Background—It is still currently held that most patients affected by the long-QT syndrome (LQTS) show QT interval prolongation or clinical symptoms. This is reflected by the assumption in linkage studies of a penetrance of 90%. We had previously suggested that a larger-than-anticipated number of LQTS patients might be affected without showing clinical signs. We have now exploited the availability of molecular diagnosis to test this hypothesis. Methods and Results—We identified 9 families with “sporadic” cases of LQTS, ie, families in which, besides the proband, none of the family members had clinical signs of the disease. Mutation screening by conventional single-strand conformational polymorphism and sequencing was performed on DNA of probands and family members to identify mutation carriers. Of 46 family members considered on clinical grounds to be nonaffected, 15 (33%) were found instead to be gene carriers. Penetrance was found to be 25%. In these families, conventional clinical diagnostic criteria ha...

Low Penetrance in the Long-QT Syndrome Clinical Impact

Assessment of proarrhythmic toxicity of newly developed drugs attracts significant attention from drug developers and regulatory agencies. Although no guidelines exist for such assessment, the present experience allows several key suggestions to be made and an appropriate technology to be proposed. Several different in vitro and in vitro preclinical models exist that, in many instances, correctly predict the clinical outcome. However, the correspondence between different preclinical models is not absolute. None of the available models has been demonstrated to be more predictive and/or superior to others. Generally, compounds that do not generate any adverse preclinical signal are less likely to lead to cardiac toxicity in humans. Nevertheless, differences in likelihood offer no guarantee compared with entities with a preclinical signal. Thus, the preclinical investigations lead to probabilistic answers with the possibility of both false positive and false negative findings. Clinical assessment of drug-induced QT interval prolongation is crucially dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. An integral part of this is a precise heart rate correction of QT interval, which has been shown to require the assessment of QT/RR relationship in each study individual. The numbers of electrocardiograms required for such an assessment are larger than usually obtained in pharmacokinetic studies. Thus, cardiac safety considerations need to be an integral part of early phase I/II studies. Once proarrhythmic safety has been established in phase I/II studies, large phase III studies and postmarketing surveillance can be limited to less strict designs. The incidence of torsade de pointes tachycardia varies from 1 to 5% with clearly proarrhythmic drugs (e.g. quinidine) to 1 in hundreds of thousands with drugs that are still considered unsafe (e.g. terfenadine, cisapride). Thus, not recording any torsade de pointes tachycardia during large phase III studies offers no guarantee, and the clinical premarketing evaluation has to rely on the assessment of QT interval changes. However, since QT interval prolongation is only an indirect surrogate of predisposition to the induction of torsade de pointes tachycardia, any conclusion that a drug is safe should be reserved until postmarketing surveillance data are reviewed. The area of drug-related cardiac proarrhythmic toxicity is fast evolving. The academic perspective includes identification of markers more focused compared with simple QT interval measurement, as well as identification of individuals with an increased risk of torsade de pointes. The regulatory perspective includes careful adaptation of new research findings.

Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling.

Impaired endothelial function following a meal rich in used cooking fat.

Recommendations for the Use of Genetic Testing in the Clinical Evaluation of Inherited Cardiac Arrhythmias Associated with Sudden Cardiac Death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Paper

The Jervell and Lange-Nielsen (JLN) syndrome affects the human cardioauditory system, associating a profound bilateral deafness with an abnormally long QT interval on the ECG. It results from mutations in KVLQT1 and ISK genes that encode the 2 subunits forming the K+ channel responsible for the cardiac and inner ear slowly activating component of the delayed rectifier K+ current (IKs). A JLN mouse model that presents typical inner ear defects has been created by knocking out the isk gene (isk-/-). This study specifically reports on the cardiac phenotype counterpart, determined in the whole animal and at mRNAs and cellular levels. Surface ECG recordings of isk-/- mice showed a longer QT interval at slow heart rates, a paradoxical shorter QT interval at fast heart rates, and an overall exacerbated QT-heart rate adaptation compared with wild-type (WT) mice. A 300-ms increase in the heart rate cycle length induces a 309+/-21% increase in the QT duration of the WT mice versus a 500+/-50% in isk-/- mice (P<0.001). It is concluded that the isk gene product and/or IKs, when present, blunts the QT adaptation to heart rate variations and that steeper QT-RR relationships reflect a greater susceptibility to arrhythmias in patients lacking IKs.

Involvement of IsK-Associated K+ Channel in Heart Rate Control of Repolarization in a Murine Engineered Model of Jervell and Lange-Nielsen Syndrome

Aims The long QT syndrome is mainly defined by QT interval prolongation (QTc >0·44s). However, data obtained in genotyped patients showed that resting QTc measurement alone may be inaccurate for ascertaining the phenotype. The aim of this study was to evaluate the diagnostic performance of QT interval rate-dependence in untreated chromosome 11-linked patients. Methods The study population consisted of 25 untreated long QT patients linked to chromosome 11 and 25 age- and gender-matched controls. QTc intervals were measured on 12-lead resting ECG recordings. From 24-h Holter recordings, the slope of the relationship between ventricular repolarization and heart rate was studied separately day and night to assess neural modulation. Mean heart rates and rate-dependences of QT and Q-maximum of T (QTm) intervals were compared between long QT patients and controls for both time periods.

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N. Menhabi

Papers

Diagnostic performance of QT interval variables from 24-h electrocardiography in the long QT syndrome