Long QT Syndrome in Adults
Long QT syndrome (LQTS) is an inherited genetic disorder associated with QT prolongation on the electrocardiogram (ECG) and ventricular tachyarrhythmias that manifest as syncope, aborted cardiac arrest (ACA), and sudden death. The arrhythmic complications are most frequent during adolescence, but can occur at any age. In our recently published article in JACC, we chose to study the factors associated with cardiac events in adults with LQTS. The aims of the study were: 1) to evaluate and risk stratify the clinical course of adult patients age 18-40 years with mutation-confirmed LQTS; 2) to evaluate the risk of life-threatening events as a specific endpoint in adults with this disorder; and 3) to determine the protective effect of beta-blockers on cardiac events in adult patients with LQTS. The clinical and ECG characteristics of 812 patients 18 years of age or older, with mutation-confirmed LQTS (428 LQT1, 302 LQT2, and 82 LQT3 gene carriers), were studied to evaluate clinical course and identify risk predictors for subsequent cardiac events–including lethal or potentially lethal outcomes–in a large population of genotype-confirmed adult patients with LQTS. The cardiac events of interest included syncope, ACA, or LQTS-related sudden cardiac death (SCD). Female gender, longer QTc intervals on the ECG, LQT2 channel mutations, and the frequency of syncopal cardiac events prior to age 18 were all associated with an increased risk of a cardiac event. Female gender, QTc ≥500 msec, and interim syncopal events during follow-up after age 18 were the significant factors associated with life-threatening ACA or SCD in adulthood. Genotype (LQT1, 2, or 3) did not enter the life-threatening event model. Beta-blockers provided approximately a 60% reduction in the risk of any cardiac event or life-threatening cardiac events (hazard ratio 0.40-0.41), with somewhat greater benefit in higher-risk subjects.

As of December 2006, nine separate genes involving more than 600 different mutations have been associated with LQTS. The genes have been numbered LQT1-9 in the chronological order in which they were identified, with the first three identified LQTS genes (LQT1, 2, and 3) accounting for more than 95% of the patients with genetic mutations (LQT1-9) reported in the literature. All but one of the reported LQTS gene mutations either directly affect the protein structure of the ion channels in the myocytes membrane and thus their associated ion-channel currents or indirectly affect the signaling pathways involving the ion-channel currents. It is for these reasons that LQTS has been called a channelopathy. The limb-lead ECG recordings in a patient with genetically confirmed LQT3 form of LQTS are presented in (Figure 1).



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ECG (limb-leads) in an adult patient with LQT3 form of LTQS. *The patient was not recieving any beta-blockers or any medication. QTc=0.58 sec.





Almost all the reported LQTS studies to date have used birth as the time origin for evaluating the clinical course of patients with this genetic disorder and these studies have focused on cardiac events dominated by syncope. From a clinical point of view, we see LQTS patients at different ages, and we want to know the subsequent clinical course, especially the likelihood of a fatal or near-fatal cardiac event due to a ventricular tachyarrhythmia (Figure 2), when viewed in light of the past history and the present clinical findings. This study is the first to determine clinically relevant risk factors in adult patients with LQTS. All study patients had to be alive at age 18 and they were then followed during their adult years until age 40. This study examined the more important ACA or SCD endpoints that have not been specifically examined in adult subjects. In addition, the study considered time-dependent beta-blocker therapy (comparing those on vs. those off beta-blockers at every point in time during follow-up) and prior or interim history of syncope as factors in the risk stratification analyses. Also, the study focused on LQTS subjects with genotype-confirmed mutations. We found that adult patients with mutation-confirmed LQTS can be risk stratified by genotype, gender, QTc duration, and prior history of a cardiac event–with clear evidence of risk reduction by beta-blocker therapy. The LQTS genotype (LQT1, 2, or 3) is an important independent risk factor among genotype-positive patients when looking at any first cardiac event (mostly syncope) during adulthood. Patients with LQT2 mutations are at a greater risk for a cardiac event than patients with LQT1 or LQT3 genotypes. Adult females had a significantly elevated risk and increased rate of cardiac events when compared to adult male patients. In adulthood, an increased QTc interval remains a significant independent predictor of cardiac events. Patients who had experienced more than one syncopal event prior to age 18 years had hazard ratios ranging from 5.4 to 12.0 depending on the number of previous events. Patients without cardiac events prior to age 18 were at reduced risk for subsequent cardiac events, but these patients still experienced LQTS-related events in their adult years. Potential lethality of LQTS in adulthood for ACA or LQTS-related sudden death was related to female gender (Figure 3), QTc duration (Figure 4), and interim syncope after age 18. No previous study included interim syncope as a risk factor in the proportional hazards risk model since syncope during adulthood cannot be used as a covariate risk factor when syncope is also utilized as an endpoint event. In our large LQTS population, we had an adequate number of ACA/SCD endpoint events exclusive of syncope to evaluate time-dependent syncope as a risk factor in the life-threatening risk-stratification model. Genotype, history of syncope before age 18, and a QTc <500 ms were not associated with ACA/SCD in the adult years. Although genotype has been considered an important predictor of cardiac events in prior studies looking at younger populations, we speculated that the risks of female gender, prolonged QTc interval, and interim time-dependent syncope supersede genotype as more significant contributing risk factors for lethal cardiac events in adulthood. Although beta-blockers are associated with a 60% reduction in life-threatening cardiac events, they do not provide complete protection against lethal events.



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Torsade de Pointes in an adult patient with Long QT syndrome.







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Probability of aborted cardiac arrest or LQTS-related sudden death in males and females during ages 18 to 40 years.







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Probability of aborted caridac arrest or LQTS-related sudden death by QTc duration during ages 18 to 40 years.





Clinical risk factors can identify adult subjects with genotype-positive LQTS who are at risk for fatal or near-fatal cardiac events. Beta-blockers are effective in reducing the frequency of potentially fatal events and should remain a mainstay of therapy in adults with this disorder. Identified high-risk LQTS patients, especially those refractory to beta-blockers, should be considered for an implantable defibrillator.

Strickberger SA, Benson DW, Biaggioni I, et al. AHA/ACCF scientific statement on the evaluation of syncope: from the American Heart Association Councils on Clinical Cardiology, Cardiovascular Nursing, Cardiovascular Disease in the Young, and Stroke, and the Quality of Care and Outcomes Research Interdisciplinary Working Group; and the American College of Cardiology Foundation In Collaboration With the Heart Rhythm Society. J Am Coll Cardiol 2006;47:473-84.

Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices–summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Am Coll Cardiol. 2002;40(9):1703-19. Full text guidelines are at ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices.