Cardioprotective pre-excitation pacing may be applied to stress or de-stress a particular myocardial region delivering of pacing pulses in a manner that causes a dyssynchronous contraction. Such dyssynchronous contractions are responsible for the desired cardioprotective effects of pre-excitation pacing but may also be hazardous. Described herein is a method and system that uses measures of ventricular dyssynchrony or a patient's physiological response to ventricular dyssynchrony to control the delivery of cardioprotective pre-excitation pacing in closed-loop fashion.