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Circulating MicroRNAs Identify Early Phenotypic Changes in Sarcomeric Hypertrophic Cardiomyopathy
Carmen C Sucharov1, Bonnie Neltner1, Ashley E Pietra2
1Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora (C.C.S., B.N.).
Insights
Circulating microRNAs (miRNAs) can help distinguish between healthy individuals and those with hypertrophic cardiomyopathy (HCM), and even stratify disease stages in sarcomere variant carriers.
Area of Science:
- Cardiovascular Genetics
- Molecular Diagnostics
- Biomarker Discovery
Background:
- Hypertrophic cardiomyopathy (HCM) is a primary genetic heart condition caused by sarcomere gene mutations.
- Clinical diagnosis of HCM often occurs late, with limited understanding of early disease progression.
- Mechanisms driving the transition from genetic predisposition to overt HCM remain unclear.
Purpose of the Study:
- To investigate the potential of circulating microRNAs (miRNAs) for stratifying disease stages in sarcomeric HCM.
- To identify specific miRNA profiles associated with different stages of HCM in variant carriers.
- To explore miRNAs as biomarkers for early detection and monitoring of HCM.
Main Methods:
- Serum samples were collected from HCM sarcomere variant carriers (clinical and subclinical) and healthy controls.
- A comprehensive array analysis was performed to profile 381 circulating miRNAs.
- Statistical methods including random forest, Wilcoxon rank sum test, and logistic regression were employed for differential expression analysis, with normalization to miRNA-320.
Main Results:
- Circulating miRNA profiles successfully differentiated healthy controls from both subclinical and clinical HCM groups.
- Distinct miRNA signatures identified clinical HCM versus subclinical HCM without early phenotypic changes.
- MiRNA profiles also distinguished between subclinical HCM with and without early phenotypic changes.
- No significant differentiation was observed between clinical HCM and subclinical HCM with early phenotypic changes, suggesting biological overlap.
Conclusions:
- Circulating miRNAs show promise as biomarkers for augmenting clinical stratification in HCM.
- These findings enhance the understanding of the transition from a healthy state to overt disease in sarcomere gene variant carriers.
- Further research into miRNA profiles could lead to improved early diagnosis and management strategies for HCM.
Background:
Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. Pathogenic germline variation in genes encoding the sarcomere is the predominant cause of disease. However diagnostic features, including unexplained left ventricular hypertrophy, typically do not develop until late adolescence or after. The early stages of disease pathogenesis and the mechanisms underlying the transition to a clinically overt phenotype are not well understood. In this study, we investigated if circulating microRNAs (miRNAs) could stratify disease stage in sarcomeric HCM.
Methods:
We performed arrays for 381 miRNAs using serum from HCM sarcomere variant carriers with and without a diagnosis of HCM and healthy controls. To identify differentially expressed circulating miRNAs between groups, multiple approaches were used including random forest, Wilcoxon rank sum test, and logistic regression. The abundance of all miRNAs was normalized to miRNA-320.
Results:
Of 57 sarcomere variant carriers, 25 had clinical HCM and 32 had subclinical HCM with normal left ventricular wall thickness (21 with early phenotypic manifestations and 11 with no discernible phenotypic manifestations). Circulating miRNA profile differentiated healthy controls from sarcomere variant carriers with subclinical and clinical disease. Additionally, circulating miRNAs differentiated clinical HCM from subclinical HCM without early phenotypic changes; and subclinical HCM with and without early phenotypic changes. Circulating miRNA profiles did not differentiate clinical HCM from subclinical HCM with early phenotypic changes, suggesting biologic similarity between these groups.
Conclusions:
Circulating miRNAs may augment the clinical stratification of HCM and improve understanding of the transition from health to disease in sarcomere gene variant carriers.
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