Mitochondrial Function of the Failing Human Heart Shows Regional Differences

Objectives: In the heart, more than 95% of ATP is provided by mitochondria through oxidative phosphorylation. Impaired ATP production is associated with increased morbidity and mortality. Thus, mitochondrial energetics play a key role in heart failure influencing disease progression. Analysis of mitochondrial function in human tissue is very challenging due to limited availability. Therefore, human atrial appendage is frequently used to study mitochondrial function. However, it is not known whether human mitochondrial function of different cardiac regions is comparable. We compared respiratory capacity of mitochondria in three different regions of the human heart: the free left ventricular wall, interventricular septum and left atrial appendage from patients with end stage heart failure.

Methods: Heart muscle specimen (free left ventricular wall [LV], interventricular septum, left atrial appendage [LAA]) were obtained from patients (n = 10) undergoing heart transplantation. Mitochondrial subpopulations (interfibrillar [IFM], subsarcolemmal [SSM]) were isolated with differential centrifugation. Citrate synthase activity was assessed and mitochondrial respiratory capacity was determined using different substrates. Mitochondrial morphology was examined via flow cytometry.

Results: Citrate synthase activity was highest in LV followed by septum and LAA (48.8 ± 5.4 vs. 34.9 ± 2.3 vs. 29.6 ± 2.9). Maximal respiratory capacity of IFM was higher compared to SSM regardless of the substrate used for fueling the respiratory chain or region of the heart. Comparing different regions of the heart, respiratory capacity of septum was more similar to LV than to LAA. Respiratory capacity of IFM and SSM in LAA was increased compared to LV. This was true for complex I substrate pyruvate and complex II substrate succinate as well as complex IV substrate TMPD. ADP-limited respiratory capacity was highest in LAA. Coupling of the respiratory chain to ATP production, evaluated by ATP/O ratio, was not different in IFM and SSM between all myocardial samples. Finally, IFM as well as SSM from LV tended to have the largest size and complexity.

Conclusions: Mitochondrial function differs within the heart depending on the region. There appear to be an association with the mechanical demand placed on the region (LAA vs Ventricle). Thus, for human studies aimed at investigating mitochondrial function, sample selection requires special care since regional findings may not be transferrable.

No conflict of interest has been declared by the author(s).