25th anniversary of the International Long-QT Syndrome Registry: an ongoing quest to uncover the secrets of long-QT syndrome.

Cardiology Unit of the Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Circulation (Impact Factor: 14.95). 04/2005; 111(9):1199-201. DOI: 10.1161/01.CIR.0000157069.91834.DA
Source: PubMed

ABSTRACT oday, it is exceptional to find a major cardiology con- gress without a session devoted to the long-QT syndrome (LQTS), but it was quite different 25 years ago when the minuscule knowledge about LQTS was paralleled only by the minute number of investigators interested in what seemed to be little more than a medical oddity. Partly by chance, the two of us had actually and independently developed a rather burning interest and curiosity for this often lethal hereditary disorder that is spiced by several unique features. 1-4 We joined forces with the goal of unraveling this mysterious disease by establishing a prospective International Registry for LQTS. The main objectives were those to gain insight into the natural history, clinical course, and efficacy of current and novel therapies. When molecular biology techniques matured to the point of making possible the identification of disease- causing genes and disease-causing mutations, what became essential was the availability of numerous and well- developed clinical pedigrees providing clear separation be- tween "affected" and "nonaffected" individuals. This is what the Registry was able to provide and where it played a decisive role in sharing with molecular biologists the ideal material for their analysis. In 1979, when the Registry was established, it did not escape us that this long-term project was likely to contribute to a better understanding and management of LQTS. Quite frankly, however, we did not anticipate the explosion of knowledge that would result from the genetic and molecular findings of the 1990s and the central role that the Registry, with its well-defined clinical phenotypes and family pedi- grees, would play in uncovering the secrets of this disorder. Additionally, we could not have fathomed the now clear evidence that LQTS indeed represents a paradigm for the understanding of sudden cardiac death in more common cardiac diseases. Objectives Our primary objective with the International LQTS Registry was to gain insight into the natural history and clinical course of this hereditary repolarization disorder so that more effec- tive therapy could be rendered to prevent the syncope and sudden death events that frequently accompanied LQTS. Impact The International LQTS Registry has enhanced our knowl- edge base of an infrequently occurring cardiac disorder, and it has become a paradigm for studying such conditions. The diagnostic criteria for LQTS have been established.5 The cardiologists associated with the Registry continue to offer physicians from around the world an opportunity to obtain advice on how to manage their LQTS patients. This exchange between the Registry cardiologists and physicians became a mutually beneficial interaction because these physicians also contributed clinical data to the Registry by willingly com- pleting enrollment and yearly follow-up data forms. This approach allowed us to gather information on an impressive number of patients and, of crucial importance for the subse- quent genetic developments, on first- and second-degree family relatives. Over the years, the growing knowledge in LQTS was shared with the profession through scientific publications, chapters in cardiology textbooks, personal com- munications, and recently, an Internet-based virtual LQTS symposium ( Subsequently, similar types of registries were established by interested investigators for other uncommon cardiac dis- orders, including hypertrophic cardiomyopathy, arrhythmo- genic right ventricular cardiomyopathy, and Brugada syn- drome. It is gratifying to know that the International LQTS Registry helped to pave the way for scientific progress in the difficult field of uncommon diseases.

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    ABSTRACT: The long QT syndrome (LQTS) is a rare hereditary disorder in which affected individuals have a possibility of ventricular tachyarrhythmia and sudden cardiac death. We investigated 62 LQTS (QTc ≥ 0.47 sec) and 19 family members whose genetic study revealed mutation of LQT gene. In the proband group, the modes of presentation were ECG abnormality (38.7%), aborted cardiac arrest (24.2%), and syncope or seizure (19.4%). Median age of initial symptom development was 10.5 yr. Genetic studies were performed in 61; and mutations were found in 40 cases (KCNQ1 in 19, KCNH2 in 10, SCN5A in 7, KCNJ2 in 3, and CACNA1C in 1). In the family group, the penetrance of LQT gene mutation was 57.9%. QTc was longer as patients had the history of syncope (P = 0.001), ventricular tachycardia (P = 0.017) and aborted arrest (P = 0.010). QTc longer than 0.508 sec could be a cut-off value for major cardiac events (sensitivity 0.806, specificity 0.600). Beta-blocker was frequently applied for treatment and had significant effects on reducing QTc (P = 0.007). Implantable cardioverter defibrillators were applied in 6 patients. Congenital LQTS is a potentially lethal disease. It shows various genetic mutations with low penetrance in Korean patients.
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    ABSTRACT: Long-QT syndrome mutations can cause syncope and sudden death by prolonging the cardiac action potential (AP). Ion channels affected by mutations are various, and the influences of cellular calcium cycling on LQTS cardiac events are unknown. To better understand LQTS arrhythmias, we performed current-clamp and intracellular calcium ([Ca2+]i) measurements on cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPS-CM). In myocytes carrying an LQT2 mutation (HERG-A422T), APs and [Ca2+]i transients were prolonged in parallel. APs were abbreviated by nifedipine exposure and further lengthened upon releasing intracellularly stored Ca2+. Validating this model, control iPS-CM treated with HERG-blocking drugs recapitulated the LQT2 phenotype. In LQT3 iPS-CM, expressing NaV1.5-N406K, APs and [Ca2+]i transients were markedly prolonged. AP prolongation was sensitive to tetrodotoxin and to inhibiting Na+-Ca2+ exchange. These results suggest that LQTS mutations act partly on cytosolic Ca2+ cycling, potentially providing a basis for functionally targeted interventions regardless of the specific mutation site.
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