Cardiac Repolarization, Long QT Syndrome
Conditions
Keywords
QT interval, beta-blocker, exercise, electrocardiogram, repolarizaton
Brief summary
Background. In congenital long QT syndrome type 1 (LQT1), episodes of ventricular tachycardia are usually triggered by exercise and can be prevented in most patients by beta-blocker therapy. In addition, LQT1 associated with a normal resting QT interval can be unmasked by the abnormal QT response to exercise testing (failure of the QT interval to shorten normally). Preliminary data from our laboratory show that the exercise QT intervals of patients with LQT1 are partially normalized by beta-blocker therapy. It is still currently not known if beta-blockers modify the QT/heart rate relationship (a primary effect on repolarization) or if the normalizing effect is due to the inability of subjects on beta-blockers to attain sufficiently high workloads (due to reduced heart rate) for prolongation to occur. Moreover, the physiologic response of the exercise QT interval to beta-blockers in healthy control subjects is not known. Objective. The objective of this study is to define the impact of beta-blocker therapy on the QT response to exercise and recovery in normal subjects. Methods. Approximately 36 healthy adult subjects age-matched to previously studied LQT1 subjects will undergo 1) screening history, 2) two weeks of beta-blocker therapy ending in an exercise test, and 3) two weeks of placebo therapy ending in an exercise test. Beta blocker and placebo will be given in random order in a double-blind fashion. The QT response to exercise and recovery will be compared between drug-free and beta-blocker-treated states. These data will be compared to those previously collected for LQT1 subjects. Implications. These results will provide new information about the effect of beta-blocker therapy on repolarization parameters in normal subjects, and will provide a context in which to interpret the previous findings that beta-blocker administration modifies the QT response to exercise in LQT1 subjects.
Interventions
DRUGPlacebo
Placebo will be given 1 pill daily for a week, then 2 pills daily, followed by the exercise test.
DRUGPropranolol LA
Subjects will receive propranolol LA 80 mg one pill daily for 1 week then 2 pills daily for 1 week followed by exercise test.
Sponsors
MetroHealth Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy normal adults, age- and gender-matched to previously studied LQT1 subjects
Exclusion criteria
* Cardiac disease * Diabetes * Hypertension * Severe allergic reaction * Asthma requiring treatment * Use of medications other than oral contraceptives, acetaminophen, nonsteroidal anti-inflammatory drugs, or synthroid or other thyroid medications * Pregnancy (subjects will be asked if they are pregnant) * Inability to sign informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| QTc Response to Exercise on Versus Off Beta-blocker. | 2 weeks on each treatment then exercise test | To minimize the effect of heart rate on QT, QT was measured at heart rates between 100 and 110 beats per minute during exercise (on and off beta-blocker) and during recovery (on and off beta-blocker). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tpeak-end Interval (Tpe) | Measured after 2 weeks on each intervention | Tpeak-end interval was measured at rest, exercise, and recovery on placebo and on propranolol. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Subjects Subjects will take propranolol LA 80 mg or placebo daily for one week then propranolol LA 160 mg for one week or 2 placebo pills, followed by the exercise test. The participants will be randomized to one of 2 sequences: placebo first or propranolol first. | 35 |
| Total | 35 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants |
| Age Continuous | 32 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 35 | 0 / 35 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 |
Outcome results
Primary
QTc Response to Exercise on Versus Off Beta-blocker.
To minimize the effect of heart rate on QT, QT was measured at heart rates between 100 and 110 beats per minute during exercise (on and off beta-blocker) and during recovery (on and off beta-blocker).
Time frame: 2 weeks on each treatment then exercise test
Population: Please note that this was a crossover study. There were 35 subjects and each subject completed both the placebo and beta-blocker arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | QTc Response to Exercise on Versus Off Beta-blocker. | During exercise | 320 ms | Standard Deviation 17 |
| Placebo | QTc Response to Exercise on Versus Off Beta-blocker. | During recovery | 317 ms | Standard Deviation 13 |
| Propranolol | QTc Response to Exercise on Versus Off Beta-blocker. | During exercise | 317 ms | Standard Deviation 16 |
| Propranolol | QTc Response to Exercise on Versus Off Beta-blocker. | During recovery | 315 ms | Standard Deviation 14 |
Secondary
Tpeak-end Interval (Tpe)
Tpeak-end interval was measured at rest, exercise, and recovery on placebo and on propranolol.
Time frame: Measured after 2 weeks on each intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Tpeak-end Interval (Tpe) | Rest | 74 ms | Standard Deviation 13 |
| Placebo | Tpeak-end Interval (Tpe) | Peak Exercise | 69 ms | Standard Deviation 13 |
| Placebo | Tpeak-end Interval (Tpe) | Recovery | 77 ms | Standard Deviation 19 |
| Propranolol | Tpeak-end Interval (Tpe) | Rest | 72 ms | Standard Deviation 13 |
| Propranolol | Tpeak-end Interval (Tpe) | Peak Exercise | 61 ms | Standard Deviation 11 |
| Propranolol | Tpeak-end Interval (Tpe) | Recovery | 68 ms | Standard Deviation 14 |