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Open research questions in Cardiac Fibrosis and Remodeling

45 unresolved questions extracted from the limitations and future-work sections of 285 Cardiac Fibrosis and Remodeling papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The nanoscale organisation of ryanodine receptor type-2 (RyR2) channels and junctophilin-2 (JPH2) shapes cardiac calcium release, but how this relationship is remodelled in right ventricular failure remains unclear.

    Structural and functional heterogeneity in cardiac RyR signalling nanodomains revealed with quantitative single molecule mapping toolkit · 2026 · DOI

  • Limitations of this study restrict clinical applications, such as accumulation of 60 mg/kg over 10 days, which is a high dose for rats, with a risk of non-cardiac death.

    Berberine ameliorates doxorubicin-induced cardiac toxicity via regulation of the SNHG14/miR-9-5p/PDK4 axis · 2026 · DOI

  • c-Myc is widely involved in the pathological process of the occurrence and development of HFrEF, but its function is highly diverse. Under normal circumstances, the heart with HFrEF exhibits high expression of c-Myc and its related signaling pathways, contributing to the pathological progression of HF through cardiac hypertrophy, cardiac fibrosis, and limiting metabolic reprogramming. However, under specific conditions, the upregulation of c-Myc might hold the potential to drive cardiomyocytes to reinitiate self-renewal, exerting a protective effect on cardiac function.

    c-Myc: an emerging participant in heart failure · 2026 · DOI

  • Overall, our findings provide evidence that transient Pb exposure during cardiomyocyte differentiation causes transcriptional changes in human cardiomyocytes that persist even after cessation of exposure, underscoring the need for further investigation into how Pb exposure may impact heart development and function.

    Human-Relevant Lead Exposure During Differentiation Alters the Transcriptomic Profile of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes · 2026 · DOI

  • A impairs post-infarction cardiac repair through dysregulated fibroblast activation and excessive extracellular matrix (ECM) deposition, yet the molecular mechanisms driving the age-associated defects remain poorly defined.

    miR-10b Mitigates Cardiac Fibrosis Associated with Aging and Myocardial Infarction via Attenuation of Lpar2 Signaling in Cardiac Fibroblasts · 2026 · DOI

  • Although platelets rapidly accumulate in the injured myocardium after myocardial infarction (MI), the mechanisms by which they coordinate the inflammatory response remain poorly understood.

    Platelet GARP-dependent activation of TGF-β1 limits inflammation and promotes cardiac repair after myocardial infarction · 2026 · DOI

  • Biologics are redefining the landscape of cardiovascular therapeutics, offering targeted, disease-modifying treatments that address previously “undruggable” mechanisms. Protein, gene, and cell biologics each present distinct advantages, enabling precise intervention in complex cardiovascular processes such as cardiac remodeling, fibrosis, and lipid metabolism. While recent breakthroughs have demonstrated the clinical potential of biologics, several critical challenges must be addressed before their full therapeutic potential can be realized.

    Biologics for cardiovascular diseases: from bench to bedside · 2026 · DOI

  • To ensure the robustness of our findings, a formal sample size calculation was conducted prior to the study’s initiation. With a two-sided significance level (α) of 0.05 and a power (1 − β) of 80%, this study estimated that a minimum of 52 AMI patients would be required to detect a clinically meaningful difference in miR-29a levels related to myocardial remodeling and fibrosis. The final cohort included 52 participants, fulfilling the calculated sample size requirement and providing sufficient statistical power for the primary analysis. post-hoc power analysis confirmed that the achieved power for detecting the observed effect size in the primary outcome exceeded expectations, further reinforcing the reliability of the reported results. However, as noted in the Limitations section, the sample size may still be insufficient for subgroup analyses or secondary endpoints with smaller effect sizes. These considerations enhance the interpretability of our findings while highlighting the need for validation in larger, multi-center studies. The modest sample size, particularly within subgroups, limits the robustness of distributional assumptions, despite our use of appropriate statistical tests. And while now standardized, the single 12-hour time point may not capture the full kinetic profile of all biomarkers, such as sST2, NT-proBNP and miR-29a. Other limitations of this study should be acknowledged. Firstly, its cross-sectional design inherently precludes the establishment of causal relationships or definitive prognostic conclusions regarding the observed associations. Secondly, the use of healthy volunteers, rather than patients with non-AMI cardiac conditions, as the control group limits the specificity of the findings for AMI pathophysiology, as the biomarker alterations could be influenced by broader cardiac serial echocardiographic follow-up data restricts our ability to correlate baseline biomarker levels with the subsequent progression of ventricular remodeling or fibrosis. Finally, the correlation analyses presented are bivariate and for potential confounding variables; therefore, the independent relationship between miR-29a and other parameters requires confirmation through future multivariable analyses in larger cohorts. the absence of lack adjustment stress.

    Early detection value of miR-29a in patients with acute myocardial infarction · 2026 · DOI

  • AE is a commonly used therapeutic method for cardiac rehabilita- tion in cardiovascular diseases (26), but its specific mechanism of action remains not fully understood.

    Aerobic exercise reduces lactate accumulation and improves cardiac function after myocardial infarction · 2026 · DOI

  • The dose-response relationships and long-term safety profiles of liraglutide in reducing collagen deposition and ROS production through AT1R downregulation have been characterized in hypertensive models, but efficacy in diabetic cardiomyopathy and post-infarction remodeling requires evaluation.

    The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics · 2026 · DOI

  • The clinical translation pathway from epigenetic therapy targeting specific histone modifications, DNA methylation, or miR-21/Spry1/ERK-MAPK axis in basic research to Phase I/II clinical trials for myocardial fibrosis has not been systematized or benchmarked.

    The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics · 2026 · DOI

  • Comparative efficacy studies directly contrasting multiple RAAS inhibitors (lisinopril, losartan, spironolactone, amlodipine) on programmed cell death pathways and fibrosis progression within the same myocardial fibrosis models are lacking, limiting understanding of differential therapeutic potency.

    The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics · 2026 · DOI

  • The relationship between FTO demethylase downregulation, elevated m6A modification levels, and altered transcript stability affecting myocardial contractile function requires mechanistic clarification regarding which specific RNA transcripts related to contractility and angiogenesis are directly regulated by dysregulated m6A in heart failure.

    The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics · 2026 · DOI

  • The anti-fibrotic effects of VCE-004 (aminoquinone cannabidiol) have been demonstrated in vitro through inhibition of TGF-β and Ang II-induced cardiac fibroblast differentiation, but in vivo validation in animal models of myocardial fibrosis and translation to clinical cardiac disease remains absent.

    The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics · 2026 · DOI

  • The Ang II-independent protective mechanism of the aldosterone receptor antagonist spironolactone in myocardial fibrosis has been observed in hypertension and myocardial infarction models, but the specific signaling pathways and molecular targets involved in this Ang II-independent pathway have not been elucidated.

    The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics · 2026 · DOI

  • The synergistic network interactions between histone modifications and other epigenetic regulatory mechanisms (DNA methylation, non-coding RNA, RNA modification) in programmed cell death and myocardial fibrosis remain poorly characterized. Specific investigation is needed into how these multilevel epigenetic mechanisms coordinately regulate cardiac fibroblast activation and cardiomyocyte apoptosis pathways.

    The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics · 2026 · DOI

  • Anti-inflammatory strategies have shown cardiovascular benefit in selected populations; yet their role in HFpEF among rheumatologic subgroups remains underexplored.

    Rheumatologic Disease as a Substrate for HFpEF: Pathophysiological Mechanisms and Clinical Implications · 2026 · DOI

  • Fibrosis is a hallmark of this transition, yet the initiating immune mechanisms during the development of HTN remain poorly understood.

    Macrophage Plasticity Drives Cardiac Dysfunction in Hypertension 2253031 · 2026 · DOI

  • Although S-palmitoylation--a reversible post-translational modification--critically governs protein localization, trafficking, and stability, its involvement in cardiac hypertrophy remains poorly characterized.

    ZDHHC14-Mediated Palmitoylation of TBK1 Promotes Pathological Cardiac Hypertrophy via Type I Interferon Signaling Activation · 2026 · DOI

  • The role of TMAO in the pathogenesis of atrial fibrillation (AF) remains uncertain.

    Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction · 2026 · DOI

  • Activation of the immune system impacts the progression of heart failure (HF), but the underlying mechanisms remain incompletely understood.

    Tricuspid valve regurgitation accelerates heart failure via a cardio-intestinal innate immune circuit · 2026 · DOI

  • Translational Relevance: Osteoarthritis patients have higher, often unrecognized, cardiovascular risk, yet preclinical models linking joint disease to cardiac dysfunction remain unexplored.

    TNFR2 Agonism as a Sex-Specific Therapy for Novel Osteoarthritis-Induced Cardiac Dysfunction · 2026 · DOI

  • Heart failure with preserved ejection fraction (HFpEF) commonly coexists with atrial fibrillation (AF), but shared mechanisms remain unclear.

    Nox4 Mediates Diastolic Function in a Genetic Model of Pitx2 Haploinsufficiency · 2026 · DOI

  • Obesity is associated with an elevated risk of pathological cardiac hypertrophy, whereas exercise confers cardioprotective effects; however, the cellular mechanisms underlying these opposing influences remain incompletely defined, particularly in females.

    Obesity-induced changes in ultrastructure and calcium release of female rat cardiomyocytes are partially reversed by aerobic exercise · 2026 · DOI

  • However, the precise morphological correlates of these therapies at the cardiomyocyte and stromal level remain insufficiently explored in experimental models.

    Experimental analysis of myocardial remodeling under combined metabolic and hemodynamic stress and its pharmacological correction · 2025 · DOI

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45 open questions have been extracted from the limitations and future-work passages of 285 Cardiac Fibrosis and Remodeling papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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