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Advances in Arrhythmia and Electrophysiology

Therapeutic Strategies for Long-QT Syndrome

Does the Molecular Substrate Matter?

Yanfei Ruan, MD; Nian Liu, MD; Carlo Napolitano, MD, PhD and Silvia G. Priori, MD, PhD

From the Molecular Cardiology Fondazione Salvatore Maugeri (Y.R., N.L., C.N., S.G.P.), Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; and the Leon H. Charney Division of Cardiology (Y.R., N.L., S.G.P.), New York University School of Medicine New York, NY

Correspondence to Silvia G. Priori, MD, PhD, Molecular Cardiology, IRCCS Fondazione Maugeri, Via Maugeri 10/10A, 27100 Pavia, Italy. E-mail spriori@fsm.it

Key Words: death, sudden • heart arrest • genetics • long-QT syndrome • tachyarrhythmias

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
The discovery of genetic defects underlying long-QT syndrome (LQTS) has allowed to identify important genotype-phenotype correlations that are now being used for risk stratification. The next challenge is to exploit the new information on the pathophysiology of the disease derived from molecular genetics to devise more effective therapies. The successful response of LQT1 patients to β-blockers, the QT-shortening action of sodium channel blockers in at least some LQT3 patients, and the importance of maintaining adequate plasma potassium levels in LQT2 patients clearly demonstrate the importance of selecting therapy in the context of the molecular substrate.

The hurdles on the road toward the development of novel therapeutic strategies are represented by the variable expressivity of the disease, the high prevalence of "private" mutations, and the role of genetic and nongenetic factors that act as modifiers of the phenotype. Given the large number of mutations identified and their phenotypic complexity, it is clearly impossible to anticipate a scenario in which each mutation will be managed through a specific therapy. However, the evidence that mutations in the LQTS gene may be clustered based on their electrophysiological profile and on their response to specific drugs may provide the rationale for the development of mutation-specific therapies.

In this article, we will review the most relevant genotype-phenotype features of LQTS and the strategies explored to develop novel therapeutic approaches.

	LQTS: An Increasingly Complex Scenario

 
Definition and Prevalence
The congenital LQTS is an inherited arrhythmogenic disease characterized by abnormally prolonged QT interval leading to life-threatening arrhythmias in the presence of a structurally normal heart.¹ Different . . . [Full Text of this Article]

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