Scheiber 2017 Europ Heart J
|High-resolution respirometry in human endomyocardial biopsies to assess myocardial mitochondrial function.|
Event: Europ Heart J
Heart failure (HF) is a rising medical and societal burden. The heart cycles about 6kg of ATP every day and myocardial energy demand exceeds that of any other organ. A pivotal role of mitochondrial respiratory chain dysfunction in HF patients has been suggested, but human studies are limited to samples assessed from heart surgery and provide contradictory results.
To establish gold-standard analysis of mitochondrial respiration in endomyocardial biopsies (EMB) for a better understanding of energy metabolism in heart failure patients, setting the platform for future studies in larger patient cohorts.
(1) Analysis of myocardial mitochondrial respiration using goldstandard high-resolution respirometry (HRR) is feasible in EMB of the interventricular septum. (2) Mitochondrial oxidative capacity is decreased in end stage HF patients compared to patients with normal left ventricular (LV) function.
We included 12 terminal HF patients suffering from ischemic (ICM 75%) or dilated (DCM 25%) cardiomyopathy undergoing left ventricular assist device (LVAD) surgery (mean age: 55±3 years; 11males, mean body mass index [BMI]: 26,6±1,2kg/m2; cardiac index [CI]: 1,5±0,1l/min*m2) and 12 heart transplant (HTX) recipients (mean age: 53±5 years; 9males, BMI: 24,3±1,0kg/m2; CI: 2,8±0,2l/min*m2, p<0.0001 compared to HF) with normal LV function without histological signs of transplant rejection. Tissue samples were obtained during LVAD surgery or routine EMB following HTX. Analysis of maximal mitochondrial oxidative capacity on citrate cycle derived substrates and octanoylcarnitine was performed ex vivo on permeabilised myocardial muscle fibres using HRR. To assess the impact of tissue acquisition on mitochondrial oxidative capacity, we compared excised myocardial samples to endoscopic harvested biopsies using an EMB bioptome in LV apex samples of LVAD patients. Aditionally, we compared oxidative capacity of LVAD- and HTX patients with normal LV function, correlating the results to CI measurements.
Mitochondrial respiration in excised versus endoscopic harvested myocardial tissue samples of LVAD patients yielded the same results (correlation: r=0,9988, p<0,0001) with preserved outer mitochondrial membrane integrity tested by cytochrome c substitution. State III respiration on glutamate and succinate was decreased by 30% in end stage HF patients compared to HTX patients with normal LV function (121±2 vs. 173±17 pmol/[s*mg], p<0.05) with a strong positive correlation to CI measurements (r=0,54, p<0,05).
HRR in human ventricular biopsy samples is feasible and provides comparable results to standard tissue aquisation. In end stage HF patients suffering from ICM or DCM mitochondrial function is altered with decreased state III respiration. This technique will therefore allow analysing larger patient cohorts with different aetiologies of HF to unravel the impact of mitochondrial respiration on HF pathophysiology.
Labels: MiParea: Respiration, Patients Pathology: Cardiovascular
Organism: Human Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: OXPHOS Pathway: F, N, NS HRR: Oxygraph-2k