Fig. 1

Directed acyclic graph highlighting the assumed potential causal relationships between CV risk factors, DNAm and cardiac age. The exposure is shown in green, mediator in blue, outcome in black, and confounders in red. The presence of CV risk factors (e.g., BMI, diabetes, hypertension, high cholesterol, and previous CVD) was associated with higher ECG-based cardiac ages. However, this relationship could be confounded by demographics (e.g., age, sex, and socio-economic position) and lifestyle varibles (e.g., physical activity, smoking and alcohol consumption), amongst others. After adjusting for the confounders and for the white cell counts, the mediator analysis identified indirect effects on ECG-based cardiac ages through DNAm AgeAccelPheno and AgeAccelGrim especially for diabetes, high cholesterol, and hypertension, accounting in general for < 40% of the total effects. This highlights the potential role of DNAm as a mediator, downstream of CV risk factors but upstream of cardiac age. Abbreviations: AgeAccel = age acceleration; ECG = electrocardiography; BMI = body mass index; CV = cardiovascular; CVD = cardiovascular diseases; DNAm = DNA methylation