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Association of Exercise Preconditioning With Immediate Cardioprotection: A Review. Importance: Exercise reduces the risk of cardiovascular events, including through an underrecognized, clinically useful form of acute cardioprotection accessible after a single episode of exercise, which is called cardiovascular preconditioning. Observations: Preclinical evidence shows that 1 to 3 episodes of exercise per week will provide strong cardioprotection; gradual, modest cardiovascular risk factor modification or physiological artery remodeling cannot fully explain these benefits. This review highlights preclinical evidence that acute exercise-induced cardiac preconditioning has the ability to activate multiple pathways to confer immediate protection against ischemic events, reduce the severity of potentially lethal ischemic myocardiac injury, and act as a physiological first line of defense. Conclusions and Relevance: Independent of the protective benefits of long-term exercise training on risk factors and adaptation of the cardiovascular system, cardiovascular preconditioning may contribute to the immediate cardioprotection of exercise. In practical terms, this means that 1 episode of exercise can create clinically relevant cardioprotection.