Response by Peterzan et al to Letter Regarding Article, “Cardiac Energetics in Patients With Aortic Stenosis and Preserved Versus Reduced Ejection Fraction”
Authors: Mark A. Peterzan, Stefan Neubauer, Christopher T. Rodgers, Oliver J. Rider
Journal: Circulation (2020)

We appreciate the interest and comments by Mahmood in regard to our recent article. 1 In this study, we have shown not only that cardiac energetics are impaired early in the aortic stenosis (AS) disease process, being present in a group of patients with moderate aortic stenosis, but also that transition to systolic failure in severe AS is not dependent on further energetic decline.Although Mahmood points out correctly that energetic impairment was not a "necessary correlate of systolic failure as assessed by LV [left ventricular] ejection fraction (LVEF)," this does not imply that it is unrelated.We would like to clarify that, because ATP demands increase with AS severity, a reduction in the capacity to deliver ATP to the myocardium, as established early in the process of AS, could increase susceptibility to systolic failure when the increasing ATP demand exceeds supply.We entirely agree that LV strain is a valuable measure in AS and related to mortality.We would simply point out that this study already presents data showing that cardiac magnetic resonance-derived global circumferential strain is related to biopsy-derived creatine kinase (CK) capacity (r=-0.52,P=0.001; Figure III in the Data Supplement).Whether CK capacity is related to mortality in AS, as it is in heart failure, 2 remains unknown.Although Mahmood is also correct that in this study "myocardial energetics assessed by the phosphocreatine to adenosine triphosphate ratio were lower in severe AS with reduced LVEF than in the non-pressure-loaded heart" but were "not different than severe AS with preserved LVEF," we would like to elaborate on 2 points.First, the phosphocreatine (PCr)/ATP measurement is a reflection of metabolite pool size, and as such a reduced PCr/ATP is, in the absence of heart failure, reflective of decreased PCr pool size.However, because ATP levels are known to be lower in heart failure, 3 a pseudonormalization of PCr/ATP occurs, making comparison across groups more complex.Because flux through the CK system is arguably a more important variable than metabolite pool size alone, this was the rationale for this study measuring both CK k f and CK total unidirectional forward flux, 4 in addition to simply PCr/ATP.We agree that correlating echocardiography-derived strain with energetics is a sound idea and that investigation of the role of energetics in timing surgical intervention is also worthy of investigation.We would, however, highlight that, although 31 P magnetic resonance spectroscopy is currently the only noninvasive way of measuring myocardial energetics, it suffers from low sensitivity and signal-tonoise ratio, and currently available techniques lack the sensitivity to reliably discern individual patient variations.With recent advances in ultrahigh field 31 P magnetic resonance spectroscopy, 5 individual patient assessment of energetics, including Gibbs free energy of ATP hydrolysis and the dynamics of the ATP synthesis and hydrolysis in the human heart in vivo are now becoming possible.