Persistent and progressive dysfunction of mitochondria following brief episodes of hypoxia in dogs with chronic heart failure
H N Sabbah, R C Gupta, K Zhang, D E LanfearAbstract
Background
Acute exacerbation of heart failure (HF) defined as worsening of chronic HF and requiring hospitalization, includes symptoms and/or signs of congestion and volume overload. Understanding the potential adverse consequences of congestion is essential for the development of new therapies to better treat these patients. Congestion can cause dyspnea but also hypoxia at the organ level. We and others have shown that even under normoxic conditions, constituent mitochondria (MITO) of the heart, kidneys and circulating monocytes are dysfunctional in HF leading to energy deprivation and potentially contributing to progressive worsening of HF.
Purpose
This study tested the hypothesis that exposure of dogs with chronic HF to brief episodes of hypoxia (HX) results in profound worsening of MITO function.
Methods
Circulating blood monocytes were isolated from 6 HF dogs (LV ejection fraction ~30% and 6 normal (NL) dogs. Monocytes were obtained at baseline and at 1, 2, and 3 weeks after exposure (during anesthesia) to 6 hours of hypoxia (HX: SpO2 reduction from 99±1% to 88±1%) or normoxia (NX: SpO2 99±1%). MITO oxygen consumption rates were measured in all samples using high-resolution respirometry. MITO bioenergetic health index (BHI), a measure of MITO energy production, was calculated as the ratio: (ATP-linked respiration X reserve capacity)/(proton leak X non-mitochondrial respiration), for all samples from all dogs.
Results
Under NX condition, BHI was not significantly different at 1, 2 and 3 weeks in NL or HF dogs compared to baseline. Under HX conditions, BHI in NL dogs decreased to from 57±4 to 31±2 at 1 week (p<0.05), recovered to 39±1 (p<0.05) at 2 weeks and returned to baseline to 65±3 at 3 weeks. Under HX conditions, BHI decreased to from 23±1 to 21±1 at 1 week, further decreased to 20±1 at 2 weeks and fell further to 15±1 (p<0.05) at 3 weeks.
Conclusion
The results indicate that brief periods of HX in dogs with chronic HF can cause sustained and progressive worsening of MITO function. This finding suggests that in patients hospitalized for worsening HF who present with HX may be at high risk of further MITO injury that can lead to deepening energy deprivation. The latter can result in worsening of LV function after hospital discharge may contribute to the need for re-hospitalization.