Therapeutic Strategies for Long-QT Syndrome

Ruan, Yijun; Liu, Nian; Napolitano, Carlo; Priori, Silvia G.

doi:10.1161/circep.108.795617

Cited by 57 publications

(14 citation statements)

References 47 publications

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“…These data are in line with observations in LQT1 patients as these patients suffer from arrhythmias during increased heart rates caused by emotional stress or exercise. The data is also in line with the beneficial effects of β-blockers in suppressing arrythmias in these patients (Ruan et al, 2008). Immunocytochemistry revealed that the KCNQ 1-G569A mutation leads to impaired trafficking and localization of the mutant channels.…”

Section: Human Ipsc-cm Models For Inherited Cardiac Arrhythmiassupporting

confidence: 79%

Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias

Hoekstra¹,

Mummery²,

Wilde³

et al. 2012

Front. Physio.

179

148

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Cardiac arrhythmias are a major cause of morbidity and mortality. In younger patients, the majority of sudden cardiac deaths have an underlying Mendelian genetic cause. Over the last 15 years, enormous progress has been made in identifying the distinct clinical phenotypes and in studying the basic cellular and genetic mechanisms associated with the primary Mendelian (monogenic) arrhythmia syndromes. Investigation of the electrophysiological consequences of an ion channel mutation is ideally done in the native cardiomyocyte (CM) environment. However, the majority of such studies so far have relied on heterologous expression systems in which single ion channel genes are expressed in non-cardiac cells. In some cases, transgenic mouse models have been generated, but these also have significant shortcomings, primarily related to species differences. The discovery that somatic cells can be reprogrammed to pluripotency as induced pluripotent stem cells (iPSC) has generated much interest since it presents an opportunity to generate patient- and disease-specific cell lines from which normal and diseased human CMs can be obtained These genetically diverse human model systems can be studied in vitro and used to decipher mechanisms of disease and identify strategies and reagents for new therapies. Here, we review the present state of the art with respect to cardiac disease models already generated using IPSC technology and which have been (partially) characterized. Human iPSC (hiPSC) models have been described for the cardiac arrhythmia syndromes, including LQT1, LQT2, LQT3-Brugada Syndrome, LQT8/Timothy syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). In most cases, the hiPSC-derived cardiomyoctes recapitulate the disease phenotype and have already provided opportunities for novel insight into cardiac pathophysiology. It is expected that the lines will be useful in the development of pharmacological agents for the management of these disorders.

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Section: Human Ipsc-cm Models For Inherited Cardiac Arrhythmiassupporting

confidence: 79%

Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias

Hoekstra¹,

Mummery²,

Wilde³

et al. 2012

Front. Physio.

179

148

View full text Add to dashboard Cite

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“…Such knowledge is important for understanding why the I Ks channel malfunctions under pathological conditions (13,14) or when congenital mutations occur to KCNQ1 or KCNE1 (15)(16)(17). This information is also useful for the design of antiarrhythmic agents targeting malfunctioning I Ks channels (18).…”

mentioning

confidence: 99%

Dynamic Partnership between KCNQ1 and KCNE1 and Influence on Cardiac IKs Current Amplitude by KCNE2

Jiang

Wang

et al. 2009

Journal of Biological Chemistry

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Cardiac slow delayed rectifier (I Ks ) channel is composed of KCNQ1 (pore-forming) and KCNE1 (auxiliary) subunits. Although KCNE1 is an obligate I Ks component that confers the uniquely slow gating kinetics, KCNE2 is also expressed in human heart. In vitro experiments suggest that KCNE2 can associate with the KCNQ1-KCNE1 complex to suppress the current amplitude without altering the slow gating kinetics. Our goal here is to test the role of KCNE2 in cardiac I Ks channel function. Pulse-chase experiments in COS-7 cells show that there is a KCNE1 turnover in the KCNQ1-KCNE1 complex, supporting the possibility that KCNE1 in the I Ks channel complex can be substituted by KCNE2 when the latter is available. Biotinylation experiments in COS-7 cells show that although KCNE1 relies on KCNQ1 coassembly for more efficient cell surface expression, KCNE2 can independently traffic to the cell surface, thus becoming available for substituting KCNE1 in the I Ks channel complex. Injecting vesicles carrying KCNE1 or KCNE2 into KCNQ1-expressing oocytes leads to KCNQ1 modulation in the same manner as KCNQ1؉KCNEx (where x ‫؍‬ 1 or 2) cRNA coinjection. Thus, free KCNEx peptides delivered to the cell membrane can associate with existing KCNQ1 channels to modulate their function. Finally, adenovirus-mediated KCNE2 expression in adult guinea pig ventricular myocytes exhibited colocalization with native KCNQ1 protein and reduces the native I Ks current density. We propose that in cardiac myocytes the I Ks current amplitude is under dynamic control by the availability of KCNE2 subunits in the cell membrane.The slow delayed rectifier (I Ks ) channel functions as a "repolarization reserve" in the heart (1). It provides needed outward currents to prevent excessive action potential prolongation when the ␤-adrenergic tone is high or when there is a blockade of the rapid delayed rectifier channel as in acquired long QT syndrome (1). The I Ks channel is composed of a pore-forming component (the KCNQ1 channel, also known as Kv7.1 or KvLQT1) and an auxiliary regulatory component (the KCNE1 subunit, also known as minK or IsK) (2, 3). KCNE1 association with KCNQ1 produces the unique I Ks channel phenotype: very slow activation and deactivation rates and a positive voltage range of activation. There has been a strong interest in understanding how KCNQ1 and KCNE1 interact with each other (4 -12). Such knowledge is important for understanding why the I Ks channel malfunctions under pathological conditions (13,14) or when congenital mutations occur to . This information is also useful for the design of antiarrhythmic agents targeting malfunctioning I Ks channels (18).More KCNE subunits (KCNE2-KCNE5) have been cloned and characterized (19). In heterologous expression systems, each of these new members of the KCNE subfamily can associate with the KCNQ1 channel and confer distinct channel phenotypes (20). KCNE3, like KCNE1, increases KCNQ1 current amplitude, whereas KCNE2, KCNE4, and KCNE5 decrease or abolish KCNQ1 current. KCNE5, like KCNE1, shifts the v...

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“…Genetic testing can additionally direct therapy in LQTS: β-blockers are highly protective in the case of LQT1 patients, moderately protective in LQT2 (Runa et al, 2008) while in LQT3 other agents such as mexiletine, flecainide, ranolazine, or propranolol are indicated (Schwartz et al, 1998; Moss et al, 2005, 2008; Ackerman et al, 2011). Hence, gene-directed therapeutic options are highly significant here.…”

Section: The Role Of Genetic Testingmentioning

confidence: 99%

The investigation of sudden arrhythmic death syndrome (SADS)—the current approach to family screening and the future role of genomics and stem cell technology

Vyas

Lambiase

2013

Front. Physiol.

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SADS is defined as sudden death under the age of 40 years old in the absence of structural heart disease. Family screening studies are able to identify a cause in up to 50% of cases-most commonly long QT syndrome (LQTS), Brugada and early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) using standard clinical screening investigations including pharmacological challenge testing. These diagnoses may be supported by genetic testing which can aid cascade screening and may help guide management. In the current era it is possible to undertake molecular autopsy provided suitable samples of DNA can be obtained from the proband. With the evolution of rapid sequencing techniques it is possible to sequence the whole exome for candidate genes. This major advance offers the opportunity to identify novel causes of lethal arrhythmia but also poses the challenge of managing the volume of data generated and evaluating variants of unknown significance (VUS). The emergence of induced pluripotent stem cell technology could enable evaluation of the electrophysiological relevance of specific ion channel mutations in the proband or their relatives and will potentially enable screening of idiopathic ventricular fibrillation survivors combining genetic and electrophysiological studies in derived myocytes. This also could facilitate the assessment of personalized preventative pharmacological therapies. This review will evaluate the current screening strategies in SADS families, the role of molecular autopsy and genetic testing and the potential applications of molecular and cellular diagnostic strategies on the horizon.

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Therapeutic Strategies for Long-QT Syndrome

Cited by 57 publications

References 47 publications

Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias

Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias

Dynamic Partnership between KCNQ1 and KCNE1 and Influence on Cardiac IKs Current Amplitude by KCNE2

The investigation of sudden arrhythmic death syndrome (SADS)—the current approach to family screening and the future role of genomics and stem cell technology

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