Abstract 4363: The Possible Mechanism of Acquired Sodium Channel mRNA Splicing Variants with Human Heart Failure
Background: Heart failure (HF) affects more than five million Americans. HF is known to be associated with ventricular arrhythmia, and sudden cardiac death is seen in almost 50% of such patients. The cardiac voltage-gated Na+ channel (SCN5a) is the main channel generating current for electrical propagation in heart muscle. Recently, we have shown that there are three SCN5a C-terminal splicing variants. mRNA abundances of two are increased dramatically in HF. Each of these variants results in prematurely truncated, nonfunctional Na+ channels and a dominant negative effect on the native channel mRNA. The downregulation of SCN5a as a result of such abnormal splicing is likely to contribute to arrhythmic risk in HF and may explain, in part, why sodium channel blocking drugs increase sudden death risk in this population. We explored the mechanism whereby SCN5a splicing becomes dysregulated in HF.
Methods: Changes in splicing factor mRNA abundances were evaluated by microarray analysis comparing human HF to normal myocardium. The data was uploaded to GeneSifter using Batch Upload with the option to use Affymetrix probe IDs. The data was log2 transformed and quantile normalized. Statistically significant genes were identified by using an unpaired Student t test ( p value <0.05 and a 5% Benjamini and Hochberg false discovery rate (FDR) correction). A range of fold change cut offs were used. Genes associated with RNA splicing were found under the biological process GO term “GO: 0008380 : RNA splicing”. The significance of the observed number of genes associated with RNA splicing was determined using z scores.
Results: A total of 47 of 181 known splicing-related genes showed significant changes at a 1.2 fold cut off. Many of these RNA binding factors (49.9%) could be classified into those two groups, those related to hypoxia (15 genes) and to inflammation (8 genes).
Conclusions: These results suggest either hypoxia or inflammation may be responsible for the abnormal splicing of the cardiac Na+ channel during HF and may open the door for therapeutic strategies to reduce arrhythmic risk during HF.