Effect Of Doxorubicin On Myocardial Bicarbonate Production From Pyruvate Dehydrogenase In Women With Breast Cancer

HomeCirculation ResearchVol. 127, No. 12Effect of Doxorubicin on Myocardial Bicarbonate Production From Pyruvate Dehydrogenase in Women With Breast Cancer Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBEffect of Doxorubicin on Myocardial Bicarbonate Production From Pyruvate Dehydrogenase in Women With Breast Cancer Jae Mo Park, Galen D. Reed, Jeff Liticker, William C. Putnam, Alvin Chandra, Katarina Yaros, Aneela Afzal, James MacNamara, Jaffar Raza, Ronald G. Hall, Jeannie Baxter, Kelley Derner, Salvador Pena, Raja Reddy Kallem, Indhu Subramaniyan, Vindhya Edpuganti, Crystal E. Harrison, Alagar Muthukumar, Cheryl Lewis, Sangeetha Reddy, Nisha Unni, Dawn Klemow, Samira Syed, Hsiao Li, Suzanne Cole, Thomas Froehlich, Colby Ayers, James de Lemos, Craig R. Malloy, Barbara Haley, Vlad G. Zaha Jae Mo ParkJae Mo Park Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Radiology (J.M.P., C.R.M.), University of Texas Southwestern Medical Center, Dallas. Electrical and Computer Engineering, The University of Texas at Dallas, Richardson (J.M.P.). Search for more papers by this author , Galen D. ReedGalen D. Reed https://orcid.org/0000-0002-2346-8429 Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. GE Healthcare, Dallas, TX (G.D.R.). Search for more papers by this author , Jeff LitickerJeff Liticker https://orcid.org/0000-0002-8191-7384 Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , William C. PutnamWilliam C. Putnam https://orcid.org/0000-0001-9338-4143 Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas Campus (W.C.P., J.R., R.G.H., R.R.K., I.S., V.E.). Search for more papers by this author , Alvin ChandraAlvin Chandra https://orcid.org/0000-0003-1753-1644 Division of Cardiology (A.C., A.A., J.M., C.A., J.d.L., C.R.M.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Katarina YarosKatarina Yaros Department of Internal Medicine (K.Y.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , Aneela AfzalAneela Afzal https://orcid.org/0000-0002-0073-8166 Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Division of Cardiology (A.C., A.A., J.M., C.A., J.d.L., C.R.M.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , James MacNamaraJames MacNamara Division of Cardiology (A.C., A.A., J.M., C.A., J.d.L., C.R.M.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , Jaffar RazaJaffar Raza Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas Campus (W.C.P., J.R., R.G.H., R.R.K., I.S., V.E.). Search for more papers by this author , Ronald G. HallRonald G. Hall https://orcid.org/0000-0002-5616-8246 Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas Campus (W.C.P., J.R., R.G.H., R.R.K., I.S., V.E.). Search for more papers by this author , Jeannie BaxterJeannie Baxter Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , Kelley DernerKelley Derner Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , Salvador PenaSalvador Pena Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , Raja Reddy KallemRaja Reddy Kallem Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas Campus (W.C.P., J.R., R.G.H., R.R.K., I.S., V.E.). Search for more papers by this author , Indhu SubramaniyanIndhu Subramaniyan Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas Campus (W.C.P., J.R., R.G.H., R.R.K., I.S., V.E.). Search for more papers by this author , Vindhya EdpugantiVindhya Edpuganti Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University, Dallas Campus (W.C.P., J.R., R.G.H., R.R.K., I.S., V.E.). Search for more papers by this author , Crystal E. HarrisonCrystal E. Harrison https://orcid.org/0000-0002-8884-2805 Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , Alagar MuthukumarAlagar Muthukumar Pathology (A.M., C.L., S.R.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , Cheryl LewisCheryl Lewis Pathology (A.M., C.L., S.R.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Sangeetha ReddySangeetha Reddy Pathology (A.M., C.L., S.R.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Nisha UnniNisha Unni Division of Hematology and Oncology (N.U., D.K., S.S., H.L., S.C., T.F., B.H.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Dawn KlemowDawn Klemow Division of Hematology and Oncology (N.U., D.K., S.S., H.L., S.C., T.F., B.H.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Samira SyedSamira Syed Division of Hematology and Oncology (N.U., D.K., S.S., H.L., S.C., T.F., B.H.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Hsiao LiHsiao Li Division of Hematology and Oncology (N.U., D.K., S.S., H.L., S.C., T.F., B.H.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Suzanne ColeSuzanne Cole Division of Hematology and Oncology (N.U., D.K., S.S., H.L., S.C., T.F., B.H.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Thomas FroehlichThomas Froehlich Division of Hematology and Oncology (N.U., D.K., S.S., H.L., S.C., T.F., B.H.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Colby AyersColby Ayers Division of Cardiology (A.C., A.A., J.M., C.A., J.d.L., C.R.M.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , James de LemosJames de Lemos https://orcid.org/0000-0003-2211-7261 Division of Cardiology (A.C., A.A., J.M., C.A., J.d.L., C.R.M.), University of Texas Southwestern Medical Center, Dallas. Search for more papers by this author , Craig R. MalloyCraig R. Malloy Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Radiology (J.M.P., C.R.M.), University of Texas Southwestern Medical Center, Dallas. Division of Cardiology (A.C., A.A., J.M., C.A., J.d.L., C.R.M.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Veterans Affairs North Texas Healthcare System, Dallas, Texas (C.R.M.). Search for more papers by this author , Barbara HaleyBarbara Haley Division of Hematology and Oncology (N.U., D.K., S.S., H.L., S.C., T.F., B.H.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author , Vlad G. ZahaVlad G. Zaha Correspondence to: Vlad G. Zaha, 5323 Harry Hines Blvd, Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4878-891X Advanced Imaging Research Center (J.M.P., G.D.R., J.L., A.A., J.B., K.D., S.P., C.E.H., C.R.M., V.G.Z.), University of Texas Southwestern Medical Center, Dallas. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas (A.C., C.L., S.R., N.U., D.K., S.S., H.L., S.C., T.F., C.R.M., B.H., V.G.Z.). Search for more papers by this author Originally published14 Oct 2020https://doi.org/10.1161/CIRCRESAHA.120.317970Circulation Research. 2020;127:1568–1570is related toMeet the First AuthorsMeet the First Author, see p 1472More than 5% of women treated for breast cancer with anthracyclines develop cardiotoxicity.1 The mechanism of injury is not fully understood, but mitochondrial damage may play a causal role. Early detection of myocardial damage due to anthracyclines is an important but unrealized objective. Hyperpolarized 13C MR spectroscopy detects fluxes through reactions essential for normal energy metabolism including PDH (pyruvate dehydrogenase) and LDH (lactate dehydrogenase).2 This study tested the hypothesis that exams of cardiac metabolism using hyperpolarized [1-13C1]pyruvate are feasible before and after conventional neoadjuvant doxorubicin chemotherapy in women with breast cancer, and that production of hyperpolarized [13C]bicarbonate or hyperpolarized [1-13C1]lactate may be sensitive to chemotherapy.The study was approved by the relevant institutional committees (STU 072016-058), under an Investigational New Drug approval (133229). All patients provided written informed consent, were >18 years old, without diabetes, with biopsy-proven breast cancer requiring neoadjuvant doxorubicin (cumulative 240 mg/m2). Patients with metastatic lesions, significant kidney, liver, cardiovascular or pulmonary disease, and MR safety restrictions were excluded. Participants continued their ordinary nutrition, activity and medications, and received standard care for breast cancer including screening with echocardiography.Experimental procedures were similar to recently published exams in human subjects.3–5 Following an overnight fast, participants arrived for study at 9:00 am, and 30 minutes before the exam ingested 48 grams of glucose. Sterile [1-13C1]pyruvate was prepared in a laminar flow hood by a licensed pharmacist. Polarization and quality assurance testing were performed using a SPINlab (GE Healthcare). Before injection, the solution passed through a 0.22 µm filter. MR studies were performed on a wide-bore 3T clinical scanner (GE Discovery 750w). The positioning of the 13C coils, a transmit Helmholtz and 8-channel receive array, was determined by participant comfort and body habitus with one or both coils anterior to the heart (Figure). 13C data were acquired from a 10-cm long-axis slice ECG-triggered in mid diastole. The excitation RF pulse was 10° every 2.8 to 3.8 seconds for 80 timepoints, total 3.7 to 5 minutes. 13C data were reconstructed and analyzed using MATLAB. Data from each coil were weighted according to the distance from the center of the LV cavity based on fiducials in a 1H image acquired with the body coil. Hyperpolarized 13C spectra were averaged over 90 seconds from injection for peak quantification and normalized to the total 13C signal (TC). Second study was completed 11±0.5 days after doxorubicin. Data analysis was completed in a blinded fashion, using objective measurement criteria. Statistical significance was evaluated using a paired t test (α=0.05, 2-tailed analysis). The sample size was 9 except echocardiography (n=8) due to missing postdoxorubicin test from patient number 4. Data are presented as mean±SE.Download figureDownload PowerPointFigure. Experimental setup, hyperpolarized 13C NMR spectra, and clinical results.A, Positioning of 8-channel paddle radiofrequency (RF) array receive coils is shown, along with an axial 1H MRI with position of the 8-channel paddle array coils (blue arcs), with fiducial markers indicating the approximate location of each loop. B, 13C MR spectra from each participant, acquired over ≈90 seconds from a bolus injection of hyperpolarized [1-13C1]pyruvate is shown. C, There was a significant decrease in [13C]bicarbonate but not [1-13C1]lactate after doxorubicin treatment, normalized to the total 13C signal (TC). D, There was no significant change in left ventricular end-diastolic volume (LVEDV) or left ventricular ejection fraction (LVEF) measured by echocardiography, but left ventricular global longitudinal strain (LVGLS) deteriorated after therapy. E, Compared with pretreatment baseline, plasma hemoglobin decreased and hs-cTnT (high-sensitivity troponin) was slightly above the upper limit of normal. The error bars denote SEM for a sample size of 9 for C and E and 8 for D.Ten patients were enrolled. One patient discontinued because of technical issues related to polarization. Of the 9 participants (age 47±5 years, 3 Black, 6 non-Hispanic White) who completed exams before and after therapy, none developed congestive heart failure. After therapy, patients had small but significant changes in hemoglobin, hs-cTnT (high-sensitivity troponin) and peak left ventricular global longitudinal strain (Figure). All participants tolerated the hyperpolarized exam well, without any adverse effects. Baseline 13C NMR spectra were similar for all participants. The fraction of [13C]bicarbonate, [1-13C1]lactate, and [1-13C1]alanine, relative to TC was 0.036±0.005, 0.448±0.023, and 0.045±0.004, respectively. After 4 cycles of doxorubicin and cyclophosphamide, there was a small decrease in hyperpolarized [13C]bicarbonate relative to TC (bicarbonate/TC=0.032±0.005, P=0.037) but no significant change in hyperpolarized [1-13C1]lactate (lactate/TC=0.44±0.04, P=0.9) or [1-13C1]alanine (alanine/TC=0.045±0.006, P=0.9). To examine the reproducibility of hyperpolarized data acquisition during the same session, 5 patients before chemotherapy and 2 patients after chemotherapy had 2 injections of hyperpolarized [1-13C1]pyruvate separated by 30 minutes. Total signal at the first and second exam in a single session for [13C]bicarbonate/TC (0.037±0.007; 0.038±0.007), [1-13C1]lactate/TC (0.061±0.005 versus 0.062±0.006), and [1-13C1]alanine/TC (0.051±0.005 versus 0.050±0.005) were not different.In conclusion, myocardial hyperpolarized 13C spectra acquired from patients with breast cancer were sensitive to cardiotoxic chemotherapy. Data were reproducible within the same visit, and serial exams are feasible and well-tolerated by patients. Doxorubicin was associated with a decrease in hyperpolarized [13C]bicarbonate/TC, consistent with subtle mitochondrial injury. Other biomarkers such as hemoglobin, hs-cTnT, and left ventricular global longitudinal strain (Figure) also changed in association with chemotherapy. Direct comparison to [18F]fluorodeoxyglucose imaging with positron emission tomography and image-based localization of the [13C]bicarbonate signal is desirable. The clinical relevance of hyperpolarized methods awaits further evaluation.Nonstandard Abbreviation and Acronymshs-cTnThigh-sensitivity troponinLDHlactate dehydrogenasePDHpyruvate dehydrogenaseTCtotal 13C signalAcknowledgmentsData sets are available from the corresponding author on reasonable request, reviewed by the Institutional Review Board and the Data Safety Monitoring Committee of the Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center.Sources of FundingThe National Institute of Health (S10OD018468, S10RR029119, P41EB015908, R01NS107409), the Welch Foundation (I-2009-20190330), The Texas Institute for Brain Injury and Repair, The Cancer Prevention and Research Institute of Texas (RP180404 and RP170003) and a donation from the Ben E. Keith Foundation.DisclosuresG.D. Reed is an employee of GE Healthcare. The other authors report no conflicts.FootnotesRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03685175.For Sources of Funding and Disclosures, see page 1569.Correspondence to: Vlad G. Zaha, 5323 Harry Hines Blvd, Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390. Email vlad.[email protected]eduReferences1. Mehta LS, Watson KE, Barac A, Beckie TM, Bittner V, Cruz-Flores S, Dent S, Kondapalli L, Ky B, Okwuosa T, et al.. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association.Circulation. 2018; 137:e30–e66. doi: 10.1161/CIR.0000000000000556LinkGoogle Scholar2. Merritt ME, Harrison C, Storey C, Jeffrey FM, Sherry AD, Malloy CR. Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR.Proc Natl Acad Sci U S A. 2007; 104:19773–19777. doi: 10.1073/pnas.0706235104CrossrefMedlineGoogle Scholar3. Cunningham CH, Lau JY, Chen AP, Geraghty BJ, Perks WJ, Roifman I, Wright GA, Connelly KA. Hyperpolarized 13C metabolic MRI of the human heart: initial experience.Circ Res. 2016; 119:1177–1182. doi: 10.1161/CIRCRESAHA.116.309769LinkGoogle Scholar4. Gallagher FA, Woitek R, McLean MA, Gill AB, Manzano Garcia R, Provenzano E, Riemer F, Kaggie J, Chhabra A, Ursprung S, et al.. Imaging breast cancer using hyperpolarized carbon-13 MRI.Proc Natl Acad Sci U S A. 2020; 117:2092–2098. doi: 10.1073/pnas.1913841117CrossrefMedlineGoogle Scholar5. Rider OJ, Apps A, Miller JJJJ, Lau JYC, Lewis AJM, Peterzan MA, Dodd MS, Lau AZ, Trumper C, Gallagher FA, et al.. Noninvasive in vivo assessment of cardiac metabolism in the healthy and diabetic human heart using hyperpolarized 13C MRI.Circ Res. 2020; 126:725–736. doi: 10.1161/CIRCRESAHA.119.316260LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesMeet the First AuthorsCirculation Research. 2020;127:1470-1472 December 4, 2020Vol 127, Issue 12Article InformationMetrics Download: 404 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.120.317970PMID: 33054563 Originally publishedOctober 14, 2020 Keywordsanthracyclinescardiotoxicitycarbon-13 magnetic resonance spectroscopymitochondria, heartpyruvate dehydrogenase complexPDF download SubjectsClinical StudiesMetabolismMyocardial BiologyBiomarkersMagnetic Resonance Imaging (MRI)