Selective Targeting of Gain-of-Function KCNQ1 Mutations Predisposing to Atrial Fibrillation

Campbell, Courtney; Campbell, Jonathan D.; Thompson, Christopher H.; Galimberti, Eleonora Savio; Darbar, Dawood; Vanoye, Carlos G.; George, Alfred L.

doi:10.1161/circep.113.000439

Cited by 32 publications

(15 citation statements)

References 38 publications

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“…A previous study showed the enhanced sensitivity of KCNQ1 gain-of-function mutations for the I Ks selective blocker HMR-1556. 26 In our study, sodium-channel blockers were shown to be effective in patients harboring SCN1B T189M. Similarly, I Kur channel blocking or I Kr channel blocking may be effective for preventing the shortening of action potential duration in patients with KCNA5 T527M or KCNH2 T436M and T895M.…”

supporting

confidence: 54%

Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation

Hayashi

Konno

Tada

et al. 2015

Circ: Arrhythmia and Electrophysiology

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Background— Few rare variants in atrial fibrillation (AF)–associated genes have been functionally characterized to identify a causal relationship between these variants and development of AF. We here sought to determine the clinical effect of rare variants in AF-associated genes in patients with lone AF and characterized these variants electrophysiologically and bioinformatically. Methods and Results— We screened all coding regions in 12 AF-associated genes in 90 patients with lone AF, with an onset of 47±11 years (66 men; mean age, 56±13 years) by high-resolution melting curve analysis and DNA sequencing. The potassium and sodium currents were analyzed using whole-cell patch clamping. In addition to using 4 individual in silico prediction tools, we extended those predictions to an integrated tool (Combined Annotation Dependent Depletion). We identified 7 rare variants in KCNA5 , KCNQ1 , KCNH2 , SCN5A , and SCN1B genes in 8 patients: 2 of 8 probands had a family history of AF. Electrophysiological studies revealed that 2 variants showed a loss-of-function, and 4 variants showed a gain-of-function. Five of 6 variants with electrophysiological abnormalities were predicted as pathogenic by Combined Annotation Dependent Depletion scores. Conclusions— In our cohort of patients with lone AF, 7 rare variants in cardiac ion channels were identified in 8 probands. A combination of electrophysiological studies and in silico predictions showed that these variants could contribute to the development of lone AF, although further in vivo study is necessary to confirm these results. More than half of AF-associated rare variants showed gain-of-function behavior, which may be targeted using genotype-specific pharmacological therapy.

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supporting

confidence: 54%

Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation

Hayashi

Konno

Tada

et al. 2015

Circ: Arrhythmia and Electrophysiology

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“…In collaboration with Dr. George’s laboratory, we investigated whether WT- KCNQ1 or the KCNQ1 -S140G familial AF mutation possess distinct pharmacological properties that may enable targeted inhibition of the I Ks -selective blocker HMR-1556. 92 While a low concentration of the blocker had little effect on WT-I Ks , it was capable of inhibiting the mutant channel. In cultured adult rabbit left atrial myocytes, expression of S140G-I Ks shortened APD but cells expressing WT-I Ks did not.…”

Section: Implications For Atrial Fibrillation Therapymentioning

confidence: 99%

The Role of Pharmacogenetics in Atrial Fibrillation Therapeutics

Darbar¹

2016

Journal of Cardiovascular Pharmacology

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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide requiring therapy. Despite recent advances in catheter-based and surgical therapy, antiarrhythmic drugs (AAD) remain the mainstay of treatment for symptomatic AF. However, response in individual patients is highly variable with over half the patients treated with rhythm control therapy experiencing recurrence of AF within a year. Contemporary AADs used to suppress AF are incompletely and unpredictably effective and associated with significant risks of proarrhythmia and non-cardiac toxicities. Furthermore, this ‘one-size’ fits all strategy for selecting antiarrhythmics is based largely on minimizing risk of adverse effects rather than on the likelihood of suppressing AF. The limited success of rhythm-control therapy is in part due to heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to AADs in individual patients. Genetic studies of AF over the last decade have revealed that susceptibility to and response to therapy for AF is modulated by the underlying genetic substrate. However, the bedside application of these new discoveries to the management of AF patients has thus far been disappointing. This may in part be related to our limited understanding about genetic predictors of drug response in general, the challenges associated with determining efficacy of response to AADs and lack of randomized genotype-directed clinical trials. Nonetheless, recent studies have shown that common AF susceptibility risk alleles at the chromosome 4q25 locus modulated response to AADs, electrical cardioversion and ablation therapy. This monograph discusses how genetic approaches to AF have not only provided important insights into underlying mechanisms but also identified AF sub-types that can be better targeted with more mechanism-based ‘personalized’ therapy.

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“…79 Although a low concentration of the blocker had little effect on WT-I Ks , it was capable of inhibiting the mutant channel. In cultured adult rabbit left atrial myocytes, expression of S140G-I Ks shortened APD but cells expressing WT-I Ks did not.…”

Section: Development Of Therapeutic Approaches For Novel Biologicamentioning

confidence: 99%

Genotype influence in responses to therapy for atrial fibrillation

Huang

Darbar

2016

Expert Review of Cardiovascular Therapy

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Introduction Over the last decade, tremendous progress has been made in defining the genetic architecture of atrial fibrillation (AF). This has in part been driven by poor understanding of the pathophysiology of AF, limitations of current therapies and failure to target therapies to the underlying mechanisms. Areas covered Genetic approaches to AF have identified mutations encoding cardiac ion channels, and signaling proteins linked with AF and genome-wide association studies have uncovered common genetic variants modulating AF risk. These studies have provided important insights into the underlying mechanisms of AF and defined responses to therapies. Common AF-risk alleles at the chromosome 4q25 locus modulate response to antiarrhythmic drugs, electrical cardioversion and catheter ablation. While the translation of these discoveries to the bedside care of individual patients has been limited, emerging evidence supports the hypothesis that genotype-directed approaches that target the underlying mechanisms of AF may not only improve therapeutic efficacy but also minimize adverse effects. Expert commentary There is an urgent need for randomized controlled trials that are genotype-based for the treatment of AF. Nonetheless, emerging data suggest that selecting therapies for AF that are genotype-directed may soon be upon us.

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Selective Targeting of Gain-of-Function KCNQ1 Mutations Predisposing to Atrial Fibrillation

Cited by 32 publications

References 38 publications

Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation

Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation

The Role of Pharmacogenetics in Atrial Fibrillation Therapeutics

Genotype influence in responses to therapy for atrial fibrillation

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