barley beta-glucan (Agostini et al. 2015), or by the administration of selected exosomes (Barile et al. 2014). To best of our knowledge, the cardiac repair following the administration of the potential epigenetic modulators will be more effective at lower doses and mainly focused to histone or RNA-based modifications. Further translational investigations should be conducted in large animal models of heart failure and humans to better address dose, timing and route of administration.