Abstract 1182 Inflammatory and metabolic alterations in the mouse model of arrhythmogenic cardiomyopathy: Cardiac [18F]-FDG distribution vs. histology

gefördert durch ein Promotionsstipendium des ARVC-Selbsthilfe e.V.

Introduction: Arrhythmogenic cardiomyopathy (ACM) is a hereditary disease with a highly variable penetrance. This disease presents with arrhythmias and sudden cardiac death. Histologically ACM is characterised by progressive loss of cardiomyocytes (CM), fibro-fatty deposition and immune cell infiltration. However, no single test demonstrates enough sensitivity for an early diagnosis of ACM.

Purpose: To explore the potential use of molecular PET imaging with glucose analogue [18F]- FDG for non-invasive diagnosis of ACM, we investigate whether cardiac FDG distribution can be correlated to echocardiographic and ex vivo data using mouse models of ACM.

Methods and Results: We generated cardiac restricted Pkp2 and Jup knockout (KO) mice, which recapitulate the ACM phenotype at 8 and 6 weeks of age, respectively. Both genes code for desmosomal proteins that are crucial for the integrity of the heart. We performed echocardiography and subsequently conducted correlative analysis of in vivo [18F]-FDG (PET) and ex vivo [18F]-FDG (autoradiography) imaging and assessed macrophage infiltration. Macrophages were detected by CD68+ staining, and further distinguished by CD206+ (M2 macrophages). H&E and PSR stainings served to assess general tissue architecture and collagen amount in the myocardium. CM cross-sectional area was measured by WGA-staining.

Echocardiography revealed systolic dysfunction, dilated ventricles and thinned ventricular walls in both models. Histology showed significantly increased collagen amounts as patchy infiltrates in the right, but also left ventricles compared to controls indicating a relatively advanced disease state.

At this disease state, in vivo [18F]-FDG uptake signals could be seen in KO animals compared to controls. In addition, ex vivo [18F]-FDG autoradiography detected areas with focal uptake, whereas control animals did not show a significant uptake. Whether those autoradiography signals correlate to sites of inflammation was assessed by CD68+ and CD206+ staining of the corresponding sections. Interestingly, areas of [18F]-FDG uptake in- and ex vivo did not correlate with areas of macrophage infiltration. Instead, the uptake in our models seemed to originate from remaining CMs located in close proximity to scarred tissue.

As [18F]-FDG is a glucose analogue, the uptake of [18F]-FDG in CMs also indicates the shift from mostly fatty acids to glucose utilization during advanced cardiac remodelling where CMs get hypertrophied. Therefore, we proposed that the uptake signal may indicate this metabolic switch and analysed cross-sectional areas of the CMs in areas with a focal [18F]-FDG uptake. We could confirm that CMs in those areas were hypertrophic suggesting metabolic remodelling.

Conclusion: Mice models of ACM present an increased cardiac F18-FDG uptake that co-localizes with regional hypertrophic cardiomyocytes and ventricular remodelling. Thus [18F]-FDG PET might be able to identify hypermetabolic areas in cardiac remodelling, suggesting a potential use of molecular PET imaging for diagnosis of ACM. Prospectively, at earlier time points [18F]-FDG uptake studies might be successful in detecting inflammation and immune cells which is worth being pursued.

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Inflammatory and metabolic alterations in the mouse model of arrhythmogenic cardiomyopathy: Cardiac [18F]-FDG distribution vs. histology
R. Groß¹, T. Williams¹, A. P. Arias Loza¹, S. Schraut¹, A. Kilinc¹, T. Higuchi¹, B. Gerull¹, für die Studiengruppe: DZHI
¹Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum Würzburg, Würzburg;
gefördert durch ein Promotionsstipendium des ARVC-Selbsthilfe e.V. Introduction: Arrhythmogenic cardiomyopathy (ACM) is a hereditary disease with a highly variable penetrance. This disease presents with arrhythmias and sudden cardiac death. Histologically ACM is characterised by progressive loss of cardiomyocytes (CM), fibro-fatty deposition and immune cell infiltration. However, no single test demonstrates enough sensitivity for an early diagnosis of ACM. Purpose: To explore the potential use of molecular PET imaging with glucose analogue [18F]- FDG for non-invasive diagnosis of ACM, we investigate whether cardiac FDG distribution can be correlated to echocardiographic and ex vivo data using mouse models of ACM. Methods and Results: We generated cardiac restricted Pkp2 and Jup knockout (KO) mice, which recapitulate the ACM phenotype at 8 and 6 weeks of age, respectively. Both genes code for desmosomal proteins that are crucial for the integrity of the heart. We performed echocardiography and subsequently conducted correlative analysis of in vivo [18F]-FDG (PET) and ex vivo [18F]-FDG (autoradiography) imaging and assessed macrophage infiltration. Macrophages were detected by CD68+ staining, and further distinguished by CD206+ (M2 macrophages). H&E and PSR stainings served to assess general tissue architecture and collagen amount in the myocardium. CM cross-sectional area was measured by WGA-staining. Echocardiography revealed systolic dysfunction, dilated ventricles and thinned ventricular walls in both models. Histology showed significantly increased collagen amounts as patchy infiltrates in the right, but also left ventricles compared to controls indicating a relatively advanced disease state. At this disease state, in vivo [18F]-FDG uptake signals could be seen in KO animals compared to controls. In addition, ex vivo [18F]-FDG autoradiography detected areas with focal uptake, whereas control animals did not show a significant uptake. Whether those autoradiography signals correlate to sites of inflammation was assessed by CD68+ and CD206+ staining of the corresponding sections. Interestingly, areas of [18F]-FDG uptake in- and ex vivo did not correlate with areas of macrophage infiltration. Instead, the uptake in our models seemed to originate from remaining CMs located in close proximity to scarred tissue. As [18F]-FDG is a glucose analogue, the uptake of [18F]-FDG in CMs also indicates the shift from mostly fatty acids to glucose utilization during advanced cardiac remodelling where CMs get hypertrophied. Therefore, we proposed that the uptake signal may indicate this metabolic switch and analysed cross-sectional areas of the CMs in areas with a focal [18F]-FDG uptake. We could confirm that CMs in those areas were hypertrophic suggesting metabolic remodelling. Conclusion: Mice models of ACM present an increased cardiac F18-FDG uptake that co-localizes with regional hypertrophic cardiomyocytes and ventricular remodelling. Thus [18F]-FDG PET might be able to identify hypermetabolic areas in cardiac remodelling, suggesting a potential use of molecular PET imaging for diagnosis of ACM. Prospectively, at earlier time points [18F]-FDG uptake studies might be successful in detecting inflammation and immune cells which is worth being pursued.
https://dgk.org/kongress_programme/jt2022/aP1240.html