Environmental factors are the largest contributors to cardiovascular disease. Here, we show that cardiac organoids incorporating an oxygen-diffusion gradient and stimulated via the neurotransmitter norepinephrine can structurally model the human heart after myocardial infarction (mimicking the gradient of infarct, border, and remote zones), and recapitulate hallmarks of myocardial infarction (such as pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also demonstrate that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could aid drug screening and development.