Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects

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.

• Long QT Syndrome
• Cardiac Repolarization

• Drug: Placebo
  Placebo will be given 1 pill daily for a week, then 2 pills daily, followed by the exercise test.
• Drug: Propranolol 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.

• Placebo Comparator: 1
  Subjects are assigned to placebo.
  Intervention: Drug: Placebo
• Active Comparator: 2
  Subjects will take propranolol LA 80 mg daily for one week then 160 mg for one week followed by the exercise test.
  Intervention: Drug: Propranolol LA

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