Cardiac Energetics in Patients With Aortic Stenosis and Preserved Versus Reduced Ejection Fraction

Abstract

Background: Why some but not all patients with severe aortic stenosis (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and flux is associated with this transition. Methods: We recruited 102 participants to 5 groups: moderate aortic stenosis (ModAS) (n=13), SevAS, left ventricular (LV) ejection fraction ≥55% (SevAS-preserved ejection fraction, n=37), SevAS, LV ejection fraction <55% (SevAS-reduced ejection fraction, n=15), healthy volunteers with nonhypertrophied hearts with normal systolic function (normal healthy volunteer, n=30), and patients with nonhypertrophied, non–pressure-loaded hearts with normal systolic function undergoing cardiac surgery and donating LV biopsy (non–pressure-loaded heart biopsy, n=7). All underwent cardiac magnetic resonance imaging and 31 P magnetic resonance spectroscopy for myocardial energetics. LV biopsies (AS and non–pressure-loaded heart biopsy) were analyzed for CK total activity, CK isoforms, citrate synthase activity, and total creatine. Mitochondria-sarcomere diffusion distances were calculated by using serial block-face scanning electron microscopy. Results: In the absence of failure, CK flux was lower in the presence of AS (by 32%, P =0.04), driven primarily by reduction in phosphocreatine/ATP (by 17%, P <0.001), with CK k f unchanged ( P =0.46). Although lowest in the SevAS-reduced ejection fraction group, CK flux was not different from the SevAS-preserved ejection fraction group ( P >0.99). Accompanying the fall in CK flux, total CK and citrate synthase activities and the absolute activities of mitochondrial-type CK and CK-MM isoforms were also lower ( P <0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity ( r =0.86, P =0.003). Conclusions: Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS and suggest that a fall in CK flux is not by itself a necessary cause of transition to systolic failure. However, because ATP demands increase with AS severity, this could increase susceptibility to systolic failure. As such, targeting CK capacity and flux may be a therapeutic strategy to prevent and treat systolic failure in AS.

Obesity modifies the energetic phenotype of dilated cardiomyopathy

“…This concept underpins the suggested role of energy metabolism in heart failure—that a mismatch between ATP delivery and supply may be the common pathway underlying systolic dysfunction. Insufficient energy supply, as measured by reduced myocardial phosphocreatine/ATP ratio (PCr/ATP) 1 and reduced ATP delivery through creatine kinase (CK), has not only been shown in the transition to heart failure in pressure overload 2 but has also been linked to mortality in dilated cardiomyopathy. 3 …”

CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases

“…The second finding identifies the capability of the cardiac metabolic network to generate ATP as the key link between systolic function and energy metabolism of the LV rather than the intracellular transport capacity of energy-rich phosphates by the creatine kinase shuttle, which was found to not be significantly different in patients with AS with preserved and reduced systolic function. 10 …”

Myocardial Energy Response to Glyceryl Trinitrate: Physiology Revisited

“…Spectral analysis was performed using the OXSA toolbox which uses a MATLAB implementation of the Advanced Method for Accurate, Robust and Efficient Spectral fitting algorithm (Purvis et al, 2017). Measurements of the CK forward rate constant k f were measured using a Triple Repetition Saturation Transfer (Schar et al, 2010) sequence with stress saturation transfer (Clarke et al, 2019) extension, as previously described (Peterzan et al, 2020;Rayner et al, 2020) and validated in human subjects (Clarke et al, 2019). A transmit/receive 31 P MRS coil with 17 cm loop transmit coil and 11 cm loop receive coil (Pulseteq, United Kingdom) was used.…”