OBJECTIVES: The objective of this study was to use electrocardiogram (ECG)-independent parameters to determine whether preconditioning (PC) exists in humans during percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Several studies suggest that both ischemia and adenosine induce PC in the human heart during PTCA. However, because almost all of these studies relied on ST-segment shifts as indicators of the severity of ischemia, their conclusions continue to be questioned, and the very existence of ischemic or adenosine PC in humans remains controversial. METHODS: Eighteen patients received either intracoronary adenosine (n = 9) or normal saline (n = 9); 10 min later, they underwent PTCA (three 2-min balloon inflations 5 min apart). RESULTS: Compared with the first inflation, in untreated patients the second and third inflations were associated with less systolic dysfunction (two-dimensional echocardiography), less diastolic dysfunction (color M-mode echocardiography), less lactate production, and less H+ release into the great cardiac venous blood. In adenosine-treated patients, the extent of all of these abnormalities during the first inflation was less than in untreated patients and did not change with subsequent inflations. CONCLUSIONS: Previous exposure to a brief episode of ischemia (first balloon inflation) or to adenosine produces concordant decreases in ECG, subjective, mechanical, and metabolic manifestations of ischemia during PTCA. These data support the concept that both ischemic PC and pharmacologic PC exist in humans and that PTCA is a useful clinical setting in which to discern their mechanism. © 2003 by the American College of Cardiology Foundation.