SUMMARY Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG trinucleotide repeat expansion in the 3′ untranslated region of DMPK gene. Heart dysfunctions occur in nearly 80% of DM1 patients and are the second leading cause of DM1-related deaths. Despite these figures, the mechanisms underlying cardiac-based DM1 phenotypes are unknown. Herein, we report that upregulation of a non-muscle splice isoform of RNA binding protein RBFOX2 in DM1 heart tissue—due to altered splicing factor and microRNA activities—induces cardiac conduction defects in DM1 individuals. Mice engineered to express the non-muscle RBFOX2 isoform in heart via tetracycline-inducible transgenesis, or CRISPR/Cas9-mediated genome editing, reproduced DM1-related cardiac-conduction delay and spontaneous episodes of arrhythmia. Further, by integrating RNA binding with cardiac transcriptome datasets from both DM1 patients and mice expressing the non-muscle RBFOX2 isoform, we identified RBFOX2-driven splicing defects in the voltage-gated sodium and potassium channels, which can alter their electrophysiological properties. Thus, our results uncover a trans -dominant role for an aberrantly expressed RBFOX2 isoform in DM1 cardiac pathogenesis.
220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATPase, and inositol trisphosphate (Ins P 3 ) receptor at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes. A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome. Here we report the identification of eight unrelated probands harboring ankyrin-B loss-of-function mutations, including four previously undescribed mutations, whose clinical features distinguish the cardiac phenotype associated with loss of ankyrin-B activity from classic long QT syndromes. Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes. The mutations are localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G in cardiomyocytes. All mutations abolish ability of ankyrin-B to restore abnormal Ca 2+ dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and Ins P 3 R in ankyrin-B +/- cardiomyocytes. This study, considered together with the first description of ankyrin-B mutation associated with cardiac dysfunction, supports a previously undescribed paradigm for human disease due to abnormal coordination of multiple functionally related ion channels and transporters, in this case the Na/K ATPase, Na/Ca exchanger, and Ins P 3 receptor.
Heart failure (HF) is a chronic disease that develops over months to years. In HF, ventricular repolarization is prolonged. We tested the hypothesis that I KCa modulates repolarization only when ventricular repolarization reserve is reduced as occurs in chronic HF, but not short term HF. Methods: A tachypacing - induced HF canine model was used, and LV midwall myocytes were isolated from 1 and 4 month HF groups, and compared to normal controls. Action potential duration at 50 (APD50) and 90% (APD90) repolarization was measured before and after the application of 100nM apamin (I KCa blocker, n=5-9 per group). Adjacent tissue (n=4 per group) was collected to measure the proteins encoding cardiac I KCa (SK2 and SK3). Results: One and 4 month HF had similar severity of HF (LVFS: 19.00 ± 1.36 vs. 15.9 ± 2.45, respectively P=NS). APD50 or APD90 in 1 month HF was no different from controls. 4 Mo HF resulted in a significant (P<0.05) APD90 prolongation compared to both control and 1 Mo HF groups, consistent with reduced repolarization reserve. Apamin significantly increased (P<0.05) APD50 and APD90 only in the 4 Mo HF group. Similarly proarrhythmic repolarization instability (beat-to-beat variability) was evident after apamin in the 4 month, but not the 1 month HF group (p<0.05). SK2 expression was unchanged between groups; SK3 was increased ~ 4 fold in both 1 month and 4 month HF group (P<0.05 vs control). Conclusions: Changes in SK protein expression do not fully explain I KCa -induced repolarization modulation. Rather, I KCa inhibition prolongs repolarization only when repolarization reserve is decreased, as occurs in chronic HF. The safety of targeting I KCa in chronic HF needs to be carefully evaluated as I KCa inhibition may increase susceptibility to ventricular arrhythmias.
Abstract This paper is the second of a series of three reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation–contraction coupling and arrhythmias: Na + channel and Na + transport . The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on Na + channel function and regulation, Na + channel structure and function, and Na + channel trafficking, sequestration and complexing.
Effectiveness of drug education classes. F S Tennant, Jr, P J Mohler, D H Drachler, and H D SilsbyCopyRight https://doi.org/10.2105/AJPH.64.5.422 Published Online: October 07, 2011
