Stunned myocardium is a syndrome of reversible contractile failure that frequently complicates coronary artery disease. Cardiac excitation is uncoupled from contraction at the level of the myofilaments. Selective proteolysis of the thin filament protein troponin I has been correlated with stunned myocardium. Here, transgenic mice expressing the major degradation product of troponin I (TnI1-193) in the heart were found to develop ventricular dilatation, diminished contractility, and reduced myofilament calcium responsiveness, recapitulating the phenotype of stunned myocardium. Proteolysis of troponin I also occurs in ischemic human cardiac muscle. Thus, troponin I proteolysis underlies the pathogenesis of a common acquired form of heart failure.