Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology.

Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart. This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit.

Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischaemic heart? Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart.

Despite advances in myocardial reperfusion therapies, acute myocardial ischaemia/reperfusion injury and consequent ischaemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischaemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signalling networks activated in the ischaemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications, and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischaemia, putting it in the context of the human 'diseasome'. Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischaemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischaemia/reperfusion injury and ischaemic heart failure in the post-genomic era.

Endothelial mitochondria and heart disease.

The endothelium is vital to the proper functioning in the heart, in particular due to its production of nitric oxide (NO) which regulates vascular tone. Damage to the endothelium contributes to the development of atherosclerosis, and hence to possible myocardial infarction and subsequent heart failure. Like most cells, endothelial cells contain mitochondria, despite their having relatively little dependence on oxidative phosphorylation for ATP production. However, endothelial mitochondria are centrally involved in maintaining the fine regulatory balance between mitochondrial calcium concentration, reactive oxygen species (ROS) production, and NO. This raises the question of whether damage to endothelial mitochondria would have repercussions in terms of the development of heart disease. In fact, increasingly nuanced techniques enabling restricted transgenic expression of antioxidant proteins in mice has demonstrated that mitochondrial ROS do contribute to endothelial damage. New pharmaceutical approaches designed to target protective molecules such as ROS scavengers to the mitochondria promise to be effective in preventing heart disease. As well as protecting cardiomyocytes, these drugs may have the added benefit of preventing damage to the endothelial mitochondria. However, much remains to be done in understanding the contribution that mitochondria make to endothelial function.