The existence of inhomogeneous distribution of coronary flow with antegrade or retrograde perfusion alone has led to alternating between these delivery routes to maximize their individual benefits. Concern over myocardial damage prevented the simultaneous application of antegrade and retrograde cardioplegic blood delivery. Based upon the predominance of retrograde drainage via Thebesian veins, and evidence that pressure-controlled intermittent coronary sinus occlusion during antegrade cardioplegic delivery enhances its distribution and protective properties, this study tests (a) the hypothesis that simultaneous aortic and coronary sinus perfusion is safe during aortic clamping, and (b) reports initial clinical application of this combined strategy in 174 patients. Five minipigs (25-30 kg) underwent 1 hr of aortic clamping with simultaneous aortic (antegrade) and coronary sinus (retrograde) perfusion at 200 ml/min with normal blood (37 degrees C) before and after 30 minutes of perfusion with either warm (37 degrees C) or cold (4 degrees C) blood cardioplegia (BCP). Furthermore, the combined strategy was used in 174 high-risk patients (NYHA class III-IV) at 3 university hospitals to perform myocardial protection during CABG or valve replacement, or a combination of both. Included were 16 patients in cardiogenic shock and 24 undergoing reoperation. In both the clinical and the experimental studies the coronary sinus pressure was always < 40 mmHg in beating or arrested hearts. Compared to control values (81.4 +/- 0.4% tissue water content), no right-ventricular (80.8 +/- 0.8%) or left-ventricular (79.5 +/- 0.3%) edema developed, no lactate was produced (control: -1.0 +/- 0.5 mg/100 g/min, empty beating: -0.64 +/- 5, and BCP arrest: -8.6 +/- 6.6).(ABSTRACT TRUNCATED AT 250 WORDS)