Novel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging.

HomeCirculation: Cardiovascular ImagingVol. 16, No. 1Novel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging Open AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialOpen AccessResearch ArticlePDF/EPUBNovel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging Andrej Ćorović, MB BChir, Deepa Gopalan, MD, Christopher Wall, MB BChir, Marta Peverelli, MD, Stephen P. Hoole, DM, Patrick A. Calvert, MD, PhD, Roido Manavaki, PhD, Tim D. Fryer, PhD, Luigi Aloj, MD, Martin J. Graves, PhD, Martin R. Bennett, MD, PhD, James H.F. Rudd, MD, PhD and Jason M. Tarkin, MBBS, PhD Andrej ĆorovićAndrej Ćorović Section of CardioRespiratory Medicine (A.C., C.W., M.P., S.P.H., P.A.C., M.R.B., J.H.F.R., J.M.T.), University of Cambridge, United Kingdom. Search for more papers by this author , Deepa GopalanDeepa Gopalan Department of Radiology, Cambridge University Hospitals NHS Trust, United Kingdom (D.G.). Search for more papers by this author , Christopher WallChristopher Wall Section of CardioRespiratory Medicine (A.C., C.W., M.P., S.P.H., P.A.C., M.R.B., J.H.F.R., J.M.T.), University of Cambridge, United Kingdom. Search for more papers by this author , Marta PeverelliMarta Peverelli Section of CardioRespiratory Medicine (A.C., C.W., M.P., S.P.H., P.A.C., M.R.B., J.H.F.R., J.M.T.), University of Cambridge, United Kingdom. Search for more papers by this author , Stephen P. HooleStephen P. Hoole https://orcid.org/0000-0002-3530-3808 Section of CardioRespiratory Medicine (A.C., C.W., M.P., S.P.H., P.A.C., M.R.B., J.H.F.R., J.M.T.), University of Cambridge, United Kingdom. Department of Cardiology, Royal Papworth Hospital NHS Trust, United Kingdom (S.P.H., P.A.C.). Search for more papers by this author , Patrick A. CalvertPatrick A. Calvert Section of CardioRespiratory Medicine (A.C., C.W., M.P., S.P.H., P.A.C., M.R.B., J.H.F.R., J.M.T.), University of Cambridge, United Kingdom. Department of Cardiology, Royal Papworth Hospital NHS Trust, United Kingdom (S.P.H., P.A.C.). Search for more papers by this author , Roido ManavakiRoido Manavaki Department of Radiology (R.M., L.A., M.J.G.), University of Cambridge, United Kingdom. Search for more papers by this author , Tim D. FryerTim D. Fryer Department of Clinical Neurosciences (T.D.F.), University of Cambridge, United Kingdom. Search for more papers by this author , Luigi AlojLuigi Aloj Department of Radiology (R.M., L.A., M.J.G.), University of Cambridge, United Kingdom. Search for more papers by this author , Martin J. GravesMartin J. Graves https://orcid.org/0000-0003-4327-3052 Department of Radiology (R.M., L.A., M.J.G.), University of Cambridge, United Kingdom. Search for more papers by this author , Martin R. BennettMartin R. Bennett https://orcid.org/0000-0002-2565-1825 Section of CardioRespiratory Medicine (A.C., C.W., M.P., S.P.H., P.A.C., M.R.B., J.H.F.R., J.M.T.), University of Cambridge, United Kingdom. Search for more papers by this author , James H.F. RuddJames H.F. Rudd Section of CardioRespiratory Medicine (A.C., C.W., M.P., S.P.H., P.A.C., M.R.B., J.H.F.R., J.M.T.), University of Cambridge, United Kingdom. Search for more papers by this author and Jason M. TarkinJason M. Tarkin Correspondence to: Jason M. Tarkin, MBBS, PhD, Section of Cardiorespiratory Medicine, University of Cambridge, Heart & Lung Research Institute, Papworth Rd, Cambridge, United Kingdom, CB2 0BB. Email E-mail Address: [email protected] https://orcid.org/0000-0002-9132-120X Section of CardioRespiratory Medicine (A.C., C.W., M.P., S.P.H., P.A.C., M.R.B., J.H.F.R., J.M.T.), University of Cambridge, United Kingdom. Search for more papers by this author Originally published17 Jan 2023https://doi.org/10.1161/CIRCIMAGING.122.014538Circulation: Cardiovascular Imaging. 2023;16Postinfarct inflammation and its resolution modulate ischemic injury after myocardial infarction (MI). While cardiac magnetic resonance imaging (MRI) is useful for assessing ventricular function, viability, and structural complications after MI, as well as detecting edema associated with acute inflammation, it lacks specificity for immune cell activity and may be less sensitive for identifying persistent, low-grade inflammation. Positron emission tomography (PET) imaging with 18F-Fluorodeoxyglucose (FDG) and other more specifically targeted tracers could have a role for quantifying infarct-related inflammation and identifying a link with adverse myocardial remodeling.1 Focal myocardial uptake of the SST2 (somatostatin receptor 2) PET tracer 68Ga-DOTATATE has been observed in patients with prior infarction2; however, the clinical relevance of this finding remains unknown. Here, we report an illustrative case from an ongoing study aimed to evaluate a novel, integrated approach for assessing postinfarct myocardial injury and inflammation using hybrid SST2 PET/MRI.A 36-year-old man with no prior medical history or cardiovascular risk factors presented with severe, sudden-onset chest pain. Cardiorespiratory examination was normal. The ECG showed sinus rhythm with evolving inferior ST-segment elevation without reciprocal changes. He underwent primary percutaneous coronary intervention to an occluded obtuse marginal branch of the left circumflex artery (Figure 1A and 1B). Reperfusion was achieved within 3 hours of symptom onset. Medical therapy with dual antiplatelet agents, a statin, beta-blocker, and angiotensin-converting enzyme inhibitor was initiated.Download figureDownload PowerPointFigure 1. Baseline 68Ga-DOTATATE positron emission tomography (PET)/magnetic resonance imaging (MRI) after myocardial infarction. A, Coronary angiography showing an occluded obtuse marginal branch of the left circumflex artery (arrow) at the time of initial myocardial infarction (MI) presentation; (B) 3-dimensional volume-rendered computed tomography coronary angiography after percutaneous coronary stenting (arrow). PET/MRI performed on day 11 post-infarct: (C, short-axis view; F, 3-chamber view) late gadolinium enhancement (LGE) MRI confirms areas of near full thickness basal infero-lateral MI (asterisk) and sub-endocardial mid to apical inferolateral infarction; (D) T1-mapping in basal short-axis view corroborating the extent of infarct (arrowhead); (E) increased 68Ga-DOTATATE PET uptake (dashed arrow) co-localizes with the area of infarct.Initial blood tests showed a total cholesterol level of 5.4 mmol/L, with triglycerides of 2.49 mmol/L, and an LDL of 3.39 mmol/L. The total white cell count was elevated at 18.4x 109/L, with a neutrophilia. The C-reactive protein level was normal at <3 mg/L and the peak hsTnI (high-sensitivity Troponin I) concentration was >25 000 ng/L (normal <58 ng/L). Echocardiography demonstrated normal left ventricular function overall with a biplane ejection fraction of 58%, akinesis of the basal-to-mid inferolateral wall, and hypokinesis of the basal-to-mid anterolateral wall.The patient was enrolled in a multi-modality cardiac imaging research study (REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04073810), involving serial 68Ga-DOTATATE PET/MRI, cardiac MRI and CT coronary angiography with 2-year follow-up. Baseline PET/MRI was performed using a hybrid PET/MRI scanner (SIGNA, GE Healthcare) on day 11 post-MI. Fifty minutes after an injection of 238 MBq 68Ga-DOTATATE, PET images were acquired for 35-minutes in a cardiac bed position. Simultaneously acquired 3T MRI included 3-plane breath-held proton weighted, blood-suppressed single-shot fast-spin echo, 2D steady-state free precession cine imaging of the ventricles, T2-weighted edema imaging, T1 and T2 mapping, and late gadolinium enhancement. Static PET images were reconstructed from list mode data using iterative time-of-flight (256×256 matrix, Q.Clear b=350), and a free-breathing 2-point DIXON MR imaging sequence for attenuation correction.Baseline MRI showed preserved left ventricular function, with persistent regional wall abnormalities (supplemental material: short-axis cine MRI acquired shortly after gadolinium contrast, Video S1). There was increased signal on T2-weighted imaging in the basal anterolateral, mid inferolateral, and apical lateral walls signifying edema, with corresponding areas of near full-thickness and sub-endocardial late gadolinium enhancement (Figures 1C, 1F, and 2A). 68Ga-DOTATATE PET demonstrated increased uptake (Figures 1E and 2G) in the infarct zone defined by late gadolinium enhancement and T1 mapping (Figure 1D). The maximum Standardised Uptake Values (SUVmax) and Tissue-to-Background Ratios (TBRmax) normalized for blood-pool activity were 2.8 and 8.0, respectively, in the infarct versus 1.3 and 3.6 in the remote myocardium.Download figureDownload PowerPointFigure 2. Comparison of baseline and 3-month follow-up 68Ga-DOTATATE positron emission tomography (PET)/magnetic resonance imaging (MRI). Baseline PET/MRI: (A) Late gadolinium enhancement (LGE) MRI showing sub-endocardial myocardial infarction (asterisk) in the mid inferolateral segment, with corresponding (C) high signal (arrowhead) on T2-weighted imaging; and (G) increased 68Ga-DOTATATE PET uptake (dashed arrow). E, Color-map demonstrates myocardium-to-muscle T2 ratio. Follow-up PET/MRI performed 102 days postinfarct: (B) T2-mapping; (D) resolution of edema on T2-weighted imaging; (F) myocardium-to-muscle T2 ratio; (H) residual infarct-related 68Ga-DOTATATE signal (dashed arrow). LGE imaging was not repeated at follow-up.Over the following 3 months, the patient remained well. Follow-up PET/MRI performed 102 days post-MI using the same scanner and imaging protocol with an injected activity of 242 MBq showed a reduction, but not resolution, of the 68Ga-DOTATATE PET signal (infarct SUVmax 2.0; infarct TBRmax 5.5; Figure 2H). Although there was no residual edema visible on T2-weighted MRI at follow-up (Figure 2D and 2F) compared with baseline (Figure 2C and 2E), quantitative T2 values were higher in the infarcted myocardium than remote region (infarct: 62 ms; remote: 51 ms; average noninfarct T2 value for scanner <53 ms; Figure 2B). In contrast to the abnormal PET and MRI findings consistent with ongoing myocardial inflammation, blood tests at day 102 showed normalization of hsTnI (15 ng/L from 206 ng/L) and reduction in NTproBNP (122 pg/mL from 362 pg/mL) levels, compared with day 11 values. High-sensitivity CRP remained low (0.27 mg/L from 0.69 mg/L).SST2 PET imaging holds major promise as a novel marker of cardiovascular inflammation across several disease entities. SSTR2 gene expression is upregulated by macrophages stimulated in vitro, and the SST2 receptor is co-expressed by CD68-positive macrophages in carotid endarterectomy specimens from stroke patients,1 as well as endomyocardial biopsies from patients with cardiac sarcoidosis and myocarditis.3 Unlike 18F-FDG, somatostatin receptor PET tracers such as 68Ga-DOTATATE have very low background activity in the healthy heart allowing for unhindered assessment of pathological myocardial inflammation without the need for dietary myocardial suppression. Indeed, clear infarct-related 68Ga-DOTATATE PET/CT uptake was observed in patients with both recent MI and chronic ischemic left ventricular dysfunction, in a post hoc analysis of the VISION study.2 The mechanism of 64Cu-DOTATATE binding to SST2 receptors expressed by inflammatory macrophages within recently infarcted myocardial tissue has been shown in a mouse model, using a combination of in vivo PET/CT imaging and ex vivo radiometric and immunologic assays.4 In that study, 64Cu-DOTATATE uptake within cell-sorted macrophages from infarcted mouse myocardium was 3-fold higher than 18F-FDG.This imaging case report highlights a newly emerging molecular imaging method for interrogating specific components of the immune response to ischemic myocardial damage. In this instance, 68Ga-DOTATATE PET uptake was closely colocalized with MRI features of recent MI, and later revealed residual inflammation that was not overtly visible on MRI, nor detected by blood biomarkers. Research is ongoing to confirm the cellular origins of post-MI 68Ga-DOTATATE PET signal within inflamed and infarcted human myocardial tissue, and to test its association with longer-term ischemic myocardial remodeling. In the future, this approach could be clinically useful for informing the design and use of advanced immunomodulatory therapies for patients with chronic ischemic cardiomyopathy. Simultaneous PET/MRI acquisition presents a unique opportunity for a truly comprehensive assessment of cardiac function, tissue characterization, and viability from MRI, alongside the superior sensitivity and inflammatory cell-specificity afforded by molecular imaging.Article InformationSources of FundingThis work was funded by grants to Dr Tarkin from the Wellcome Trust (Clinical Research Career Development Fellowship, 211100/Z/18/Z); and the British Heart Foundation (Clinical Research Training Fellowship for Dr Ćorović, FS/CRTF/20/24035).This work was additionally supported by the Cambridge BHF Centre of Research Excellence (18/1/34212); the NIHR Cambridge Biomedical Research Centre; the Cancer Research UK Cambridge Centre (A25177); and the Wolfson Brain Imaging positron emission tomography/magnetic resonance imaging team.Supplemental MaterialVideo S1Disclosures None.FootnotesSupplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.122.014538.Correspondence to: Jason M. Tarkin, MBBS, PhD, Section of Cardiorespiratory Medicine, University of Cambridge, Heart & Lung Research Institute, Papworth Rd, Cambridge, United Kingdom, CB2 0BB. Email [email protected]ac.ukReferences1. Thackeray JT, Bengel FM. Molecular imaging of myocardial inflammation with positron emission tomography post-ischemia: a determinant of subsequent remodeling or recovery.JACC Cardiovasc Imaging. 2018; 11:1340–1355. doi: 10.1016/j.jcmg.2018.05.026CrossrefMedlineGoogle Scholar2. Tarkin JM, Calcagno C, Dweck MR, Evans NR, Chowdhury MM, Gopalan D, Newby DE, Fayad ZA, Bennett MR, Rudd JHF. 68Ga-DOTATATE PET identifies residual myocardial inflammation and bone marrow activation after myocardial infarction.J Am Coll Cardiol. 2019; 73:2489–2491. doi: 10.1016/j.jacc.2019.02.052CrossrefMedlineGoogle Scholar3. Polte CL, Bollano E, Oldfors A, Dudás A, Lagerstrand KM, Himmelman J, Bobbio E, Karason K, van Essen M, Bergh N. Somatostatin receptor positron emission tomography/computed tomography in giant cell myocarditis: a promising approach to molecular myocardial inflammation imaging.Circ Cardiovasc Imaging. 2022; 15:e013551. doi: 10.1161/CIRCIMAGING.121.013551LinkGoogle Scholar4. Toner YC, Ghotbi AA, Naidu S, Sakurai K, van Leent MMT, Jordan S, Ordikhani F, Amadori L, Sofias AM, Fisher EL, et al. Systematically evaluating DOTATATE and FDG as PET immuno-imaging tracers of cardiovascular inflammation.Sci Rep. 2022; 12:6185. doi: 10.1038/s41598-022-09590-2CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 2023Vol 16, Issue 1 Advertisement Article InformationMetrics © 2022 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://doi.org/10.1161/CIRCIMAGING.122.014538PMID: 36649455 Originally publishedJanuary 17, 2023 Keywordsmagnetic resonance imagingpositron emission tomographyreceptors, somatostatininflammationmyocardial infarctionPDF download Advertisement SubjectsImagingMagnetic Resonance Imaging (MRI)Nuclear Cardiology and PET