Sleep disorders are associated with increased morbidity and mortality from coronary heart disease, but the underlying mechanisms are not fully understood. Cuproptosis, a copper-dependent form of cell death, has been implicated in myocardial injury. This study investigated the role of sleep fragmentation (SF) in exacerbating myocardial ischemia-reperfusion (MI/RI) injury and the molecular mechanisms involved. Chronic SF in male mice led to elevated copper levels in the heart, increased myocardial cuproptosis and apoptosis, and worsened MI/RI outcomes. Mechanistically, SF promoted sympathetic overactivity, increased the germination of myocardial sympathetic nerve terminals, and elevated norepinephrine levels, which inhibited VPS35 expression and impaired ATP7A-related copper transport, leading to copper overload in cardiomyocytes. Copper overload further exacerbated cuproptosis and apoptosis, which could be rescued by sympathetic nerve excision or copper chelation. The study highlights the brain-heart interaction in sleep disorders and suggests potential therapeutic targets for intervention.Sleep disorders are associated with increased morbidity and mortality from coronary heart disease, but the underlying mechanisms are not fully understood. Cuproptosis, a copper-dependent form of cell death, has been implicated in myocardial injury. This study investigated the role of sleep fragmentation (SF) in exacerbating myocardial ischemia-reperfusion (MI/RI) injury and the molecular mechanisms involved. Chronic SF in male mice led to elevated copper levels in the heart, increased myocardial cuproptosis and apoptosis, and worsened MI/RI outcomes. Mechanistically, SF promoted sympathetic overactivity, increased the germination of myocardial sympathetic nerve terminals, and elevated norepinephrine levels, which inhibited VPS35 expression and impaired ATP7A-related copper transport, leading to copper overload in cardiomyocytes. Copper overload further exacerbated cuproptosis and apoptosis, which could be rescued by sympathetic nerve excision or copper chelation. The study highlights the brain-heart interaction in sleep disorders and suggests potential therapeutic targets for intervention.