Investigation of the effects of physiological and vasodilation-induced autonomic activation on the QTc Interval in healthy male subjects

Abstract

Aims: Drug-induced prolongation of the QTc interval is an important marker for potential proarrhythmic action. Prolongation of the QTc interval results from alteration of the ionic currents that regulate cardiac repolarisation. Such effects may result from direct drug action or alternatively they could also occur indirectly by drug-induced modulation of autonomic tone, which is known to regulate cardiac repolarization. This study examined the effects of physiological and drug-induced autonomic activation on heart rate, QT and QTc intervals.

Methods: We studied 29 healthy male subjects aged 18-30 years. Electrocardiographs were recorded before and during autonomic activation induced by mental activation, standing, exercise and glyceryl trinitrate (GTN) (0.5 mg sublingual)-induced vasodilation in the presence and absence of beta-blockade (atenolol 100 mg daily for 4 days). QT intervals were measured manually by electronic callipers and corrected using the Fridericia formula.

Results: Heart rates were significantly increased during mental arithmetic, standing, exercise and GTN and this effect was significantly attenuated by atenolol, except for mental activation. QTc intervals were significantly reduced on standing and exercise and this was significantly attenuated by atenolol during exercise. In contrast, GTN increased QTc intervals (Delta = 5.7 ms, confidence interval +/- 3.2 ms, P < 0.005) and this was not attenuated by atenolol.

Conclusions: Alteration in QTc intervals may result from physiological manoeuvres and vasodilation, interventions known to induce autonomic activation. We suggest that QTc prolongation due to GTN is indirectly mediated and unlikely to carry any proarrhythmic effect. Understanding whether drug-induced QTc prolongation is directly or indirectly mediated may be important to determine any potential proarrhythmic risk.

Figure 1

Study protocol. Subjects were connected to the ECG apparatus and then lay supine in a low-stimulation environment for 30 min, during which an ECG was recorded at 5-min intervals. A series of physiological manoeuvres were then undertaken, consisting of mental activation (M/A), Valsalva manoeuvre (V/S), lying and standing (L/S) and exercise (Ex). The GTN protocol commenced at 120 min from baseline. Subjects received 0.5 mg of GTN sublingually and ECGs were recorded after 1, 2 and 3 min. They were then asked to stand for 3 min and ECGs were recorded at 4 and 6 min post dose, after which they lay supine for the remainder of the study

Figure 2

Changes in heart rate (upper panel), QT intervals (middle panel) and QTc intervals (lower panel) in response to mental activation (MA), standing from supine, exercise (running on the spot for 100 steps), at 3 min following sublingual GTN (while supine), and at 6 min following GTN (while standing). Data are shown as means ±95% CI for controls (□) and following 4 days' treatment with atenolol 100 mg daily (▪). Changes for standing and exercise are shown for group A (subjects given atenolol before study session 1) and group B (atenolol given before study session 2) separately as a period effect was observed for heart rate and QT on standing and for QTc on exercise. (*Significant attenuation following treatment with atenolol.)