Inflammation, Metabolism and Epigenetics in Valvular Heart Diseases

Valvular heart disease (VHD) is the third most common form of cardiovascular disease and is strongly prevalent in the elderly, rising from 2.8% in individuals aged 60-74 to 13.1% in over 75’s. Senile degeneration of anatomically normal valves is the dominant cause of adult forms of VHD. Increasing life expectancy and ageing populations predict that VHD will be the forthcoming cardiac epidemic. The onset of clinical symptoms is generally acknowledged as a poor prognostic indicator. Owing to the advanced and severe disease burden, VHD rapidly progresses towards significantly high event rates, deterioration and malfunctioning, being a major source of morbidity, mortality and health care cost. Yet, there are no current pharmacological interventions capable of delaying or halting VHD progression. Surgical valve replacement remains the elective therapeutic choice and several limitations entail expensive treatments, hospital readmission and reintervention.

Molecular, cellular and interstitial events activate multifactorial and complex cues with a significant contribution by valve interstitial (VIC) and endothelial (VEC) cells. Accumulating evidence shows that both inflammatory infiltrates and valve resident cells trigger inflammatory responses mechanistically relevant during the initiation of VHD. Such inflammation may underpin metabolic switches in activated VIC and VEC to accommodate the high energetic requirements of pathologic synthetic phenotypes and the surrounding microenvironment. Similar to cytokines and growth factors, it is now becoming evident that metabolites can raise regulatory effects on a vast array of functional and epigenetic regulators, which might be pharmacologically targetable. Different miRNoma signatures have been described in specific forms of VHD. Non-coding RNA regulation emerges as a potential and exciting alternative to unravel unknown targets and develop tailored-therapies and tissue-engineered heart valve substitutes. Adding to the complexity, new publications suggest sex-specific differences in valve pathology with enhanced pro-apoptotic, pro-inflammatory and pro-osteogenic profiles in males, while a pro-angiogenic and pro-fibrotic profile may prevail in females. Revisiting the pathogenesis of VHD is, therefore, required so that novel therapeutic approaches can be developed against specific druggable targets. A better understanding of the interplay among inflammation, metabolism and epigenetic regulation might improve current therapies and patient management.

In order to provide a comprehensive overview of VHD, the aim of this Research Topic is to gather interdisciplinary research contributions, including basic, translational and clinical science that explore the interplay among inflammation, metabolism and epigenetic alterations on the molecular mechanisms underpinning VHD. Studies that reveal novel risk factors and development of therapeutic alternatives are encouraged and a special focus, but not exclusive, will be given to recent findings suggesting divergent sex-dependent mechanisms of VHD.

Keywords: valvular heart disease, inflammation, metabolism, epigenetics, non-coding RNAs, gender dimorphism

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