β-Blocker Therapy Failures in Symptomatic Probands with Genotyped Long-QT Syndrome
- First Online:
- Cite this article as:
- Chatrath, R., Bell, C.M. & Ackerman, M.J. Pediatr Cardiol (2004) 25: 459. doi:10.1007/s00246-003-0567-3
- 207 Views
β-Blocker therapy is one of the principal therapies for congenital long-QT syndrome (LQTS). However, breakthrough cardiac events occur while being treated with β-blockers. We sought to determine the frequency of and clinical correlates underlying β-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 β-blocker therapy. The study cohort comprised 28 such patients: 18 KCNQ1/KVLQT1(LQT1), 7 KCNH2/HERG (LQT2), and 3 SCN5A (LQT3). The prescribed β-blocker was atenolol (12), propranolol (10), metoprolol (4), and nadolol (2). β-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 β-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 β-blocker therapy. Treatment with atenolol, young age at diagnosis, initial presentation with ACA, KVLQT1 genotype, and noncompliance may be important factors underlying β-blocker therapy failures.
KeywordsLong QT syndromeDrugsRisk factorsBeta-blockers
Congenital long-QT syndrome (LQTS) is an inherited “channelopathy” that may manifest clinically as syncope, seizures, aborted cardiac arrest, or death. Approximately two-thirds of congenital LQTS is due to mutations scattered among five genes encoding cardiac ion channel subunits: KCNQ1/KVLQT1 (LQT1), KCNH2/HERG (LQT2), SCN5A (LQT3), KCNE1/minK (LQT5), and KCNE2/MiRP1 (LQT6). Left untreated, the mortality rate may be as high as 50% within 10 years . β-Blocker therapy remains the primary drug therapy for LQTS. Ward  in 1964 reported the beneficial effect of β-blockers while treating his first patient with LQTS. In 1975, Schwartz et al.  observed a dramatic response to β-blockers in 203 symptomatic LQTS patients. Here, the mortality decreased from 73% to 6% after initiation of β-blocker therapy. Subsequent studies [6, 8] confirmed the general efficacy of β-blockers in LQTS. However, in nearly 20–25% of patients, β-blockers are not protective, as these patients continue to have recurrent breakthrough cardiac events .
In a large study on the efficacy of β-blocker therapy in congenital LQTS, Moss and colleagues found that β-blocker therapy resulted in a major reduction in cardiac events . Despite an overall reduction in cardiac events, 32% of previously symptomatic patients experienced a breakthrough cardiac event while receiving β-blocker therapy. Risk factors for breakthrough cardiac events included history of syncope or aborted cardiac arrest (ACA) and diagnosis prior to 10 years of age . With this high degree of β-blocker failure, β-blocker therapy in these high-risk LQTS patients may not provide adequate protection from sudden cardiac death (SCD).
In general, all β-blockers have been considered equally efficacious in LQTS with most patients treated with atenolol, propranolol, metoprolol, or nadolol. In fact, Moss et al.  did not detect a difference in efficacy among these four different β-blockers. Importantly, however, this large study included asymptomatic, genotype-positive individuals. It is well known that 40% of LQTS patients are destined for asymptomatic longevity, perhaps without any interventions whatsoever including β-blocker therapy. Because of this, inclusion of asymptomatic subjects might obscure a difference in the efficacy among different β-blockers. For this reason, we elected to analyze the response to β-blocker therapy only in genotyped LQTS probands who by definition presented due to symptoms attributable to LQTS.
With the availability of genotyping and therapeutic advances such as implantable cardioverter-defibrillators (ICD) therapy, it is important to determine the factors underlying failure of β-blocker therapy in LQTS patients so that future recurrence of cardiac events can be prevented. Therefore, we sought to determine possible reasons underlying failure of β-blocker therapy in symptomatic probands with genotyped LQTS, including genotype, initial presentation, type and dosing of β-blocker used, presence of concomitant QT-prolonging drugs, and compliance.
The study cohort was selected from the patients seen and evaluated at a single institution’s LQTS clinic and restricted to genotyped LQTS probands who presented with symptoms attributable to LQTS and who were receiving β-blocker therapy. By definition, LQTS probands without an established genotype (approximately 25%) and genotype-positive, asymptomatic family members were excluded. Although mutational analysis is ongoing for over 450 symptomatic probands with a suspected channelopathy, this retrospective analysis was confined to those symptomatic probands who were receiving their primary LQTS care from this clinic. Patients seeking only a second opinion clinical evaluation and genetic testing were excluded. Informed consent was obtained for genotyping from each proband, and the study was reviewed and approved by the Institutional Review Board of the Mayo Foundation. Medical records were reviewed retrospectively and an up-to-date follow-up was obtained. The information retrieved from the records included age at diagnosis, sex, maximum and baseline QTc, genotype, initial presentation, the type of β-blocker prescribed and its total dose and dosing schedule, use of concomitant QT-prolonging drugs, compliance, and combination therapy with pacemakers or ICDs.
Follow-up visits were reviewed for breakthrough cardiac events and possible β-blocker therapy failure. A β-blocker therapy failure was defined as a breakthrough cardiac event, including syncope, aborted cardiac arrest (ACA), appropriate ICD therapy or sudden death occurring while on a β-blocker. By definition, a clinical event was required to constitute a “breakthrough,” and thus Holter recordings of asymptomatic, nonsustained ventricular tachycardia were excluded. The number and type of a breakthrough cardiac events were recorded, as were the changes made in therapeutic management after the event.
The presence or absence of a breakthrough cardiac event with respect to genotype, initial presentation, and β-blocker was determined by using the Fisher exact test. A p value < 0.05 was considered statistically significant. A univariate analysis was done to define any risk factors such as age at diagnosis, sex, QTc, and initial presentation as ACA that might predispose to occurrence of a breakthrough cardiac event. The period of time free from breakthrough after initiating β-blocker therapy was determined by Kaplan-Meier analysis.
Probands with Apparent β-Blocker Therapy Failure
Clinical profile of patients with breakthrough cardiac events
Age at diagnosis
Max QTc (ms)
Event at diagnosis
Changes after breakthrough events (s)
Follow-up since last event (mo)
Total dose (mg/kg/d)
4 (2 Propranolol 2 Atenolol)
3 Syncope 1 ACA
Atenolol ICD Nadolol
5 (1 Propranolol 4 Atenolol)
1 Syncope 4 ACA-ICD therapy
Atenolol ICD Propranolol
2 (2 Atenolol)
2 ACA-ICD therapy
Initial β-blocker therapy with respect to genotype of study cohort
Of the 7 probands experiencing a β-blocker therapy failure, 4 initially had a breakthrough cardiac event on atenolol and 3 on propranolol (p = NS). Of the 15 cardiac events, 2 can be attributed to patient-admitted noncompliance (1 on propranolol and 1 on atenolol). No patient was receiving concomitant QT-prolonging drugs. Of the remaining “true or compliant” β-blocker therapy failures (n = 13 cardiac events), 10 occurred on atenolol and 3 on propranolol (p = 0.03). Atenolol was replaced with nadolol in 2, metoprolol in 1, and propranolol in 1, and the dose of current β-blocker was increased in 3. The mean duration of follow-up for these 7 patients without any further breakthrough cardiac events was 46.9 ± 18.4 months (range 24–73 months).
Probands with Multiple Breakthrough Events
Multiple breakthrough cardiac events were observed in 3 of the 7 patients who failed β-blocker therapy. One such patient (case 1, Table 1) had presented within the first week of life with bradycardia and recurrent apneic spells. Her initial two syncopal breakthrough events occurred during treatment with propranolol at 14 months and 5 years of age. After 9 symptom-free years, propranolol was changed to atenolol, due to depression and fatigue at age 15. Within a month following the switch to atenolol, she presented with ACA requiring in-the-field external defibrillation by first responders. An ICD was placed and the dose of atenolol was increased from 1 to 1.25 mg/kg/day. Despite these changes, she experienced a breakthrough syncopal event and was subsequently placed on nadolol and has remained event free these past 12 months. Another patient (case 4, Table 1) experienced a total of 5 breakthrough cardiac events. The first event (syncope with seizures) occurred on propranolol therapy that was then replaced by atenolol. Because of this β-blocker therapy failure and her resting QTc (600 ms), she also received an ICD. Subsequently, she experienced 4 appropriate ICD therapies for torsades while on atenolol despite an exercise stress test demonstrating a significant decrease in maximum heart rate (data not shown). Her β-blocker therapy was switched back to propranolol and she has remained event free for nearly 2 years. Case 6 received two appropriate ICD therapies for torsades while on atenolol. The dose of atenolol was increased from 50 to 100 mg QD in her case, and she has not had any events for the last 20 months.
Similar to previous studies [7, 10], we observed that 25% of symptomatic probands with genotyped LQTS experienced a breakthrough cardiac event while receiving β-blocker therapy. Statistically, these breakthrough events occurred more commonly in those probands presenting with LQTS symptoms early in life and during atenolol therapy. In addition, the majority of the probands with a β-blocker therapy failure were LQT1 genotype, and 60% of the probands presenting with ACA subsequently experienced a breakthrough cardiac event.
Sympathetic Imbalance and Mechanism of β-Blockers in LQTS
β-Blockers represent first-line therapy among the currently available options for congenital LQTS. This therapeutic strategy has been based primarily on exquisite sensitivity of LQTS patients to β-adrenergic-stimulating factors such as physical and emotional stress. The precise cellular mechanism of β-blockers in prevention of arrhythmias in LQTS is not well defined. β-Blockers may attenuate the β-adrenergic receptor-mediated enhancement of L-type calcium channels, hence restoring the balance of ion channel forces involved in generating arrhythmias . Propranolol has been shown to either decrease or prevent an increase in transmural dispersion of repolarization in response to strong sympathetic stimulation, thereby exerting its antiarrhythmic effect. Clinical studies [12, 13] involving LQTS patients have found propranolol to be effective in suppressing repolarization abnormalities during sympathetic stimulation with epinephrine.
Aborted Cardiac Arrest and β-Blocker Therapy Failures
In the study from the International LQTS Registry  involving 869 patients, β-blockers were associated with a significant decrease in cardiac events. Of the 869 patients, there were 581 probands and 288 affected family members. Interestingly, 32% of the patients who were symptomatic before starting β-blockers experienced recurrent cardiac events within the next 5 years. Furthermore, 14% of the patients who presented with ACA as their initial event were likely to have another cardiac arrest within 5 years after initiating β-blockers, with half of these occurring within the first 6 months .
Similar to these observations from the International LQTS Registry , our single-institution clinical experience with LQTS also implicated presentation with ACA as a risk factor for subsequent breakthrough cardiac events on β-blockers. Sixty percent of the probands presenting with ACA had a subsequent documented β-blocker therapy failure, including 2 who received an appropriate ICD therapy while on atenolol. Three of the 7 probands who had a breakthrough cardiac event on β-blockers had presented with ACA as their initial event. Also, we observed that probands who failed β-blocker therapy were younger at the time of diagnosis as compared to those who did not.
Genotype and β-Blocker Therapy Failures
Understanding the molecular basis for LQTS has enabled important genotype–phenotype correlations, gene-specific arrhythmic triggers, and gene-specific responses to epinephrine to emerge [2, 3, 10]. Data from the International LQTS Registry  suggests that the frequency of cardiac events such as syncope, ACA, or sudden death is significantly higher in patients with LQT1 (63%) or LQT2 (46%) than in those with LQT3 (18%). The cumulative mortality through the age of 40 years was similar in all genotypes, but the lethality per cardiac event was highest in LQT3 . In a study  evaluating the genotype–phenotype correlations in LQTS, of the 162 LQT1 patients treated with β-blockers, 31 (19%) had recurrences, including 7 cardiac arrests or sudden death. On β-blockers, there were significantly fewer recurrences in patients with LQT1 compared to those with LQT2 or LQT3 . However, the β-blockers used in these patients were not specified.
Our study indicates that the majority (6 of 7) of β-blocker therapy failures occurred in LQT1 patients, although this did not achieve a statistical significance. Of the 18 LQT1 patients, 6 (33%) experienced a breakthrough event while on β-blocker therapy, compared to 14% (1/7) LQT2 probands. In addition, 4 LQT1 probands have experienced aborted cardiac arrest requiring external defibrillation or appropriate ICD therapy while on β-blocker therapy.
In contrast, Vincent et al.  have presented an abstract detailing the effectiveness of β-blocker therapy in a cohort of 124 LQT1 patients. In this study , only 65% of patients were symptomatic and the β-blocker therapy failures were mostly attributed to noncompliance or presence of concomitant QT-prolonging drugs. Previously, Itoh et al.  studied 18 LQTS patients (13 with LQT1 and 5 with LQT2), and showed that patients with LQT1 responded better to β-blockers than those with LQT2. In their cohort, 12 of 13 with LQT1 responded to β-blocker, vs 1 of 5 with LQT2 (p = 0.0077). Patients who did not have any syncopal episode during the follow-up period of 7.2 ± 4.8 years were considered responders. The majority (72%) of the patients were taking propranolol. Of the remaining five, 3 were taking atenolol, 1 bisoprolol, and 1 carteolol. In this study , due to the small sample size and most patients on propranolol, efficacy of various β-blockers could not be compared.
Shimizu et al.  studied the effects of β-adrenergic agonists and antagonists in LQT1, LQT2, and LQT3 canine pharmacologic models and observed that propranolol completely suppressed the development of torsades in LQT1 model, largely suppressed it in LQT2, but was capable of inducing torsades in LQT3. In fact, these data suggested that isoproterenol, a β-agonist, may play a protective role in LQT3 and that β-blockade may in fact be proarrhythmic in this subset of LQTS patients. In the largest study to date regarding β-blocker therapy in congenital LQTS, Moss et al.  did not demonstrate a protective effect of β-blockers in LQT3 consistent with this in vitro model. Our study contained only 3 patients with LQT3.
Are All β-Blockers Equally Protective in LQTS?
Perhaps, the disparities between LQTS genotype and response to β-blockers described previously can be attributed to different practices with respect to type of β-blocker used by the various centers for the treatment of LQTS. It is widely viewed that all β-blockers are equally effective. Hence, physicians typically choose atenolol, propranolol, nadolol, or metoprolol and make “lateral” substitutions if/when side effects become an issue. No studies to date have called into question the uniform efficacy between the various β-blockers. In fact, Moss and colleagues  did not observe a difference in the apparent efficacy among these four β-blockers. However, over one-third of their study subjects included genotype-positive, asymptomatic individuals, who may remain asymptomatic without any therapy. Inclusion of such asymptomatic patients may mask detection of a less effective β-blocker.
In our study, a significantly greater number of breakthrough cardiac events was seen during treatment with atenolol compared to propranolol. While 2 of the 15 breakthrough events were attributed to patient-acknowledged noncompliance, 10 of the remaining 13 events occurred during β-blocker therapy with atenolol, including 8 ACA/appropriate ICD therapies in 4 probands. Previously, Dorostkar and colleagues evaluated the efficacy of combination β-blocker therapy and continuous pacing in 37 patients with LQTS and found that 8 (22%) medically compliant patients experienced syncope or aborted cardiac arrest during concomitant pacing therapy . Interestingly, although not commented on during their study, 5 of these 8 patients (62%) were taking atenolol.
Practical Considerations for the Practicing Clinician
Based on the observations from the International LQTS Registry and this study reflecting a single institution’s experience with LQTS, we agree with the recommendation for secondary prevention ICD therapy for individuals presenting with aborted cardiac arrest or resuscitated sudden cardiac death. More important perhaps, this study sounds a cautionary note regarding the primary medical therapy of LQTS with β-blockers. There is concern that perhaps all β-blockers are not equally protective in LQTS and therefore should not be viewed as equivalent choices.
While prescribing β-blockers for LQTS, it is important to consider the total dose, dosing schedule, and adverse effects. While propranolol and nadolol are nonselective β-blockers (block β1- and β2-receptors as well as some α-blockade), atenolol and metoprolol are relatively cardioselective β1-blockers. Propranolol is well absorbed orally but has a low bioavailability due to high first-pass metabolism in the liver. Unless long-acting preparations are used, the short plasma half-life of propranolol (3–5 h) requires frequent dosing (tid to qid) to keep up therapeutic levels. Lipid solubility of propranolol causes side effects involving the central nervous system, such as depression.
On the other hand, atenolol is perhaps one of the best-tolerated β-blockers, with fewer neuropsychiatric side effects likely secondary to its lower lipid solubility and decreased blood–brain barrier penetration. In addition, atenolol is frequently prescribed just once a day, because of its longer plasma half-life (6–9 h). Probably due to the above reasons, atenolol is becoming more popular than propranolol for treatment of LQTS.
However, this study suggests that atenolol may not be sufficiently protective for the treatment of LQTS. In particular, we are concerned about the typical practice of once-a-day dosing. Interestingly, we observed that most of the patients who had a breakthrough cardiac event on atenolol were receiving it once a day. It may be that this recommended dosing schedule is inadequate from a pharmacokinetic standpoint to achieve adequate steady-state levels throughout the day. At a minimum, we recommend twice-a-day dosing of atenolol if chosen.
Indeed, regardless of the chosen β-blocker, there is marked interindividual variation in the metabolism of β-blockers and therefore equally effective oral doses may vary considerably. Trough and peak levels of propranolol can be determined, but the clinical utility is unclear. Exercise stress testing to demonstrate blunting of the chronotropic response to maximum exercise may be a reasonable surrogate for the assessment of adequate β-blockade. Unfortunately, at least one patient with appropriate ICD therapies while on atenolol displayed such a blunted response in this study. Recently, assays for CYP2D6 genotype which encodes one of the principal cytochrome P450 enzymes involved in the metabolism of β-blockers have become available. Perhaps, some of the patients with multiple breakthrough events are “rapid metabolizers.”
For asymptomatic patients, prophylactic treatment with atenolol is likely adequate, but perhaps no therapy for a significant number of genotype-positive, asymptomatic individuals is equally protective. A large randomized study involving atenolol vs other β-blocker vs no β-blocker therapy in genotype-positive, asymptomatic individuals is needed to discern how best to treat this ever-growing subset of LQTS. However, because the propensity for atenolol breakthroughs seen here may stem from fundamental differences in the β-blocker rather than simply suboptimal dosing regimens, we are concerned about the use of atenolol β-blocker therapy in symptomatic patients.
The major limitation of our study is the small size of the study cohort, related to our preselected population of only symptomatic probands with genotyped LQTS for the reasons previously outlined. The statistical analyses and the interpretation are thus limited by these small numbers. However, these observations warrant calling attention to these possible factors that may underlie failure of β-blocker therapy in symptomatic LQTS patients, particularly since atenolol is increasingly becoming the most commonly prescribed β-blocker.
In this study cohort, 25% of genotyped, symptomatic LQTS probands failed β-blocker therapy. Young age and treatment with atenolol may be key mitigating factors underlying β-blocker therapy failures. In addition, the majority of breakthrough events occurred in patients with LQT1. In the small subset presenting with ACA, 60% had a subsequent breakthrough event. Clinical management of symptomatic LQTS patients with β-blockers alone needs to be modified in high-risk patients in order to prevent or minimize breakthrough cardiac events. Future studies are necessary to investigate further this notion that all β-blockers may not afford equivalent protection in LQTS.
This work was supported by a Clinical Scientist Development Award to MJA from the Doris Duke Charitable Foundation.