Genetic testing helps diagnose Long QT syndrome

Apr 16 2006

Long QT syndrome is an uncommon, and sometimes fatal, heart rhythm disorder that is often present from birth. It gets its name from the peculiar pattern of the electrocardiogram (ECG or EKG) seen in people with the disease. It affects one in every 3,000 people in the United States.

If untreated, half the people with symptomatic LQTS will die within 10 years after the first symptoms are noticed. People at risk of LQTS include children, teenagers and young adults with unexplained fainting, near drowning, seizures or a history of cardiac arrest.

In this new study, Mayo Clinic researchers discovered the epinephrine QT stress test -- in which a patient is given a medication that stimulates the heart in a way similar to exercise -- reveals concealed type 1 long QT syndrome with a high level of accuracy, says Michael J. Ackerman, M.D., Ph.D., senior author of the study and director of Mayo Clinic's Long QT Syndrome Clinic and Sudden Death Genomics Laboratory.

The epinephrine QT stress test can expose LQT1 at a 75 percent positive prediction rate weeks before confirmation through a blood test for LQTS genetic testing; this blood test became available to doctors across the country beginning in 2004. In addition, the epinephrine QT stress test can provide subsequent physiological confirmation of a LQT1 genetic test result, Dr. Ackerman says.

While LQTS in some people can be diagnosed by the prolonged QT interval on an ECG, nearly 50 percent of LQTS -- particularly type 1 LQTS, the most common subtype -- may go unnoticed because the patient's resting ECG is normal, he says.

"The diagnosis of LQTS remains a daunting challenge," Dr. Ackerman says. "The ECG feature of LQTS can be difficult to recognize or can be entirely absent on a standard ECG. The results of this study show us we have one more tool to expose, unmask and accurately diagnosis this potentially lethal syndrome."

From 1999 to 2002, 147 individuals, ages 8-59, had an epinephrine QT stress test conducted as part of a referral to Mayo Clinic's Long QT Syndrome Clinic. The study involves one of the largest groups of patients evaluated by the epinephrine QT stress test. Results showed patients with LQT1 had a paradoxical lengthening of the QT interval during infusion of the epinephrine.

A prolongation of the uncorrected QT interval by more than 30 milliseconds during infusion of low-dose epinephrine was associated with a positive predictive value of 76 percent for LQT1 even if the resting ECG was completely normal. Furthermore, nearly every patient (96 percent) with established LQT1 displayed this paradoxical lengthening of the QT interval, Dr. Ackerman says.

In another recent study, published in the Journal of the American College of Cardiology in February, a team of researchers examined the use of genetic testing for LQTS based on an initial clinical diagnosis and subsequent referral to Mayo Clinic by physicians across the country.

Between 1997 and 2004, 541 consecutive unrelated patients were referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing. Overall, LQTS-causing genetic mutations were discovered in more than half (272 out of 541) of the patients.

In comparing patients who were diagnosed with LQTS and those who were not, important clinical differences were recognized, says Dr. Ackerman, who led the study. Now, with the maturation of LQTS genetic testing from the research arena to a clinical diagnostic test, physicians need to know and understand the performance characteristics of genetic testing, he says. For example, the study revealed that when the patient's clinical profile fit the LQTS label completely, the detection rate of the genetic test was approximately 75 percent. In addition, the investigators noted that percentage of mutation-positive genetic tests varied tremendously among the physicians utilizing the research genetic test, ranging from 0 percent to 80 percent, suggesting the need for further education.

The results of the genetic testing should help educate physicians on how to recognize, evaluate and diagnose LQTS, Dr. Ackerman says. "To have all the warning signs and not have the diagnosis made is tragic," he says. "But labeling a patient prematurely with long QT syndrome carries its own dark side because it can cause anxiety for the family and lead to intervention and physical activity restrictions. These tests will help us be more definitive in diagnosis."

Treatment for LQTS patients varies depending on each case, but options include medication or the placement of an implantable cardioverter defibrillator.