Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease

Richard E. Jones; Anja V. Gruszczyk; Christina Schmidt; Daniel J. Hammersley; Lukas Mach; Michael Lee; Joyce Wong; Ming Yang; Suzan Hatipoglu; Amrit S. Lota; Sam N. Barnett; Rebecca Toscano-Rivalta; Ruth Owen; Shahzad Raja; Fabio De Robertis; Hassiba Smail; Anthony De-Souza; Ulrich Stock; Peter Kellman; Julian Griffin; Marc Emmanuel Dumas; Jack L. Martin; Kourosh Saeb-Parsy; Ali Vazir; John G.F. Cleland; Dudley J. Pennell; Sunil K. Bhudia; Brian P. Halliday; Michela Noseda; Christian Frezza; Michael P. Murphy; Sanjay K. Prasad

doi:10.1038/s44161-023-00312-z

Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease

Richard E. Jones, Anja V. Gruszczyk, Christina Schmidt, Daniel J. Hammersley, Lukas Mach, Michael Lee, Joyce Wong, Ming Yang, Suzan Hatipoglu, Amrit S. Lota, Sam N. Barnett, Rebecca Toscano-Rivalta, Ruth Owen, Shahzad Raja, Fabio De Robertis, Hassiba Smail, Anthony De-Souza, Ulrich Stock, Peter Kellman, Julian GriffinMarc Emmanuel Dumas, Jack L. Martin, Kourosh Saeb-Parsy, Ali Vazir, John G.F. Cleland, Dudley J. Pennell, Sunil K. Bhudia, Brian P. Halliday, Michela Noseda, Christian Frezza, Michael P. Murphy, Sanjay K. Prasad^*

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Letter › peer-review

1 Citation (Scopus)

Abstract

Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

Original language	English
Pages (from-to)	733-745
Number of pages	13
Journal	Nature Cardiovascular Research
Volume	2
Issue number	8
Early online date	7 Aug 2023
DOIs	https://doi.org/10.1038/s44161-023-00312-z
Publication status	Published - 7 Aug 2023

Bibliographical note

Funding Information:
We thank the LMS/NIHR Imperial Biomedical Research Centre Flow Cytometry Facility for the support. We also thank M. Joseph (Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust) and A. Yesudass (Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust) for performing the CMR imaging and J. Orlandy (Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust) for providing research nurse support. This work was supported by a National Heart and Lung Institute Foundation grant awarded to S.K.P., R.E.J. and D.J.H. Additionally, the study was supported by an Intermediate Clinical Research Fellowship awarded to B.P.H. (FS/ICRF/21/26019). Work in the M.P.M. laboratory was supported by the Medical Research Council UK (MC_UU_00015/3) and by a Wellcome Trust Investigator award (220257/Z/20/Z). M.E.D. is funded by the NIHR Imperial Biomedical Research Centre; by grants from the French National Research Agency (ANR-10-LABX-46 (European Genomics Institute for Diabetes)); by the National Center for Precision Diabetic Medicine–PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001); by the European Union (FEDER); by the Hauts-de-France Regional Council (agreement 20001891/NP0025517); by the European Metropolis of Lille (agreement 2019_ESR_11); by Isite ULNE (R-002–20-TALENT-DUMAS), also jointly funded by ANR (ANR-16-IDEX-0004-ULNE); and by the Hauts-de-France Regional Council (20002845). This work was, in part, supported by a grant to M.N. from the British Heart Foundation and Deutsches Zentrum für Herz-Kreislauf-Forschung (BHF/DZHK) (SP/19/1/34461) and by a grant from the Chan Zuckerberg Foundation (2019-202666, M.N.). A National Heart and Lung Institute PhD studentship to M.N. supports S.N.B. L.M. is supported by a British Society for Heart Failure Research Fellowship. C.F. is supported by the Medical Research Council UK (MRC_MC_UU_12022/6), the CRUK Programme Foundation award (C51061/A27453), an ERC Consolidator Grant (ONCOFUM, ERC819920) and by the Alexander von Humboldt Foundation in the framework of the Alexander von Humboldt Professorship, endowed by the Federal Ministry of Education and Research. The work of C.S. was funded by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Skłodowska-Curie grant agreement number 722605 and the Alexander von Humboldt Professorship to C.F. J.G.F.C. is supported by British Heart Foundation Centre of Research Excellence award RE/18/6/34217.

Data Availability Statement

The metabolomic data are presented in the Supplementary Data Table and are deposited on Metabolomics Workbench46 under accession number ST002736. All sequencing data generated and analyzed here have been deposited at the European Genome-phenome Archive under accession number EGAS00001007351 and are available upon reasonable request.

Code availability
The detailed code for the metabolomic analysis can be found at https://github.com/ChristinaSchmidt1/AMBITION_study. All code used to analyze snRNA-seq data can be found at https://github.com/NosedaLab/AMBITION_study.

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Cite this

Jones, R. E., Gruszczyk, A. V., Schmidt, C., Hammersley, D. J., Mach, L., Lee, M., Wong, J., Yang, M., Hatipoglu, S., Lota, A. S., Barnett, S. N., Toscano-Rivalta, R., Owen, R., Raja, S., De Robertis, F., Smail, H., De-Souza, A., Stock, U., Kellman, P., ... Prasad, S. K. (2023). Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease. Nature Cardiovascular Research, 2(8), 733-745. https://doi.org/10.1038/s44161-023-00312-z

Jones, RE, Gruszczyk, AV, Schmidt, C, Hammersley, DJ, Mach, L, Lee, M, Wong, J, Yang, M, Hatipoglu, S, Lota, AS, Barnett, SN, Toscano-Rivalta, R, Owen, R, Raja, S, De Robertis, F, Smail, H, De-Souza, A, Stock, U, Kellman, P, Griffin, J, Dumas, ME, Martin, JL, Saeb-Parsy, K, Vazir, A, Cleland, JGF, Pennell, DJ, Bhudia, SK, Halliday, BP, Noseda, M, Frezza, C, Murphy, MP & Prasad, SK 2023, 'Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease', Nature Cardiovascular Research, vol. 2, no. 8, pp. 733-745. https://doi.org/10.1038/s44161-023-00312-z

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title = "Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease",

abstract = "Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.",

author = "Jones, {Richard E.} and Gruszczyk, {Anja V.} and Christina Schmidt and Hammersley, {Daniel J.} and Lukas Mach and Michael Lee and Joyce Wong and Ming Yang and Suzan Hatipoglu and Lota, {Amrit S.} and Barnett, {Sam N.} and Rebecca Toscano-Rivalta and Ruth Owen and Shahzad Raja and {De Robertis}, Fabio and Hassiba Smail and Anthony De-Souza and Ulrich Stock and Peter Kellman and Julian Griffin and Dumas, {Marc Emmanuel} and Martin, {Jack L.} and Kourosh Saeb-Parsy and Ali Vazir and Cleland, {John G.F.} and Pennell, {Dudley J.} and Bhudia, {Sunil K.} and Halliday, {Brian P.} and Michela Noseda and Christian Frezza and Murphy, {Michael P.} and Prasad, {Sanjay K.}",

note = "Funding Information: We thank the LMS/NIHR Imperial Biomedical Research Centre Flow Cytometry Facility for the support. We also thank M. Joseph (Royal Brompton and Harefield Hospitals, Guy{\textquoteright}s and St. Thomas{\textquoteright} NHS Foundation Trust) and A. Yesudass (Royal Brompton and Harefield Hospitals, Guy{\textquoteright}s and St. Thomas{\textquoteright} NHS Foundation Trust) for performing the CMR imaging and J. Orlandy (Royal Brompton and Harefield Hospitals, Guy{\textquoteright}s and St. Thomas{\textquoteright} NHS Foundation Trust) for providing research nurse support. This work was supported by a National Heart and Lung Institute Foundation grant awarded to S.K.P., R.E.J. and D.J.H. Additionally, the study was supported by an Intermediate Clinical Research Fellowship awarded to B.P.H. (FS/ICRF/21/26019). Work in the M.P.M. laboratory was supported by the Medical Research Council UK (MC_UU_00015/3) and by a Wellcome Trust Investigator award (220257/Z/20/Z). M.E.D. is funded by the NIHR Imperial Biomedical Research Centre; by grants from the French National Research Agency (ANR-10-LABX-46 (European Genomics Institute for Diabetes)); by the National Center for Precision Diabetic Medicine–PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001); by the European Union (FEDER); by the Hauts-de-France Regional Council (agreement 20001891/NP0025517); by the European Metropolis of Lille (agreement 2019_ESR_11); by Isite ULNE (R-002–20-TALENT-DUMAS), also jointly funded by ANR (ANR-16-IDEX-0004-ULNE); and by the Hauts-de-France Regional Council (20002845). This work was, in part, supported by a grant to M.N. from the British Heart Foundation and Deutsches Zentrum f{\"u}r Herz-Kreislauf-Forschung (BHF/DZHK) (SP/19/1/34461) and by a grant from the Chan Zuckerberg Foundation (2019-202666, M.N.). A National Heart and Lung Institute PhD studentship to M.N. supports S.N.B. L.M. is supported by a British Society for Heart Failure Research Fellowship. C.F. is supported by the Medical Research Council UK (MRC_MC_UU_12022/6), the CRUK Programme Foundation award (C51061/A27453), an ERC Consolidator Grant (ONCOFUM, ERC819920) and by the Alexander von Humboldt Foundation in the framework of the Alexander von Humboldt Professorship, endowed by the Federal Ministry of Education and Research. The work of C.S. was funded by the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under Marie Sk{\l}odowska-Curie grant agreement number 722605 and the Alexander von Humboldt Professorship to C.F. J.G.F.C. is supported by British Heart Foundation Centre of Research Excellence award RE/18/6/34217. ",

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T1 - Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease

AU - Jones, Richard E.

AU - Gruszczyk, Anja V.

AU - Schmidt, Christina

AU - Hammersley, Daniel J.

AU - Mach, Lukas

AU - Lee, Michael

AU - Wong, Joyce

AU - Yang, Ming

AU - Hatipoglu, Suzan

AU - Lota, Amrit S.

AU - Barnett, Sam N.

AU - Toscano-Rivalta, Rebecca

AU - Owen, Ruth

AU - Raja, Shahzad

AU - De Robertis, Fabio

AU - Smail, Hassiba

AU - De-Souza, Anthony

AU - Stock, Ulrich

AU - Kellman, Peter

AU - Griffin, Julian

AU - Dumas, Marc Emmanuel

AU - Martin, Jack L.

AU - Saeb-Parsy, Kourosh

AU - Vazir, Ali

AU - Cleland, John G.F.

AU - Pennell, Dudley J.

AU - Bhudia, Sunil K.

AU - Halliday, Brian P.

AU - Noseda, Michela

AU - Frezza, Christian

AU - Murphy, Michael P.

AU - Prasad, Sanjay K.

N1 - Funding Information: We thank the LMS/NIHR Imperial Biomedical Research Centre Flow Cytometry Facility for the support. We also thank M. Joseph (Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust) and A. Yesudass (Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust) for performing the CMR imaging and J. Orlandy (Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust) for providing research nurse support. This work was supported by a National Heart and Lung Institute Foundation grant awarded to S.K.P., R.E.J. and D.J.H. Additionally, the study was supported by an Intermediate Clinical Research Fellowship awarded to B.P.H. (FS/ICRF/21/26019). Work in the M.P.M. laboratory was supported by the Medical Research Council UK (MC_UU_00015/3) and by a Wellcome Trust Investigator award (220257/Z/20/Z). M.E.D. is funded by the NIHR Imperial Biomedical Research Centre; by grants from the French National Research Agency (ANR-10-LABX-46 (European Genomics Institute for Diabetes)); by the National Center for Precision Diabetic Medicine–PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001); by the European Union (FEDER); by the Hauts-de-France Regional Council (agreement 20001891/NP0025517); by the European Metropolis of Lille (agreement 2019_ESR_11); by Isite ULNE (R-002–20-TALENT-DUMAS), also jointly funded by ANR (ANR-16-IDEX-0004-ULNE); and by the Hauts-de-France Regional Council (20002845). This work was, in part, supported by a grant to M.N. from the British Heart Foundation and Deutsches Zentrum für Herz-Kreislauf-Forschung (BHF/DZHK) (SP/19/1/34461) and by a grant from the Chan Zuckerberg Foundation (2019-202666, M.N.). A National Heart and Lung Institute PhD studentship to M.N. supports S.N.B. L.M. is supported by a British Society for Heart Failure Research Fellowship. C.F. is supported by the Medical Research Council UK (MRC_MC_UU_12022/6), the CRUK Programme Foundation award (C51061/A27453), an ERC Consolidator Grant (ONCOFUM, ERC819920) and by the Alexander von Humboldt Foundation in the framework of the Alexander von Humboldt Professorship, endowed by the Federal Ministry of Education and Research. The work of C.S. was funded by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Skłodowska-Curie grant agreement number 722605 and the Alexander von Humboldt Professorship to C.F. J.G.F.C. is supported by British Heart Foundation Centre of Research Excellence award RE/18/6/34217.

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N2 - Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

AB - Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

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Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease

Abstract

Bibliographical note

Data Availability Statement

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Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease

Abstract

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Data Availability Statement

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