Understanding why women under 50 develop different types of heart disease could transform cardiovascular prevention strategies. While men typically suffer heart attacks from unstable plaques that rupture, younger women more often experience coronary events from plaque erosion—a fundamentally different mechanism that current research has largely overlooked. Scientists analyzed gene expression patterns in vascular smooth muscle cells from 151 human heart donors to decode these sex-specific differences. They discovered two distinct female-biased gene regulatory networks that control how blood vessel cells behave during atherosclerosis development. The first network drives inflammatory responses, while the second—centered around actin remodeling pathways—governs how cells contract and reshape blood vessels. Single-cell sequencing of actual atherosclerotic plaques confirmed these networks operate differently in male versus female tissue. Most significantly, researchers identified MYH9 (myosin heavy chain 9) as a master regulatory gene that orchestrates fibrous plaque formation through contractile and vascular development pathways. This finding challenges the assumption that atherosclerosis follows identical pathways across sexes. The discovery has immediate clinical relevance since fibrous plaques—the type more common in younger women—are notoriously difficult to detect with standard imaging and often cause sudden cardiac events without warning. Current prevention guidelines, developed primarily from male-dominated studies, may inadequately protect women. This sex-specific molecular framework could inform development of targeted therapies and diagnostic approaches tailored to women's cardiovascular biology, potentially preventing thousands of premature cardiac deaths annually.