Cardiac αVβ3 integrin expression following acute myocardial infarction in humans

Abstract

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: 18F-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: 18F-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 18F-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). 18F-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), 18F-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: 18F-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.

Conflict of interest statement

Competing interests: None declared.

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Figures

Figure 1

αvβ3 integrin expression in patient with recent myocardial infarction (MI). Adjacent fresh-frozen and cryosectioned biopsies from the peri-infarct area of a patient with recent anterior MI are shown. Immunohistochemical staining for (A) αvβ3 integrin displayed multiple regions of positive staining that co-localise to regions of staining for vascular endothelial cells (CD31), (B) visible at ×4 magnification. At ×20 magnification, these regions of αvβ3 staining (C) correspond predominantly to arterioles and the microvasculature (D) and also to regions of staining for smooth muscle actin (SMA) (E), representative of both arterioles (co-staining with CD31) and myofibroblasts. There were relatively few macrophages (F).

Figure 2

Dynamic analysis of 18F-fluciclatide uptake is shown. Axial and sagittal CT angiographies of the thorax in a patient with recent anterior myocardial infarction (A) are shown. The time-activity curves generated from the descending aorta and the apical interventricular septum (blue crosshairs) show increased uptake in the infarct relative to blood pool. Optimal contrast between 18F-fluciclatide tissue and blood pool activity was observed after 40 min (dotted line, B). The positron emission tomography image in the axial and sagittal plane shows increased uptake within the apical septum, although there is some background activity (C). Patlak analysis of regions of interests placed in the interventricular septum confirms integrin binding, as evidenced by the gradient of the slope and the y-intercept (D) and, using a Ki-generated image, we can better identify and delineate focal uptake within myocardium (E). A region of remote myocardium within the same patient generates a Patlak curve with significantly lower gradient and intercept in comparison (F).

Figure 3

18F-Fluciclatide uptake in acute myocardial infarction (MI) is shown. 18F-Fluciclatide uptake in three patients with recent subendocardial MI is shown. Patient 1, 13 days after anterior MI, displaying a short-axis positron emission tomography (PET) image of the left ventricle with crescentic 18F-fluciclatide uptake (A) that correlates with the interventricular septum and anterior wall on CT angiography (B). The fused PET/CT-angiography image (C) shows this uptake to correspond exactly with the region of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) (D). Further delineation of myocardial uptake on PET/CT is clearer in the two-chamber view (E) and on a fused CT/three-dimensional-Patlak image, which shows this uptake to follow a watershed-pattern emerging from the coronary stents present in the left anterior descending coronary artery (F) (see online supplementary video file 1). (G) and (H) Patient 2, 8 days following anterior MI, displaying focal uptake of 18F-fluciclatide in the anterior wall and apex in the three-chamber view on PET/CT (G) which corresponds to the region of infarction on LGE CMR imaging (H). (I) and (J) Patient 3, showing focal uptake of 18F-fluciclatide in the inferior wall 19 days following MI on PET/CT (I) that again corresponds to the infarction on CMR LGE imaging (J).

Figure 4

18F-Fluciclatide uptake in myocardial infarction (MI) is shown. Uptake of 18F-fluciclatide in (A) patients with acute MI at 2 and 10 weeks, patients with chronic total occlusion and healthy control subjects is shown. Uptake was greatest at 2 weeks after MI (B). 18F-Fluciclatide uptake in the acute MI group was greater in regions of hypokinesis when compared with sites of normal function or akinesis (C). This translated to a higher 18F-fluciclatide uptake in those regions which subsequently improved in function on follow-up cardiac magnetic resonance (D). CTO, chronic total occlusion; TBR, tissue-to-background ratio. WMA, wall motion abnormality.