Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

Abstract

Cardiac mechanical function is supported by ATP hydrolysis, which provides the chemical free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the capacity for ATP synthesis and associated free energy to drive cellular processes. Yet it remains unclear if and how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. We hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic constriction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to assess relationships between metrics of whole-organ pump function and myocardial energetic state. A multi-scale computational model of cardiac mechano-energetic coupling was used to identify and quantify the contribution of metabolic dysfunction to observed mechanical dysfunction. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates as well as a reduction in total levels of adenine nucleotides and creatine in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats are correlated with impaired mechanical function, consistent with the overall hypothesis. Furthermore, computational analysis of myocardial metabolism and contractile dynamics predicts that increased levels of inorganic phosphate in TAC compared to control animals kinetically impair the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.

A Journalistic Break Through

“…This issue of Function will found a journalistic effort aimed at resolving a long-standing challenge of how to publish complex computer models and simulations together with the related experimental studies required for validation of these models. The studies by Lopez et al “Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts” 1 were based upon hypotheses developed from a multiscale mathematical model. Using this combination of computer simulation and experimental studies the investigators were able to integrate the mechanistic effects of changes of adenosine triphosphate, adenosine diphosphate, and phosphate levels with crossbridge kinetics, muscle dynamics, and whole-organ cardiac function observed in the failing heart.…”

“…First, most physiologists/biochemists/molecular biologists are not mathematically trained. Second, for those that are a rigorous and detailed exposition of computational models as complex as that employed by Lopez et al 1 can easily overshadow the important experimental aspects of the study. Likewise, an evaluation of the rigor and fidelity of mathematical and computational aspects of analyses such as these can overwhelm a review process that should be primarily focused on the significance of the hypotheses and the credibility of the experimental results and conclusions.…”

Computational/Experimental Interrogation of the Failing Heart—A Perspective on “Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts”

“…The article by Lopez et al “Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts” 1 contributes importantly to our understanding both conceptually and experimentally. Using a rodent model of heart failure produced by transverse constriction of the aorta (TAC), the authors have provided strong evidence that with the reduction of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) in the failing heart, there was a compensatory buildup of inorganic phosphate (Pi).…”

“…This has provided a unique quantitative and mechanistic framework upon which complex relationships can be predicted and experimentally tested. The different components of the overall system illustrated in figure 1 of Lopez et al 1 were modularly developed and scaled to determine the effects of alterations of myocyte metabolic function upon whole-organ metabolic function, and the computation of these effects drove the module that determined the emergent properties of cardiac ventricular function including the ventricular–ventricular mechanical interactions and the related stress-strain relationships of the intact heart. The modules representing the metabolic functions of the cell were represented in great detail which is the strongest aspect of this analysis.…”

“…The utility of this combined experimental-computational approach is nicely demonstrated in figure 8 of Lopez et al 1 describing data on myocyte phosphate metabolite pools and mitochondrial oxidative capacity which were utilized in the model of myocardial energetics to thereby predict the cytosolic ATP, ADP, and Pi concentrations. By comparing the energetic phenotypes of the sham rats to those of the TAC heart failure rats, the causal relationships underlying these predictions were determined.…”