Neural Control of Heart Rate Is an Arrhythmia Risk Modifier in Long QT Syndrome

Schwartz, Peter J.; Vanoli, Emilio; Crotti, Lia; Spazzolini, Carla; Ferrandi, Chiara; Goosen, Althea; Hedley, Paula L.; Heradien, Marshall; Bacchini, Sara; Turco, Annalisa; Rovere, Maria Teresa La; Bartoli, Antonella; George, Alfred L.; Brink, Paul A.

doi:10.1016/j.jacc.2007.09.069

Cited by 101 publications

(103 citation statements)

References 26 publications

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“…The data unequivocally show that KCNQ1-A341V is a mutation associated with unusual clinical severity. This finding, together with the recent evidence that genetically mediated neural control of heart rate may modulate arrhythmic risk in LQT1 patients, 24 begins to unravel the old and puzzling observation of the large heterogeneity in the clinical manifestations of LQTS. We do not believe that this mutation is unique in its clinical phenotype, and we believe that other mutations, more likely to be located in functionally important areas probably within the transmembrane region and close to the pore or in the S4 domain, confer a risk for life-threatening arrhythmias higher than that associated with other mutations.…”

Section: Discussionmentioning

confidence: 92%

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

et al. 2007

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Background-The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)-causing mutation (KCNQ1-A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families. Methods and Results-Seventy-eight patients, all with a single KCNQ1-A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484Ϯ42 versus 485Ϯ45 ms (PϭNS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485Ϯ43 versus 465Ϯ38 ms) (all PϽ0.001). Arrhythmic risk remained higher (PϽ0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite ␤-blocker therapy. Conclusions-The hot spot KCNQ1-A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS.

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Section: Discussionmentioning

confidence: 92%

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

et al. 2007

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“…In October 2011 12 Brisk variations in autonomic response increase the arrhythmic risk in A341V LQT1 patients. 13 Also, polymorphisms in ␣-and ␤-adrenergic receptors (enhancing the autonomic response) are found more often in symptomatic than nonsymptomatic KCNQ1-A341V carriers. 13 In the present study, we investigated the molecular control of I Ks during ␤AR stimulation, hypothesizing that A341V provides a useful case to advance understanding of the I Ks macromolecular signaling complex, and to obtain novel insights into the determinants of phenotypic severity by A341V and other LQT1 mutations.…”

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confidence: 99%

Dominant-Negative Control of cAMP-Dependent I _Ks Upregulation in Human Long-QT Syndrome Type 1

Heijman

Spätjens

Seyen

et al. 2012

Circulation Research

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Rationale:The mutation A341V in the S6 transmembrane segment of KCNQ1, the ␣-subunit of the slowly activating delayed-rectifier K ؉ (I Ks ) channel, predisposes to a severe long-QT1 syndrome with sympathetictriggered ventricular tachyarrhythmias and sudden cardiac death.Objective: Several genetic risk modifiers have been identified in A341V patients, but the molecular mechanisms underlying the pronounced repolarization phenotype, particularly during ␤-adrenergic receptor stimulation, remain unclear. We aimed to elucidate these mechanisms and provide new insights into control of cAMPdependent modulation of I Ks . Methods and Results:We characterized the effects of A341V on the I Ks macromolecular channel complex in transfected Chinese hamster ovary cells and found a dominant-negative suppression of cAMP-dependent Yotiao-mediated I Ks upregulation on top of a dominant-negative reduction in basal current. Phosphomimetic substitution of the N-terminal position S27 with aspartic acid rescued this loss of upregulation. Western blot analysis showed reduced phosphorylation of KCNQ1 at S27, even for heterozygous A341V, suggesting that phosphorylation defects in some (mutant) KCNQ1 subunits can completely suppress I Ks upregulation. Functional analyses of heterozygous KCNQ1 WT:G589D and heterozygous KCNQ1 WT:S27A, a phosphorylation-inert substitution, also showed such suppression. Immunoprecipitation of Yotiao with KCNQ1-A341V (in the presence of KCNE1) was not different from wild-type. Key Words: ion channels Ⅲ long-QT syndrome Ⅲ potassium Ⅲ torsade de pointes T he slowly activating delayed-rectifier K ϩ current (I Ks ) contributes importantly to cardiac repolarization. In large mammals, including humans, it has a small amplitude under basal isolated-myocyte conditions but forms a sizable repolarization reserve that is recruited when the action potential duration (APD) prolongs and during ␤-adrenergic receptor (␤AR) stimulation. 1,2 I Ks is carried by a macromolecular channel complex consisting of a homotetramer of pore-forming ␣-subunits encoded by KCNQ1 (Kv7.1), KCNE1 ␤-subunits, 3,4 and the regulatory A-kinase anchoring protein Yotiao, which binds to the KCNQ1 C-terminus. 5 There are also multiple interactions with other proteins. During ␤AR stimulation, when cAMP levels rise, phosphorylation of KCNQ1 at N-terminal position S27 is controlled by protein kinase A (PKA) and protein phosphatase 1 that are localized to the complex by Yotiao, thereby providing local control of I Ks enhancement. 5 Anchored PKA also phosphorylates Yotiao itself, thereby further enhancing I Ks . 6 An intact C-terminus of KCNE1 is critical for the PKA-dependent upregulation of I Ks . 7 Congenital defects (long-QT syndrome types 1 and 5; LQT1, LQT5; Jervell and Lange-Nielsen syndrome), pharmacological inhibition, 8 and acquired loss of I Ks , 9 can all result in QT-interval prolongation and enhanced susceptibility to ventricular tachyarrhythmias, notably torsade de pointes. These arrhythmias occur predominantly during conditions of exerc...

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“…Lower heart rates (HR) were associated with lower risk of attacks (9,14) in persons with QTc <500ms. With a QTc >500ms virtually everybody had episodes consistent with this being recognized as a major risk predictor.…”

Section: Severity Of the A341 Mutationmentioning

confidence: 99%

The long QT syndrome in South Africa

Brink

Corfield

2017

SAHJ

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Neural Control of Heart Rate Is an Arrhythmia Risk Modifier in Long QT Syndrome

Cited by 101 publications

References 26 publications

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

Dominant-Negative Control of cAMP-Dependent I _Ks Upregulation in Human Long-QT Syndrome Type 1

The long QT syndrome in South Africa

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Neural Control of Heart Rate Is an Arrhythmia Risk Modifier in Long QT Syndrome

Cited by 101 publications

References 26 publications

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

Dominant-Negative Control of cAMP-Dependent I Ks Upregulation in Human Long-QT Syndrome Type 1

The long QT syndrome in South Africa

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Dominant-Negative Control of cAMP-Dependent I _Ks Upregulation in Human Long-QT Syndrome Type 1