Autonomic Control of Heart Rate and QT Interval Variability Influences Arrhythmic Risk in Long QT Syndrome Type 1

Abstract

BACKGROUND A puzzling feature of the long QT syndrome (LQTS) is that family members carrying the same mutation often have divergent symptoms and clinical outcomes. OBJECTIVES We tested the hypothesis that vagal and sympathetic control, as assessed from spectral analysis of spontaneous beat-to-beat variability of RR and QT intervals from standard 24-hour electrocardiogram Holter recordings, can modulate the severity of LQTS type 1 (LQT1) in 46 members of a South-African LQT1 founder population carrying the clinically severe KCNQ1-A341V mutation. METHODS Nonmutation carriers (NMCs, n = 14) were compared with mutation carriers (MCs, n = 32), 22 with and 10 without major symptoms. We assessed the effect of circadian rhythm and of beta-blocker therapy over traditional time and frequency domain RR and QT variability indices. RESULTS The asymptomatic MCs differed significantly from the symptomatic MCs and from NMCs in less vagal control of heart rate and more reactive sympathetic modulation of the QT interval, particularly during daytime when arrhythmia risk for LQT1 patients is greatest. CONCLUSIONS The present data identify an additional factor contributing to the differential arrhythmic risk among LQT1 patients carrying the same mutation. A “normal” autonomic control confers a high risk, whereas patients with higher sympathetic control of the QT interval and reduced vagal control of heart rate are at lower risk. This differential “autonomic make-up,” likely under genetic control, will allow refinement of risk stratification within LQTS families, leading to more targeted management.

A Refined Multiscale Self-Entropy Approach for the Assessment of Cardiac Control Complexity: Application to Long QT Syndrome Type 1 Patients

“…This finding suggests that AMCs are also different from NMCs, thus allowing us to hypothesize that AMCs have a peculiar genetic make-up playing a significant role in limiting the severity of their disease and providing them a key advantage for survival with respect to SMCs. This conclusion supports previous observations about the differences of the sympathetic modulation among NMCs, AMCs and SMCs [45], reporting that the sympathetic control is higher in AMCs, while those of NMCs and SMCs are similar. It is noteworthy that traditional time domain indexes utilized in clinics [18,19,46] cannot distinguish AMCs from SMCs (Table 1).…”

“…This finding suggested that having a reduced complexity of the cardiac control both at the level of sinus node and ventricles during DAY (i.e., when the arrhythmic risk is greatest in LQT1) is a protective factor [13]. Since AMCs are characterized by a more reactive sympathetic control [45] and a less reactive vagal regulation [45][46][47], this reduced complexity of the sympathetic control might be the result of the synchronization of neural inputs operating at slightly different temporal scales performed by the higher sympathetic driver [43,48]. However, this study added a new, relevant, piece of information.…”

“…It is noteworthy that traditional time domain indexes utilized in clinics [18,19,46] cannot distinguish AMCs from SMCs (Table 1). Only a less frequently exploited time domain index such as the σ 2 QT can [45] (Table 1), thus suggesting that indexes derived from the multiscale complexity analysis are worth to be considered in addition to more traditional time domain parameters in clinics. We stress that the multiscale complexity analysis of HP is sufficient to separate AMCs and SMCs, thus rendering useless the extraction of the QT interval series and making the proposed analysis immediately applicable to HP series routinely extracted from 24-hour Holter recordings.…”

Techniques for Ventricular Repolarization Instability Assessment From the ECG

“…Other approaches to assess repolarization variability use parametric modeling [42], [75], [76]. While in [76] Porta et al investigate variability of the RT interval, in [42] Almeida et al explore QTV, and in [75] the variability from the R peak to the T wave end (RTe) is considered. The use of RT instead of QT avoids the need to determine the end of the T wave, which is usually considered to be problematic.…”

“…The association between increased repolarization variability and risk for VT/VF was also shown in [80] for post-MI patients with severe left ventricular (LV) dysfunction. In [75] an index quantifying autonomic control of HR and RTe was shown to separate symptomatic LQTS carriers from asymptomatic ones and controls.…”