Molecular Mechanisms and Multi-Omics Integration in Heart Failure: From Pathophysiology to Precision Medicine

Heart failure (HF) is a complex and heterogeneous clinical syndrome defined by progressive structural, functional, and molecular alterations in the myocardium, representing a significant global health challenge. Beyond haemodynamic compromise, HF arises from intricate interactions among neurohormonal activation, chronic inflammation, oxidative stress, mitochondrial dysfunction, impaired calcium handling, and extracellular matrix remodelling. These processes drive maladaptive cardiac remodelling and progressive functional decline across multiple HF phenotypes, including HF with reduced (HFrEF), mildly reduced (HFmrEF), and preserved ejection fraction (HFpEF). Recent advances in molecular biology have highlighted the critical roles of genomic, epigenetic, and transcriptomic mechanisms in the progression of HF. DNA methylation, histone modifications, chromatin remodelling, and non-coding RNAs regulate gene expression in response to environmental and metabolic stimuli, thereby connecting systemic risk factors to cardiac dysfunction. Proteomic and post-translational modifications, such as phosphorylation, acetylation, and redox signalling, modulate protein function and contribute to contractile impairment and metabolic dysregulation. Metabolomic studies have revealed significant changes in myocardial energy metabolism, including reduced oxidative capacity, decreased metabolic flexibility, and limited bioenergetic reserves. The integration of multi-omics approaches—including genomics, transcriptomics, proteomics, metabolomics, and epigenomics—has provided unprecedented insight into the biological heterogeneity of HF, facilitating the identification of distinct molecular subtypes and novel therapeutic targets. Systems biology and network-based analyses, supported by artificial intelligence and machine learning, enable the synthesis of complex datasets and enhance risk classification, prognosis, and personalised treatment approaches. This narrative review synthesises the current understanding of the molecular mechanisms underlying HF, with particular emphasis on the interplay between metabolic and epigenetic regulation in disease progression. It also highlights emerging translational opportunities, including omics-based biomarkers, targeted therapies, and precision medicine approaches. Despite significant advances, challenges remain in translating these findings into clinical practice, underscoring the need for standardised methodologies, extensive validation, and integrative frameworks. Ultimately, a systems-level, multi-omics perspective is crucial for redefining HF as a biologically stratified condition in the landscape of advancing tailored cardiovascular medicine.