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Cited by 204Cardiovascular Function and Risk FactorsCardiomyopathy and Myosin StudiesMitochondrial Function and Pathology

Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium

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Smith, Craig S., Bottomley, Paul A., Schulman, Steven P., Gerstenblith, Gary, Weiss, Robert G.·2006·Circulation
DOI 10.1161/circulationaha.106.613646PMC PMC1808438
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Abstract

Background— The progression of pressure-overload left ventricular hypertrophy (LVH) to chronic heart failure (CHF) may involve a relative deficit in energy supply and/or delivery. Methods and Results— We measured myocardial creatine kinase (CK) metabolite concentrations and adenosine triphosphate (ATP) synthesis through CK, the primary energy reserve of the heart, to test the hypothesis that ATP flux through CK is impaired in patients with LVH and CHF. Myocardial ATP levels were normal, but creatine phosphate levels were 35% lower in LVH patients (n=10) than in normal subjects (n=14, P <0.006). Left ventricular mass and CK metabolite levels in LVH were not different from those in patients with LVH and heart failure (LVH+CHF, n=10); however, the myocardial CK pseudo first-order rate constant was normal in LVH (0.36±0.04 s −1 in LVH versus 0.32±0.06 s −1 in normal subjects) but halved in LVH+CHF (0.17±0.06 s −1 , P <0.001). The net ATP flux through CK was significantly reduced by 30% in LVH (2.2±0.7 μmol · g −1 · s −1 , P =0.011) and by a dramatic 65% in LVH+CHF (1.1±0.4 μmol · g −1 · s −1 , P <0.001) compared with normal subjects (3.1±0.8 μmol · g −1 · s −1 ). Conclusions— These first observations in human LVH demonstrate that it is not the relative or absolute CK metabolite pool sizes but rather the kinetics of ATP turnover through CK that distinguish failing from nonfailing hypertrophic hearts. Moreover, the deficit in ATP kinetics is similar in systolic and nonsystolic heart failure and is not related to the severity of hypertrophy but to the presence of CHF. Because CK temporally buffers ATP, these observations support the hypothesis that a deficit in myofibrillar energy delivery contributes to CHF pathophysiology in human LVH.

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  • The same quantitative 31P magnetic resonance spectroscopy protocols used in this study previously revealed significant reductions in myocardial creatine kinase flux in patients with non-ischemic dilated cardiomyopathy and in patients with left ventricular hypertrophy secondary to hypertension.

    “The same quantitative 31P magnetic resonance spectroscopy protocols for measuring human myocardial metabolite concentrations and CK kinetics used here, previously revealed significant reductions in myocardial CK flux inpatients with non-ischemic dilated cardiomyopathy7, and left ventricular hypertrophy secondary to hypertension6.”

    From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [6]

  • This study extends the observation of reduced kf and creatine kinase flux from patients with heart failure and pressure-overload hypertrophy to patients with genetic hypertrophy due to the Arg403Gln mutation.

    “The present work extends the observation of reduced kf and CK flux in patients who have both heart failure and hypertrophy produced by pressure overload6, to those with hypertrophy of genetic origin–specifically those with an Arg403Gln point mutation in MH.”

    From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [6]

  • The magnitude of the creatine kinase flux reduction in this hypertrophic cardiomyopathy cohort is comparable to, though less than, the 50-65% reductions previously observed in other heart failure patients.

    “Indeed, the magnitude of the reduction is comparable, albeit less than, the 50–65% reductions observed previously in other heart failure patients6,7.”

    From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [6]

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  • When inorganic phosphate was estimated at 1 μmol/g wet weight, the free energy of ATP hydrolysis was similar in patients with Arg403Gln hypertrophic cardiomyopathy and controls.

    “With inorganic phosphate [Pi] conservatively estimated at 1μmol/g wet wt6,7 in both control and HC patients, the free-energy release with ATP hydrolysis is similar in both groups (ΔG~ATP. −58.5±0.4 vs −58.3±1.3 kJ/mol).”

    From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [6]

    The Results compare ATP concentrations and creatine kinase flux in patients with left ventricular hypertrophy and controls, but do not report ATP-hydrolysis free energy in Arg403Gln hypertrophic cardiomyopathy. A search of our copy for Arg403Gln, inorganic phosphate at 1 μmol/g wet weight, and the stated free-energy values found no passage addressing that comparison. (LLM, conf=0.76)

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Research works printed but not linked: 13

  1. 10.1161/circ.91.6.1814 · DOI
  2. 10.1161/circ.103.11.1570 · DOI
  3. 10.1161/circ.99.17.2261 · DOI
  4. 10.1161/circ.86.6.1451253 · DOI
  5. 10.1161/res.60.6.2954720 · DOI
  6. 10.1161/res.67.6.2147129 · DOI
  7. 10.1161/circ.92.1.15 · DOI
  8. 10.1161/circ.100.24.2425 · DOI
  9. 10.1161/circ.97.25.2536 · DOI
  10. 10.1161/circ.104.15.1844 · DOI
  11. 10.1161/res.89.2.153 · DOI
  12. 10.1161/circ.44.2.181 · DOI
  13. 10.1161/res.14.4.294 · DOI

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Authors
Smith, C. S., Bottomley, P. A., Schulman, S. P., Gerstenblith, G., & Weiss, R. G.
Affiliations
Johns Hopkins University (US)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2006-09-12
Volume
114
Issue
11
Pages
1151-1158
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.106.613646
PMC
PMC1808438
OpenAlex
W2111571221
Cited by
204
References
53
Citations by year
2026: 4 · 2025: 8 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 12 · 2019: 13 · 2018: 8 · 2017: 11 · 2016: 11 · 2015: 12 · 2014: 11 · 2013: 13 · 2012: 9
FWCI
7.82
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Donald W. Reynolds Foundation
  • National Heart, Lung, and Blood Institute (HL61912, HL-63030, R01HL063030, R01HL061912, R01HL056882, HL56882)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
creatine kinase, adenosine triphosphate, left ventricular hypertrophy, chronic heart failure, myocardial energy metabolism, phosphocreatine, ATP turnover, pressure overload, heart failure pathophysiology
MeSH terms
Adenosine Triphosphate, Adult, Aged, Cardiac Output, Low, Creatine Kinase, Energy Metabolism, Female, Heart, Heart Ventricles, Humans, Male, Middle Aged, Myocardium, Severity of Illness Index, Hypertrophy, Left Ventricular, Disease Progression

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