Investigated population and electrocardiographic recordings

A collection of Holter recordings previously analysed for a different purpose was used²⁴. Altogether 639 healthy subjects participated at six different clinical pharmacology studies. All subjects were screened before enrolment and all had a normal resting ECG and normal clinical investigation as mandated in clinical pharmacology research²⁵. Clinical conduct of the studies including the procedures of electrocardiogram acquisition adhered strictly to the relevant guidelines and regulations^25,26. All these studies were ethically approved by the institutional ethics bodies (Focus in Neuss; Parexel in Baltimore, Bloemfontein, and Glendale; PPD in Austin; and Spaulding in Milwaukee). All subjects gave informed written consent to the participation. All the source studies were conducted in accordance with the Helsinki declaration.

As previously described²⁴, each of the studies included repeated 12-lead day-time Holter recordings in each participant. The recordings were made during multiple baseline days. During these baseline days, study protocols included repeated provocative manoeuvres with the aim of capturing wide heart rates ranges in each participant. The postural provocative manoeuvres included time-points during which the study subjects were, per protocol, in undisturbed supine, unsupported sitting, and unsupported standing positions. In addition to these, other study per-protocol time-points required the subjects to maintain strict supine positions. The Holter recordings used Mason-Likar electrode positions. Clinical conduct of the baseline days did not differ between individual units. The investigation described in this text utilized the baseline Holter recordings when the subjects were off any medication, did not smoke, and refrained from consuming caffeinated drinks. Further details of the clinical pharmacology studies are therefore irrelevant.