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Background: Atherosclerotic cardiovascular disease (ASCVD) continues to be the predominant cause of mortality and morbidity worldwide. Atherosclerosis is driven mainly by modifiable traditional risk factors such as smoking, hypertension, dyslipidaemia, diabetes, and obesity. However, a significant portion of the population exhibits none of these traditional risk factors but might still suffer from a cardiovascular event. Additionally, current strategies for risk prediction demonstrate several limitations, particularlyamong younger individuals who are classified as low to intermediate risk for future ASCVD, where the risk is often underestimated. Potential approaches to more accurately identify individuals at elevated risk prior to their first ASCVD event encompass the identification of novel biomarkers and the utilisation of imaging techniques to visually assess early ASCVD. Several biomarkers, such as non-HDL and remnant cholesterol, have emerged as promising future risk markers due to their increasingly acknowledged role in the development of atherosclerosis.Other proposed risk markers are the ABO and RhD blood groups, which have previously been associated with increased susceptibility to ASCVD. However, the role of the RhD blood group in atherogenesis is more uncertain. Nonetheless, numerous aspects of the pathophysiological processes underlying atherosclerosis remain unclear, and by investigating associations between various risk markers and subclinical atherosclerosis, this might further deepen our understanding of early disease mechanisms, and possibly also contribute to the improvement of prevention strategies. Furthermore, the quality of laboratory data in studies concerning risk markers has infrequently been examined, and the true error frequency in laboratory information remains undetermined.

Aim: The overall aim was to contribute to the development of personalised ASCVD prevention strategies by deepening our knowledge about risk markers linked to the early onset of cardiovascular disease. Specifically, the aim was to evaluate the associations between subclinical carotid atherosclerosis and a set of potential risk markers, including ABO and RhD blood groups, as well as the novel lipid biomarkers non-HDL and remnant cholesterol. Furthermore, the quality of laboratory information, with an emphasis on post-analytical errors, was examined.

Methods: All participants were part of the VIPVIZA study, a pragmatic trial focusing on cardiovascular disease prevention, including 3532 participants. VIPVIZA measures traditional risk factors, such as plasma lipid levels, and includes ultrasound examinations of the carotid arteries to evaluate subclinical atherosclerosis. Subclinical atherosclerosis is defined as carotid plaques and increased carotid intima-media thickness (cIMT). Data on ABO and RhD blood groups were obtained by linking VIPVIZA to the SCANDAT database, a registry of blood group information from individuals who have undergone blood grouping, regardless of the indication. To ensure the accuracy of laboratory information, all lipid variables were validated, and the transcription errors were corrected.

Results: The RhD antigen was associated with subclinical atherosclerosis in a cross-sectional study. This was represented by young RhD-negative individuals with CVD heredity having increased cIMT compared to RhD+ individuals. In the same study population, young male RhD– individuals also had higher levels of non-HDL, LDL, and remnant cholesterol. For the ABO blood groups, no association with subclinical atherosclerosis or dyslipidaemia was identified. Regarding lipids, increasing LDL and non-HDL cholesterol levels were associated with increased odds for carotid plaques and increased cIMT. However, no independent association was seen between remnant cholesterol and subclinical atherosclerosis when adjusting for the risk conferred by LDL cholesterol. Regarding the accuracy of laboratory information, the frequency of transcription errors in the lipid variables of the VIPVIZA database was 0.55% in 2019 and halved after an educational intervention to 0.25% in 2023. In 15% of the cases, the error had the potential of leading to an incorrect SCORE-2 risk category and, thus, an incorrect ASCVD risk assessment.

Conclusions: The RhD antigen, LDL, and non-HDL cholesterol were all associated with subclinical atherosclerosis in these cross-sectional studies and may play a role in personalised ASCVD prevention in the future. The finding regarding RhD is novel and has not been previously reported. Thus, further research is required before clinical implementation is appropriate. The role of the ABO antigens and remnant cholesterol in atherosclerotic disease remains conflicting and needs further elucidation. In the future, it is likely that multiple risk markers will be combined with imaging diagnostics to more accurately predict an individual's risk of cardiovascular disease. Moreover, manual transcriptions of laboratory data should be minimised in both scientific studies and clinical practice to be able to achieve non-erroneous ASCVD risk assessments.