Common Ancestry-specific Ion Channel Variants Predispose to Drug-induced Arrhythmias

Circulation ◽  
2022 ◽  
Author(s):  
Yuko Wada ◽  
Tao Yang ◽  
Christian M. Shaffer ◽  
Laura L. Daniel ◽  
Andrew M. Glazer ◽  
...  
Keyword(s):  
Sodium Current ◽  
Common Ancestry ◽  
Drug Induced ◽  
Reference Allele ◽  
Qt Intervals ◽  
Cardiac Sodium Channel ◽  
Induced Pluripotent ◽  
Type 3 ◽  
Congenital Long Qt Syndrome

Background: Multiple reports associate the cardiac sodium channel gene ( SCN5A ) variants S1103Y and R1193Q with type 3 congenital long QT syndrome (LQTS) and drug-induced LQTS. These variants are, however, too common in ancestral populations to be highly arrhythmogenic at baseline: S1103Y allele frequency is 8.1% in Africans and R1193Q 6.1% in East Asians. R1193Q is known to increase late sodium current (I Na-L ) in cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) but the role of these variants in modulating repolarization remains poorly-understood. Methods: We determined the effect of S1103Y on QT intervals among Africans in a large electronic health record. Using iPSC-CMs carrying naturally occurring or genome-edited variants, we studied action potential durations (APDs) at baseline and after challenge with the repolarizing potassium current (I Kr ) blocker dofetilide, and I Na-L and I Kr at baseline. Results: In 1479 African subjects with no confounding medications or diagnoses of heart disease, QT in S1103Y carriers was no different from that in non-carriers. Similarly, baseline APD was no different in cells expressing the Y allele (SY, YY cells) compared to isogenic cells with the reference allele (SS cells). However, I Na-L was increased in SY and YY cells and the I Na-L blocker GS967 shortened APD in SY/YY but not SS cells (p<0.001). I Kr was increased almost 2-fold in SY/YY cells compared to SS cells (tail current: 0.66±0.1 vs 1.2±0.1 pA/pF, p<0.001). Dofetilide challenge prolonged APD at much lower concentrations in SY (4.1 nM [IQR 1.5-9.3], n=11) and YY (4.2 nM [1.7- 5.0], n=5) than in SS cells (249 nM [22.3-2905], n=14, p<0.001 and p<0.01, respectively) and elicited afterdepolarizations in 8/16 SY/YY cells but only in 1/14 SS cells. R1193Q cells similarly displayed no difference in baseline APD but increased I Kr and increased dofetilide sensitivity. Conclusions: These common ancestry-specific variants do not affect baseline repolarization, despite generating increased I Na-L . We propose that increased I Kr serves to maintain normal repolarization but increases the risk of manifest QT prolongation with I Kr block in variant carriers. Our findings further emphasize the need for inclusion of diverse populations in the study of adverse drug reactions.

scholarly journals Targeting the Microtubule EB1-CLASP2 Complex Modulates Na V 1.5 at Intercalated Discs

2021 ◽  
Author(s):  
Gerard A Marchal ◽  
Mariam Jouni ◽  
David Y Chiang ◽  
Marta Pérez-Hernández Duran ◽  
Svitlana Podliesna ◽  
...  
Keyword(s):  
Sodium Current ◽  
Induced Pluripotent Stem Cell ◽  
Loss Of Function ◽  
Whole Cell ◽  
Intercalated Discs ◽  
Cardiac Sodium Channel ◽  
Optical Reconstruction ◽  
Induced Pluripotent ◽  
And Function

Rationale: Loss-of-function of the cardiac sodium channel Na V 1.5 causes conduction slowing and arrhythmias. Na V 1.5 is differentially distributed within subcellular domains of cardiomyocytes, with sodium current (I Na ) being enriched at the intercalated discs (ID). Various pathophysiological conditions associated with lethal arrhythmias display ID-specific I Na reduction, but the mechanisms underlying microdomain-specific targeting of Na V 1.5 remain largely unknown. Objective: To investigate the role of the microtubule (MT) plus-end tracking proteins end binding protein 1 (EB1) and CLIP-associated protein 2 (CLASP2) in mediating Na V 1.5 trafficking and subcellular distribution in cardiomyocytes. Methods and Results: EB1 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) resulted in enhanced whole-cell I Na , increased action potential (AP) upstroke velocity (V max ), and enhanced Na V 1.5 localization at the plasma membrane as detected by multi-color stochastic optical reconstruction microscopy (STORM). Fluorescence recovery after photobleaching (FRAP) experiments in HEK293A cells demonstrated that EB1 overexpression promoted Na V 1.5 forward trafficking. Knockout of MAPRE1 in hiPSC-CMs led to reduced whole-cell I Na , decreased V max and AP duration (APD) prolongation. Similarly, acute knockout of the MAPRE1 homolog in zebrafish (mapre1b) resulted in decreased ventricular conduction velocity and V max as well as increased APD. STORM imaging and macropatch I Na measurements showed that subacute treatment (2-3 hours) with SB216763 (SB2), a GSK3β inhibitor known to modulate CLASP2-EB1 interaction, reduced GSK3β localization and increased Na V 1.5 and I Na preferentially at the ID region of wild type murine ventricular cardiomyocytes. By contrast, SB2 did not affect whole cell I Na or Na V 1.5 localization in cardiomyocytes from Clasp2-deficient mice, uncovering the crucial role of CLASP2 in SB2-mediated modulation of NaV1.5 at the ID. Conclusions: Our findings demonstrate the modulatory effect of the MT plus-end tracking protein EB1 on Na V 1.5 trafficking and function, and identify the EB1-CLASP2 complex as a target for preferential modulation of I Na within the ID region of cardiomyocytes.

scholarly journals Functional Consequences of the SCN5A-p.Y1977N Mutation within the PY Ubiquitylation Motif: Discrepancy between HEK293 Cells and Transgenic Mice

2019 ◽  
Vol 20 (20) ◽  
pp. 5033 ◽  
Author(s):  
Simona Casini ◽  
Maxime Albesa ◽  
Zizun Wang ◽  
Vincent Portero ◽  
Daniela Ross-Kaschitza ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Sodium Current ◽  
Hek293 Cells ◽  
Compensatory Mechanisms ◽  
Cardiac Sodium Channel ◽  
Functional Consequences ◽  
Py Motif ◽  
Type 3

Dysfunction of the cardiac sodium channel Nav1.5 (encoded by the SCN5A gene) is associated with arrhythmias and sudden cardiac death. SCN5A mutations associated with long QT syndrome type 3 (LQT3) lead to enhanced late sodium current and consequent action potential (AP) prolongation. Internalization and degradation of Nav1.5 is regulated by ubiquitylation, a post-translational mechanism that involves binding of the ubiquitin ligase Nedd4-2 to a proline-proline-serine-tyrosine sequence of Nav1.5, designated the PY-motif. We investigated the biophysical properties of the LQT3-associated SCN5A-p.Y1977N mutation located in the Nav1.5 PY-motif, both in HEK293 cells as well as in newly generated mice harboring the mouse homolog mutation Scn5a-p.Y1981N. We found that in HEK293 cells, the SCN5A-p.Y1977N mutation abolished the interaction between Nav1.5 and Nedd4-2, suppressed PY-motif-dependent ubiquitylation of Nav1.5, and consequently abrogated Nedd4-2 induced sodium current (INa) decrease. Nevertheless, homozygous mice harboring the Scn5a-p.Y1981N mutation showed no electrophysiological alterations nor changes in AP or (late) INa properties, questioning the in vivo relevance of the PY-motif. Our findings suggest the presence of compensatory mechanisms, with additional, as yet unknown, factors likely required to reduce the “ubiquitylation reserve” of Nav1.5. Future identification of such modulatory factors may identify potential triggers for arrhythmias and sudden cardiac death in the setting of LQT3 mutations.

scholarly journals Torsades de Pointes after Ondansetron Infusion in 2 Patients

2017 ◽  
Vol 44 (5) ◽  
pp. 366-369 ◽  
Author(s):  
Danny Y. Lee ◽  
Tri Trinh ◽  
Sion K. Roy
Keyword(s):  
Risk Factors ◽  
Receptor Antagonist ◽  
Qt Interval ◽  
Ventricular Arrhythmias ◽  
Torsades De Pointes ◽  
Qt Prolongation ◽  
Drug Induced ◽  
Qt Intervals ◽  
Type 3

Drugs that prolong the electrocardiographic QT interval increase the risk of ventricular arrhythmias, particularly torsades de pointes. Ondansetron, a 5-hydroxytryptamine type 3 receptor antagonist antiemetic, is one such drug. We present the cases of 2 patients who were given intravenous ondansetron and subsequently developed torsades de pointes. Both had normal QT intervals at baseline but were discovered to have risk factors that predisposed them to drug-induced QT prolongation and ventricular arrhythmias. We briefly review the mechanisms for torsades de pointes caused by QT-prolonging medications, describe characteristics that increase patients' susceptibility to drug-induced QT prolongation, and call attention to the risk of ventricular arrhythmias in patients who are given ondansetron.

scholarly journals Acute interstitial nephritis and drug-induced systemic lupus erythematosus due to chlorthalidone and amiodarone: A case report

2020 ◽  
Vol 8 ◽  
pp. 2050313X2091002 ◽  
Author(s):  
Umut Selamet ◽  
Ramy M Hanna ◽  
Anthony Sisk ◽  
Lama Abdelnour ◽  
Lena Ghobry ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Interstitial Nephritis ◽  
Lupus Erythematosus ◽  
Kidney Biopsy ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Systemic Lupus ◽  
Drug Induced ◽  
Systemic Manifestations

Drug-induced lupus erythematosus has features distinct from primary systemic lupus erythematosus. It can occur with a wide variety of agents that result in the generation of anti-histone or other types of antibodies. Systemic manifestations of drug-induced systemic lupus erythematosus may include renal dysfunction due to circulating immune complexes or due to other immune reactions to the culprit medication(s). Acute interstitial nephritis occurs due to DNA–drug or protein–drug complexes that trigger an allergic immune response. We report a patient who developed acute kidney injury, rash, and drug-induced systemic lupus diagnosed by serologies after starting chlorthalidone and amiodarone. A renal biopsy showed acute interstitial nephritis and not lupus-induced glomerulonephritis. It is important to note that systemic lupus erythematosus and acute interstitial nephritis can occur together, and this report highlights the role of the kidney biopsy in ascertaining the pathological diagnosis and outlining therapy in drug-induced lupus erythematosus.

scholarly journals MULTIPLE ALLELE APPROACH TO THE STUDY OF GENES IN DROSOPHILA MELANOGASTER THAT ARE INVOLVED IN IMAGINAL DISC DEVELOPMENT

Genetics ◽  
1978 ◽  
Vol 89 (2) ◽  
pp. 355-370 ◽  
Author(s):  
Allen Shearn ◽  
Grafton Hersperger ◽  
Evelyn Hersperger ◽  
Ellen Steward Pentz ◽  
Paul Denker
Keyword(s):  
Drosophila Melanogaster ◽  
Phenotypic Variation ◽  
Mutant Allele ◽  
Imaginal Disc ◽  
Reference Allele ◽  
Multiple Allele ◽  
Significant Difference ◽  
Chromosome Mutations ◽  
Cold Sensitive

ABSTRACT The phenotypes of five different lethal mutants of Drosophila melanogaster that have small imaginal discs were analyzed in detail. From these results, we inferred whether or not the observed imaginal disc phenotype resulted exclusively from a primary imaginal disc defect in each mutant. To examine the validity of these inferences, we employed a multiple-allele method. Lethal alleles of the five third-chromosome mutations were identified by screening EMS-treated chromosomes for those which fail to complement with a chromosome containing all five reference mutations. Twenty-four mutants were isolated from 13,197 treated chromosomes. Each of the 24 was then tested for complementation with each of the five reference mutants. There was no significant difference in the mutation frequencies at these five loci. The stage of lethality and the imaginal disc morphology of each mutant allele were compared to those of its reference allele in order to examine the range of defects to be found among lethal alleles of each locus. In addition, hybrids of the alleles were examined for intracistronic complementation. For two of the five loci, we detected no significant phenotypic variation among lethal alleles. We infer that each of the mutant alleles at these two loci cause expression of the null activity phenotype. However, for the three other loci, we did detect significant phenotypic variation among lethal alleles. In fact, one of the mutant alleles at each of these three loci causes no detectable imaginal disc defect. This demonstrates that attempting to assess the developmental role of a gene by studying a single mutant allele may lead to erroneous conclusions. As a byproduct of the mutagenesis procedure, we have isolated two dominant, cold-sensitive mutants.

scholarly journals Elucidating the role of Cavin1 in drug-induced long QT syndrome (diLQTS)

2021 ◽  
Vol 13 (2) ◽  
pp. 228-229
Author(s):  
Z. Al Sayed ◽  
C. Pereira ◽  
C. Jouve ◽  
J. Hulot
Keyword(s):  
Long Qt Syndrome ◽  
Long Qt ◽  
Drug Induced ◽  
Qt Syndrome

scholarly journals The role of quantitative deep capillary plexus in the pathogenesis of type 3 macular neovascularization: an optical coherence tomography angiography study

2021 ◽  
Author(s):  
Marina Concilio ◽  
Federica Fossataro ◽  
Daniela Montorio ◽  
Mariapaola Giordano ◽  
Gilda Cennamo
Keyword(s):  
Optical Coherence Tomography ◽  
Optical Coherence Tomography Angiography ◽  
Early Stage ◽  
Study Groups ◽  
Control Group ◽  
Main Role ◽  
Optical Coherence ◽  
Capillary Plexus ◽  
Type 3

Abstract Purpose To quantitatively investigate the role of deep capillary plexus (DCP) in patients affected by type 3 macular neovascularization (MNV), compared to patients with reticular pseudodrusen (RPD) eyes and healthy controls, using optical coherence tomography angiography (OCTA). Methods In this prospective observational study, a total of seventy-eight eyes of 78 patients were included. Group 1 consisted of 40 eyes of 40 patients with stage 1 of type 3 MNV (22 males, 18 females, mean age 73.7, SD ± 6.60) and group 2 included 38 eyes of 38 patients with RPD (17 males, 21 females, mean age 73.2, SD ± 4.55). The control group included 40 eyes of 40 healthy subjects (20 males, 20 females, mean age 71.4, SD ± 6.36 years). We evaluated the retinal vessel density (VD) of superficial capillary plexus (SCP) and deep capillary plexus (DCP) using OCTA. Results Patients with diagnosis of type 3 MNV showed statistically lower values of VD in DCP with respect to controls and to RPD group (p < 0.001), while there were no statistical differences between RPD and control group in macular region. No significant differences in VD of SCP were detected among the three study groups. Conclusion OCTA provides a reproducible, non-invasive detailed quantitative analysis of retinal vascular features and changing in early-stage type 3 MNV patients, which allowed to shed the light on the main role of DCP ischemia in the development of type 3 MNV.

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