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

Figures

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  Figure 1.. A schematic of adenine nucleotide transfer pathways in the heart. This figure shows simple diffusion of ATP, ADP, and inorganic phosphate (Pi), and CK-facilitated transport operating in the ATP-generating direction (rate constant kf) and PCr-generating direction (rate constant kr). In oxidative muscle under normoxic conditions, cytosolic CK isoforms (CK-MM, -MB, -BB) typically work in the ATP-generating direction, whereas mitochondrial CK works in the PCr-generating direction. Forward CK flux is defined by kf×[PCr], where kf is the pseudo–first-order unidirectional rate constant in the ATP-generating direction measured using saturation transfer 31P magnetic resonance spectroscopy. This should be distinguished from CK total activity (VMax), which represents maximal velocity in the presence of saturating amounts of substrate and requires destructive freeze-extraction chemicals. ANT indicates adenine nucleotide transfer; CK, creatine kinase; PCr, phosphocreatine; and VDAC, voltage-dependent anion channel;

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  Figure 2.. Validation of noninvasive assessment of CK activity. A, Representative spectra constituting the triple repetition time saturation transfer method for estimating CK kf in a cardiac voxel of interest. B, Absolute CK activity measured from left ventricular biopsy correlated with CK capacity estimated by total creatine×kf (adjusted for supine scanning). Dante (Delays Alternating with Nutation for Tailored Excitation) is the pulse sequence used for selective saturation of γATP or the control position methods to assess, and in vivo CK capacity, which has been estimated as CK total activity×[total creatine]. CK indicates creatine kinase; 2,3-DPG, 2,3-diphosphoglycerate; PCr, phosphocreatine; and TR, repetition time.

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  Figure 3.. Cardiac magnetic resonance parameters for the study groups. LV ejection fraction (A). LV end-diastolic volume index (B), LV mass index (C), magnetic resonance spectroscopy–derived PCr/ATP ratio (D), CK kf (E), and forward CK flux (F) in nonhypertrophied, non–pressure-loaded healthy volunteer hearts (NHv),in non–pressure-loaded hearts with normal LVEF undergoing LV biopsy (NHBx), and in hearts with moderate AS (Mod-AS), SevAS with preserved (SevASpEF) and reduced (SevASrEF) ejection fraction. For between-group comparison, *P<0.05, **P<0.01, ***P<0.001; otherwise P>0.05. AS indicates aortic stenosis; CK, creatine kinase; LVEDVi, indexed left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LV, left ventricular; LVMi, left ventricular mass index; and PCr, phosphocreatine.

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  Figure 4.. LV biopsy obtained creatine concentration and CK and CS activities. CK total activity (A), CS activity (B), total creatine concentration (C), estimated CK capacity (D) from nonhypertrophied, non–pressure-loaded hearts (NH), severe aortic stenosis with preserved (SevAS-pEF) and reduced ejection fraction (SevAS-rEF) undergoing valve replacement surgery. *Post hoc pairwise tests significant versus NHBx. †Post hoc pairwise tests significant versus SevAS-pEF. CK indicates creatine kinase; and NHBx, non–pressure-loaded heart biopsy.

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  Figure 5.. CK isoform activities in the study groups. CK isoform activity (IU/mg protein) (A through D) and CK isoform activity relative to total CK activity (from left to right: MtCK, CK-MM, CK-MB, and CK-BB) in 1 control and 2 AS groups (E through H). *Post hoc pairwise tests significant versus NH. †Post hoc pairwise tests significant versus SevAS-pEF. AS indicates aortic stenosis; CK, creatine kinase; CK-MM, CK-MB, and CK-BB, creatine kinase MM, MB, and BB isoforms; MtCK, mitochondrial type creatine kinase isoform; NHBx, non–pressure-loaded heart biopsy; SevASpEF, severe aortic stenosis with preserved ejection fraction; and SevAS-rEF, severe aortic stenosis with reduced ejection fraction.

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  Figure 6.. Relationship between CK activity and ATP diffusion distance. A and B, Single unsegmented and segmented scanning electron microscopy slice of a human cardiomyocyte from a patient with severe aortic stenosis with reduced systolic function. Intermediate dark clusters (segmented yellow) represent mitochondria. Magnification 6000×, voltage 3 kV, dwell time 3 ms, pressure 0.188 Torr, image size 4000×4000 pixel (37.6×37.6 µm), slice thickness 100 nm. C, Scatterplot of CK total activity against median diffusion distance calculated by 3-dimensional serial block-face scanning electron microscopy. CK indicates creatine kinase.

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  Figure 7.. Central illustration: the effect of pressure loading on myocardial energetics. In comparison with the normal heart (A) energetic impairment occurs in the presence of pressure loading from aortic stenosis (AS) and is established by moderate AS (B). Although creatine kinase (CK) capacity reduces (green line) as AS severity increases (blue line) to severe (C) and is lowest in systolic failure (D), ATP delivery (CK flux, red line) at rest does not alone fall lower than that seen in moderate AS. As ATP demand increases with increasing AS severity and left ventyricular hypertrophy (black dotted line), this exceeds prevailing ATP delivery. In summary, energetic impairment in the CK system is present early in AS, and although it does not appear alone to be sufficient for transition to systolic decline in AS, it may nevertheless increase susceptibility to failure as ATP turnover demands increase.