Novel applications of positron emission tomography in the non-invasive assessment of cardiovascular disease

Objective Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The αvβ3 integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether αvβ3 integrin expression determines myocardial recovery following MI. Methods F-Fluciclatide (a novel αvβ3-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR. Results F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p<0.001). There was no F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBRmean 0.71±0.06 vs 0.70±0.03, p=0.83). F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=−0.20, p=0.38), F-fluciclatide uptake was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. Conclusion F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery. Trial registration number NCT01813045; Post-results. INTRODUCTION Ischaemic heart disease remains the leading cause of death globally, with over 1 million people suffering acute myocardial infarction (MI) per year in the USA alone. As the acute management of MI improves, the number of patients surviving acute myocardial injury is higher than ever before. In this population, adverse cardiac remodelling and the syndrome of delayed heart failure represent the major cause of morbidity. Understanding reparative mechanisms following infarction is becoming increasingly important. Repair following MI is triggered by a complex interaction of neurohormonal activation and upregulation of angiogenic and pro-fibrotic transcription factors that initiate the restoration of a capillary network through angiogenesis and re-endothelialisation, as well as extracellular matrix (ECM) remodelling through macrophage accumulation and fibroblast activation. This interplay of angiogenesis, inflammation and fibrosis determines the extent of preservation and restoration of myocardial integrity. In some circumstances, maladaptive persistent processes may encourage remodelling and scarring to extend into the myocardium long after the initial causative injury. This may lead to progressive ventricular dilatation, ventricular dysfunction and heart failure. The αvβ3 integrin is a transmembrane cell surface receptor that facilitates migration, proliferation and interaction with the ECM, thereby allowing cells to respond to, and in turn modify, their extracellular environment. Expressed at low levels by quiescent endothelial cells, αvβ3 integrin is markedly upregulated in states of angiogenesis within the myocardium after infarction. 4 In addition, preclinical and clinical studies document αvβ3 integrin expression by both activated cardiac myofibroblasts and macrophages during margination and chemotaxis. Thus, αvβ3 integrin expression appears central to the coordination of repair following MI. In this study, we investigated the expression of αvβ3 integrin following MI using the novel αvβ3 integrin-selective radiotracer, F-fluciclatide, combined with cardiac positron emission tomography (PET), CT and cardiovascular MRI (CMR). The study aims to describe and characterise the uptake of this radiotracer and to correlate it with clinical markers of disease severity and functional recovery in patients with recent MI. METHODS PET/CT scanning with F-fluciclatide and CMR were performed in three groups of participants recruited from Royal Infirmary of Edinburgh between July 2013 and February 2015. Exclusion criteria were age <40 years, women of childbearing potential not taking contraception, severe renal failure (serum creatinine >2.8 mg/dL) or hepatic failure (Child-Pugh grade B or grade C), atrial 607 Jenkins WSA, et al. Heart 2017;103:607–615. doi:10.1136/heartjnl-2016-310115 Coronary artery disease To cite: Jenkins WSA, Vesey AT, Stirrat C, et al. Heart 2017;103:607–615. ► Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ heartjnl-2016-310115). 1British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 2Clinical Research Imaging Center, University of Edinburgh, Edinburgh, UK 3Edinburgh Molecular Imaging Ltd, Edinburgh, UK 4Division of Cardiovascular Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK Correspondence to Dr William S A Jenkins, British Heart Foundation Centre for Cardiovascular Science, Chancellors Building, 49 Little France Crescent, University of Edinburgh, Edinburgh EH16 4SB, UK; williamjenkins@ doctors.net. uk MRD and DEN contributed equally. Received 6 June 2016 Revised 16 September 2016 Accepted 20 September 2016 Published Online First 7 December 2016 group.bmj. com on February 1, 2018 Published by http://heart.bmj. com/ Downloaded from