Key result
Decompensated right ventricular failure was associated with 56 differentially expressed ion channel genes compared to healthy controls, notably characterized by the downregulation of voltage-gated calcium and sodium channels.
Why the study?
Arrhythmias contribute to most deaths in pulmonary hypertension, but the mechanisms underlying electrical remodeling, particularly ventricular arrhythmias, remain elusive.
Does right ventricular decompensation in pulmonary arterial hypertension alter the transcriptomic expression of cardiac ion channels?
Does right ventricular decompensation in pulmonary arterial hypertension alter the transcriptomic expression of cardiac ion channels?
Identifying transcriptomic changes in RV channelopathies in PAH reveals potential new therapeutic targets like BTK inhibitors or TRPP antagonism for treating associated ventricular arrhythmias.
Ion channel remodeling in decompensated RV failure is hypothesis-generating; extends animal transcriptomics but requires human validation before targeting arrhythmias.
Arrhythmias in the setting of right-ventricular (RV) remodeling contribute to majority of deaths in patients with pulmonary hypertension. However, the underlying mechanism of electrical remodeling remains elusive, especially ventricular arrhythmias. Here, we analyzed the RV transcriptome of pulmonary arterial hypertension (PAH) patients with compensated RV or decompensated RV and identified 8 and 45 differentially expressed genes known to be involved in regulating the electrophysiological properties of excitation and contraction of cardiac myocytes, respectively. Transcripts encoding voltage-gated Ca2+ and Na+ channels were notably decreased in PAH patients with decompensated RV, along with significant dysregulation of KV and Kir channels. We further showed similarity of the RV channelome signature with two well-known animal models of PAH, monocrotaline (MCT)- and Sugen-hypoxia (SuHx)-treated rats. We identified 15 common transcripts among MCT, SuHx, and PAH patients with decompensated RV failure. In addition, data-driven drug repurposing using the channelome signature of PAH patients with decompensated RV failure predicted drug candidates that may reverse the altered gene expression. Comparative analysis provided further insight into clinical relevance and potential preclinical therapeutic studies targeting mechanisms involved in arrhythmogenesis.
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Park et al. (2023) studied Pulmonary arterial hypertension with compensated or decompensated right ventricular failure (n=39). Decompensated right ventricular failure vs. Compensated right ventricular failure or healthy donor right ventricle was evaluated on Differential expression of ion channel genes (channelome) (p=<0.05). Decompensated right ventricular failure was associated with 56 differentially expressed ion channel genes compared to healthy controls, notably characterized by the downregulation of voltage-gated calcium and sodium channels.
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