Letter from the Editor

Dear Readers, A 22-year-old man is referred to an electrophysiologist after family members were diagnosed with long QT syndrome (LQTS). Several paternal relatives had died from a cardiac arrest at a young age, including his aunt, grandfather, and two of his second cousins. The most recent death was in a 27-year-old second cousin, after which relatives were advised to see a physician. The patient has never had syncope, presyncope, rapid palpitations, or other cardiac symptoms. He is otherwise healthy and not taking any medications. His physical examination is normal. The patient recently had an electrocardiogram, an exercise stress test, and an echocardiogram that were reportedly normal. Another electrocardiogram was performed in the office and is shown below. The sinus rate was 55 bpm. The T-wave appears slightly abnormal with possible notching in lead II, but the QT and QTc intervals were 434 and 415 msec, respectively. When confronted with a patient with a family history of LQTS, the typical approach is to inspect the electrocardiograms for evidence of a prolonged QT interval or an abnormal T-wave morphology. However, it has been shown in recent years that patients can have LQTS despite a relatively normal QT interval. Therefore, when screening family members of cardiac arrest victims, it can be difficult to reassure patients that they are not at risk. In some cases, provocative testing can be revealing, but the diagnosis still hinges on the electrocardiogram. In January 2011, Goldenberg et al¹ published a multicenter registry study in the Journal of the American College of Cardiology that was designed to assess the clinical course and identify risk factors for life-threatening events in patients with LQTS but a normal QT interval. They found that genetic data, including information regarding mutation characteristics and the LQTS genotype, identify patients who are at increased risk for sudden death in this overall lower risk LQTS subgroup. Clinical and genetic risk factors for sudden death were examined in 3,386 genotyped subjects under age 40 years who had been categorized as having LQTS. About 14% of the patients had a QTc considered normal (≤440 ms). They found that the risk of cardiac arrest by the age of 40 years was lower in patients with a normal QTc (4%) compared to patients with a prolonged QTc (15%), but was significantly higher than unaffected family members (0.4%). Goldenberg et al also found that mutation characteristics were related to risk in patients with a normal QTc interval (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1:LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3:LQTS type 2, hazard ratio: 8.04; p = 0.07). Clinical factors, including gender and QTc duration, were associated with a significant increased risk only in patients with a prolonged QTc interval (female age >13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002). Based on this registry data, it would be reasonable to recommend genetic testing for family members of patients with LQTS to help with the diagnosis and prognosis. In fact, the patient presented here had actually undergone genetic testing using a FAMILION® test one year prior to being referred. The test was positive for a gene mutation that is associated with long QT 2 syndrome and was found in the index case for the family. The mutation was a class I variant, frameshift mutation in the KCNH2/HERG gene, Ala1144fs, involving the c-terminal, cytoplasmic protein region. Based on his strong family history of sudden death and the results of genetic testing, this patient was considering defibrillator therapy in the absence of an abnormal electrocardiogram. Data from the recent Goldenberg study make one think twice before reassuring a patient with a strong family history of sudden death that they are normal, and therefore at low risk, based solely on conventional clinical information.

Reference

1. Goldenberg I, Horr S, Moss AJ, et al. Risk for Life-Threatening Cardiac Events in Patients With Genotype-Confirmed Long-QT Syndrome and Normal-Range Corrected QT Intervals. J Am Coll Cardiol 2011;57:51-59.