Oxygen Transport Impairment in the Failing Heart: A Histology-Image-Based Computational Analysis

Myocardial reactive interstitial fibrosis (RIF) is a common feature in heart failure (HF) and is associated with changes in the structure and function of the heart. The impact of interstitial space enlargement and accumulation of interstitial collagen on oxygen transport from capillaries to cardiomyocytes during RIF is not fully understood.

To address this issue, we developed a histology-image-based computer modeling approach to estimate the spatial profile of pO₂ in tissue samples from the myocardium of healthy dogs and dogs with HF.

The analysis shows that both interstitial space enlargement and RIF significantly limit tissue oxygenation, as evidenced by a ~ 47% lower pO₂ in cardiomyocytes from HF dogs compared to normal dogs. Tissue hypoxia is primarily driven by the enlargement of interstitial space for severe RIF. The reduction in tissue pO₂ for mild and moderate RIF, however, is primarily driven by the fibrosis-related functional changes in the oxygen diffusivity and maximum oxygen consumption rates. Multivariate linear regression shows cardiomyocyte pO₂ significantly drops with interstitial area fraction (IAF) and rises with capillary area fraction (CAF) (R² = 0.761, p = 0.003). Our analysis suggests the strong performance of the CAF/IAF ratio in predicting tissue oxygenation (r = 0.91, R² = 0.824, p = 0.0001) through the coupling of interstitial expansion-impaired diffusion with reduced microvascular oxygen supply per tissue volume.

These findings provide quantitative evidence that interstitial space enlargement and RIF substantially affect O₂ transport from capillaries to cardiomyocytes in HF that could lead to significant regional tissue hypoxia.