Abstract 16103: Alternative Cardiac Sodium Channel Splicing in Circulating White Blood Cells of Heart Failure Patients
Background: Previously, we have reported that SCN5A, the gene encoding the α-subunit of the cardiac Na+ channel, has two mRNA alternative splicing variants that are upregulated in human heart failure (HF). These splicing variants do not form functional channels, and their presence reduces conduction velocity between cardiomyocytes. Therefore, abnormal Na+ channel splicing may contribute to arrhythmic risk in HF. Further studies indicated that splicing factors RBM25 and hLuc7A lead to the abnormal mRNA processing. Our published data also show that immortalized B cells express cardiac Na+ channel variants identically to those in heart tissue and may serve as a surrogate for abnormal cardiac splicing. We tested whether white blood cell (WBC) Na+ channel mRNA splicing varied as a function of the presence or absence of HF.
Methods: One hundred eighty adult patients were recruited into this study, 45 controls without HF (Ejection Fraction (EF) > 60%) and 135 with HF (EF < 35%). Patients with congenital heart disease, infections, and inflammatory conditions were excluded. Total RNA was extracted from WBCs. The mRNA abundances of SCN5A, SCN5A variants, and the splicing factors RBM25 and hLuc7a were determined by real-time PCR.
Results: The ratio of WBC SCN5A variants E28C or E28D to the full-length SCN5A transcript was increased in HF patients as compared to the control group. The average fold inductions were 5.0 ± 2.7 and 7.0 ± 3.5 for SCN5A variants E28C and E28D respectively (p<0.05). These changes were greater than those observed in cardiac tissue. The WBC mRNA abundances of RBM25 and hLuc7a also were increased in HF. The average increases for RBM25 and hLuc7A were 67.0 ± 7.8% and 73.0 ± 9.3% respectively (p<0.05). These changes were similar to those in heart tissue which we reported before.
Conclusions: A distinct pattern of increased pathogenic splicing factors and abnormal Na+ channel splicing was present in circulating WBCs of HF patients, suggesting that WBC mRNA splicing may be affected by the same processes as occur in the heart and that WBC mRNA splicing may serve as a surrogate for the arrhythmic risk related to Na+ channel downregulation in the heart.
- © 2010 by American Heart Association, Inc.