?-Blocker Therapy Failures in Symptomatic Probands with Genotyped Long-QT Syndrome

Abstract

Beta-blocker therapy is one of the principal therapies for congenital long-QT syndrome (LQTS). However, breakthrough cardiac events occur while being treated with beta-blockers. We sought to determine the frequency of and clinical correlates underlying beta-blocker therapy failures in genotyped, symptomatic LQTS probands. The medical records were analyzed only for genotyped LQTS probands who presented with a LQTS-attributable clinical event and were receiving beta-blocker therapy. The study cohort comprised 28 such patients: 18 KCNQ1/KVLQT1(LQT1), 7 KCNH2/HERG (LQT2), and 3 SCN5A (LQT3). The prescribed beta-blocker was atenolol (12), propranolol (10), metoprolol (4), and nadolol (2). Beta-blocker therapy failure was defined as breakthrough cardiac events including syncope, aborted cardiac arrest (ACA), appropriate implantable cardioverter-defibrillator (ICD) therapy, or sudden death occurring while on beta-blocker therapy. During a median follow-up of 46 months, 7/28 (25%) LQTS probands experienced a total of 15 breakthrough cardiac events. Their initial presentation was ACA (3), bradycardia during infancy (2), and syncope (2). The underlying genotype was KVLQT1 (6) and HERG (1). Two breakthroughs were attributed to noncompliance. Of the 13 breakthroughs occurring while compliant, 10 occurred with atenolol and 3 with propranolol (p = 0.03). In this study cohort, one-fourth of genotyped LQTS probands failed beta-blocker therapy. Treatment with atenolol, young age at diagnosis, initial presentation with ACA, KVLQT1 genotype, and noncompliance may be important factors underlying beta-blocker therapy failures.

Genetic and Clinical Advances in Congenital Long QT Syndrome

“…78, 79 Atenolol, not included in the aforementioned study, appears to be less effective, according to a study performed in (only) 28 genotyped patients with a median follow-up of 46 months. 80 Of the 3 major genotypes of LQTS, β-blocker therapy is extremely effective in LQT1 because of the prominent involvement of adrenergic stimulation in its pathogenesis. 11, 70 Pure β-blockers are less effective in LQT2 than LQT1, possibly because of α1A adrenoreceptor-mediated IKr reduction.…”

High Efficacy of β-Blockers in Long-QT Syndrome Type 1

“…We suspect the prevalence of these 2 causes of ␤-blocker failure was similar in prior studies, [3][4][5][6] but an evaluation of their influence on events in the other LQTS genotypes is warranted.…”

“…1,17 He was a previously asymptomatic 9-year-old boy reported as fully compliant on 1.0 mg · kg Ϫ1 · d Ϫ1 atenolol, perhaps a small dose for Jervell, Lange-Nielsen syndrome, and a potentially less effective ␤-blocker. 4 He had been started on propranolol shortly after birth and was switched to atenolol 3 years before his death. Among the 35 noncompliant patients, all 8 fatal or near-fatal events occurred after long-standing withdrawal of ␤-blocker therapy (Ն21 days) despite a ␤-blocker prescription at adequate doses.…”

“…[3][4][5][6] Whether these events are due to inherent limitations of ␤-blocker or avoidable factors is unknown. Implantable cardioverter-defibrillators (ICDs) are being used increasingly in LQTS patients, and these "failures" are used to justify implantation in patients without a cardiac arrest and even as initial therapy, including in children and teenagers in whom ICDs produce many complications [7][8][9][10] and impair quality of life without always preventing sudden death.…”

Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases

“…The values for these variables were obtained from multiple articles (see below) and reviewed by two authors who are clinical experts (Ackerman and Berul). We also drew on data derived from 541 consecutive, unrelated patients who were 17,18 and that 20 years of life were saved for each death averted (based on diagnosis at age 20 and that our study timeframe ends at age 40. Data were not available to estimate quality-adjusted life years saved, although it is highly unlikely these results would have been different).…”