Molecular Imaging of Interstitial Alterations in Remodeling Myocardium After Myocardial Infarction

Borne, Susanne W.M. van den; Isobe, Satoshi; Verjans, Johan; Petrov, Artiom; Løvhaug, Dagfinn; Li, Peng; Zandbergen, H. Reinier; Ni, Youping; Frederik, Peter M.; Zhou, Jun; Arbo, Bente E.; Rogstad, Astri; Cuthbertson, Alan S.; Chettibi, Salah; Reutelingsperger, Chris; Blankesteijn, W. Matthijs; Smits, J. F. M.; Daemen, Mat J.A.P.; Zannad, Faı̈ez; Vannan, Mani A.; Narula, Navneet; Pitt, Bertram; Hofstra, Leonard; Narula, Jagat

doi:10.1016/j.jacc.2008.07.067

Cited by 141 publications

(127 citation statements)

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“…Even after 4 mo, the focal accumulation remained at a higher level than in the sham group. The similar distribution pattern of arginine-glycineaspartic acid--based tracer in models of myocardial ischemia has been observed by other groups (40,41). In contrast, 18 F-FBEM-Cys 40 -exendin-4 showed a dramatically different uptake pattern.…”

Section: Discussionsupporting

confidence: 83%

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PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

et al. 2012

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Glucagonlike peptide (GLP-1) and its receptor (GLP-1R) exhibit cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in both animal studies and clinical trials. However, the kinetics of GLP-1R expression in the infarcted/ischemic myocardium has not yet been explored. The purpose of this study was to monitor the presence and time course of regional myocardial GLP-1R expression after MI/R with noninvasive PET. Methods: Male Sprague-Dawley rats underwent a 45-min transient left coronary artery occlusion, followed by reperfusion. The myocardial infarction was confirmed by electrocardiogram and cardiac ultrasound. In vivo PET was performed to determine myocardial uptake of 18 F-FBEM-Cys 40 -exendin-4 at different time points after reperfusion. The localization of 18 F-FBEM-Cys 40 -exendin-4 accumulation was determined by coregistering 18 F-FDG PET and CT images. Ex vivo autoradiography, GLP-1R immunohistochemical staining, and Western blot analysis were performed to confirm the PET results. Results: Myocardial origin and infarcted/ischemic area localization of 18 F-FBEM-Cys 40 -exendin-4 accumulation was confirmed by coregistration of small-animal CT and 18 F-FDG images. At 8 h after MI/R, tracer uptake in the infarcted/ischemic region was 0.37 6 0.05 percentage injected dose per gram, significantly higher than that in the control group (P , 0.01). The localized tracer uptake decreased, relative to the 8-h time point, but was still significantly higher than the control group on days 1 and 3 after MI/R. At 2 wk after MI/R, the tracer uptake in the affected area showed no significant difference, compared with that in the healthy myocardium. Autoradiography showed the same trend of 18 F-FBEM-Cys 40 -exendin-4 uptake in the myocardial infarcted/ischemic area. The specificity of tracer uptake into ischemic myocardium was supported by decreased tracer uptake after the rats were pretreated with an excess amount of unlabeled exendin-4. Immunohistochemical staining and Western blotting of GLP-1R protein of excised cardiac sections confirmed that the change in uptake observed by PET corresponded to a change in GLP-1R expression. Conclusion: Noninvasive PET using 18 F-FBEM-Cys 40 -exendin-4 revealed a dynamic pattern of GLP-1R upregulation in the infarcted/ischemic area after MI/R. The imaging results will deepen our understanding of the mechanism of the cardioprotective effect of GLP-1 and its analogs and potentially provide guidance for optimization of the time frame of therapeutic intervention.

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Section: Discussionsupporting

confidence: 83%

“…The fused images clearly showed localization of 18 F-FBEM-Cys 40 -exendin-4 within the myocardium at 1 d after MI/R. 18 F-FBEM-cys 40 -exendin-4 signal detected with PET corresponded to anterolateral myocardium and was clearly separated from the intercostal muscle layer.…”

Section: Image Colocalizationmentioning

confidence: 92%

PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

et al. 2012

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“…Myocardial collagen fibers are consisted of type I, type II and type V fibrillar collagen. These types of collagen are synthesized by fibroblasts and account for about 90% of all the collagen within the heart [19][20][21]. Interstitial collagen networks support the architecture and the arrangement of the cardiomyocytes during the cardiac cycle and the improves force transferred to the ventricular chambers.…”

Section: Discussionmentioning

confidence: 99%

Myocardial Reaction to Energy Drinks in a Guine a Pig: Structural Changes

et al. 2017

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SummaryThe aim of this study was to evaluate myocardial changes in a short-haired guinea pig (Cavia porcellus L) after everyday use of energy drinks for 60 days. The experiments were carried out on 11 male guinea pigs, age of 2 months, with a mean weight of 220±0.2 g. The guinea pigs were randomly grouped into a control group of 5 guinea pigs and experimental group of 6. Experimental group guinea pigs were orally administered energy drinks 4 ml per day as a single oral dose. After the 60 days experiment, the quantitatively evaluated structures of myocardial interstitial collagen in the left ventricle using automated image analysis system, which was connected to Olympus BXx51 microscope. Assessment was performed with Image-Pro Plus 5.1 analysis system. We calculated volume and perimeter of the interstitial fibrillar collagen in the left ventricular myocardium, the number of separate fibers in the field of view were counted. In total, there was evaluated 100 fields of view in the control group and 120 fields of view in the experimental group. Statistical analysis was performed using statistical package SPSS Statistics 20 and Microsoft Excel. We used bifactorial analysis of variance (ANOVA) to compare histomorphometric parameters between the two groups. We assessed that the difference between parameters was up to 1% and the individual specific effect was counting for 50% (p < 0.05). Variation of the features was much larger within the experimental group, when compared to the control group. Maximum average values of the fibrillar collagen volume, perimeter and the number of separate fibers in the field of view were 1.2 times larger in the experimental group than in the control group. Repeated energy drink consumption acts as external factor stimulating adaptive remodeling processes. Quantative structural changes of fibrillar collagen in left ventricle of experimental group animals are reaction to a stress factor. Unbalanced changes of fibrillar collagen may determine inadequate remodeling and become a reason for pathogenesis.

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“…14 Preclinical studies have shown feasibility of visualizing avb 3 integrin 15,16 (on myofibroblasts), angiotensin-converting enzyme (ACE), 17 angiotensin II receptor type 1 (AT1), 18 and coagulation factor XIII. 19 Although initial small scale clinical pilot studies have been performed for some of these tracers, [20][21][22] no definitive studies have been performed.…”

Section: See Related Article Pp 1114-1123mentioning

confidence: 99%

Playing slot to hitting the jackpot in molecular imaging: On probability of uncovering subcellular pathogenesis vs achieving clinical applicability

Haas

Narula

2018

Journal of Nuclear Cardiology

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Myocardial infarction (MI), despite optimal reperfusion therapy, results in substantial loss of muscle tissue through apoptosis and necrosis. The repair process post MI is traditionally divided into consecutive and partly overlapping inflammation, proliferation, and maturation phases. The initial phase is characterized by infiltration of inflammatory cells removing cellular debris, and formation of new blood vessels. Matrix metalloproteinases (MMP) and other proteolytic enzymes secreted by inflammatory cells facilitate these processes. During the proliferatory phase, fibroblasts transdifferentiate into myofibroblasts and deposit collagen in the infarct area. This is mediated by a variety of growth factors, including components of a local reninangiotensin-aldosterone system. In the final phase, the newly formed scar is consolidated through cross-linking of collagen fibers and other extracellular matrix components. The extracellular matrix plays an important role in the healing process, and an imbalance between matrix deposition and degradation can lead to adverse myocardial remodeling spiraling to heart failure. Excessive collagen deposition beyond the infarct area contributes to myocardial stiffening and loss of contractile function. On the other hand, inadequate deposition of collagen or excessive collagen degradation can lead to infarct expansion, aneurysm formation, left ventricular (LV) dilation, and even cardiac rupture.MMP are a group of zinc-dependent enzymes that degrade a large variety of extracellular matrix proteins. Approximately 25 MMP have been described and classified in the functional subgroups gelatinases, collagenases, stromelysins, and membrane-type MMP. Extensive preclinical work has suggested detrimental effect of the gelatinases MMP-2 and MMP-9. Genetic knockout of MMP-9 1,2 and MMP-2 3 restricted inflammatory response and removal of necrotic tissue and collagen deposition after experimental MI; this was associated with reduction in LV dilation and incidence of of LV rupture. Moreover, knockout of endogenous tissue inhibitors of metalloproteinases (TIMP) resulted in increased hypertrophy, dilation, and cardiac dysfunction.4,5 Also, animal studies have shown that pharmacologic MMP inhibitors reduce remodeling.6,7 Therapeutic MMP inhibition has not been successfully translated to clinical efficacy.Targeting of cardiac MMP activity has been reported using optical imaging 8 and nuclear imaging [9][10][11] probes. A non-invasive SPECT imaging of MMP activity has been reported in experimental MI in mice employing Tc-99 m-labeled broad-spectrum MMP inhibitor RP805. 10 When comparing with control mice, uptake in infarct area was fivefold higher from week 1 to 3, with slight reduction over time. Interestingly, uptake was also twofold higher in remote area, suggesting that remote imaging could become feasible. In a follow-up study by the same group, the same probe was evaluated in a larger infarct model in porcine experiments.

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Molecular Imaging of Interstitial Alterations in Remodeling Myocardium After Myocardial Infarction

Abstract: Radiolabeled CRIP allows for noninvasive visualization of interstitial alterations during cardiac remodeling, and is responsive to antiangiotensin treatment. If proven clinically feasible, such a strategy would help identify post-MI patients likely to develop heart failure.

Cited by 141 publications

References 37 publications

PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

Myocardial Reaction to Energy Drinks in a Guine a Pig: Structural Changes

Playing slot to hitting the jackpot in molecular imaging: On probability of uncovering subcellular pathogenesis vs achieving clinical applicability

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