Author + information
- Jason M. Tarkin, PhD, MBBS,
- Claudia Calcagno, MD, PhD,
- Marc R. Dweck, MD, PhD,
- Nicholas R. Evans, PhD, MB BChir,
- Mohammed M. Chowdhury, MB ChB,
- Deepa Gopalan, MD,
- David E. Newby, PhD, FMedSci,
- Zahi A. Fayad, PhD,
- Martin R. Bennett, PhD, FMedSci and
- James H.F. Rudd, MD, PhD∗ (, )@jhfrudd
- ↵∗Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, ACCI, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom
Myocardial infarction (MI) healing occurs in 2 phases: first an inflammatory phase, where clearance of necrotic debris occurs, followed by a reparative phase characterized by angiogenesis, granulation tissue formation, and attempts to repair the extracellular matrix. While efficient healing relies on coordinated mobilization of monocytes to the damaged myocardium, with resolution of the acute inflammatory response by ∼10 to 14 days, excessive inflammation impairs myocardial salvage and promotes adverse cardiac remodeling.
In ischemic heart failure, pro-inflammatory macrophages persist long after the formation of healed scar in remote and border zones of the infarcted, remodeled heart because of maladaptive changes in the mononuclear phagocytic network and spleen (1). An accurate means of diagnosing harmful inflammation after an MI is urgently needed.
We previously demonstrated that 68Ga-DOTATATE, a somatostatin receptor subtype-2 positron emission tomography (PET) ligand, could identify pro-inflammatory macrophages within atherosclerotic plaques (2). Here, in this substudy of our original prospective observational study, we examined whether 68Ga-DOTATATE could reveal residual post-infarction myocardial inflammation.
Patients with an MI within 3 months treated by percutaneous coronary intervention (“recent MI,” n = 6), and patients with a past history of MI and echocardiography data available from after their event (“old MI,” n = 6), were included. Patients with equivocal culprit arteries, and those managed medically or with coronary artery bypass grafting surgery, were excluded.
ECG-gated PET imaging was performed as previously described (2). Maximum standardized uptake values (SUVmax) and tissue-to-blood ratios (TBRmax), normalized for blood pool activity in the superior vena cava, were derived blinded to clinical details in each of the 16 myocardial segments.
Myocardial 68Ga-DOTATATE and 18F-FDG PET signals were compared: 1) within infarcted and noninfarcted segments; 2) to each other; and 3) to tracer activity in the thoracic vertebral bone marrow as an experimental marker of systemic inflammation, using standard nonparametric statistical tests (all data median [interquartile range (IQR)] unless stated). Recently infarcted myocardial segments were defined by clinically adjudicated (treated) culprit artery territories, with individual anatomical variation verified by angiography. In patients with old MI, infarcted myocardium was determined by echocardiographic wall motion abnormalities (hypokinesia/akinesia), assessed independently of the study and prior to enrollment.
Demographics were similar for recent MI (age 74 years [IQR: 64 to 78 years], 83% male) and old MI (age 59 years [IQR: 56 to 72 years], all male) patients. There were 3 ST-segment elevation MIs, which were all old MIs. PET imaging occurred 35 days (range 21 to 80 days) after recent MIs, and 7 years (range 1.8 to 22 years) after old MIs, with 2 days (range 1 to 21 days) in between 68Ga-DOTATATE and 18F-FDG scans.
68Ga-DOTATATE signals were higher in infarcted compared with noninfarcted myocardium in patients with both recent MI (SUVmax 1.60 [IQR: 1.45 to 2.11] vs. 1.33 [IQR: 1.25 to 1.52]; p = 0.03; TBRmax 2.33 [IQR: 1.55 to 2.71] vs. 1.80 [IQR: 1.32 to 2.22]; p = 0.03) and old MI (SUVmax 2.22 [IQR: 2.03 to 2.50] vs. 1.78 [IQR: 1.63 to 2.13]; p < 0.0001; TBRmax 2.79 [IQR: 2.47 to 3.23] vs. 1.89 [IQR: 1.52 to 2.36]; p < 0.0001).
Unlike 68Ga-DOTATATE, which exhibited very low background myocardial binding in all patients, avid myocardial 18F-FDG uptake (basal inferoseptum SUVmax >5) rendered 5 (42%) scans uninterpretable despite 6-h pre-scan fasting. In the readable scans, the 2 tracers showed reasonable agreement in the myocardium (r = 0.38, 95% confidence interval [CI]: 0.20 to 0.53; p < 0.0001). Despite high liver and spleen 68Ga-DOTATATE activity, focal myocardial signals were clearly distinguishable in all 5 patients with inferior infarcts.
Bone marrow 68Ga-DOTATATE signals were highly correlated with both infarct-related myocardial inflammation detected by 68Ga-DOTATATE (r = 0.83 [95% CI: 0.48 to 0.95]; p = 0.001), and metabolic bone marrow activity measured by 18F-FDG (r = 0.64 [95% CI: 0.08 to 0.89]; p = 0.03).
We found that 68Ga-DOTATATE identified active inflammation in recently infarcted myocardium, as well as old ischemic injury. Our observations agree with existing clinical data (3), but contradict findings in mice (4). 68Ga-DOTATATE binding in chronically damaged myocardium, particularly at the infarct border (Figure 1), likely reflects residual macrophage-driven inflammation; however, histological validation is needed. While tracer binding to myocytes and/or fibroblasts are possible alternative explanations, transcriptomic data from infarcted mouse hearts (5) indicates that SSTR2 is not expressed in these cell types.
Residual myocardial inflammation detected by 68Ga-DOTATATE could represent an important prognostic biomarker to study disease mechanisms and test novel therapies for the inflamed, failing heart.
Please note: Dr. Tarkin has been supported by the Wellcome Trust (104492/Z/14/Z, 211100/Z/18/Z) and the National Institute for Health Research. Dr. Calcagno has been supported by the National Institutes of Health (NIH) (P01 HL131478, R01 HL071021, R01HL135878) and the American Heart Association (16SDG27250090). Dr. Evans has been supported by the National Institute for Health Research and Dunhill Trust (RTF44/0114). Dr. Chowdhury has been supported by the British Heart Foundation (FS/16/29/31957). Dr. Fayad has been supported by the NIH (P01 HL131478, R01 HL071021, R01 HL128056, R01HL135878, NBIB R01 EB009638) and the American Heart Association (14SFRN20780005). Dr. Rudd has been supported by the Higher Education Funding Council for England, the National Institute for Health Research Cambridge Biomedical Research Centre, the Wellcome Trust, the British Heart Foundation, and the Cambridge Center for Mathematics in Healthcare. This research was conducted in accordance with the study protocol approved by the local research ethics committee (14/EE/0019), Good Clinical Practice, and the Declaration of Helsinki. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188). Damini Dey, PhD, served as Guest Associate Editor for this letter.
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