Defining cardiovascular-kidney-metabolic progression by a cardiovascular endpoint: a built-in circularity

This commentary refers to ‘Clonal haematopoiesis and cardiovascular-kidney-metabolic syndrome: a cohort study’, by A. Chang et al., https://doi.org/10.1093/eurheartj/ehag655 and the discussion piece ‘Clonal haematopoiesis and the cardiovascular-kidney-metabolic continuum’, by A. Chang and M. C. Honigberg, https://doi.org/10.1093/eurheartj/ehag858. We read with interest the study by Chang et al. examining the association of clonal haematopoiesis of indeterminate potential (CHIP) with cardiovascular-kidney-metabolic (CKM) syndrome.1 The authors provide an important analysis linking CHIP, inflammatory proteomic signatures, and adverse cardiovascular outcomes. However, we question whether these longitudinal findings truly demonstrate CKM progression or largely reflect the already established association between CHIP and cardiovascular disease (CVD). The primary longitudinal outcome was progression from CKM stages 0–3 to stage 4. Yet, stage 4 is defined by the development of clinical CVD, such as coronary artery disease or heart failure. Thus, among participants without CVD at baseline, ‘progression to CKM stage 4’ essentially meant developing CVD. This is important because CHIP is already known to be tightly associated with several cardiovascular outcomes.2 Therefore, showing that CHIP predicts a composite of cardiovascular events does not necessarily mean that it predicts progression of the broader, multi-component CKM syndrome. The magnitude of the reported associations further reinforces this concern. The strongest associations were observed for specific cardiovascular outcomes: spliceosome and JAK2 CHIP were associated with heart failure with hazard ratios (HRs) of 2.62 (95% CI 2.01–3.41) and 2.79 (95% CI 1.58–4.91), respectively, and JAK2 CHIP was associated with peripheral artery disease with an HR of as high as 3.80 (95% CI 1.81–7.98). Interestingly, the signal became substantially weaker when examined within the broader CKM construct: non-DNMT3A CHIP was associated with progression to stage 4 with an HR of 1.24 (95% CI 1.17–1.31), while any CHIP had an HR of only 1.13 (95% CI 1.09–1.17); its cross-sectional association with greater CKM severity was only minimal (OR 1.04; 95% CI 1.01–1.08). This striking dilution suggests that the apparent CKM-level signal is largely inherited from its cardiovascular component rather than reflecting an independent multi-component CKM phenomenon.