Similar Patterns of Mitochondrial Dysfunction in Heart Failure of Rats and Humans

Objective: Impaired mitochondrial energy production characterizes heart failure and is associated with increased morbidity and mortality. However, analyzing vital human tissue especially heart muscle poses some challenges. Significance of animal heart failure models for disease assessment in human is questionable and transferability of the results remains unclear. We compared cardiac mitochondrial respiratory capacity of end stage heart failure patients undergoing LVAD-implantation or heart transplantation with our heart failure rats.

Methods: Heart muscle biopsies were obtained from patients undergoing LVAD implantation (n = 18) or heart transplantation (n = 2). In rats, heart failure was induced by transverse aortic constriction. Heart failure was diagnosed clinically and echocardiographically. Mitochondrial subpopulations interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria were isolated with differential centrifugation. Citrate synthase activity was assessed and mitochondrial respiratory capacity was determined using different substrates.

Results: After 20 weeks of pressure overload, there was significant evidence for heart failure in rats, characterized by lung congestion (lung weight increased by 165%, p < 0.001) and reduced ejection fraction (control vs. PO EF 68.2 ± 2.0 vs. 47.8 ± 1.6; p < 0.001). Mitochondrial respiration was significantly reduced in heart failure (state 3 respiration pyruvate IFM 717 ± 108 vs. 198 ± 15, p < 0.01 SSM 407 ± 72 vs. 185 ± 14, p < 0.01) and there was significantly more reduction in IFM. In humans, similar values were obtained for the two subpopulations isolated from the intraoperative samples. Importantly the heart failure induced equalization of state 3 respiration in rats between SSM and IFM was also present in human samples. Uncoupling with DNP was able to increase respiratory capacity in both human mitochondrial subpopulations, indicating that ATP synthase was one factor limiting respiratory capacity. In rats, respiratory capacity was also limited.

Conclusion: Heart Failure is associated with significant impairment of mitochondrial function in failing heart muscle in rats. Human failing myocardium displays the same mitochondrial signature. Although a true control group is missing, the results suggest significant disturbances also in human mitochondrial function and also imply that the rat model of pressure overload heart failure may be clinically relevant.