Progressive deterioration of left ventricular (LV) function is a characteristic feature of the heart failure (HF) state. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known but may be related to progressive intrinsic dysfunction, degeneration and loss of viable cardiocytes. In the present study, we tested the hypothesis that accumulation of collagen in the cardiac interstitium (reactive interstitial fibrosis, RIF), known to occur in HF, results in reduced capillary density (CD = capillary/fiber ratio) and increased oxygen diffusion distance (ODD) which can lead to hypoxia and dysfunction of the collagen encircled myocyte. Studies were performed in LV tissue obtained from 10 dogs with chronic HF (LV ejection fraction 26 +/- 1%) produced by multiple sequential intracoronary microembolizations. In each dog, CD and ODD were evaluated in LV regions that manifested severe RIF (volume fraction 16 +/- 2%) and in LV regions of little or no RIF (volume fraction 4 +/- 1%). In regions of severe RIF, CD was significantly decreased compared to regions of no RIF (0.92 +/- 0.02 vs. 1.05 +/- 0.03) (P < 0.003). Similarly, ODD was significantly increased in regions of severe RIF compared to regions of no RIF (15.3 +/- 0.4 vs. 12.2 +/- 0.3 microns) (P < 0.001). These data suggest that in dogs with chronic HF, constituent myocytes of LV regions which manifest severe RIF may be subjected to chronic hypoxia; a condition that can adversely impact the function and viability of the collagen encircled cardiocyte.