From Blood Clone to Myocardial Lesion: A Tissue-Provenance Framework for Clonal Haematopoiesis in Heart Failure

Clonal haematopoiesis (CH) is increasingly associated with heart failure, adverse cardiac remodelling and cardiovascular mortality. Yet most human evidence begins and ends in different anatomical compartments: the mutation is detected in blood, whereas the phenotype is measured in the heart. The intervening biological sequence is usually inferred rather than demonstrated. This Mini Focused Review reframes CH-associated heart failure as a tissue-provenance problem. We propose a six-level tissue-provenance framework that distinguishes circulating clone detection, effector-lineage attribution, myocardial entry, spatial localisation, lesion-concordant cellular behaviour and longitudinal phenotype linkage. Experimental studies of TET2, DNMT3A, JAK2V617F, ASXL1, PPM1D and TP53 support driver-specific inflammatory and remodelling phenotypes, while human tissue studies show that mutation-bearing cardiovascular macrophages need not be preferentially enriched to be biologically abnormal. Heart transplantation provides a particularly informative human test system because recipient genotype, cellular provenance, serial endomyocardial tissue and evolving pathology can be interrogated within the same patient. A practical programme combining blood sequencing, targeted tissue genotyping, cellular phenotyping, spatial localisation and longitudinal histopathology could distinguish circulating association from lesion participation. The immediate translational priority is therefore anatomical attribution rather than broader CH screening.