Imaging Post-Infarct Myocardial Inflammation with ⁶⁸Ga-DOTATATE PET/MRI and insights into COVID-19 associated myocardial injury

i) Post-Infarct Myocardial Inflammation and Imaging Background: Inflammation and its resolution modulate post-infarct myocardial injury. An excessive or prolonged inflammatory phase after myocardial infarction (MI) may contribute to adverse cardiac remodelling. ⁶⁸Ga-DOTATATE is a PET radiotracer with high affinity for somatostatin receptor subtype 2 (SST2), which has been shown to be up-regulated in pro-inflammatory macrophages. Aims: To investigate the role of hybrid ⁶⁸Ga-DOTATATE PET/MRI for tracking post-infarct myocardial inflammation and predicting adverse cardiac remodelling post-MI, as well as to identify potential systemic and blood biomarker correlates of myocardial ⁶⁸Ga-DOTATATE PET signal. Methods: In a prospective observational cohort study, participants with recent MI underwent hybrid ⁶⁸Ga-DOTATATE PET/MRI within 2 weeks of infarction (t₀), and again after 3 months (t_3M). Participants additionally underwent CT coronary angiography at baseline, and a full cardiac MRI scan at 1 year (t_1Y). Participants with a prior history of MI, heart failure, previous coronary intervention or bypass grafting, were excluded. Blood samples were taken at the time of imaging for the quantification of circulating immune cell subsets using mass cytometry by time-of-flight (CyTOF) and for serum proteomic analysis. ⁶⁸Ga-DOTATATE maximum Standardised Uptake Values (SUV_max) were derived for myocardial segments with late gadolinium enhancement (LGE; “infarct”) as well as for segments without LGE and myocardium remote from the infarct. Assessments of regional wall motion; segmental strain and T1/T2 mapping values; left ventricular volumes and biplane ejection fraction, were performed from cardiac MRI at t₀ and t_1Y. Regions of interest for quantification of ⁶⁸Ga-DOTATATE PET signal were also derived for the ascending and descending aorta, vertebrae and non-culprit coronary arteries. *Ex vivo*, cardiac histological specimens from patients with a recent history of MI or ischaemic cardiomyopathy were immuno-stained for SST2, CD3, CD80, CD206/mannose receptor and CD68. Results: 38 participants in total were recruited (mean age 60 [SD 9] years; 32 [84%] male and 6 [16%] female), of whom 22 (58%) had ST elevation MI and 16 (42%) had non-ST elevation MI. The mean peak troponin at baseline was 16665ng/L (range 408 to >25,000ng/L) and the mean LVEF on pre-discharge echocardiogram was 49% (range 28%-61%). 36 (95%) participants had a follow-up ⁶⁸Ga-DOTATATE PET/MRI at t_3M and all 38 participants had a full cardiac MRI at t_1Y. At t₀, ⁶⁸Ga-DOTATATE PET signal demonstrated a clear ability to distinguish infarct from remote myocardial regions. Furthermore, on segmental analysis, akinetic or hypo-kinetic myocardial segments has a significantly higher mean SUV_max than normo-kinetic segments. Segmental myocardial ⁶⁸Ga-DOTATATE SUV also significantly correlated with peak segmental strain and segmental T1 values. At t_3M, there was a significant decline in infarct ⁶⁸Ga-DOTATATE SUV, in keeping with resolving myocardial inflammation, which was paralleled by a decline in high sensitivity Troponin, high sensitivity C reactive protein and NTproBNP levels. Immunostaining of histological specimens from patients with recent MI or ischaemic cardiomyopathy revealed co-localisation of SST2 with CD68, supporting the conclusion that the myocardial ⁶⁸Ga-DOTATATE PET signal was derived, at least in part, from macrophages. After multivariable adjustment, the mean SUV_max of the infarct at t3M, but not t0, was significantly positively associated with left ventricular dilatation at t1Y (delta EDVi; p=0.038). The t_3M/t₀ ratio of the mean infarct SUV_max appeared to be an even stronger predictor of volumetric remodelling outcome. After statistical feature selection and multiple comparisons adjustments, a number of biomarkers were associated with the post-MI myocardial PET signal, including serum programmed death-ligand 1 (PD-L1) levels at both t₀ and t_3M which were significantly negatively associated with the mean SUV_max of the infarct at t_3M. Conclusions: This is the first prospective study of serial ⁶⁸Ga-DOTATATE PET/MRI in patients after MI. Our results indicate that ⁶⁸Ga-DOTATATE PET is a useful tool for assessing post-infarct myocardial inflammation and that higher persistent ⁶⁸Ga-DOTATATE PET signal at t_3M may be linked to adverse remodelling outcomes. We further identify several biomarkers including serum PD-L1 levels at t₀ and t_3M as a potentially useful predictor of *in situ* myocardial inflammation as quantified by ⁶⁸Ga-DOTATATE PET. ii) COVID-19 related myocardial injury and imaging Background: Cardiac injury is a well-recognised complication of acute COVID-19 infection, with varied aetiologies ranging from myocarditis to endothelial dysfunction, micro-embolic phenomena and acute coronary syndromes. While persistent cardiac symptoms in patients with post-acute COVID-19 syndrome (PACS) are also common, the underlying cause is less well understood. A variety of imaging abnormalities have been described on cardiac magnetic resonance imaging (MRI) in the post-COVID setting and immune system dysregulation has been implicated both in determining acute disease severity as well in the development of PASC. To our knowledge, only one previously published study has specifically examined the link between cardiac imaging abnormalities after COVID-19 infection and immune profiling of the affected individuals, which was also limited to quantification of peripheral immune cell populations. Aims: To examine cardiac involvement associated with COVID-19 infection using imaging and deep immunophenotyping employing mass cytometry by time-of-flight (CyTOF) as well as serum proteomic analysis. Methods: Participants who had a history of COVID-19 infection and suspected cardiac involvement but no prior history of myocardial infarction or heart failure and no history of recent systemic immunosuppression, were recruited between October 2020 and February 2022. Participants were recruited on the basis of either troponin I (TnI) elevation (>99th percentile upper reference limit), new onset heart failure not attributable to another cause or unexplained ongoing cardiac symptoms after their initial COVID-19 infection. Participants underwent full cardiac MRI with late gadolinium enhancement (LGE) imaging, peripheral blood cell immunophenotyping using mass cytometry by time-of-flight (CyTOF) and serum proteomic analysis (Olink® Target 96 Inflammation Panel). Results: 21 participants (mean age 47 (SD 13) years, 71% female) were enrolled, who either had PACS (n=17), suspected acute COVID myocarditis (n=2), or new-onset heart failure attributed to prior COVID infection (n=2). MRI showed a non-ischaemic pattern of LGE and/or visually overt myocardial oedema in 8 (38%) patients, including 5 (24%) with PACS. A further patient had impaired ventricular function in the absence of LGE. In total, 9 (43%) patients had MRI abnormalities defined as either a non-ischaemic pattern of LGE, oedema or ventricular impairment. Participants with MRI abnormalities exhibited differences in CyTOF and proteomic biomarker expression compared with participants without such abnormalities, including: increased CCL3, CCL4, CCL7 (MCP-3), CXCL1, FGF21, FGF23, IL-13, PD-L1 and ST1A1 levels, as well as CD4+ Th2-like cells; but decreased CD8+ T effector memory cells, including PD1+ CD8+ T cells and CD8+ αβ T cells. Using Lasso regression analysis including all baseline clinical characteristics, higher CCL7 (MCP-3) levels and lower CD8+ TEM cells were the strongest predictors of an abnormal MRI finding, with a composite AUC of 0.96. Conclusions: Cardiac involvement after COVID-19 infection in patients with MRI abnormalities is associated with CCL7 (MCP-3) elevation, a chemokine known to be important in viral myocarditis, as well as decreased CD8+ T effector memory cells. These findings potentially give insight into the pathogenesis of cardiac-specific involvement post-COVID-19.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Corovic, Andrej

Advisors dc:contributor.advisor

• Tarkin, Jason
• Rudd, James

• COVID-19
• inflammation
• myocardial infarction
• positron emission tomography
• somatostatin receptor

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/24b60aa3-f119-47a0-9562-fbc521987f60/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.109972

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/370577