The Blood Is Not the Heart: Clonal Haematopoiesis, Tissue-Restricted Mitochondrial Heteroplasmy and the Bidirectional Error of Cardiogenetic Attribution

Purpose of Review: Cardiovascular genomic interpretation frequently relies upon peripheral-blood DNA, although blood-derived variation does not necessarily represent the genome of diseased cardiac tissue. Conversely, clinically relevant mitochondrial DNA (mtDNA) heteroplasmy may be insufficiently represented in blood. This review examines these opposing errors of cardiogenetic attribution and proposes PROVENANCE-CV, a compartment-resolved framework distinguishing variant provenance, pathogenicity, cardiovascular mechanism and clinical utility.Recent Findings: Large-scale genomic investigations published in 2026 demonstrate that numerous age-associated blood mtDNA variants become detectable through haematopoietic clonal expansion, whereas multitissue analyses establish substantial anatomical heterogeneity of mitochondrial variation. Direct human cardiac investigations demonstrate both tissue-localised molecular abnormalities and clinically informative relationships between blood and myocardial measurements. Experimental and human studies additionally implicate selected haematopoietic clones in cardiovascular pathology through mechanisms that do not require the initiating mutation to reside within cardiomyocytes.Summary: Blood-centred interpretation risks attributing haematopoietic variation to intrinsic cardiac disease or excluding tissue-restricted pathogenic variation following a negative blood result. PROVENANCE-CV proposes five independently evaluated evidentiary gates and an uncertainty-aware adjudication protocol. A copy-number-weighted mixture model demonstrates how changes in cellular composition can alter bulk heteroplasmy without corresponding changes in within-lineage mutation burden. Prospective validation against established, guideline-concordant genetic assessment is proposed using independently corroborated classification, reproducibility and clinical utility. The framework is not a validated diagnostic instrument; its principal contribution is a falsifiable method for distinguishing specimen identity from molecular pathogenicity and cardiovascular causation.