CHEST Guidelines-Alternative-Splicing-of-the-Cardiac-Sodium-Channel

Alternative-Splicing-of-the-Cardiac-Sodium-Channel

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This study explores the role of alternative splicing of the cardiac sodium channel gene SCN5a in pulmonary arterial hypertension (PAH). The researchers examined the presence of nonfunctional splice variants (SVs) of SCN5a in patients with PAH and their potential contribution to metabolic dysregulation in the heart. Previous research indicates that these SVs can cause stress in the endoplasmic reticulum and mitochondria, leading to significant cardiac issues. This study hypothesized that SCN5a splicing might contribute to metabolic reprogramming in PAH.<br /><br />The pilot study involved 11 PAH patients and 11 matched control subjects and sought to determine circulating SCN5a SVs levels and their correlation with right ventricular (RV) function and mitochondrial respiration. Findings showed that circulating SCN5a SV mRNA levels were significantly elevated in PAH patients compared to controls and tracked with increased markers of glycolysis and oxygen consumption in peripheral blood mononuclear cells (PBMCs). There was also a significant correlation observed between the SV levels and RV uptake of glucose, indicating altered metabolic activity in the RV, although these did not correlate with other tests such as echocardiography or BNP levels.<br /><br />The study suggests a link between alternative splicing of SCN5a and the metabolic changes observed in PAH. Although underpowered to detect specific mitochondrial and HIF-1a expression changes, the results highlight a possible novel mechanism in PAH involving SCN5a splicing. These findings could someday lead to new biomarkers for disease monitoring and management of PAH-related complications like sudden cardiac death, though further studies with larger sample sizes are necessary to confirm these initial observations. Limitations include small sample size and lack of tissue-level analysis, indicating the need for further research in this area.

Keywords

alternative splicing

SCN5a

pulmonary arterial hypertension

nonfunctional splice variants

metabolic dysregulation

right ventricular function

mitochondrial respiration

glycolysis

biomarkers

sudden cardiac death