Further Insights into the Effect of Quinidine in Short QT Syndrome Caused by a Mutation in HERG

Wolpert, Christian; Schimpf, Rainer; Giustetto, Carla; Antzelevitch, Charles; Cordeiro, Jonathan M.; Dumaine, Robert; Brugada, Ramón; Hong, Kui; Bauersfeld, Urs; Gaïta, Fiorenzo; Borggrefe, Martin

doi:10.1046/j.1540-8167.2005.04470.x

Cited by 181 publications

(173 citation statements)

References 12 publications

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“…Clinical and biophysical research efforts have enabled the investigation of possible therapeutic interventions, such as quinidine, which was found to improve (prolong) the QT interval in mutation carriers and which is presently recommended in patients who cannot receive a defibrillator or who have received multiple implantable cardioverter-defibrillator (ICD) shocks. 90,95 Metabolism-Sensing ATP-Sensitive K ؉ Channel Variants Heart failure (HF) is a disease with a high prevalence of SCA and arrhythmias. The significance of the sarcolemmal ATPsensitive K ϩ (K ATP ) channel for cardiac protection from HF is indicated by mutations that produce abnormal channel phenotypes with compromised metabolic signaling in patients with inherited cardiomyopathy.…”

Section: Lehnart Et Al Inherited Arrhythmias Nhlbi-ord Consensus Repomentioning

confidence: 99%

“…99 From a therapeutic point of view, the first line of therapy in individuals recovered from SCA or with a history of syncope is the implantation of an ICD. 90 Although some of the class III antiarrhythmic agents appear suitable for SQTS1, 91,95,100 no specific pharmacological treatment for SQTS2 and SQTS3 is yet known. Similar to LQTS, SQTS is a polygenetic disease highlighting the need to characterize each individual form to specifically direct therapeutic approaches.…”

Section: Current Challenges and Important Issues For Future Studiesmentioning

confidence: 99%

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Inherited Arrhythmias

et al. 2007

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Abstract-The National Heart, Lung, and Blood Institute and Office of Rare Diseases at the National Institutes of Health organized a workshop (September 14 to 15, 2006, in Bethesda, Md) to advise on new research directions needed for improved identification and treatment of rare inherited arrhythmias. These included the following: (1) Na ϩ channelopathies; (2) arrhythmias due to K ϩ channel mutations; and (3) arrhythmias due to other inherited arrhythmogenic mechanisms. Another major goal was to provide recommendations to support, enable, or facilitate research to improve future diagnosis and management of inherited arrhythmias. Classifications of electric heart diseases have proved to be exceedingly complex and in many respects contradictory. A new contemporary and rigorous classification of arrhythmogenic cardiomyopathies is proposed. This consensus report provides an important framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular biology and novel therapeutic approaches in cardiology, as well as the introduction of many recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy in consensus with a recent American Heart Association Scientific Statement.

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Section: Lehnart Et Al Inherited Arrhythmias Nhlbi-ord Consensus Repomentioning

confidence: 99%

Section: Current Challenges and Important Issues For Future Studiesmentioning

confidence: 99%

Inherited Arrhythmias

et al. 2007

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“…These distinctions are similar to those reported between SQT1 patients (Ϫ0.54 ms/bpm) and noncarrier controls (Ϫ1.29 ms/bpm. 23 AF is known to be associated with 20% to 30% of Brugada syndrome cases 24 and with a similar or higher fraction of short-QT cases. 25 The high incidence of AF in the present cohort is therefore not unexpected.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

et al. 2007

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Background-Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. Methods and Results-Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca v␤2b ), CACNA2D1 (Ca v␣2␦1 ), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca v 1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals Յ360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the ␣ 1 -and ␤ 2b -subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca v 1.2 channels but normal trafficking of channels containing G490R Ca v 1.2 or S481L Ca v␤2b -subunits. Conclusions-This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals. Key Words: arrhythmia Ⅲ genetics Ⅲ electrophysiology Ⅲ tachycardia Ⅲ fibrillation C ardiac arrhythmias are responsible for an estimated 1 million cases of syncope and sudden cardiac death (SCD) among Europeans and Americans each year. 1 Cardiac arrhythmias can be acquired as a consequence of coronary heart disease or may be secondary to familial or inherited syndromes. The past decade has witnessed an explosion of information linking cardiac ion channel mutations with a wide variety of inherited arrhythmia syndromes. 2 The long-QT syndrome has been associated with 10 different Clinical Perspective p 449genes, in large part owing to the pioneering studies of Keating and coworkers. The LQT8 form of long-QT syndrome, also known as Timothy syndrome, is associated with gain-offunction mutations in cardiac calcium channel activity. 3,4 The cardiac L-type calcium channel is a protein complex formed by at least 3 subunits, ␣ 1 , ␤, and ␣ 2␦ . The pore-forming Ca v 1. subunit, encoded by CACNB2b, modulates calcium channel activity in the human heart and enables trafficking by suppressing an endoplasmic reticulum retention signal in the I-II loop of the ␣ 1 -subunit. 5 The short-QT syndrome (SQTS), a clinical entity first described in 2000,6 has been associated ...

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“…Additionally, quinidine also restored the heart rate dependence of QT interval towards an adaptation range of normal subjects. (26) Although studied extensively, the exact mechanism of its action for now remains incompletely understood. We have to keep in mind, however, that short QT interval can be a consequence of several gain-and loss-of-function mutations.…”

Section: Long Qt Syndromementioning

confidence: 99%

“…While measuring subtle variation in QT interval duration is technically challenging, new methodology (28,29) has enabled investigators to study the effect of disease states on ventricular repolarization variability, and the prognostic value of the QT interval variability measurement. QT variability has been shown to be elevated in congestive heart failure (CHF) (28), ischemia (31), and some types of hypertrophic cardiomyopathy (26). Increased QT variability was also found to predict appropriate implantable cardioverter-defibrillator shocks in the MADIT-II (Multicenter Automatic Defibrillator Implantation Trial-II) study (33), as well as total mortality and sudden death in post-myocardial infarction patients without implantable cardioverter-defibrillators (34).…”

Section: Clinical Applicationmentioning

confidence: 99%