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α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.

Choi JI, Wang C, Thomas MJ, Pitt GS - PLoS ONE (2016)

Bottom Line: Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS.We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism.In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019).

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine; and Ion Channel Research Unit, Duke University Medical Center, Durham, NC, United States of America.

ABSTRACT
Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58 ± 0.10 in WT vs. 0.90 ± 0.11 in A390V, p = 0.048; vs. 0.88 ± 0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS.

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A drug-induced long-QT syndrome patient with the p.E409Q variant in SNTA1.(A) A 12-lead resting electrocardiogram (ECG) from the proband during the post-arrest period showed markedly prolonged QT intervals. The QTc was 562 ms, and the notched T wave was noted. (B) The QTc interval was normalized and the T wave notch disappeared 2 months after aborted sudden cardiac death. (C) Pedigree of the family. An arrow is the proband with p.E409 variant. (D) Sequence conservation across species for A390V and E409Q versus normal in SNTA1. SCA, sudden cardiac arrest; and VF, ventricular fibrillation.
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pone.0152355.g001: A drug-induced long-QT syndrome patient with the p.E409Q variant in SNTA1.(A) A 12-lead resting electrocardiogram (ECG) from the proband during the post-arrest period showed markedly prolonged QT intervals. The QTc was 562 ms, and the notched T wave was noted. (B) The QTc interval was normalized and the T wave notch disappeared 2 months after aborted sudden cardiac death. (C) Pedigree of the family. An arrow is the proband with p.E409 variant. (D) Sequence conservation across species for A390V and E409Q versus normal in SNTA1. SCA, sudden cardiac arrest; and VF, ventricular fibrillation.

Mentions: A 36 year old previously healthy man with no family history of sudden cardiac death or LQTS suffered a witnessed cardiac arrest while exercising. At the time of his arrest his medications included amitriptyline, pseudoephedrine, and famotidine. His initial rhythm was ventricular fibrillation from which he was successfully resuscitated with an external countershock. Coronary angiography showed no evidence of coronary artery disease. Cardiac MRI showed an EF of 65% with no evidence of right ventricular dysplasia. ECGs in the post-arrest period were notable for prolonged QT intervals (repeated QTc measurements > 480 ms; the longest was 597 ms) (Fig 1A). ECGs obtained in the month after the arrest and in all follow up visits showed normal QT intervals (all QTc measurements <440 ms) after discontinuation of amitriptyline, pseudoephedrine, and famotidine (Fig 1B).


α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.

Choi JI, Wang C, Thomas MJ, Pitt GS - PLoS ONE (2016)

A drug-induced long-QT syndrome patient with the p.E409Q variant in SNTA1.(A) A 12-lead resting electrocardiogram (ECG) from the proband during the post-arrest period showed markedly prolonged QT intervals. The QTc was 562 ms, and the notched T wave was noted. (B) The QTc interval was normalized and the T wave notch disappeared 2 months after aborted sudden cardiac death. (C) Pedigree of the family. An arrow is the proband with p.E409 variant. (D) Sequence conservation across species for A390V and E409Q versus normal in SNTA1. SCA, sudden cardiac arrest; and VF, ventricular fibrillation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814026&req=5

pone.0152355.g001: A drug-induced long-QT syndrome patient with the p.E409Q variant in SNTA1.(A) A 12-lead resting electrocardiogram (ECG) from the proband during the post-arrest period showed markedly prolonged QT intervals. The QTc was 562 ms, and the notched T wave was noted. (B) The QTc interval was normalized and the T wave notch disappeared 2 months after aborted sudden cardiac death. (C) Pedigree of the family. An arrow is the proband with p.E409 variant. (D) Sequence conservation across species for A390V and E409Q versus normal in SNTA1. SCA, sudden cardiac arrest; and VF, ventricular fibrillation.
Mentions: A 36 year old previously healthy man with no family history of sudden cardiac death or LQTS suffered a witnessed cardiac arrest while exercising. At the time of his arrest his medications included amitriptyline, pseudoephedrine, and famotidine. His initial rhythm was ventricular fibrillation from which he was successfully resuscitated with an external countershock. Coronary angiography showed no evidence of coronary artery disease. Cardiac MRI showed an EF of 65% with no evidence of right ventricular dysplasia. ECGs in the post-arrest period were notable for prolonged QT intervals (repeated QTc measurements > 480 ms; the longest was 597 ms) (Fig 1A). ECGs obtained in the month after the arrest and in all follow up visits showed normal QT intervals (all QTc measurements <440 ms) after discontinuation of amitriptyline, pseudoephedrine, and famotidine (Fig 1B).

Bottom Line: Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS.We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism.In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019).

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine; and Ion Channel Research Unit, Duke University Medical Center, Durham, NC, United States of America.

ABSTRACT
Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58 ± 0.10 in WT vs. 0.90 ± 0.11 in A390V, p = 0.048; vs. 0.88 ± 0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS.

Show MeSH
Related in: MedlinePlus