The new trend is epigenetics, a field advancing with more galloping steps than technology. A heightened interest in epigenetics is followed by advanced insights into health and diseases, especially in those affected by heritable changes in gene expression patterns that are not accompanied by alterations of the DNA sequence (1, 2). The chemical modifications occurring to the genome to regulate gene expression are referred to as epigenetic changes. Methylation of CpG islands at the level of DNA is the most studied epigenetic modification. Methylation occurs within gene promoters and consists of an addition of methyl groups to the DNA molecule which represses gene transcription when it is located in close proximity to a gene (e.g., gene promoter or gene body) (3). Other epigenetic modifications are also important and worth focusing the studies on. Histone modifications and non-coding RNAs (ncRNAs) are as critical as they play a crucial role in disease development by controlling gene expression (4). Methylation, acetylation, ubiquitination, phosphorylation, and ADP-ribosylation are considered post-translational modifications (PTM) that occur on histone levels thus influencing the histone conformation and, hence, chromatin accessibility (5). Whereas ncRNAs are found to participate in many physiological and pathological processes by modulating the transcriptional output from the genome. Together with DNA methylation and histone PTM, they are recognized as powerful regulators of gene expression and are heavily implicated in human diseases (6–8).

Importantly, compelling evidence has shown that epigenetic signals promote phenotypic changes by modulating genes controlling cardiovascular homeostasis. Once acquired, epigenetic changes can be relatively stable and persist over time. However, these changes have shown to be reversible upon cessation of different stimuli, and most importantly, they are amenable to pharmacological intervention. The possibility to pharmacologically erase detrimental epigenetic changes to prevent disease is fascinating and is gaining increasing attention. The epi-drug era has begun and with it the competition among research groups and (big)pharmas for the development of novel and effective drugs. New approaches for the development of new therapeutic strategies aim at targeting various epigenetic factors that introduce, recognize, or remove modifications at the level of DNA/histones. Three families of epigenetic proteins – readers, writers, and erasers – are on focus as druggable targets; they can be conveniently manipulated thus highlighting the importance of developing these drugs. Successful development and handling of epi-drugs will help to define better policies for the treatment of a plethora of diseases (9, 10).

Pythagoras became the pioneer of pharmacogenetics bringing the very first evidence when he observed that fava beans resulted in potentially fatal hemolysis in some, but not all individuals. Nowadays this phenomenon is recognized as the most trivial enzymatic deficiency and is linked to glucose-6-phosphate dehydrogenase deficiency (G6PD) (11). The term “pharmacogenetics” wasn’t used until the 1950s when Vogel coined the term in reference to the discovery of some enzyme polymorphisms and dedicated a whole section in his chapter on “modern problematics of human genetics” (12). Albeit initially conceived as an esoteric matter, numerous studies have fashioned this field of research throughout the years. Pharmacogenetics can come in help to solve the conundrums as to why different people, but also different populations, respond variably to the same medication. Studies have revealed that gene mutation is not the reason for these responses, but the alteration in gene-editing enzymes is (13, 14). The suffix “omics,” which is often used interchangeably with the former one, is added to the term. Both fields are important as they focus on the study of variability in drug response due to heredity and are seen as promising in the improvement of drug therapy. Progressive advances in pharmacogenetics gave rise to pharmacogenomics (15, 16). It is known that epigenomics influences drug development and approval. Although the relevance and the contribution of these fields to personalized medicine remain to be studied, there is ample evidence to support its efficacy and effectiveness. The FDA itself strongly supports the progress in these fields (17). The variability in response to different medical treatments or drugs, regardless of different factors (environmental, biological, or genetic), requires further studies which can easily take advantage of the established background in pharmacogenetics and pharmacogenomics (16, 17). In large-scale, epigenomic studies are of growing importance. The epigenetic drug discovery and drug development processes are moving the attention toward epi-drugs as a major factor with potential use in precision medicine (18). On the other hand, understanding the genetics’ contribution to drug failure and drug toxicity may help not only in the development of new treatments but also to improve the safety, efficacy, and costs of already existing drugs. Yet, integrating pharmacogenetics into clinics remains a challenging motion (18). A crucial step is the establishment of pharmacogenetic networks that can help in the collection and centralization of pharmacogenetic information. More than ever, we need pharmacogenomic inspections to study gene patterns and disease-causing genes. These investigations aspire to look closely at the expression of the whole sets of genes to further consider modifications through drug manipulation (14, 18).

A major public health problem, and the leading cause of mortality worldwide is cardiovascular disease (CVDs) with heart failure (HF) dominating the scene (19). HF currently affects 26 million people worldwide and 15 million people only in Europe. Most importantly, a 46% in HF prevalence is expected by the year 2030. This growing burden is certainly the result of a poor understanding of the disease and the factors involved in its development. Several studies have shown that non-cardiomyocyte cell populations significantly contribute to cardiac remodeling in HF. Recent studies now point to the activation of resident fibroblasts as the underlying cause of fibrosis. However, de novo generation of fibroblasts from endothelium and circulating hematopoietic cells has also been proposed to significantly contribute to fibrosis in the setting of HFpEF. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, a recent study found that high-temperature requirement, a serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and HF by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β) (20). Together with fibroblasts, factors secreted by (dysfunctional) endothelial cells have shown to modulate cardiomyocytes hypertrophy, contractility and fibrosis, thus accelerating the progression toward HF (21). Future studies should unveil the role of epigenetic signals in the functional crosstalk among different cell types in the pathogenesis of HF.

Actually, epigenetic changes have an impact on modulating chromatin accessibility to transcription factors and gene expression. Modulation of epigenetic signals and manipulation of alterations in chromatin modifying enzymes may represent a new effective therapy for HF patients (22). In this perspective, it is crucial to head the treatments toward medicine based on one’s genetic composition, disease phenotype, and molecular makeup. A useful tool to identify patients who can benefit from specific drugs is genome mapping (23). Epigenetic alterations are proven to be restored and epigenetic therapies have arisen. Suitable epi-drugs candidates seem to be of potential use in CVDs in general and HF in particular (24, 25). Brand-new epi-drugs have started to gain importance. They are either in process of preclinical studies or being tested in clinical trials. Moreover, various existing cardiovascular drugs were recently shown to have possible epigenetic effects. The use of epi-drugs in the clinical arena might enable personalized therapies and could help implement existing cardiovascular therapies to improve HF care and patient prognosis (26).

Epigenetics is essential for normal organismal development and cellular functioning. Exposure to environmental stressors and an unhealthy lifestyle can alter epigenetic modifying enzymes and thus the chromatin landscape (Figure 1) (27). Three major risk factors for the development of HF – diabetes, obesity, and aging – are seen to increase the prevalence and mortality of the disease. Noteworthy, these conditions are linked to epigenetic changes (28–31). These changes can cause detrimental modifications of the epigenetic landscape, consequently increasing the risk of, or directly provoking, HF (Figure 2). Alterations of gene expression play a dominant role in governing cardiac remodeling and disease pathogenesis. Found in such conditions, the heart itself undergoes functional and structural remodeling that encompasses considerable transcriptional reprogramming (32). By this background, understanding the mechanisms governing gene expression is of paramount importance. Many transcription factors don’t change in their abundance but only in their activity, suggesting a pivotal role of posttranslational events (33, 34). Consequently, both, direct modifications of transcription factors and modifications of chromatin to alter gene accessibility play a role in affecting enzyme activity and transcriptional reprogramming. This is explained by the broad importance gained by the regulation of transcript stability and transcript translation through microRNAs. DNA/histone modifications and non-coding RNA remain molecular transducers of environmental stimuli to control gene expression. Evidence in the field indicates that epigenetic regulation could be an important biological layer that actively participates in CVD and HF phenotypes, and its modulation could be a promising and innovative therapeutic tool to improve the diagnosis, prognosis, and treatment of HF (35).

ncRNAs, unlike the other epigenetic regulators, are nucleic acid-based molecules that variously modulate gene expression. Regulation by small ncRNAs is another mechanism for epigenetic regulation of gene expression. Means by which ncRNAs govern gene expression can be post-transcriptional silencing, interference with transcriptional machinery, and regulation of splicing. ncRNAs are classified in small ncRNA, consisting of three main components: microRNAs (miRNAs), small interfering RNAs (siRNAs), piwi-interacting RNAs (piRNAs), and long ncRNAs (lncRNAs) (50).

We know that epigenetics changes as we age and although our cells carry exactly the same genes, they look and act differently. The same can be said regarding the patterns of epigenetic modification that vary among individuals, tissues, and in different cells within the same tissue. Noteworthy, the advantage of a cell-specific drug in the context of CVD will be the narrowing of the broader effects drugs may have on other cell types in the same tissue/organ or other tissue or organs in the body. This limitation can be addressed through advances in techniques targeting specific cell types and gene loci. There is an emerging role of RNA therapies in this direction. For example, the synthetic siRNA Inclisiran exerts a liver specific suppression of PCSK9 expression and has a low side effect profile. In a randomized, single-blind, placebo-controlled, phase 1 trial was observed a significant reduction in circulating PCSK9 and LDL-C levels on hypercholesterolemia patients, thus leading to a reduction of cardiovascular risk (64). Although cell specific epigenetic therapies are still lacking in CVD patients, recent clinical trials have shown that systemic targeting of specific miRs improves cardiac damage in HF (65). Indeed, a first-in-human evidence phase 1b randomized, double-blind, placebo-controlled clinical study, recently showed that miR-132 inhibition was safe and led to leading to positive trends in myocardial fibrosis markers. The use of the first miRNA drug, CDR132L, was associated with promising beneficial effects in patients with chronic HF (66). Despite the cells in our bodies have identical genome, it is thought they can differentiate distinct tissues and organs via cell-specific variations in gene expression. This variation in gene expression can be further used to design specific drugs. Therefore, more than on cell-specific way, epi-drugs act upon the epigenetic changes that occur in a particular disease to a particular tissue, organ, or system. Still, it remains a challenge to a successful epigenetic drug design since epigenetic enzymes often work in multimeric complexes and this complicates the translation of in vitro efficiency to in vivo efficacy. Epi-drugs can have broader effects; therefore, this is considered as a limitation of epigenetic therapy. However, technical advances facilitating specific epigenetic editing may provide solution to address this limitation. Considering the galloping steps in the epigenetic and epigenetic pharmacology fields, we still can’t know how far we are as it is the limitation of the research and therapies with the ability to modulate the epigenome are still limited. Over the last few years, several widely used and very well-known drugs are endowed with epigenetic effects (Table 1). For instance, despite the broad usage of metformin as a first-line medication for the treatment of type 2 diabetes (T2D), it was fascinating to find out that this drug can also act as an epi-drug. It is already reported the beneficial role of metformin in lowering the risk of CVDs mortality and cancer, however, its role as an epigenetic editing drug was reported much later (67, 68). In a follow-up study including T2D and hypertensive patients, long-term prescription of metformin was effective in improving left ventricular diastolic function and hypertrophy, thus, decreasing the incidence of new-onset HFpEF (69). It is proposed that metformin promotes phosphorylation and activation of AMPK, thus inhibiting the gluconeogenic genes. AMPK is a major regulator of cellular metabolism, and its activation impacts numerous pathways, including epigenetic processes (70). Through AMPK activation and consequently histone modifications, this drug, promotes either increase or decrease in the expression of several genes Metformin also indirectly increases HAT1 activity. This was observed in a mouse embryonic fibroblast model where HAT1 phosphorylation occurred via AMPK (71). By contrast, metformin treatment led to reduced activity of two important co-activators of multiple genes involved in inflammation and glucogenesis, HATs p300 and the CREB-binding protein. Both phenomena are highly represented among HF patients (72–74). Another group of novel epi-drugs worth mentioning is sodium-glucose co-transporter-2 inhibitors (SGLT2I). It is reported not only their role in lowering the risk of HF hospitalization in T2D patients but also in lowering all-cause mortality, regardless of the presence of diabetes (75). The SGLT2i dapagliflozin was recently shown to exert cardiac and renal protective effects. The drug modulates important miRNAs involved in the pathophysiology of HF, such as miR199a-3p and miR30e-5p that are involved in the regulation of PPARδ levels mitochondrial fatty acid oxidation (76, 77). The SGLT2i empagliflozin was also reported to increase renal protection and prevent cardiac fibrosis, thus improving cardiac hemodynamics in experimental models of HF (78–81). One of the most studied mechanisms in the development of HF is DNA methylation. Hydralazine – a recent vasodilator with beneficial effects in HF – was also shown to exert epigenetic effects by decreasing the expression of DNA methyltransferase 1. Moreover, this drug can modulate calcium homeostasis in cardiomyocytes by decreasing promoter methylation of SERCA2a while enhancing SERCA2a protein and activity (82). Epigenetic effects of this drug are also linked with specific gene expression through methylation of CpG islands in the gene promoters (83). Statins are known to upregulate the levels of miRNA-221/222 (downregulation of which is related to coronary heart disease) (84), upregulate levels of miR-22 (involved in angiotensin II-mediated cardiac hypertrophy) (85), restore the levels of miRNA-483 (modulator of CTGF via Krüppel-like factor 4) (86), and modulate several others (87). They can reverse subtelomeric methylation of DNA in T2D patients (88) and provoke epigenetic changes through Sirt1 transcription modulation. The latter is linked with the regulation of inflammatory and apoptotic mechanisms, which are important in cardiovascular risk prevention (89).

Other compounds with epigenetic effects on HF are folates, omega-3 polyunsaturated fatty acids (PUFAs), and some organosulfur compounds. Folates are known for having a role in the prevention of CVD, although the exact mechanisms are yet to be elucidated (90, 91). They are differently known as methyl donors able to generate S-adenosylmethionine. This serves as a methyl-donor for methyltransferase needed for the methylation of cytosine in DNA or lysine in histones (92). Folate deficiency can lead to global DNA hypomethylation, which is strongly related to CVDs (93), or to endothelial dysfunction, as they act as epigenetic regulators of the transcription of the mitochondrial adaptor p66^Shc (94). P66^Shc is a crucial driver of myocardial dysfunction which is strongly related to HF (4, 95, 96). PUFAs on the other hand, are seen as effective in managing, preventing, and lowering the risk of death in HF patients (97, 98). For instance, a very recent study showed that lower plasma levels of docosahexaenoic acid had a significantly higher incidence of all-cause death in HFpEF patients (99). Moreover, PUFAs are associated with an impact on cardiac fibrosis, cardiac remodeling and function, and a lower risk for recurrent HF hospitalization (100–102). DNA methylation-sensitive mechanisms are held responsible for PUFAs’ effects on the epigenome (103). The organosulfur compounds are mostly represented by Brassicaceae botanical family and are recognized for their beneficial effects on the cardiovascular system (104–106). Evidence shows they modulate gene activity through posttranslational covalent modification of nucleosome histone proteins. For instance, the well-known representative of this group, sulforaphane, acts through direct downregulation of HDAC enzyme activity in different cell types (Table 2) (107). It was previously reported to modulate the Nrf2 pathway, thus preventing fibrosis and vascular remodeling (108). Through the inhibition of DNMTs and HDACs, sulforaphane reduced methylation levels while enhancing Ac-H3 enrichment on the Nrf2 promoter. Epigenetic remodeling of the Nrf2 promoter may lead to sustained upregulation of the transcription factor with subsequent antioxidant effects on the failing heart (109).

It is known that sex can influence cardiovascular epigenetics thus highlighting a need of considering sex-based epi-drugs for the modulation of HF-related features. To date only few exploratory studies are available and additional investigations are required to better understand how sex (and gender) affect the epigenetic landscape in cardiac cells. Sex-differences in the epigenetic regulation of myocardial hypertrophy and inflammation would also imply a sex-based, personalized approaches when designing epi-drugs. For example, an interplay between sex hormones and sex-specific epigenetic mechanisms has shown to underline the gender dimorphism in HF prevalence. Estrogen and androgen receptors bind to hormone response elements and recruit the histone acetyltransferases CREB binding protein (CBP) and E1A binding protein p300 (EP300) to the DNA (110) strongly suggesting that sex hormone may directly regulate DNA and histone-modifying enzymes to impact the epigenetic processes in a sex-specific manner in the development of the spectrum of HFpEF and its course. Future studies will help to tailor epigenetic-editing interventions also based on sex and gender.

Epigenome’s flexibility has led to the exploitation and development of a variety of epigenetic compounds (Table 3), many of which are already approved by the FDA for the treatment of different diseases. These drugs cause epigenetic changes by targeting at least one of the three main epigenetic mechanisms: DNA methylation, histone modification, and ncRNA. The first documentation on epi-drugs dates with the DNA methyltransferase inhibitors, 5-azacytidine, and 5-aza-2′-deoxycytidine. Both these compounds have a high structural similarity with cytidine. Additionally, structurally similar analogs were seen as antimetabolites capable of interfering with the normal function of the natural ones (111). Later, HDCA inhibitors like Romidepsin and hydroxamic acid were discovered and with them, a myriad of new epigenetic compounds is now being developed and tested, thanks to active research in the field (112). In the next paragraphs, we will focus on epi-drugs with an impact on CVDs, with emphasis on HF treatment.

Even though epigenetic modifications acquired during the lifetime can be passed to the progeny, still these changes are reversible and amenable to pharmacological intervention. Recent evidence suggests that targeting epigenetic changes is possible and relatively safe. Indeed, clinical studies conducted so far in cancer patients did not show significant effect of these drugs on the incidence of second malignancies or any other severe, unanticipated toxicity. That having said, most available epi-drugs lack specificity toward selected transcriptional programs and cell types. Cell-specific epigenetic editing by epi-drugs is the next challenge in pharmaceutical research. The recent unveiling of new epigenetic compounds is of paramount importance given the paucity of available treatments for HF patients, especially those with HFpEF. Further research is needed to better define selective epigenetic therapies able to selectively modulate transcriptional programs in specific cell types (i.e., cardiomyocytes, fibroblast, endothelial cells). A better definition of these important aspects will shed light on the importance and potential effectiveness of epi-drugs in the setting of HF.

FP, SC, and EG conceptualized the manuscript. EG wrote the manuscript. FP guided the writing process. SM assisted in drafting the manuscript. SA assisted in organizing and shaping the figure. VC, SC, and FP revised the manuscript critically and provided important intellectual content. All authors have contributed significantly.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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