The human heart requires a considerable amount of energy (10 W at rest to 100 W during exercise) for basal metabolism, activation processes and work to circulate blood (heart rate × stroke volume × arterial blood pressure). The energy is released by oxidation of fatty acids, lactate and glucose and is transferred to ATP in the mitochondrial matrix. Heat is liberated in oxidative phosphorylation of ADP – normal mitochondrial efficiency is about 75% – increasing myocardial temperature. When the ATP is used to do any work (mechanical, chemical or osmotic), at least part of the free energy of ATP hydrolysis is also released as heat. Measurement of heat production by heart muscle has already yielded important information on cardiomyocyte function and malfunction. The interpretation of heat produced by cardiomyocytes involves identification of the heat source, which is complicated because basal metabolism, activation processes, contraction and metabolic recovery processes occur simultaneously. In this issue of The Journal of Physiology, Pham et al. (2017) report important progress: they demonstrate how activation heat can be determined at different sarcomere lengths in isolated myocardial trabeculae of the rat.
Activation heat is the heat associated with an action potential, calcium release into the cytosol, and the lowering of the cytosolic calcium concentration by the Na+–Ca2+ exchanger, sarcoplasmic reticulum and sarcolemmal calcium pumps, and mitochondrial heat due to ATP formation for the ion fluxes. Mitochondrial calcium cycling may also contribute, reducing mitochondrial efficiency. Activation heat has previously been estimated by reducing the length of the myocardial preparation until force production becomes undetectable. This estimate is based on the assumptions that cross‐bridges do not contribute to heat production at very short sarcomere length, and that calcium release from the sarcoplasmic reticulum is independent of sarcomere length. An alternative method is the use of butanedione monoxime (BDM), which reversibly inhibits cross‐bridge cycling and is generally used in the dissection of heart muscle preparations. However, the affinity of BDM for myosin is low, which requires either a high concentration to inhibit cross‐bridge cycling completely (50 mm) or a series of measurements with lower concentrations and extrapolation to zero force. Unfortunately, as discussed by Pham et al., BDM is not specific at the concentration required to determine activation heat because it is a chemical phosphatase and may have osmotic effects on basal heat production.
The Auckland based investigators developed an extremely sensitive (thermal resolution 10 nW) flow‐through calorimeter allowing the determination of force as well as heat at different sarcomere lengths. The determination of activation heat can be accomplished following the discovery of the myosin II inhibitor blebbistatin (Straight et al. 2003) and the observation that blebbistatin does not affect calcium transients in cardiomyocytes (see Pham et al. for references). Blebbistatin is a light sensitive but otherwise irreversible myosin II inhibitor; 15 μmol l−1 is sufficient to inhibit force development of myocardial preparations completely. Pham et al. show that activation heat is similar in preparations from the left and right side of rat heart at physiological temperature and heart rate and is independent of sarcomere length.
Millions of people suffer from chronic heart failure. Energy metabolism is compromised in the hearts of these patients (Neubauer, 2007) and mechanical efficiency (work for pumping/energy input) may be reduced (Knaapen et al. 2007; Wong et al. 2011). The causes of the energy deficit and efficiency reduction are usually not precisely known, and therefore possibilities for targeted therapy are limited. Any type of suboptimal functioning of a cardiomyocyte organelle is likely to reduce myocardial efficiency, and fundamentally different treatments will be optimal depending on, for instance, malfunctioning of the sarcoplasmic reticulum calcium cycling, contractile filaments, or mitochondria.
Since it is now possible to determine activation heat in isolated heart muscle preparations, it is also possible to determine cross‐bridge heat under steady state conditions by subtraction, and to determine mechanical efficiency of the cross‐bridges. When mitochondrial efficiency is reduced, activation heat will increase and cross‐bridge efficiency will decrease.
The advantage of the trabecular preparation is that cardiomyocytes are arranged in parallel to the longitudinal axis of the muscle and that the preparations are sufficiently thin to prevent the occurrence of hypoxic cores. The number of studies using isolated intact myocardial preparations (papillary muscles and trabeculae) to investigate energetics peaked around 1990. Nowadays the preparations are used only in a few laboratories. In view of the effort to improve the therapy of chronic heart failure, a revival of the use of the preparation can be anticipated. The separation of myocardial energy fluxes will allow the discovery of the origin of derangements of fluxes in chronically failing hearts. In addition, effects of interventions can be tested in various models of chronic heart failure in vitro. This is expected to improve targeted therapy of chronic heart failure.
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Competing interests
None declared.
Linked articles This Perspective highlights an article by Pham et al. To read this article, visit https://doi.org/10.1113/JP274174.
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