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Heart Failure: New Paradigms in Molecular Pathology and Mechanistic Regulation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 November 2026 | Viewed by 550

Special Issue Editors


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Guest Editor
1. Department of Internal Medicine, S. Elia Hospital, 93100 Caltanissetta, Italy
2. Molecular and Clinical Medicine PhD Program, University of Palermo, 90133 Palermo, Italy
Interests: diabetic complications; cardiovascular diabetology; stroke pathogenesis; endothelial dysfunction

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Guest Editor
1. Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
2. Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
Interests: internal medicine; heart failure; arterial hypertension; cerebrovascular; cardiovascular diseases; systemic inflammation; vascular dysfunction
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Special Issue Information

Dear Colleagues,

Heart failure (HF) remains a major global health challenge, characterized by rising prevalence, substantial morbidity, and a persistently high socioeconomic burden. Despite significant progress in diagnostic tools and therapeutic strategies, the underlying molecular and immune mechanisms driving HF onset, progression, and organ–organ interactions are not fully understood. In particular, the complex interplay between systemic inflammation, immune dysregulation, cellular stress responses, metabolic pathways, and neurohormonal activation is increasingly recognized as a central determinant of disease trajectory.

Advances in multi-omics profiling, including transcriptomics, proteomics, and microRNA analyses, have opened new opportunities for characterizing HF phenotypes across the spectrum of reduced, mildly reduced, and preserved ejection fraction. Moreover, the emerging relevance of inter-organ communication—especially within the heart–kidney, heart–lung, and heart–brain axes—highlights the need for integrated, mechanistic research capable of bridging molecular biology with clinical outcomes.

This Special Issue, “Heart Failure: New Paradigms in Molecular Pathology and Mechanistic Regulation,” aims to gather high-quality original research and comprehensive reviews exploring novel molecular pathways, immune signatures, biomarkers, and therapeutic implications in HF. Contributions focusing on translational insights, precision-medicine strategies, and innovative experimental models are particularly welcome. Our goal is to advance current understanding and stimulate the development of new diagnostic and therapeutic approaches.

Dr. Carlo Domenico Maida
Dr. Mario Daidone
Guest Editors

Manuscript Submission Information

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Keywords

  • heart failure
  • molecular mechanisms
  • immune regulation
  • inflammation
  • microRNA
  • biomarkers
  • cardio–renal axis
  • translational medicine

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Published Papers (1 paper)

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Review

39 pages, 3016 KB  
Review
Molecular Mechanisms and Multi-Omics Integration in Heart Failure: From Pathophysiology to Precision Medicine
by Carlo Domenico Maida, Gaetano Pacinella, Mario Daidone, Mariarita Margherita Bona, Stefania Scaglione, Rachele Malfitano, Rosario Norrito, Giuliano Cassataro, Luigi Dell’Ajra, Sergio Ferrantelli, Gabriele Angelo Vassallo and Antonino Tuttolomondo
Int. J. Mol. Sci. 2026, 27(11), 4814; https://doi.org/10.3390/ijms27114814 - 27 May 2026
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Abstract
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 [...] Read more.
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. Full article
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