Decreased mitochondrial oxidative phosphorylation capacity in the human heart with left ventricular systolic
Nis Stride1, Steen Larsen, Martin Hey-Mogensen
1Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3b, DK-2200 Copenhagen, Denmark. nis.stride@gmail.com
Insights
Heart failure with left ventricular systolic dysfunction (LVSD) is linked to reduced mitochondrial oxidative phosphorylation (OXPHOS) capacity, especially in fatty acid metabolism. This suggests mitochondrial dysfunction contributes to the energetic deficit in heart failure.
Area of Science:
- Cardiology
- Mitochondrial Biology
- Biochemistry
Background:
- Heart failure (HF) with left ventricular systolic dysfunction (LVSD) involves altered substrate utilization and energy production.
- The role of mitochondrial dysfunction in the cardiac phenotype of LVSD remains unclear.
Purpose of the Study:
- To investigate mitochondrial oxidative phosphorylation (OXPHOS) capacity in LVSD myocardium.
- To compare OXPHOS capacity in patients with and without LVSD.
Main Methods:
- Myocardial biopsies from LVSD (LVEF <45%) and control (LVEF >45%) patients.
- Measurement of mitochondrial respiration using non-fatty acid substrates and medium-chain fatty acid (MCFA).
- Assessment of mitochondrial creatine kinase (miCK) capacity.
Main Results:
- Maximal OXPHOS capacity with non-fatty acid substrates was significantly lower in LVSD patients.
- MCFA oxidation elicited approximately 40% lower respiration in LVSD compared to controls.
- ADP sensitivity for miCK was highest in the LVSD group.
Conclusions:
- Human LVSD exhibits significantly diminished OXPHOS capacity, particularly in MCFA oxidation.
- This finding provides a potential mechanism for the compromised energetic state observed in HF.
- Reduced reliance on fatty acid utilization may be a hallmark of HF with LVSD.
Aims:
Heart failure (HF) with left ventricular systolic dysfunction (LVSD) is associated with a shift in substrate utilization and a compromised energetic state. Whether these changes are connected with mitochondrial dysfunction is not known. We hypothesized that the cardiac phenotype in LVSD could be caused by reduced mitochondrial oxidative phosphorylation (OXPHOS) capacity and reduced mitochondrial creatine kinase (miCK) capacity. The study aim was to test mitochondrial OXPHOS capacity in LVSD myocardium compared with OXPHOS capacity in a comparable patient group without LVSD.
Methods And Results:
Myocardial biopsies were obtained from the left ventricle during cardiac valve or left ventricular assist device (LVAD) surgery. Patients were stratified according to left ventricular ejection fraction (LVEF) into LVSD (LVEF <45%, n = 14) or CONTROL (LVEF >45%, n = 15). Mitochondrial respiration was measured in muscle fibres with addition of non-fatty acid substrates or octanoyl-l-carnitine, a medium chain fatty acid (MCFA). The in situ enzyme capacity of miCK was determined from APD titrations in the presence or absence of creatine. Maximal OXPHOS capacity with non-fatty acid substrates was lower in the LVSD group compared with the CONTROL group (P ≤ 0.05). ADP sensitivity always increased significantly (P ≤ 0.05) with the addition of creatine, after which the sensitivity was highest (P ≤ 0.05) in LVSD compared with CONTROL. The stimulation of OXPHOS from octanoyl-l-carnitine titrations elicited ∼40% lower respiration in LVSD compared with CONTROL (P ≤ 0.05).
Conclusion:
Human LVSD is associated with markedly diminished OXPHOS capacity, particularly in MCFA oxidation. This offers a candidate mechanism for a compromised energetic state and decreased reliance on fatty acid utilization in HF.
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