Abstract 17021: Disruption in Circadian Rhythms Triggers Arrhythmias & Sudden Death in LQT3 Mice

Abstract

Introduction: The autosomal dominant long QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the pore-forming cardiac sodium channel α-subunit Na V 1.5 ( Scn5a ). A major challenge for treating LQT3 patients is predicting when or if a potentially life-threatening cardiac event (syncope or cardiac arrest) will strike. For example, longitudinal data from five LQT3 families with the Δ1505-1507KPQ mutation show only 33% of patients are symptomatic, and most symptomatic patients suffered only a single event (n = 46 patients; average age = 41 ± 23 years; average QTc interval = 510 ± 50 ms). The data suggest external stressors play a key role for triggering cardiac events in LQT3. Hypothesis: Disruptions in circadian rhythms can act as an external stressor to trigger LQT3-releated cardiac events. Methods: We disrupted the circadian rhythms in older wild type (WT) or Scn5a +/ΔKPQ mice using an established model of chronic jet lag (chronic light phase advance or CPA). The light cycle was advanced 6 hours every 4 days for 65 days. Mice were monitored using in vivo telemetry before and during CPA. Heart size and cardiac fibrosis were measured using immunohistochemistry. Results and Conclusions: Actograms for both WT and Scn5a +/ΔKPQ mice showed that CPA disrupted diurnal activity patterns. Before starting CPA, the Scn5a +/ΔKPQ mice had longer heart rate corrected QT (QTc) intervals compared to WT mice (Pre-WT = 45 ± 2 ms vs. Pre- Scn5a +/ΔKPQ = 54 ± 7 ms, n = 5, p<0.05). Twenty days after CPA, the QTc intervals in Scn5a +/ΔKPQ mice became even longer (CPA-WT = 47 ± 2 ms vs. CPA- Scn5a +/ΔKPQ = 63 ± 6 ms, p<0.05 compared to Pre-WT and Pre- Scn5a +/ΔKPQ ). Shockingly, all 5 of the Scn5a +/ΔKPQ mice undergoing CPA died within 65 days. Most deaths occurred after repeating patterns of premature contractions or prolonged episodes of bradycardia. In contrast, none of the age-matched control Scn5a +/ΔKPQ mice died (n = 5). Compared to the hearts of control Scn5a +/ΔKPQ mice, the hearts from CPA Scn5a +/ΔKPQ mice did not show changes in size or thickness but had more fibrosis (control = 9 ± 2%, CPA = 15 ± 2%; p<0.05). These data show that chronic disruption of circadian rhythms in Scn5a +/ΔKPQ mice exacerbates QTc prolongation, increases arrhythmias, and causes premature mortality.