Background and Purpose Increase in high‐frequency beat‐to‐beat heart rate oscillations by torsadogenic hERG blockers appears to be associated with signs of parasympathetic and sympathetic co‐activation which cannot be assessed directly using classic methods of heart rate variability analysis. The present work aimed to find a translational model that would allow this particular state of the autonomic control of heart rate to be assessed. Experimental Approach High‐frequency heart rate and heart period oscillations were analysed within discrete 10 s intervals in a cohort of 200 healthy human subjects. Results were compared to data collected in non‐human primates and beagle dogs during pharmacological challenges and torsadogenic hERG blockers exposure, in 127 genotyped LQT1 patients on/off β‐blocker treatment and in subgroups of smoking and non‐smoking subjects. Key Results Three states of autonomic modulation, S1 (parasympathetic predominance) to S3 (reciprocal parasympathetic withdrawal/sympathetic activation), were differentiated to build a new model of heart rate variability referred to as high‐frequency autonomic modulation. The S2 state corresponded to a specific state during which both parasympathetic and sympathetic systems were coexisting or co‐activated. S2 oscillations were proportionally increased by torsadogenic hERG‐blocking drugs, whereas smoking caused an increase in S3 oscillations. Conclusions and Implications The combined analysis of the magnitude of high‐frequency heart rate and high‐frequency heart period oscillations allows a refined assessment of heart rate autonomic modulation applicable to long‐term ECG recordings and offers new approaches to assessment of the risk of sudden death both in terms of underlying mechanisms and sensitivity.