Lessons from LQT1 and LQT2 syndromes
In addition of iatrogenic TdP, loss of function mutations on potassium
repolarizing channels could lead to TdP in a mechanism supposed to
involve QT prolongation in LQT1 and LQT2 syndromes. Nevertheless,
despite of confirmed mutations, QTc prolongation is concealed in 25% of
these patients approximately (Goldenberg et al., 2011). In the present
study, patients with concealed QTc prolongation was characterised by a
QTc<450 ms in males and QTc<470ms in females using
the Bazett formula (Page et al., 2015). To tempt to decipher impact of
mutations on HFAM biomarkers of TdP risk depending on magnitude of QTc
prolongation, we analysed ECGs from the THEW cohort of untreated LQT1
and LQT2 patients with QTc prolongation and concealed QTc prolongation
compared to healthy individuals (Table 2). Applying the HFAM model
(Supplemental Figures 127 to 134) shows higher sympathetic activity
level (increase in S3) and HFQT oscillations in patients with QTc
prolongation than in patients with concealed QTc prolongation in both
types of LQT syndrome (Figure 6). This phenomenon occurs during the
light period of the circadian cycle where patients are assumed to be
majorly in standing up position. The S2 oscillations proportion in
patients with QTc prolongation tended also to be higher but the
difference with concealed QTc prolongation patients did not reach the
statistical significance threshold. This global increase (S2+S3) in
sympathetic activity appears with both mechanisms responsible for QT
prolongation, i.e. decrease in IKs current for LQT1 and
decrease in IKr current in LQT2 respectively. Since
magnitude of HFHR oscillations were unchanged (Table 2) in both LQT
syndromes when compared to patients with concealed QTc prolongation, the
increase in HFQT oscillations seen in patients with QTc prolongation is
rather attributed to increase in sympathetic activity according to the
vertical shift mechanism of the HFHR/HFQT relationship as described
earlier for torsadogenic hERG blockers (Champéroux et al., 2016).
Comparison of subgroups of patients exhibiting concealed QTc
prolongation to the healthy subjects’ sample also provides interesting
information. Indeed, despite no noticeable difference in QTc, QT
interval is prolonged both in LQT1 and LQT2 patients when compared to
healthy subjects. This difference is related to lower heart rate levels
(Table 2) due to an increase in parasympathetic activity (increase S1
oscillations and lowering in HFAM ratio). In parallel, HFQT oscillations
are increased over the whole circadian cycle. Like dofetilide at low and
high dose, an increase in parasympathetic activity is mainly observed
for lower level of QT/QTc prolongation whereas sympathetic activity is
increased depending on magnitude of QT prolongation in both LQT syndrome
types.