Integrative transcriptomic analysis revealed the roles and prognostic value of ion channels in hypertrophic...

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular conditions, which may be linked to ion channel dysfunction. In decades, Genetic studies in HCM patients have shown that multiple gene mutations in potassium and calcium ion channels, which may contribute to HCM progression. The direct relationship between HCM and ion channels still needs to be clarified.

We compared the transcriptomic differences between patients with HCM and control populations across three different datasets, and further screened through clustering and enrichment analysis, to identify hub differential expressed ion channels (DEICs) in HCM progression. By constructing pathological features of myocardial hypertrophy, fibrosis, and fibroblast activation, we sought to explore the associations between hub DEICs levels and these pathological features. Subsequently, we used single-cell RNA sequencing (scRNAseq) to clarify the expression characteristics of hub DEICs in different cells and spatial transcriptomic analysis to determine the transcriptomic features of the regions. Based on these hub DEICs, we constructed a prognostic model to evaluate its diagnostic value. Furthermore, we conducted immunoinfiltration analysis to explore their relationship with cardiac inflammatory responses. Finally, we verified these four hub genes expression alteration in transverse aortic constriction (TAC) mice.

Based on three transcriptome sequence datasets, we found 17 ion channels have same expression change in at least two datasets. Trough clustering and enrichment analysis, we narrowed down to four hub DEICs in all datasets, KCNC4, KCNN3, ANO1, CACNA2D3. Additionally, we found that the expression levels of these four genes were significantly associated with myocardial hypertrophy, fibrosis, and fibroblast activation. Further, through scRNAseq, we found that these four genes are primarily expressed in cardiomyocytes. Subsequently, using spatial transcriptomic sequencing, we observed that the regions where these genes were detected exhibited distinct fibrotic characteristics. Based on these hub DEICs, we constructed an expression model and found that their expression levels hold significant diagnostic value for HCM. Additionally, through immunoinfiltration analysis, we identified a correlation between the expression levels of hub DEICs and changes in macrophage proportions. We also found that the changes in gene expression observed in the TAC model were consistent with the aforementioned results.

In this study, through integrative transcriptomic sequencing, we identified four ion channels significantly associated with the development of HCM. Furthermore, in our mechanistic exploration, we found that these associations may be linked to core pathological changes such as myocardial hypertrophy, fibrosis and changes in macrophage proportions.