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.

Study Overview

• Status: Completed
• Conditions: Long QT Syndrome; Cardiac Repolarization
• Intervention / Treatment: Drug: Placebo; Drug: Propranolol LA

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 1; Subjects are assigned to placebo.	Drug: Placebo; Placebo will be given 1 pill daily for a week, then 2 pills daily, followed by the exercise test.
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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	2 weeks on each treatment then exercise test

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tpeak-end Interval (Tpe)	Tpeak-end interval was measured at rest, exercise, and recovery on placebo and on propranolol.	Measured after 2 weeks on each intervention

Collaborators and Investigators

• Sponsor: MetroHealth Medical Center
• Investigators: Principal Investigator: Elizabeth S Kaufman, MD, MetroHealth Medical Center

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: December 26, 2007
• First Submitted That Met QC Criteria: December 26, 2007
• First Posted (Estimate): January 9, 2008

Study Record Updates

• Last Update Posted (Estimate): July 30, 2013
• Last Update Submitted That Met QC Criteria: July 29, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: exercise; QT interval; electrocardiogram; beta-blocker; repolarizaton
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Long QT Syndrome; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Propranolol
• Other Study ID Numbers: IRB07-00418; NIH grant, GCRC MO1 RR000080