Significance Cardiovascular disease remains the world’s leading killer, despite the widespread use of cholesterol-lowering medicines. Recent studies suggest a portion of this residual risk may result from the clonal expansion of cells within the atherosclerotic plaques of diseased blood vessels. How these cells promote inflammation and whether they can be therapeutically targeted remain unclear. The current study suggests that clonally expanding cells may cause disease by triggering the complement cascade while evading immune surveillance. However, these cells also appear to be susceptible to therapies that reactivate phagocytic clearance pathways, suggesting a potential treatment approach for heart disease similar to current oncology efforts directed against the cancer stem cell.