Seamless networks of myocardial bioenergetics

One of the least settled questions in cardiovascular physiology is which steps in the cascades of ATP production, transport and utilization limit the maximum performance of a normal heart or contribute to the dysfunction of a failing heart. In this issue of The Journal of Physiology, Dzeja et al. (2011) bring us one step closer to unravelling the seamless web of myocardial oxidative phosphorylation (OXPHOS) turnover. Using state of the art methods with ¹⁸O and ¹³C isotopes, ³¹P-NMR, and mass spectrometry, these investigators elegantly demonstrate the intricate networks of mitochondrial ATP production, such that the removal of one pathway can stimulate and activate multiple compensatory mechanisms in the maintenance of a normal total high energy phosphate turnover rate. By using engineered mouse models lacking creatine kinase isoforms, they demonstrate the relationship between diminished PCr turnover rate, phosphotransfer capacity, and the level of increase of dynamics of β-phosphoryls of ADP/ATP and G-6-P, and γ-/β-phosphoryls of GTP, thus suggesting compensatory turnover pathways of high energy phosphate through adenylate kinase (AK), glycolytic and guanine nucleotide phosphotransfer. This is a masterpiece of biochemical investigation which definitively demonstrates the robustness of energetic pathways at the cellular level.

What factors regulate mitochondrial ATP production in the normal in vivo heart? This question has been puzzling scientists for over half a century, and yet we still do not have a consensus. The heart is the organ that pumps 10 tons of blood every day; it has the highest ATP turnover rate. Balaban et al. (1986) used nuclear magnetic resonance (NMR) spectroscopy to monitor the concentration of creatine phosphate (PCr) and ATP during a stepwise increase in cardiac work states of canine hearts in vivo. Over a cardiac work state range of rate-pressure products (RPP) of 5000–25,000 mmHg beats min^-1, the myocardial concentrations of PCr and ATP remained unchanged, as well as the relative concentration of free adenosine diphosphate (ADP), suggesting that factors other than the concentrations of these compounds are involved in the regulation of the rate of mitochondrial OXPHOS within the range of the cardiac work state being studied. Remarkable stability of intracellular PCr and ATP/ADP contents during heart workload and respiration rate changes (Balaban et al. 1986) suggest that efficient energetic signal communication systems operate between ATP consumption and ATP synthesis sites with minimal concentration gradients (Dzeja & Terzic, 2003). However, in dogs the cardiac work state can reach levels much higher than the range being investigated. In fact, these investigators and others (Zhang et al. 1999) later found that beyond this range of high cardiac work state (greater than 50,000 mmHg beats min^-1), the myocardial free ADP level does indeed change, suggesting that at very high work states myocardial free ADP may participate in the regulation of mtOXPHOS in normal in vivo hearts. Beside adenine nucleotide and P_i signals, which may provide direct and strictly stoichiometric account of energy utilization and transformation balance, another regulator of cell energy metabolism is intracellular Ca²⁺, which surges during stress, activates a number of metabolic enzymes and primes energetic system for anticipated energy usage increase (Saks et al. 2006).

From the cardiovascular physiological perspective, the question is: Do limitations in the pathways of ATP turnover cause the dysfunction of failing hearts?Ingwall et al. (1985) compared myocardial creatine kinase activity, isozyme composition, and total creatine content in myocardial biopsy samples from normal hearts and hearts of patients with severe left ventricular hypertrophy (LVH), and first reported that changes in the myocardial creatine kinase system occur in LVH patients. Using a canine model of severe LVH secondary to pressure overload, Zhang et al. (1993) demonstrated that in vivo LVH hearts are associated with myocardial energetic inefficiency characterized by a decrease in myocardial PCr/ATP ratio, which is linearly related to the severity of LV chamber dysfunction and hypertrophy, but is independent from the persistent myocardial ischaemia. The question of whether the stepwise blockade of the CK system could result in a dose response LV chamber dysfunction in the in vivo normal heart was examined recently by Xiong et al. (2011). Within an observation window of 30 min, both normal LV systolic pressure and LV ejection fraction, as well as the myocardial high energy phosphate levels and PCr/ATP ratio, were maintained despite the complete inhibition of CK activity by iodoacetamide (IAA), as evidenced by undetectable CK forward flux, suggesting that CK inhibition alone does not restrict LV chamber function acutely in the in vivo normal heart. So what is going on? The report by Dzeja et al. sheds new light on this question. Namely, when one of the important pathways in the bioenergetics networks is removed (in this case the CK system), the supporting systems of AK, glycolytic and guanine nucleotide phospho-transfer pathways are all activated in support of the demand for high energy phosphate at the contractile apparatus end.

Are failing hearts energy starved? I believe so, considering the existing evidences. However, such a statement remains unsubstantiated, as within the in vivo heart, redundant multiple support systems of myocardial ATP production, transport and utilization exist, such that inhibition of one mechanism does not impair the LV chamber contractile performance. In the in vivo failing heart, the robust ATP turnover systems, such as CK, mitochondrial electron transport system, AK, glycolytic and guanine nucleotide phosphotransfer pathways, may all be impaired. Consequently, the severity of each of the alterations of these systems contributes and relates to the severity of the LV dysfunction of failing hearts. Therefore, from a translational perspective future therapies aimed at reducing the energy demand of the failing ventricle, to synchronize to ATP delivery rate, are more likely to work better than those aiming at increasing one of the pathways of ATP production.