Anatomical-electrical coupling of cardiac axes: Definitions and population variability for advancing personalised ECG interpretation

Electrocardiogram (ECG) recordings are affected by the heart’s three-dimensional orientation within the thorax, i.e., the anatomical axis. Various cardiac conditions can cause the anatomical axis to shift and/or alter the pattern of electrical activation, leading to changes in the electrical axis. Nevertheless, there remains a lack of a formal, population-level study of the interplay between the cardiac anatomical and electrical axes and the factors that affect them. In this context, this study aimed to: (1) propose standardised definitions for the cardiac anatomical and electrical axes, (2) characterise their population-wide interplay in healthy conditions, (3) evaluate the impact of hypertension on their distribution and (4) identify associations with phenotypical and disease characteristics. Using cardiac magnetic resonance images and 12-lead ECGs from ~39,000 UK Biobank participants, patient-specific, paired biventricular geometries and vectorcardiograms were constructed. Five anatomical and four electrical axis definitions were computed, with the optimal pair of definitions selected based on their mutual alignment in 3D space within 28,000 healthy subjects. Accordingly, the anatomical axis was defined as the vector from the apex to the spatial centre of the four valves, and the electrical axis as the direction of the maximum QRS dipole. Mean angular separation in 3D, ΔAE3D, was 145.0° ± 16.8° in the healthy cohort. The electrical axes exhibited a much larger variability, and strong evidence of anatomical-electrical coupling was identified. Increasing BMI notably affected the anatomical axis, rotating the heart more horizontally—a pattern mirrored by the electrical axis. Both axes were also significantly influenced by sex and, to a lesser extent, age. The axes were then studied in the sub-cohort of ~3,500 UK BioBank participants with primary hypertension, where a similar rotational pattern as that with increasing BMI was revealed. Finally, phenome-wide association studies in the 39,000 participants reveal associations between the axes angular metrics and phenotypes signalling an increased afterload, and an association to hypertension among other clinical conditions. These findings underscore the complex anatomical-electrical interplay and highlight the potential of cardiac axes biomarkers for an improved clinical ECG interpretation and disease characterisation.Author summary: Electrocardiograms (ECGs) are among the most widely used tools in cardiac diagnostics, capturing the electrical potential on the skin’s surface that reflects the heart’s electrical activity. This signal is influenced by the heart’s orientation and position within the chest—factors often overlooked during ECG interpretation. In this study, we examined the anatomical axis as the heart’s orientation and the electrical axis as a 3D spatial representation of the heart’s electrical activity, exploring their interactions in both healthy individuals and those with hypertension. Using cardiac magnetic resonance imaging and ECGs from about 39,000 UK Biobank participants, we investigated how factors such as body mass index, age, sex, and hypertension affect these axes and their coupling. We found that increased BMI, male sex, and hypertension are associated with a more horizontal heart orientation and electrical axis, emphasising complex anatomical-electrical interaction. Our findings also show association with health outcomes, pointing out the importance of accounting for patient-specific variations and suggest that considering these factors could lead to more accurate and personalised ECG interpretation.