Long QT Syndrome Patients With Mutations of the SCN5A and HERG Genes Have Differential Responses to Na ⁺ Channel Blockade and to Increases in Heart Rate

Abstract

This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. These findings also suggest that LQT3 patients may be more likely to benefit from Na+ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates. Conversely, LQT2 patients may be at higher risk to develop syncope under stressful conditions because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval when heart rate increases.

The congenital long QT syndromes from genotype to phenotype: clinical implications

“…Clearly, they are not as well protected by b-blocker therapy as patients with the other two forms of LQTS. In 1995, we made the unexpected observation that at low heart rates LQT3 patients seem to have excessive further prolongation of already long QT intervals [38]. This finding was followed by the observation that, during the night when heart rate decreases, QTc is prolonged even further [39].…”

“…within 1 month from the identification in LQTS patients of mutations in SCN5A, the cardiac Na + channel gene, we attempted to shorten the QT interval in LQT3 patients by using the Na + channel blocker mexiletine [38,40]. The rationale for this approach was strengthened by the evidence that most SCN5A mutations increase a late Na + inward current [41,42], that this delayed inactivation can be antagonized by mexiletine [42], and that in the first experimental model for LQT2 and for LQT3 mexiletine effectively counteracts the action potential prolongation produced by interventions mimicking the effects mutations on SCN5A [43].…”

Pharmacological approach to the treatment of long and short QT syndromes

“…LQT2 patients are able to achieve maximal heart rate and changes in QT interval are negligible (Swan et al, 1999;Takenaka et al, 2003). In contrast, patients with LQT3 have a normal physiological response to exercise and abbreviate their QT interval below baseline values (Schwartz et al, 1995).…”

“…So, it is intuitive that blockade of I Na might be of therapeutic benefit, especially in this subtype of LQTS. Schwartz et al (1995) was first to report genotype-specific treatment in LQTS with mexiletine, a class IB sodium channel blocker which blocks the late I Na current and hence abbreviates the QT interval in LQT3 patients. While the benefits of Class IB agents are clearly apparent in experimental models of LQT3, data from studies utilizing the perfused-wedge preparation indicate that mexiletine is also effective in abbreviating the TDR and suppressing TdP in LQT1 and LQT2 models (Fig.…”

“…Abbreviation of QT interval with exercise is most pronounced in LQT3 as compared to LQT1 and LQT2 because of the steeper QT-RR relationship (Schwartz et al, 1995;Shimizu & Antzelevitch, 1997. Moreover, LQT3 patients are at highest risk of TdP when heart rate is slow.…”