Mechanical Unloading of the Human Left Ventricle Reduces Maximal Respiratory Chain Capacity but Optimizes ATP Producing Machinery

Objectives: In heart failure (HF), reduced left ventricular ejection fraction (LVEF) is associated with inadequate energy production of the cardiac muscle. Mitochondria, delivering the majority of ATP, are compromised. Implantation of a left ventricular assist device (LVAD) is one of two ultimate treatment options able to normalize cardiac output. LVAD support also causes left ventricular unloading. We thus assessed the impact of mechanical unloading of the human left ventricle on mitochondrial function.

Methods: Heart muscle specimen of the left ventricle were obtained from HF patients undergoing LVAD implantation (chronic HF, CHF: n = 38) and patients undergoing cardiac transplantation from LVAD (LVAD unloading: n = 7). Mitochondrial subpopulations (interfibrillar [IFM], subsarcolemmal [SSM]) were isolated immediately after retrieval from the operating room with differential centrifugation. Citrate synthase activity was assessed and mitochondrial respiratory capacity was determined using different substrates.

Results: Patients were 59 ± 1.6 years, 93% were male, 39% had ischemic, and 61% dilative cardiomyopathy. Mean INTERMACS class was 3 ± 0.2. Mitochondria were successfully isolated in all samples. Citrate synthase activity as a marker of mitochondrial mass tended to be higher in left ventricle of patients with LVAD unloading (LVAD unloading vs. CHF: 47.1 ± 6.3 vs. 37.2 ± 3 U/g tissue). Independent of loading status, maximal respiratory capacity was higher in IFM compared with SSM. In LVAD unloaded patients, maximal respiratory capacity was lower with all measured substrates compared with CHF, consistent with less mechanical demands on the muscle with unloading. The lowest values were observed with complexes II, III and IV substrates (Succinate: LVAD vs. no LVAD: 459 ± 37 vs. 631 ± 32 natomsO/min/mg protein). However, coupling of the respiratory chain to ATP production as measured by the ATP/O ratio was higher in unloaded patients (pyruvate: LVAD vs. no LVAD: 1.71 ± 0.08 vs. 1.42 ± 0.04 nmol ATP/natoms O) suggesting better function of the ATP producing machinery. This observation was the same in IFM and SSM.

Conclusion: LVAD unloading in HF patients appears to result in optimization of the ATP producing machinery increasing efficacy of ATP production. Reduced maximal respiratory capacity in the unloaded state may reflect the reduced mechanical demands on the unloaded hearts. The results suggest that the failing heart maintains metabolic flexibility.