Myocardial infarction (MI) is a common cause of global morbidity and mortality and has caused nearly half of all deaths across Europe, more than 24 million deaths in the United States, and approximately 7–18% of the global 1-year mortality (Nichols et al., 2014; Reed et al., 2017). Atherosclerosis develops in the younger age group and persists for several decades, resulting in MI or other lethal cardiovascular diseases such as heart failure, stroke, and sudden death (Weintraub et al., 2011). Lifestyles changes and effective therapeutic strategies such as diet, abstinence from cigarettes and alcohol, percutaneous coronary intervention, and coronary artery bypass graft resulted in a considerable reduction in MI-induced mortality (Cokkinos and Pantos, 2007; Nichols et al., 2014; Xue et al., 2021). Although patients with MI increased, the life expectancy of patients is almost unaffected (Shibata et al., 2015; Thygesen et al., 2018). A New England Journal of Medicine study reported no evidence comparing an initial invasive strategy to an initial conservative approach to decrease cardiovascular risk or deaths in a median of 3.2 years (Maron et al., 2020). Thus, finding novel biomarkers is necessary for early MI detection. Patients with coronary artery disease (CAD) or MI repeatedly exhibited positive family history (Mayer et al., 2007). Familial genetic defects with an autosomal dominant form resulted in MI in humans (Wang et al., 2003). MI is a complex disease involving both environmental and genetic factors and their interactions. Genetic polymorphisms for numerous genes through atherosclerosis, inflammation and thrombogenesis pathways may account for the susceptibility to MI and severe CAD consequences (Chen et al., 2007). With improved resequencing technology, the gene identification and confirmation methodology can be used for reference in CAD. This enables researchers to better quantify CAD risk in early life, formulate more efficient therapeutic approaches, and reduce the individual probability of developing MI (Damani and Topol, 2007). Genetic linkage studies were performed in both human and animal models to identify these gene polymorphisms. Several genetic association studies have revealed numerous genes and biological pathways (Newton-Cheh and O’Donnell, 2004).

Research work on epigenetics and epigenomics in this field has made remarkable progress and attracted numerous geneticists, molecular biologists, oncologists, and cardiologists. Advancements in epigenetic areas have offered a fresh perspective on human diseases and ushered a new era in genomics by exploring the role of environmental interaction and genetic heritability in disease pathology (Portela and Esteller, 2010; Cao et al., 2014). The heritability of cardiovascular diseases such as myocardial infarction can vary depending on sex, age, and environmental and lifestyle conditions (Saban et al., 2014; Dorn and Matkovich, 2015; Sen et al., 2016; Cavalli and Heard, 2019; Asllanaj et al., 2020; Deegan et al., 2021). Epigenetics is currently a popular biological research area. The term “epigenetics” generally suggests all genetic variations of gene expression regulation except nucleotide sequence and chromatin organisation depending on DNA sequences (Egger et al., 2004; Abi Khalil, 2014). Thus, epigenetic mechanisms related to gene expression regulation are chromatin-based and not involving any DNA sequence changes (Cao et al., 2014). Epigenetic inheritance is a critical mechanism that maintains the dynamic and stable propagation of gene activity states from cells of the last generation to those of the following generation (Kim, 2013; Abi Khalil, 2014).

Epigenetic regulatory processes encompass diverse molecular mechanisms such as DNA methylation (DNAm), histone post-translational modifications, and RNA-based mechanisms such as long non-coding RNAs, lncRNAs, and microRNAs (Kim et al., 2009). In several cases, the epigenetic changes reflect responses to environmental and lifestyle factors, resulting in persistent dynamic changes in gene expression that affect the course of cardiovascular disease. Epigenetic regulators have been increasingly targeted in cancer therapeutics. Thus, epigenetic regulatory mechanisms for cancer and CAD must be explored and are significant in the oncology and cardiology fields (Ding et al., 2018). The epigenome expression can fundamentally differ from different cell types, possibly modulating single cell gene expression by organising nuclear architecture in chromosomes, suppressing or promoting transcription factor access to DNA, and regulating gene expression (Wang and Chang, 2018). Epigenetics dysregulation is considered the cause of many human disorders, such as severe cardiovascular diseases, due to the significance of differential gene regulation in cellular differentiation and application function (Abi Khalil, 2014; Yang et al., 2015; Prasher et al., 2020). Through the search of PubMed, we have summarized a large amount of literature related to epigenetics, aiming to gain insight into their potential application in MI (In Figure 1 -Flow Chart). The present review focused on the crucial role of epigenetic regulatory mechanisms in MI.

Normal DNA methylation, among the central mechanisms regulating gene expression, can decide a severe cardiovascular event (Nurnberg et al., 2020). However, aberrant DNAm with genome-wide hypomethylation and CpG island hypermethylation is also observed in CAD (Breton et al., 2014; Sharma et al., 2014). The development of epigenetic epidemiology increases the probability to investigate the correlations of genomic coding, modifiable exposures, and disease phenotype manifestations. As a vital epigenetic modification type, DNAm plays a significant role as a potential mechanism of such correlations (Zhong et al., 2016). DNA methylation represents a pre-transcriptional modification that can alter the transcriptional process by adding methyl groups onto specific DNA nucleotides (Ma et al., 2014). The process leads to inactive gene expression because the methyl binding protein binds transcriptional factors and DNA. Hypomethylation is more common in most diseases than hypermethylation (Movassagh et al., 2011). DNAm, together with genetic mechanisms, is crucial for natural evolution and maintenance under specific gene expression patterns among mammals. Simultaneously, it is also dynamic and reversible for the regulating effect of genetic mechanisms (Fardi et al., 2018). DNAm pattern changes and the resulting differentially methylated regions have focused on numerous studies on normal development and disease (Ziller et al., 2013). Several studies report the value of epigenetic processes as disease biomarkers, with multiple studies associating DNAm with clinical events (Locke et al., 2019).

DNAm is the most promising target for accurate diagnosis, prognosis, and treatment (Koch et al., 2018). A lack of DNAm markers has been successfully translated into clinical applications. However, the recent improvements in DNA sequencing and other molecular biomedical science technologies result in DNA methylation-based biomarkers exhibiting colossal potential for transforming the treatment and observation of diseases like MI and cancer (Gallardo-Gómez et al., 2018). Several reports reported the role of DNAm in regulating cardiovascular risk factors and myocardial protection in MI, particularly those related to lipid metabolism and myocardial protection against ischaemia (for the detailed description, Table 1). Talens et al. (2012) reported that the risk and developmental components of MI in women are linked to DNA methylation marks at specific loci that were earlier sensitive to prenatal conditions. Aldehyde dehydrogenase 2 (ALDH2) is crucial for protection against myocardial ischaemia. Regulatory T (Treg) cells have been shown to play a protective role in experimental atherosclerosis. Demethylation of the DNA encoding the transcription factor forkhead box P3 (FOXP3) was found to be essential for the stable maintenance of the suppressive properties of Tregs. Lei et al. (Jia et al., 2013)demonstrated that reduction in Treg cells is associated with ACS in atherosclerotic patients. Epigenetic suppression of FOXP3 might lead to down-regulation of Treg cells, and in turn increase the risk of ACS. The Notch pathway plays a key role in stimulating mammalian cardiomyocyte proliferation during development and in the early postnatal life; Analysis of Notch-responsive promoters in adult cardiomyocytes showed marks of repressed chromatin and irreversible CpG DNA methylation (Felician et al., 2014). Wang et al. (2015) proved the correlation between aberrant hypermethylation at CpG sites in animal models in ALDH2 promoter upstream sequence and myocardial ischaemia injury that possibly lead to ALDH2 downregulation after MI. The modulative effects of DNAm on cardiac function, carcinogenesis, and recovery after ischaemic injury, thrombosis, and altered endothelial function in patients with MI have also been investigated. DNA methylation significantly changes following MI. The gene expression proves the correlation of cardiac injury-related epigenetic changes with branched-chain amino acid metabolism (Ward-Caviness et al., 2018). Mathias et al. (Rask-Andersen et al., 2016) observed more than a hundred significant genes for MI pathogenesis or recovery. Similarly, Farzana et al. (Yousuf et al., 2020) reported that hypermethylation of the ABO gene promoter seemingly increases the AMI risk in the hospitalised MI population. Otherwise, gestational diabetes mellitus induced offspring cardiac oxidative stress and DNA hypermethylation, resulting in an epigenetic down-regulation of Sirt1 gene and aberrant development of heart ischemia-sensitive phenotype, which suggests that Sirt 1-mediated signaling is the potential therapeutic target for the heart ischemic disease in offspring (Chen et al., 2019). Not only that, Diabetes increases the vulnerability of STEMI patients to post-MI HF by down-regulating SLN promoter methylation, which further regulates SERCA2a activity via increasing cardiac SLN expression (Liu Z. et al., 2020). Interleukin-6 (IL-6) is implicated in the pathogenesis of coronary heart disease, and IL-6 expression has associated with the level of DNA methylation of its gene promoter. There are two findings suggest that an increase in IL-6 gene expression and its DNA hypomethylation promoter are associated with acute myocardial infarction and CABG surgery patients (Zuo et al., 2016; Mohammadpanah et al., 2020).

Studies have revealed the complementary expression patterns of lipid metabolism, calcium regulation, and methylation of related genes in peripheral blood leucocyte samples of patients with MI (Agha et al., 2019). These CpGs sites and genes stress the correlation of ion regulation, lipid metabolism, and inflammation in the MI biological mechanisms (Fernández-Sanlés et al., 2021). Thus, the new DNA methylation sequencing technology can identify potential target sites related to the aberrant epigenetic regulation of MI (Koseler et al., 2020). Additionally, the sites stated by two studies (Guarrera et al., 2015; Nakatochi et al., 2017) are candidates for further assessment as underlying MI biomarkers. These results exhibited that DNA methylation could be used as a major molecular process linking genetic variations to MI susceptibility.

Histone modification is the primary mechanism in epigenetic regulation, including post-transcriptional modifications, and the most common modifications are phosphorylation, acetylation, methylation, and ubiquitination (Tingare et al., 2013). Such post-transcriptional modifications exert vital biological functions on multiple cellular processes such as cell cycle and metabolism control, DNA repair, and gene transcription (Tang and Zhuang, 2019). Histone deacetylases (HDACs) belonging to transcriptional regulators can serve as a post-translational modifier with different cardiac pathophysiology roles. The basic experiment exhibited that HDAC inhibitors benefit against arrhythmia, MI, cardiac remodelling, hypertension, and fibrosis (Eom and Kook, 2014). Additionally, HDACs are strongly associated with other vascular disorders such as neointima formation, atherosclerosis, and vascular calcification (McKinsey, 2011). Zhang L. et al. (2018) reported acute HDAC effects as positive and negative regulators for pathological cardiac remodelling. Wang J. et al. (2020) uncovered the histone modification profile in the early stage of MI of mice and proved that the modulation of histone modifications could involve inflammation and angiogenesis through adjusting promoters and super enhancers and joining cardiac remodelling pathological processes.

Additionally, the protective effect and therapeutic potential of HDACs were verified by cardiac disease pathogenesis, including suppressing cardiac fibrosis; enhancing angiogenesis; preventing electrical remodelling; and regulating apoptosis, autophagy, and cell cycle arrest (Chun, 2020). Studies exhibited that HDAC enzyme suppression has become a potential candidate for decreasing reperfusion impairment (Xie et al., 2019). Ting et al. (Zhao et al., 2007) reported the use of trichostatin A (TSA) as an efficient HDAC inhibitor to imitate early pharmacologic preconditioning. TSA significantly improved post-ischaemic ventricular function recovery and reduced infarct size during early and delayed preconditioning.

The vital role of HDACs in CVD was greatly emphasized in the past. However, few studies have focused on the association between MI and HDACs (Chen X. et al., 2020). Several studies described the effect of HDACs on vascular dysfunction and MI. Although HDAC could prevent the pathological process of MI in most cases, some HDACs might exacerbate it. Thus, the present study summarised the mechanism and treatment with HDACs, discussed the use of available medicine, and suggested a direction for future clinical studies. The fundamental mechanisms of HDAC action include induction of cardiomyocyte autophagy, augmentation of cardiac remodelling, enhancement of myocardial repairs, and improvement of myocardial ischaemic injury. HDAC inhibitor prevented post-MI cardiac remodelling and depended upon the recovery of autophagosome processing for cardiac fibroblasts. Both clinical trials and animal studies indicated that the HDAC inhibitor TSA could reverse hypoxia-induced impaired autophagic flux and resulted in a 40% reduction in cell death (Wang Y. et al., 2018). Another anticancer, HDAC inhibitor SAHA decreased the myocardial infarct size in an animal model by autophagic flux induction (Xie et al., 2014). HDAC suppression facilitated cardiac repairs and neovascularisation of the infarcted myocardium. Zhang et al. (2012a) proved that c-kit + cardiac stem cell (CSC) preconditioning through HDAC inhibition with trichostatin could substantially increase c-kit + CSC-derived myocytes and microvessels and reinforce in vivo functional recovery of MI. However, it is still unclear if specific HDAC4 suppression can modulate CSCs to promote myocardial repair and maintain cardiac performance. HDAC inhibition facilitated c-kit + CSCs to be differentiated into cardiac lineage commitments in vitro, whereas HDAC4 overexpression weakened c-kit + CSC-derived cardiogenesis (Zhang et al., 2014).

Additionally, some studies reported that gut microbiota possibly affected the post-MI acetylation levels and tissue repair by influencing butyric acid production (Song et al., 2021). These results prove the role of HDAC4 inhibition in promoting CSC-derived cardiac regeneration and improving cardiac function recovery. Zhang et al. (2018c) demonstrated for the first time that transgenic HDAC overexpression is crucial for the regulation of cardiac function and remodelling.

Although HDAC activation could serve as a regulator of cardiac function in MI, activated HDAC overexpression augmented remodelling. Santhosh et al. (Mani et al., 2015) proved that HDAC inhibition could stimulate myogenesis and angiogenesis under an incubated embryonic stem cell model. HDAC inhibition prevents cardiac remodelling through the stimulation of endogenous regeneration. Additionally, HDAC inhibition improved post-MI myocardial functional recovery through the prevention of myocardial remodelling and a decrease in myocardial and serum tumour necrosis factor α (Zhang et al., 2012b). Thus, HDAC inhibition maintains cardiac performance and relieves myocardial remodelling through the simulation of endogenous cardiac regeneration. Lin et al. (2020) proved that HDAC inhibition could stimulate proteasome-dependent degradation of HDAC4, which may be related to HDAC4 sumoylation to provoke such protective effects. Du et al. (2015) discovered that HDAC inhibition avoids cell death, promotes cell-viability, and decreases ROS production and apoptosis of cardiomyocytes under exposure to H/R. These studies offer a novel understanding of the molecular mechanism of HDAC inhibition and the potential development of specific HDAC inhibitors as new MI therapies.

Although more than 90% of human genomes cannot encode proteins, they exhibit high transcriptional activity and generate a broad spectrum for non-coding RNAs having regulatory and structural functions (Mattick et al., 2010). MicroRNAs (miRNAs), small interference RNAs (siRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) exert regulatory functions or diagnostic potential against CVDs (Poller et al., 2018). All non-coding RNAs are MI biomarkers (Wang and Jing, 2018). The present study also analysed these ncRNAs and associated interactions in regulating cardiomyocyte apoptosis, inflammation, angiogenesis, and fibrosis following the acute setting to understand their potential in acute MI treatment (Guo Y. et al., 2017; Poller et al., 2018). The present review summarises the latest advances and future applications for non-coding RNAs as MI biomarkers and focuses on the diagnostic value, prognostic potential and therapeutic effect in such RNAs. Several animals and clinical studies demonstrated the diagnostic value, prognostic potential and therapeutic effect for MI associated miRNAs.

The advent of high throughput epigenome mapping technologies has ushered in a new era of multi-omics where powerful tools can now delineate and record different layers of genomic output. Epigenetics play a central role in the regulation of many important biological processes. Despite significant technological advances for epigenetic profiling, there is still a need for a systematic understanding of how epigenetics shapes biological pathway, and disease pathogenesis (Angarica and Del Sol, 2017). DNA methylation and histone modifications and numerous techniques had been invented to analyze epigenetic processes not only at the level of specific genes, but also to analyze epigenetic changes that occur in defined regions of the genome as well as genome-wide. These technologies that are currently driving the field of epigenetics will greatly facilitate continued expansion of this exponentially growing discipline of genetics. A major breakthrough in the analysis of DNA methylation occurred with the development of bisulfite methylation sequencing (Wang and Chang, 2018). It used to be a gold-standard for detection of DNA methylation largely because it allows identification of 5-methylcytosine. This leading method of DNA methylation analysis has led to numerous subsequent methods such as Methylation Specific PCR and so on. Many proteins interact with RNA to modulate RNA-based epigenetic processes. Reaserches usually used the tools available to detect direct and indirect interactions between specific proteins and RNA in vivo. This is best achieved through the RNA immunoprecipitation technique (RIP). The uses of the RIP technique are vast and may be applied to epigenetics to help unravel the increasingly appreciated role of RNA in epigenetic processes (Tollefsbol, 2011). Beside, with the rapid development of technology, a number of epigenetic tests have emerged, such as Infinium Methylation450/850 BeadChips (450/850K), Methylated DNA immunoprecipitation-sequencing (MeDIP-Seq), Methylation-specificPCR (MSP),Pyrosequencing; Reduced representation bisulfite sequencing (RRBS), EWAS and so on (Feng and Lou, 2019). Researches should strictly choose appropriate detection methods according to the research direction. The availability of ultra-deep sequencing of genomic will transform the medical in analysis of the causes of disease, development of new drugs and diagnostics fields in the near future (Pareek et al., 2011).

DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it is the central role of epigenetics in cancer (Dawson and Kouzarides, 2012). Most of the drug research and development carried out from the perspective of epigenetics are related to tumors (Asano, 2020). At the same time, dietary intake has also presented significant influence on human health and disease development and nutritional modifications have proven important in prevention, but also the treatment of disease (Lundstrom, 2019). There are many epigenetic drugs have been identified in the past decade that effectively prevented or treated atherosclerosis and myocardial ischemia in several translational animal models, raising the possibility to combat coronary heart disease by targeting epigenetic processes also in humans. We have summarized several epigenetic therapy agents and strategies that may be associated with myocardial infarction by searching published reviews, including DNMT inhibitors, TET2 activators, Histone deacetylase inhibitors (Pickell et al., 2020), Sirtuin activating compounds, EZH2 inhibitors, BET inhibitor and other target epigenetic processes in atherosclerosis and associated vascular diseases (Schiano et al., 2015; Voelter-Mahlknecht, 2016; Xu et al., 2019). Interestingly, some dietary compounds, including polyphenols, cocoa, and folic acid, can modulate DNA methylation status, whereas statins may promote epigenetic-based control in CVD prevention through histone modifications (Voelter-Mahlknecht, 2016). Unfortunately, according to our knowledge, no epigenetically active agents or drugs targeting histone acetylation and/or methylation have thus far entered clinical trials for MI, nor have any of the latter been approved by the US Food and Drug Administration. The complex relationship between epigenetic regulation and MI development clearly demands further studies (Voelter-Mahlknecht, 2016).

MI exhibits the maximum morbidity, mortality, and effect on life quality among CVDs worldwide. Considerable progress has been attained in the discovery of MI genetic bases. Though the prospects entailed by understanding and controlling transcription through studies on histone and DNA modifications has received extensive attention, the reading of histone marks once placed shouldn’t been ignored in. executing gene expression, including bromodomain extra-terminal ((BET) (Borck et al., 2020). Some studies suggest that BET-containing family of epigenetic reader proteins, including BRD2, BRD3, BRD4 and the testis-restricted BRDT, provides a robust example of how epigenetic reader proteins can orchestrate transcriptional programs, provide new insight into mechanism of action and regulating effect and offer potentially novel therapeutic strategies in cardiovascular (Lin and Du, 2020; Li L. et al., 2021). Inhibition of BET epigenetic reader proteins might thus represent a promising therapeutic strategy to prevent adverse vascular remodelling (Dutzmann et al., 2021). BRD4, as a BET family member, plays an important role in critical biological processes. WU et al. found that BRD4 expression was up-regulated in human and mouse hypertrophied hearts, and importantly these effects were modulated by reactive oxygen species generation (Zhu W. et al., 2020). In one study, it has been reported that BETs are critical effectors of pathologic cardiac remodeling via their ability to co-activate defined stress-induced transcriptional programs in the heart (Auguste et al., 2020). Taken together, with the in-depth study of epigenetics, the secrets of related mechanisms will gradually be revealed.

The research on MI genetics contributes to early detection and the ability to provide personalised medical care. The MI pathophysiology would be progressively deciphered, demonstrating that genetics and epigenetics expedited MI onset and progression, enriching candidate methods (Nakatochi et al., 2017). Interactions between the genetic, epigenetic, and environmental factors constitute the critical factors of MI onset. The emergence of new genetic methods such as genome wide association analyses (GWAS) avoided some of these restrictions. GWAS analyses have exhibited that although different nationalities have different susceptibility genes and degrees of MI, multiple crucial loci have been identified for MI by GWAS (Takeuchi et al., 2012; Wakil et al., 2016). Epigenetic studies in cardiovascular medicine will improve our understanding of the molecular pathogenesis of MI and most importantly, facilitate novel biomarker identification, improved disease prevention, and new therapeutic strategies in managing MI. Future research should clarify how epigenetic mechanisms affect the MI process and prognosis to identify new drug targets and therapeutic strategies for MI. Although there is no specific drug for the epigenetic action of MI in clinic, currently available therapies, such as those using statins to promote epigenetic-based control in cardiovascular disease prevention through histone modifications, are already moving towards an exploitation of these mechanisms.