Trigger-specific syncope in patients with long QT syndrome associated with differential risk of subsequent life-threatening events and response to therapy

1. Syncopal episodes triggered by adrenergic factors were linked to the greatest risk of subsequent life-threatening events (LTE) in patients with long QT syndrome (LQTS) type 1, followed by type 2. In contrast, no risk was observed among patients with type 3 LQT.

2. Only patients diagnosed with LQT type 2 faced an elevated risk of subsequent life-threatening events for syncopal episodes related to nonadrenergic triggers.

Evidence Rating Level: 2 (Good)

Study Rundown: Congenital LQTS, an inherited channelopathy, increases the risk of cardiac events like syncope or severe LTEs such as cardiac arrest and sudden death. These events are specific to the most common LQTS genotypes (LQT types 1 to 3), each associated with distinct triggers. In this study, the hypothesis was that unique triggers for syncope (adrenergic (AD) vs. non-adrenergic (non-AD)) would exhibit varying connections with subsequent LTEs, considering genotype differences and responses to β-blocker therapy. This cohort study identified a link between triggers of syncope episodes, the likelihood of subsequent LTEs, and the response to therapy based on genotype. One limitation of this study is the relatively notable proportion of unreported triggers for LTEs, potentially affecting the accuracy of cross-tabulation analyses and may undermine the validity of the findings. In conclusion, these findings could potentially enhance the risk assessment and management tailored to specific genotypes in LQTS.

Click to read the study in JAMA Cardiology

Relevant Reading: Effectiveness of Implantable Cardioverter-Defibrillators to Reduce Mortality in Patients with Long QT Syndrome

In-Depth [retrospective cohort]: This retrospective cohort study comprised 2938 patients enrolled from July 1979 to July 2021 confirmed to have the LQT type 1, 2, or 3 genetic variants from five international LQTS registries. Cardiac syncope events were classified into two primary categories based on their reported triggers: AD, including syncope during arousal triggers and exercise, and non-AD, encompassing syncope at rest and various other triggers. The primary endpoint was to observe the initial instance of an LTE.

The occurrence of an initial syncope event triggered by AD was shown to be the most significant indicator for future LTEs for patients with LQT1 (1331, 45%), correlating with an almost 8-fold rise in risk for subsequent LTEs (hazard ratio (HR): 7.61; 95% CI: 4.18-14.20; P < 0.001). Conversely, the link between a primary syncope triggered by non-AD factors and the risk of subsequent LTE was not statistically significant (HR: 1.50; 95% CI: 0.21-4.77; P = 0.97). Patients with LQT2 (1106, 38%) were shown to have both initial syncope trigger categories (AD and non-AD) exhibit comparable risks for subsequent LTEs (AD trigger HR: 3.07; 95% CI: 1.66-5.67; P = 0.001; non-AD trigger HR: 3.45; 95% CI: 1.96-6.06; P < 0.001). There was no significant association between patients with LQT3 experiencing specific triggers and subsequent LTEs. In individuals with LQT1, β-blocker therapy correlated with a 70% decrease in the risk of LTE (HR: 0.30; 95% CI: 0.15-0.64; P = 0.002), while those with LQT2 experienced a 53% risk reduction (HR: 0.47; 95% CI: 0.24-0.94; P = 0.03) associated with the same therapy.

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