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Genetic defects predictive of adverse events in patients with long QT syndrome
Jons C. Sci Transl Med. 2011;3:76ra28.
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Mutations that caused a slow activation of the potassium current channel strongly correlated with an increased risk for cardiac events in patients with long QT type 1 syndrome, one of the most common forms of long QT syndrome.
In a recent study, Coeli M. B. Lopes, PhD, and fellow researchers examined 17 mutations found in 387 patients with long QT type 1 (LQT1) syndrome from four long QT syndrome international registries. They correlated the clinical phenotype of patients (n=314) with cellular electrophysiological characteristics resulting from an array of mutations in the slow potassium current channel alpha-subunit KCNQ1 to determine whether there was an association between channels with a decreased rate of current activation and an increased risk for cardiac events, which included syncope, aborted cardiac arrest requiring defibrillation and sudden cardiac death.
They found there was a direct association between channels with a decreased rate of current activation and an increased risk for events (HR=2.02). This association was independent of the clinical parameters used for risk stratification.
Furthermore, for patients with moderate QT prolongation, which was defined as a QT interval of less than 500 ms, slower activation independently predicted an increased risk for cardiac events (HR=2.10), although length of QT interval did not.
“The appropriate clinical care for LQT1 patients with modest corrected QT prolongation is not well established, with many patients remaining untreated,” Lopes and colleagues wrote. “Identification of high-risk mutations in this population could lead to more aggressive treatment in the population at risk and better patient care.”
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The rate at which progress is being made in the long QT syndrome and other genetic cardiovascular diseases is really astounding. In the decade and a half since the initial identification of disease genes that harbor causative mutations, literally hundreds of different mutations have been identified in thousands of patients, and newer technologies are likely to increase these numbers even faster. This study is one of the first to combine clinical features (the observed QT interval), and biophysical features of specific mutations (activation rate of mutant channels in vitro in this case) to predict outcomes like syncope or death. Understanding why some patients have these outcomes and some don't, even with the same mutation, is one of the big challenges in this area. Advances in the field will provide important lessons not only for this syndrome but also for genome science in general as we acquire the ability to rapidly sequence full human genomes.
– Dan Roden, MD
Cardiology
Today Editorial Board member
Disclosures: Dr. Roden reports consulting for Merck, Sanofi, Dai-ichi Sankyo, and Astellas. He receives royalties on a patent on a genetic variant predicting drug-induced long QT syndrome.
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