Hypertrophic cardiomyopathy (HCM), one of the most common autosomal-dominant cardiomyopathies with an estimated prevalence of 1:200–1:500 [1], is characterized by heterogeneous clinical manifestations, including ventricular arrhythmias, asymptomatic cases, and sudden death, that result from gene–environmental influences and the failure of protective processes [2, 3]. Despite the unclear pathological mechanisms, there is a correlation between multiple factors that contribute to the HCM condition, including heterozygous mutations in genes that encode structural and/or regulatory proteins in the sarcomere of cardiac cells, particularly MYBPC3 and MYH7 [3, 4], and other mechanisms, including mitochondrial dysfunction and oxidative stress, which contribute significantly to cardiac remodeling and hypercontraction to generate a feedback loop driven by increased energy demand [5]. Significant correlations exist between microRNAs (miRNAs) and several pathobiological processes, including alterations in sarcomeric proteins [4]. miRNAs mediate several pathophysiological processes in the post-transcriptional regulation of cardiac protein production [4, 6] and play important regulatory roles; thus, aberrant miRNA production contributes to the pathogenesis of myocardial diseases [4, 7].

Current therapeutic strategies for hypertrophic cardiomyopathy focus primarily on symptom control and hemodynamic improvement, including beta-blockers, calcium-channel blockers, septal reduction therapies, and, more recently, cardiac myosin inhibitors [5]. However, these approaches do not directly address the molecular mechanisms underlying disease progression. In this context, circulating microRNAs have emerged as promising molecular regulators of myocardial hypertrophy and fibrosis. Although miRNA-based therapies are not yet clinically available, accumulating experimental evidence suggests that miRNAs may represent future therapeutic targets, in addition to their role as noninvasive biomarkers. Understanding their relationship with structural remodeling may therefore help develop more personalized therapeutic strategies in HCM [3, 4, 5, 6, 7, 8].

Precise correlations between genotypes and phenotypes in HCM are lacking. Family members with the same genetic mutation may exhibit distinct HCM symptoms, conferring phenotypic heterogeneity [8]. Non-coding RNAs, such as circRNAs and miRNAs, have emerged as potential diagnostic and prognostic biomarkers and therapeutic targets [4, 6, 9]. This review aimed to quantify the correlation between circulating miRNAs and structural and functional cardiac parameters in patients with HCM.

This systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [10]. The study was registered with PROSPERO (https://www.crd.york.ac.uk/PROSPERO/; registration number CRD420251058653).

This systematic meta-analysis comprehensively explored the correlation between circulating miRNAs and clinical and structural parameters of HCM. It reinforced the role of miRNAs as potential molecular biomarkers for both diagnosis and monitoring of disease progression [2, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]. Aggregated data from 11 observational studies, including 633 patients with HCM, showed a moderate overall positive correlation (p 0.001) between miRNA levels and clinical and structural variables. This moderate strength of association gains importance when considering the phenotypic heterogeneity characteristic of HCM and the difficulties in establishing robust correlations between genotype and phenotype. The significant heterogeneity between studies (I² = 60.1%) highlights the variability in effect sizes, which can be attributed to the diversity of methods, samples, and outcomes analyzed.

Pooled analyses stratified by clinical outcomes showed significant positive correlations between miRNA levels and indicators of myocardial fibrosis and ventricular hypertrophy. In contrast, the association with left ventricular systolic dysfunction, as assessed by ejection fraction, did not reach statistical significance, suggesting that the miRNAs studied may be more strongly related to structural remodeling than to contractile function. This dissociation may be explained by the relative preservation of systolic function in most patients with HCM, particularly in early-stage disease.

Garmany et al. [22] demonstrated a relationship between circulating miRNA levels and the activation of inflammatory, acute-phase signaling, IL-6, and hypertrophy pathways, which lead to clinical outcomes such as inflammation, hypertrophy, and fibrosis. Osmak et al. [23] reinforced these pathways by highlighting that the clinical outcomes of fibrosis and sudden cardiac death overlap with elevated miRNA levels in HCM. These studies contribute to our understanding of the regulatory pathways of miRNAs in the pathophysiology and complications of HCM.

Besides clusters, more specific anatomical parameters, such as IVS thickness, LVMI, and MWT, correlated positively with circulating miRNA levels. For example, the LVMI (r = 0.53; 95% CI: 0.38–0.65; p 0.001) and MWT (r = 0.40; 95% CI: 0.05–0.67; p = 0.028) showed significant differences. These findings consolidate the association between myocardial miRNA expression and the degree of structural hypertrophy, reinforcing and confirming those that focus on the pathophysiological conformations between miRNAs and cardiovascular diseases [7, 24, 25, 26, 27].

Subgroup analyses allowed the identification of specific miRNAs with greater discriminative power. Among the biomarkers with significant positive correlation, the following stand out: miR-29a/miR-29a-3p, miR-21, miR-199a-5p, and miR-27a [2, 12, 13, 17]. MiR-29a/miR-29a-3p (r = 0.53, 95% CI: 0.35–0.67; p 0.001) was the most robust and consistent marker; its association with fibrosis is consistent with the previous literature describing its role in the regulation of collagen and the extracellular matrix. MiR-21 showed a significant correlation (r = 0.55; 95% CI, p 0.001). This miRNA is strongly implicated in fibrogenesis and ventricular remodeling pathways and is considered a key regulator of cardiac fibroblast activation. MiR-199a-5p and miR-27a both correlated with structural parameters, with correlation coefficients greater than 0.40, and low heterogeneity between studies.

In contrast, miRNAs such as miR-155 and miR-19b showed a significant negative correlation with cardiac outcomes with high consistency, indicating a potential protective or associative role in less severe disease states. However, miR-10b/miR-10b-5p and miR-1/miR-1-3p did not demonstrate statistically significant correlations. This suggests that not all miRNAs studied have equivalent clinical applicability, reinforcing the need for individualized functional validation of these biomarkers. Other studies found correlations between miR-1-3p and miR-1 and hypertrophy [14, 15, 27, 28].

The heterogeneity observed in several analyses, especially among miRNAs grouped by type, highlights the biological differences in the regulatory and expression pathways of these small noncoding RNAs. This reinforces the need for specific approaches for each miRNA of interest and discourages the use of generic panels without prior validation owing to the high genetic and clinical heterogeneity of HCM [29, 30, 31].

In the clinical context of HCM, our findings reinforce the association between circulating miRNA expression profiles and relevant phenotypic disease manifestations, such as myocardial hypertrophy, fibrosis, and sudden cardiac death. Ventricular hypertrophy, a key feature of HCM, significantly correlated positively with miRNAs, such as miR-21, miR-199a-5p, and miR-27a, particularly with respect to structural parameters, including left ventricular mass index and maximum wall thickness. Myocardial fibrosis, which contributes to diastolic dysfunction and arrhythmic risk, is robustly associated with miR-29a, which is regulates the extracellular matrix. Regarding sudden cardiac death, although this outcome was not directly quantified in the pooled statistical analysis, individual studies indicated elevated levels of proinflammatory and pro-fibrotic miRNAs in patients with severe arrhythmic events, suggesting a possible future applicability of these markers in arrhythmic risk stratification [22, 23]. The results indicate a direct relationship between the levels of specific miRNAs and the most relevant clinical components of HCM, indicating their potential as complementary tools in prognostic assessment and, eventually, in personalized therapeutic decision-making.

Early detection of HCM is clinically challenging, especially in asymptomatic patients or those with milder disease, for whom imaging tests may not be conclusive in the early stages [30, 32]. Findings regarding circulating miRNAs, particularly miR-29a, miR-21, and miR-199a-5p, which robustly correlate with hypertrophy and fibrosis, have encouraged the development of noninvasive and low-cost screening tests. Blood collection and analysis by real-time PCR (qPCR) can complement current clinical and genetic assessments to identify individuals at risk who may require more complex cardiac examinations, such as echocardiography or MRI. This represents a significant advancement, enabling cardiologists and general practitioners to perform more effective screening, utilize diagnostic imaging resources more efficiently, and optimize patient management from the earliest stages.

Although most studies in our review focused on correlation analysis, only three assessed diagnostic performance and reported area under the curve (AUC) values ranging from 0.71 to 0.92; these preliminary data suggest that miRNAs, either alone or in combination, may differentiate patients with HCM from healthy individuals or between disease subtypes. However, these studies were limited by small sample sizes, a lack of standardization in miRNA quantification, and heterogeneous reference standards. Further prospective studies incorporating predefined diagnostic thresholds and multivariate models are needed to validate these findings and establish clinical cutoff values.

The translational potential of circulating miRNAs depends on their mechanistic relevance. For example, miR-21 and miR-29a are known modulators of fibrosis-related pathways, whereas miR-199a-5p is associated with cardiomyocyte hypertrophy. These associations suggest that, beyond serving as biomarkers, miRNAs could eventually be therapeutic targets or part of gene expression panels to inform personalized treatment strategies. As miRNA profiling technologies advance, integrating molecular signatures into HCM phenotyping may enhance precision medicine in cardiomyopathy care.

Genetics plays a central role in HCM, with the disease primarily caused by heterozygous mutations in genes that encode sarcomeric proteins, such as $\beta$-myosin heavy chain (MYH7) and cardiac myosin-binding protein C (MYBPC3) [1, 2, 3, 4]. However, the complex phenotypic heterogeneity of HCM, in which family members with the same genetic mutation exhibit distinct symptoms, is a significant clinical challenge [4, 5]. miRNAs may offer an additional layer of understanding. Although genetic mutations are the primary triggers, miRNA expression can modulate the severity and clinical manifestations of the disease, acting as post-transcriptional intermediaries that influence cardiac remodeling, fibrosis, and hypertrophy [31, 32]. Thus, integrating the analysis of circulating miRNAs with the patient’s genetic profile could refine risk stratification, offer a more complete view of the disease, and facilitate the development of more individualized management strategies to overcome the limitations of isolated genotype-phenotype correlation [19, 23, 24].

Beyond diagnosis, miRNA-based therapeutic approaches for HCM are emerging areas of research with transformative clinical potential [33]. As miRNAs play crucial roles in the post-transcriptional gene regulation of cardiac proteins and are implicated in fibrogenesis and hypertrophy pathways, they are not only biomarkers but also potential targets for novel therapies [32, 33]. Pharmacological modulation of specific miRNA expression (e.g., inhibition of pro-hypertrophic miRNAs or activation of antifibrotic miRNAs) may offer an innovative strategy to slow or reverse pathological cardiac remodeling. This suggests the need for treatments that directly target molecular pathomechanisms, complementing or even surpassing current therapies that primarily target symptoms. Although still in the research phase, a deeper understanding of the correlations between miRNAs and clinical outcomes is the first fundamental step toward translating this knowledge into interventions that can effectively modify the course of HCM and improve patient quality of life [32, 34, 35].

We provide consistent evidence of the association between circulating miRNA levels and the clinical and structural parameters of HCM. miRNAs, such as miR-29a, miR-21, and miR-199a-5p, exhibited statistically significant correlations with markers of cardiac remodeling, particularly hypertrophy and fibrosis, suggesting their potential as noninvasive biomarkers in the diagnosis and prognosis of the disease. Future studies should focus on prospective, longitudinal cohorts to validate the prognostic value of circulating microRNAs in hypertrophic cardiomyopathy. Standardization of miRNA detection methods and integration with genetic background, imaging findings, and clinical outcomes will be essential to improve reproducibility and clinical applicability. These advances may allow circulating miRNAs to serve not only as biomarkers of disease severity, but also as tools for personalized risk stratification and therapeutic decision-making in HCM.

The data that support the findings of this meta-analysis are available from the corresponding author upon reasonable request.

Conceptualization: ASMJ, HLO, KBAL, Data curation: ASMJ, HLO, KBAL. Formal analysis: HLO, KBAL. Methodology: HLO and KBAL. Project administration: ASMJ. Resources: ASMJ. Supervision: ASMJ. Validation: ASMJ, HLO, and KBAL. Writing - original draft: HLO, KBAL, ASMJ. Writing - review and editing: HLO, KBAL, ASMJ. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

The authors would like to express their gratitude to all individuals who contributed to the development of this manuscript. We also thank the peer reviewers for their valuable comments and suggestions.

This research received no external funding.

The authors declare no conflicts of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/FBS47633.