Mitochondrial Function in Human Heart Failure is Dependent on Etiology, Severity, and the Presence of Diabetes

Objectives: Heart failure is a complex multisystem clinical syndrome and characterized by energy deprivation. It is not surprising, that mitochondria as ATP delivering organelles, display compromised function. Furthermore, it is known that mitochondrial function is compromised with diabetes. The relationship between heart failure and diabetes is bidirectional with an increased risk of heart failure patients to develop additional diabetes. However, it is not known how respiratory capacity of mitochondria may be influenced by diabetes in heart failure patients. Furthermore, factors like etiology and severity of heart failure may also be associated with changes in mitochondrial function. Our aim was to assess the effect of diabetes, as well as etiology, and severity of disease on mitochondrial function in heart failure patients.

Methods: Left ventricular heart biopsies were obtained from patients undergoing LVAD implantation (n = 31). Mitochondria were isolated with differential centrifugation. Citrate synthase activity was assessed and mitochondrial respiratory capacity was determined using specific substrates. Patient characteristics (etiology, presence of diabetes, and INTERMACS) were determined directly before LVAD implantation.

Results: Citrate synthase activity as a marker of mitochondrial mass was unchanged independent of conditions. Maximal respiratory capacity of mitochondria in patients with ischemic (ICM) heart failure was lower compared to dilative (DCM) heart failure (ICM vs. DCM: palmitoylcarnitine/malate: 655 ± 51 vs. 471 ± 20 natomsO/min/mg protein). Such changes were present for respiratory capacity with all complex specific substrates. Interestingly, heart failure patients with diabetes presented with reduced respiratory capacity and increased ADP limited respiration indicating impaired control of mitochondrial activity. In addition, more severe heart failure (INTERMACS levels 1–2 compared to 3–4) was associated with significantly lower ADP/O ratios with glutamate and palmitoylcarnitine as specific complex-I substrates, indicating lower efficiency of ATP production per oxygen consumed.

Conclusion: In heart failure diabetes, ICM and more severe disease are associated with deterioration of mitochondrial function. Thus, mitochondrial function may be an important target for heart failure therapy.