This systematic review focusing on CM-sEVs revealed

The gap

Evidence profile

Sourced from the future work and limitations of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 3 representative gaps

• RNA methylation in cardiovascular remodeling: Molecular mechanisms, biomarkers, and therapeutic strategies (2026) · Molecular Biology Reports · doi

  In conclusion, m6A and m5C RNA methylation are dynamic and reversible post-transcriptional modifications that play pivotal roles in cardiovascular homeostasis and disease. These modifications exhibit temporal and spatial specificity, influencing cardiac development, IRI, and pathological remodeling. Additionally, the regulatory factors associated with m6A and m5C display disease-specific expression patterns, positioning them as potential biomarkers for early diagnosis, disease monitoring, and prognosis assessment. However, despite notable progress, significant challenges Molecular Biology Reports (2026) 53:717 1 3Page 13 of 18 717 Fig. 3 Translational pipeline of RNA methylation-based therapies in cardiovascular disease improvements in cardiovascular disease prevention and treatment. remain. Our current understanding of RNA methylation dynamics at the single-cell and subpopulation levels is limited, hindering precise disease classification and targeted interventions. Furthermore, the interactions between m6A, m5C, and other regulatory layers, including DNA methylation, histone modification, and non-coding RNA regulation, need further elucidation. The development of efficient, cardiac-specific delivery systems for RNA methylation modulation remains underdeveloped, posing a challenge for clinical translation. Looking forward, the integration of mechanistic studies with translational and clinical research will be crucial. Advances in high-resolution sequencing, single-cell multiomics, and precision gene editing are expected to accelerate discoveries in this field. By combining these innovations with therapeutic development, RNA methylation holds great promise for enhancing early diagnosis, improving risk stratification, and facilitating more personalized interventions.

  generalfuture workevidence 5/5
  Keywords: methylation disease cardiovascular specific development modifications cardiac regulatory early diagnosis significant molecular biology reports page
• The Origin and Application of Cardiomyocyte-Derived Small Extracellular Vesicles: A Systematic Review (2026) · International Journal of Medical Sciences · doi

  This systematic review focusing on CM-sEVs revealed that Ldb3, CD172a, and Ambra1 are potential specific molecular markers of CM-sEVs. These markers can be used to trace the origin of CM-sEVs and serve as potential diagnostic biomarkers for diseases based on peripheral blood, with broad clinical application prospects. These studies also offer a research paradigm for identifying markers of sEVs from different cellular sources. Furthermore, cardiomyocyte-specific markers such as miR-208a, cTnT/Tnnt2, and α-MHC/Myh6 can be used to aid in the identification of CM-sEVs. The proteins and ncRNAs carried by CM-sEVs show dynamic changes across different CVDs, highlighting their potential clinical value in early diagnosis, disease monitoring, and prognosis evaluation. Moreover, CM-sEVs mediate communication among cardiomyocytes, fibroblasts, endothelial cells, and immune cells, thereby highlighting the molecular injury and repair. crosstalk underlying cardiac However, these potential characteristic markers of https://www.medsci.org Int. J. Med. Sci. 2026, Vol. 23 2274 CM-sEVs may partially overlap with those of sEVs immune cells. derived from skeletal muscle or Therefore, further validation is required. In addition, effective in vivo isolation methods for CM-sEVs are lacking, and the dynamic changes and regulatory mechanisms of CM-sEVs cargos during different disease stages remain unclear. These limitations restrict therapeutic application of CM-sEVs in CVDs.

  generallimitationsevidence 5/5
  Keywords: sevs markers potential different cells specific molecular used diagnostic clinical application dynamic changes cvds highlighting
• Circular RNAs: key orchestrators of pathological remodeling in heart failure (2026) · Vessel Plus · doi

  CircRNAs represent a paradigm of multidimensional, highly integrated regulation in the molecular pathology of HF. They not only participate in myocardial remodeling by regulating key processes such as myocardial hypertrophy, cardiomyocyte apoptosis, myocardial fibrosis, inflammatory responses, and calcium signaling pathways, but also form complex signaling networks with miRNAs, RBPs, exosomes, and their own encoded small peptides, demonstrating their potential as upstream integration hubs in the HF pathology process. This bidirectional regulatory characteristic - the existence of both pro-pathogenic and protective circRNAs - provides the possibility of precise intervention, making selective molecular intervention targeting specific circRNAs or their downstream axes the theoretical basis for “directional correction” of myocardial pathological processes. Simultaneously, the stability and detectability of circRNAs in blood and EVs make them potential biomarkers for the diagnosis, risk stratification, and dynamic monitoring of HF and myocardial infarction, potentially driving the development of personalized medicine strategies. Page 16 of 20 Wang et al. Vessel Plus. 2026;10:21 Despite this commitment, the process of translating basic research into clinical applications is fraught with numerous challenges, including complex expression patterns, differences between animal models and human physiology, as well as significant obstacles in treatment delivery and safety. Future research will need to combine large mammalian models, human tissue samples, and exosome or nucleic acid modification technologies to enhance the feasibility and safety of circRNA-related therapeutic strategies. The key point is that current literature primarily relies on the pressure overload model, which predominantly induces concentric hypertrophy. The specific role of circRNA in diastolic hypertrophy caused by volume overload remains largely unexplored. Since pressure overload and volume overload activate distinctly different mechanical signal transduction pathways, it is imperative to conduct research using the volume overload model in the future to comprehensively characterize circRNA profiles under various biomechanical stress conditions. Moreover, given the well-recognized sex differences in HF epidemiology, remodeling patterns, and clinical outcomes, future investigations should incorporate sex as a biological variable to determine whether circRNA expression profiles and regulatory networks exhibit sex-specific characteristics[91]. Speculatively, by modulating calcium signaling and excitation-contraction coupling, circRNAs may serve as potential therapeutic targets for arrhythmias and contractile dysfunction, highlighting a novel translational avenue beyond conventional structural remodeling interventions. Furthermore, recent studies have implicated circRNAs in anthracycline-induced cardiotoxicity, in which they modulate cardiomyocyte apoptosis, oxidative stress, and mitochondrial dysfunction in doxorubicin-treated models, thereby expanding their relevance to chemotherapy-related cardiac injury[92]. In conclusion, circRNAs are not merely tools for dissecting disease mechanisms; they are foundational to a forward-thinking vision for cardiovascular medicine, representing a key translational breakthrough for diagnosing and treating HF. DECLARATIONS Authors’ contributions Made substantial contributions to the conception, performed literature search, and wrote the initial draft of the manuscript: Wang X Assisted in design of the study, literature collection, discussions, and coordination of the manuscript: Sun W Provided critical guidance, reviewed and revised the manuscript, and approved the final version for submission: Gong W, Nie S All authors read and approved the final manuscript.

  generalfuture workevidence 5/5
  Keywords: circrnas myocardial overload circrna manuscript remodeling hypertrophy signaling potential specific models future literature volume molecular

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