International Journal of Molecular Medical Science, 2024, Vol.14, No.2, 132-143 http://medscipublisher.com/index.php/ijmms 136 HHD. Reproducibility is also essential, as biomarkers must yield consistent results across different populations, cohorts, and laboratory settings to facilitate widespread clinical adoption. Furthermore, biological relevance is vital. Biomarkers should be involved in the pathophysiological mechanisms of HHD, such as hypertrophy, fibrosis, and inflammation, providing insights into disease mechanisms beyond their diagnostic utility. Accessibility and non-invasiveness are preferred, meaning biomarkers should ideally be detectable in easily accessible biological fluids like blood, urine, or saliva (Ojji et al., 2020). This facilitates frequent monitoring with minimal patient discomfort. Additionally, predictive and prognostic value is important; biomarkers should help predict the onset of HHD in at-risk individuals and provide prognostic information about disease progression and response to therapy. Lastly, regulatory approval and standardization are necessary. Biomarkers must meet regulatory standards and be validated through large-scale clinical trials, with standardized assays and protocols for clinical application (Bhargava et al., 2017). 4.2 Methods of epigenetic biomarker discovery The discovery of epigenetic biomarkers in hypertensive heart disease involves several advanced technologies aimed at identifying differential epigenetic modifications associated with disease states. These methods encompass genome-wide analyses, targeted analyses, and multi-omics integration techniques. Epigenome-wide association studies (EWAS) are a primary method for identifying DNA methylation biomarkers. This approach uses platforms such as the Illumina Infinium HumanMethylation450 BeadChip to perform high-density mapping of methylation sites across the genome. For example, Berillo et al. (2020) used this platform to identify differentially methylated loci in myocardial tissues and blood samples from patients with dilated cardiomyopathy, revealing significant epigenetic loci associated with myocardial dysfunction. These loci have potential as biomarkers for heart failure (Rask-Andersen et al., 2016; Berillo et al., 2020). Next-Generation Sequencing (NGS) technologies, such as whole-genome bisulfite sequencing and RNA sequencing, provide comprehensive profiles of DNA methylation and non-coding RNA expression. These profiles help identify potential biomarkers and their regulatory networks (Meder et al., 2017) (Table 1). Chromatin Immunoprecipitation Sequencing (ChIP-seq) identifies histone modifications and transcription factor binding sites across the genome, elucidating the regulatory landscapes associated with HHD. Bioinformatics and computational analysis are crucial for analyzing large datasets generated by NGS and other high-throughput technologies. These tools help identify candidate biomarkers and predict their functional roles. Validation studies are essential, using quantitative PCR, bisulfite sequencing, and other molecular techniques to confirm the robustness and clinical relevance of the biomarkers in independent cohorts and experimental models (Li et al., 2022). 4.3 Specific biomarkers identified Several specific epigenetic biomarkers have been identified in HHD. DNA methylation patterns are prominent among these biomarkers. Lysosomal Associated Transmembrane Protein 5 (LAPTM5) has been identified as a potential diagnostic marker for hypertensive left ventricular hypertrophy (LVH). LAPTM5 expression is significantly correlated with left ventricular wall thickness and electrocardiogram (ECG) parameters in hypertensive patients (Li et al., 2022). Additionally, differential DNA methylation at CpG sites in genes related to cardiac function and recovery, such as those involved in the renin-angiotensin-aldosterone system (RAAS), has been linked to myocardial infarction and other cardiovascular conditions (Rask-Andersen et al., 2016). Histone modifications also play a significant role in HHD. Specific histone modifications, such as increased H3K27 acetylation and decreased H3K27 trimethylation, have been associated with the activation and repression of genes involved in cardiac hypertrophy and fibrosis (Gonzalez-Jaramillo et al., 2019). Non-coding RNAs (ncRNAs) are crucial epigenetic regulators in HHD. MicroRNAs (miRNAs) such as miR-21 are upregulated in hypertensive hearts and promote fibrosis by targeting anti-fibrotic genes. Additionally, miR-7-5p and miR-26b-5p have been identified as biomarkers for LVH in hypertensive patients, showing
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