Arthur A.M. Wilde

A calcium sensor in the sodium channel modulates cardiac excitability

Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal ‘IQ’ domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation—a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.

Unmasking of Brugada Syndrome by Lithium

Background—The characteristic ECG pattern of ST-segment elevation in V1 and V2 in the Brugada syndrome is dynamic; it is often intermittently present in affected individuals and can be unmasked by sodium channel blockers, including antiarrhythmic drugs and tricyclic antidepressants. We report here 2 patients who developed the Brugada ECG pattern after administration of lithium, a commonly used drug not previously reported to block cardiac sodium channels. Methods and Results—Lithium induced transient ST-segment elevation (type 1 Brugada pattern) in right precordial leads at therapeutic concentrations in 2 patients with bipolar disorder. Lithium withdrawal in the patients resulted in reversion to type 2 or 3 Brugada patterns or resolution of ST-T abnormalities. In Chinese hamster ovary cells transfected with SCN5A, which encodes the cardiac sodium channel, lithium chloride caused concentration-dependent block of peak INa at levels well below the therapeutic range (IC50 of 6.8±0.4 &mgr;mol/L). Conclusions—The widely used drug lithium is a potent blocker of cardiac sodium channels and may unmask patients with the Brugada syndrome.

Predicting the Long-QT Genotype From Clinical Data From Sense to Science

In the past 3 decades, the congenital long-QT syndrome (LQTS) has emerged as an important paradigm for understanding arrhythmogenesis. An understanding of the electrophysiological basis of arrhythmias in LQTS has now merged with new molecular genetics, solving some problems and raising new ones both in clinical management and in basic arrhythmia mechanisms (for review, see Roden and Spooner1 ). In this scientific evolution, the international LQT registry has proved to be of paramount importance. Since 1979, data from this registry have proved to be of great value for the diagnosis, prognosis, and management of LQT patients and their relatives, and in more recent years, data from the registry represent a reliable source for attempts to correlate phenotype with genotype and vice versa. We now understand that LQTS can arise as a result of mutations in multiple genes, each encoding an ion channel structural unit. Because ion channels have different time and voltage characteristics, it is tempting to speculate that the clinical presentation may be gene specific, and indeed emerging data support this idea (Table⇓). Phenotypical differences in genetically distinct forms of LQTS may include every aspect of the clinical presentation, ie, the ECG appearance of the ST-T–wave patterns and arrhythmias, symptoms that trigger arrhythmias, QT dynamics during exercise or other triggers, efficacy of different treatment modalities, and the clinical course of affected patients (Table⇓). View this table: Table 1. Clinical Characteristics in Common Forms of LQTS A gene-differentiating potential has indeed been shown for symptom-related triggers: swimming and acoustic stimuli typically trigger events in LQT1 and LQT2 patients, respectively.2 3 4 5 QT dynamics during exercise vary between genotypes,6 7 and data from the registry have suggested that the clinical course (age of onset, prognosis, etc) relies to some extent on the underlying gene defect.8 Finally, gene-specific ST-T …