Clonal haematopoiesis and the cardiovascular–kidney–metabolic continuum

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 ‘Defining CKM progression by a cardiovascular endpoint: a built-in circularity’, by A. Kazory and A. Koratala, https://doi.org/10.1093/eurheartj/ehag857. We thank Drs Kazory and Koratala for their thoughtful response to our recent report on clonal haematopoiesis of indeterminate potential (CHIP) and cardiovascular–kidney–metabolic (CKM) syndrome.1 The authors note that development of clinical cardiovascular disease (CVD) was used to determine progression to Stage 4 CKM. However, Stage 4 was not an outcome definition created for our study; clinical CVD defines Stage 4 within the established CKM staging framework. Now codified in multi-society guidelines,2 the CKM syndrome framework conceptualizes CKM as a continuum culminating in clinical CVD at Stage 4. Accordingly, evaluating whether an exposure is associated with transition from Stages 0–3 to Stage 4 is consistent with the framework itself. We respectfully wish to clarify that this does not create ‘built-in circularity.’ Clonal haematopoiesis of indeterminate potential does not contribute to the definition of CKM stage or the Stage 4 outcome; rather, our analysis asked whether baseline CHIP was cross-sectionally associated with CKM stage and prospectively associated with transition to a prespecified CKM stage. That CHIP has previously been associated with CVD informs the interpretation of this finding, but does not make the analysis circular.