Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure.
Enhanced I<sub>Na,L</sub> occurs in long QT syndrome 3 (LQTS 3) patients, and under a number of pathological and pharmacological cardiovascular conditions, including bradycardia, myocardial ischemia, reperfusion injury, and heart failure.
The purpose of this article was to investigate whether HuR regulates SCN5A mRNA expression and whether manipulation of HuR benefits arrhythmia control in HF.
Our previous studies showed that in ischemic and nonischemic heart failure (HF), the voltage-gated cardiac Na<sup>+</sup> channel α subunit (SCN5A) mRNA is abnormally spliced to produce two truncated transcript variants (E28C and D) that activate the unfolded protein response (UPR).
We envision that SCN5A measurements using PET imaging may serve as a novel diagnostic tool to stratify arrhythmia risk and assess for progression of heart failure in patients with a broad spectrum of cardiovascular diseases.
After controlling for covariates, patients with HF who had received an appropriate ICD intervention had higher expression levels of both WBC-derived SCN5A variants compared with patients with HF with ICDs who had not received appropriate ICD intervention (odds ratio, 3.25; 95% CI, 1.64-6.45; p = 0.001).
When investigating SCN5A splicing abnormalities in heart failure (HF), we found that 47 of 181 known splicing regulators were upregulated in HF compared to controls, which indicates that splicing regulation may play a key role in HF.
Mutations in the SCN5A gene encoding NaV1.5 have been linked to changes in the Na current leading to a variety of arrhythmogenic phenotypes, and alterations in the NaV1.5 expression level, Na current density, and/or gating have been observed in acquired cardiac disorders, including heart failure.
We hypothesized that the S1103Y cardiac sodium channel SCN5A variant influences the propensity for ventricular arrhythmias in black patients with heart failure and reduced ejection fraction.
Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes.
Correspondingly, the relative mRNA levels of the neuronal isoforms SCN1a and SCN8a increased 2.5- and 2.7-fold, respectively; SCN3a did not change, whereas SCN5a decreased by approximately 60% in HF.