Natural History of Myocardial α_vβ₃ Integrin Expression After Acute Myocardial Infarction: Correlation with Changes in Myocardial Blood Flow

DISCUSSION

The present study reported in vivo, in humans, an increased α_vβ₃ integrin expression in the infarcted myocardium 1 wk after STEMI. The levels of α_vβ₃ integrin expression remained stable at 1 mo after STEMI and partially decreased at 3 mo, suggesting that angiogenesis remains active 3 mo after the infarct. Moreover, there were significant weak correlations between the segmental levels of α_vβ₃ integrin expression at 1 wk and the subsequent improvements in stress MBF, MFR, and wall motion analysis.

The kinetics of angiogenesis after MI in humans remain poorly understood (2). The results reported here on myocardial α_vβ₃ integrin expression in vivo in the human infarcted myocardium found persistent activity at 1 mo, followed by a partial decline at 3 mo. The present results are consistent with the serial changes in vascular endothelial growth factor levels observed in several studies within the peripheral blood of patients with acute MI. These levels were reported to peak at 6 wk and subsequently decline to baseline levels at 5 mo (18). Another study found a progressive increase in vascular endothelial growth factor levels that started on the first day after acute MI, peaked at 2 wk, and then subsequently declined (19). Hence, it can be thought that this prolonged increase is necessary to preserve the remaining myocardium and limit hypoxic cellular destruction.

The prolonged α_vβ₃ integrin upregulation found here agrees with previous studies using radiolabeled RGD peptides after MI (4,11,20,21). In a rat model, the uptake of the ¹⁸F-galacto-RGD tracer was detected only 3 d after MI and reached its highest levels between 1 and 3 wk; the levels were still detectable after 6 mo. Moreover, the evolution of ¹⁸F-galacto-RGD tracer uptake correlated well with neovascularization as assessed by immunohistochemical CD31 staining (4). Similarly, the uptake pattern of ¹⁸F-AlF-NOTA-PRGD2, in the infarcted area at various time points after MI, also started after only 3 d and peaked between 1 and 3 wk; a subsequent partial decrease was reported 4 mo after MI (20). In humans, Jenkins et al. (11) found that ¹⁸F-labeled RGD uptake was increased within 2 wk in the infarcted myocardium. It persisted but was reduced after approximately 10 wk. There was no uptake found at sites of established old infarctions. It is of note that in the present study, an examination of established old infarction sites was not conducted since none of the participants had an MI history before acute STEMI. Nevertheless, in our trial evaluating tumoral angiogenesis (NCT02666547), which includes some patients with a prior history of MI, we do not observe any visually positive uptake of ⁶⁸Ga-NODAGA-RGD in the myocardium.

The present study reported significant correlations between the segmental levels of α_vβ₃ integrin at 1 wk and the subsequent improvements in clinically relevant physiologic parameters, such as stress MBF, MFR, and wall motion analysis. Although the correlations were weak, they were determined using the Spearman rank correlation coefficient, which is insensitive to outliers. Additionally, the alignment of PET findings could have been more accurate, since distinct radiotracers (with high-energy positrons) and acquisitions were used. A stronger effect of these correlations can be assumed, which means that the correlations are likely relevant. Notably, a slightly stronger correlation was observed between α_vβ₃ integrin expression levels and improvements in MFR, which is considered a more robust independent prognostic factor than is stress MBF (22). Furthermore, no correlation was found between α_vβ₃ integrin expression levels and subsequent changes in rest MBF, a parameter unrelated to clinical outcomes and unaffected by post-MI recovery (23,24). The significant but weak correlation between α_vβ₃ integrin expression levels at 1 wk and functional outcomes aligns with previous challenges to translate microscopic levels of angiogenesis into functional improvements. For example, Wu et al. reported only trends toward lower perfusion defects and metabolism deficits in vascular endothelial growth factor–treated animal models, without statistically significant changes (25). Nevertheless, as here, several studies suggested that elevated α_vβ₃ integrin expression after ischemic myocardial injury is associated with subsequent improvement in regional left ventricular function (6,11,12,26,27). Recently, using the same PET tracer with ⁶⁸Ga-NODAGA-RGD, Nammas et al. reported in humans that α_vβ₃ integrin expression levels 1 wk after MI were linked to regional and global systolic dysfunction, as well as elevated left ventricular filling pressure, and predicted improved global left ventricular function 6 mo after MI (12). Despite these insights, further studies are warranted to better understand whether the angiogenic response is associated with functional recovery.

Variability was observed in the temporal pattern of ⁶⁸Ga-NODAGA-RGD uptake, with a notable increase found at 1 mo in 2 participants. Interestingly, the 2 participants affected were those experiencing the most severe infarcts. On the basis of these findings, it remains uncertain whether this increase in ⁶⁸Ga-NODAGA-RGD uptake is related to intensified reendothelialization and angiogenesis or indicates a shift toward myofibroblast cell types, suggesting an intensified fibrotic response. This delayed phase of repair is characterized by a reduction in inflammation and angiogenesis and a reorganization of the extracellular matrix through myofibroblast-driven type I and III collagen production (1). This more intense uptake during follow-up in infarcted areas where perfusion is most profoundly reduced, with a trend toward a delayed 1-mo peak, may reflect the need for a more intense healing process in those tissues.

The present trial had several limitations. Inflammatory cells and fibroblasts can express integrins such as α_vβ₃ (7–10), which can lead to reduced specificity. This may explain the weak correlations found between the 1-wk ⁶⁸Ga-NODAGA-RGD uptake and the subsequent improvements in flow, as well as the absence of correlation found from 1 mo onward. The positron range is higher for ⁶⁸Ga than for ¹⁸F, which may affect image quality, especially in relatively small moving structures. Nevertheless, ⁶⁸Ga-NODAGA-RGD has the advantage of straightforward synthesis at room temperature with high radiochemical yield and purity. It can be radiolabeled rapidly (<30 min) and in a fully automated good-manufacturing-practice–compliant manner. Furthermore, the on-site availability of ⁶⁸Ge/⁶⁸Ga generators for centers without access to a cyclotron makes it a good alternative for ¹⁸F-labeled compounds. Moreover, a higher uptake of multimeric RGD tracers than of monomeric tracers was reported (28). A multimodal imaging strategy, such as PET/MRI, could precisely delineate the area at risk and its border zone. The study would have been strengthened by an independent measure of regional function using echocardiography or MRI. Furthermore, the contribution of nonspecific uptake to ⁶⁸Ga-NODAGA-RGD accumulation cannot be excluded. However, positive uptake was found in segments with preserved perfusion and in segments with low perfusion, and as radiolabeled RGD-based peptides have shown rapid clearance from the circulation (4,14), it seems unlikely that nonspecific uptake related to changes in vascular permeability played a major role. Finally, the potential impact of standard medication regimens for coronary artery disease (e.g., statins, antihypertensives) on the uptake of ⁸²Rb or ⁶⁸Ga-NODAGA-RGD remains uncertain.