Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer

David T Gamble; James Ross; Hilal Khan; Andreas Unger; Lesley Cheyne; Amelia Rudd; Fiona Saunders; Janaki Srivanasan; Sylvia Kamya; Graham Horgan; Andrew Hannah; Santosh Baliga; Carlo Gabriele Tocchetti; Gordon Urquhart; Wolfgang A Linke; Yazan Masannat; Ahmed Mustafa; Mairi Fuller; Beatrix Elsberger; Ravi Sharma; Dana Dawson

doi:10.1161/CIRCIMAGING.123.015782

Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer

David T Gamble, James Ross, Hilal Khan, Andreas Unger, Lesley Cheyne, Amelia Rudd, Fiona Saunders, Janaki Srivanasan, Sylvia Kamya, Graham Horgan, Andrew Hannah, Santosh Baliga, Carlo Gabriele Tocchetti, Gordon Urquhart, Wolfgang A Linke, Yazan Masannat, Ahmed Mustafa, Mairi Fuller, Beatrix Elsberger, Ravi SharmaDana Dawson^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin.

METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy.

RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013).

CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes.

REGISTRATION: URL: https://www.

CLINICALTRIALS: gov; Unique identifier: NCT04467411.

Original language	English
Article number	e015782
Pages (from-to)	817-826
Number of pages	10
Journal	Circulation. Cardiovascular imaging
Volume	16
Issue number	10
Early online date	17 Oct 2023
DOIs	https://doi.org/10.1161/CIRCIMAGING.123.015782
Publication status	Published - 17 Oct 2023

Bibliographical note

Acknowledgments
The fellow (Dr Gamble) recruited participants, scheduled, coordinated, and performed all clinical imaging investigations, patients skeletal muscle biopsies and venesection, conducted mitochondrial copy number analysis of muscle biopsies under supervision, analyzed all data, performed statistical analyses under supervision, and drafted this article. H. Khan and A. Rudd helped with the investigations and reviewed and contributed to this article. S. Baliga provided the healthy volunteer skeletal muscle biopsies. Dr Ross designed and developed the protocol for cardiac and skeletal muscle spectroscopy. L. Cheyne supervised muscle biopsy analyses. Drs Unger and Linke performed the skeletal muscle transmission electron microscopy and immunofluorescence confocal microscopy investigations. Dr Horgan is the study statistician. Drs Urquhart, Masannat, Elsberger, Fuller, Mustafa, and Sharma identified and recruited participants and reviewed and contributed to this article. Drs Hannah, Sharma, and Saunders contributed to the design of the study. D. Dawson (PI) designed the study, obtained funding (together with Drs Sharma and Masannat) and regulatory approvals, supervised the unfolding of the study, its analyses and revised the article drafts.

Sources of Funding
Tenovus Scotland G18.01, D. Dawson and Dr Sharma, Friends of Anchor 2019, Grampian National Health Service-Endowments (Drs Sharma and Masannat), British Health Foundation PG/18/35/33786 to D. Dawson funded DG salary and BHF FS/RTF/20/30009 to D. Dawson funded AR salary.

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© 2023 The Authors. Circulation: Cardiovascular Imaging is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
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Cite this

Gamble, D. T., Ross, J., Khan, H., Unger, A., Cheyne, L., Rudd, A., Saunders, F., Srivanasan, J., Kamya, S., Horgan, G., Hannah, A., Baliga, S., Tocchetti, C. G., Urquhart, G., Linke, W. A., Masannat, Y., Mustafa, A., Fuller, M., Elsberger, B., ... Dawson, D. (2023). Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer. Circulation. Cardiovascular imaging, 16(10), 817-826. Article e015782. https://doi.org/10.1161/CIRCIMAGING.123.015782

Gamble, DT, Ross, J, Khan, H, Unger, A, Cheyne, L, Rudd, A, Saunders, F, Srivanasan, J, Kamya, S, Horgan, G, Hannah, A, Baliga, S, Tocchetti, CG, Urquhart, G, Linke, WA, Masannat, Y, Mustafa, A, Fuller, M, Elsberger, B, Sharma, R & Dawson, D 2023, 'Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer', Circulation. Cardiovascular imaging, vol. 16, no. 10, e015782, pp. 817-826. https://doi.org/10.1161/CIRCIMAGING.123.015782

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title = "Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer",

abstract = "BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin.METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy.RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013).CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT04467411.",

author = "Gamble, {David T} and James Ross and Hilal Khan and Andreas Unger and Lesley Cheyne and Amelia Rudd and Fiona Saunders and Janaki Srivanasan and Sylvia Kamya and Graham Horgan and Andrew Hannah and Santosh Baliga and Tocchetti, {Carlo Gabriele} and Gordon Urquhart and Linke, {Wolfgang A} and Yazan Masannat and Ahmed Mustafa and Mairi Fuller and Beatrix Elsberger and Ravi Sharma and Dana Dawson",

note = "Acknowledgments The fellow (Dr Gamble) recruited participants, scheduled, coordinated, and performed all clinical imaging investigations, patients skeletal muscle biopsies and venesection, conducted mitochondrial copy number analysis of muscle biopsies under supervision, analyzed all data, performed statistical analyses under supervision, and drafted this article. H. Khan and A. Rudd helped with the investigations and reviewed and contributed to this article. S. Baliga provided the healthy volunteer skeletal muscle biopsies. Dr Ross designed and developed the protocol for cardiac and skeletal muscle spectroscopy. L. Cheyne supervised muscle biopsy analyses. Drs Unger and Linke performed the skeletal muscle transmission electron microscopy and immunofluorescence confocal microscopy investigations. Dr Horgan is the study statistician. Drs Urquhart, Masannat, Elsberger, Fuller, Mustafa, and Sharma identified and recruited participants and reviewed and contributed to this article. Drs Hannah, Sharma, and Saunders contributed to the design of the study. D. Dawson (PI) designed the study, obtained funding (together with Drs Sharma and Masannat) and regulatory approvals, supervised the unfolding of the study, its analyses and revised the article drafts. Sources of Funding Tenovus Scotland G18.01, D. Dawson and Dr Sharma, Friends of Anchor 2019, Grampian National Health Service-Endowments (Drs Sharma and Masannat), British Health Foundation PG/18/35/33786 to D. Dawson funded DG salary and BHF FS/RTF/20/30009 to D. Dawson funded AR salary.",

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doi = "10.1161/CIRCIMAGING.123.015782",

language = "English",

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pages = "817--826",

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T1 - Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer

AU - Gamble, David T

AU - Ross, James

AU - Khan, Hilal

AU - Unger, Andreas

AU - Cheyne, Lesley

AU - Rudd, Amelia

AU - Saunders, Fiona

AU - Srivanasan, Janaki

AU - Kamya, Sylvia

AU - Horgan, Graham

AU - Hannah, Andrew

AU - Baliga, Santosh

AU - Tocchetti, Carlo Gabriele

AU - Urquhart, Gordon

AU - Linke, Wolfgang A

AU - Masannat, Yazan

AU - Mustafa, Ahmed

AU - Fuller, Mairi

AU - Elsberger, Beatrix

AU - Sharma, Ravi

AU - Dawson, Dana

N1 - Acknowledgments The fellow (Dr Gamble) recruited participants, scheduled, coordinated, and performed all clinical imaging investigations, patients skeletal muscle biopsies and venesection, conducted mitochondrial copy number analysis of muscle biopsies under supervision, analyzed all data, performed statistical analyses under supervision, and drafted this article. H. Khan and A. Rudd helped with the investigations and reviewed and contributed to this article. S. Baliga provided the healthy volunteer skeletal muscle biopsies. Dr Ross designed and developed the protocol for cardiac and skeletal muscle spectroscopy. L. Cheyne supervised muscle biopsy analyses. Drs Unger and Linke performed the skeletal muscle transmission electron microscopy and immunofluorescence confocal microscopy investigations. Dr Horgan is the study statistician. Drs Urquhart, Masannat, Elsberger, Fuller, Mustafa, and Sharma identified and recruited participants and reviewed and contributed to this article. Drs Hannah, Sharma, and Saunders contributed to the design of the study. D. Dawson (PI) designed the study, obtained funding (together with Drs Sharma and Masannat) and regulatory approvals, supervised the unfolding of the study, its analyses and revised the article drafts. Sources of Funding Tenovus Scotland G18.01, D. Dawson and Dr Sharma, Friends of Anchor 2019, Grampian National Health Service-Endowments (Drs Sharma and Masannat), British Health Foundation PG/18/35/33786 to D. Dawson funded DG salary and BHF FS/RTF/20/30009 to D. Dawson funded AR salary.

PY - 2023/10/17

Y1 - 2023/10/17

N2 - BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin.METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy.RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013).CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT04467411.

AB - BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin.METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy.RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013).CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT04467411.

U2 - 10.1161/CIRCIMAGING.123.015782

DO - 10.1161/CIRCIMAGING.123.015782

M3 - Article

C2 - 37847761

SN - 1941-9651

VL - 16

SP - 817

EP - 826

JO - Circulation. Cardiovascular imaging

JF - Circulation. Cardiovascular imaging

IS - 10

M1 - e015782

ER -

Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer

Abstract

Bibliographical note

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