Genetic Cardiomyopathy; How do different Disease-causing Mutations influence Type of Cell Death and Fibrosis Pattern of the Myocardium

Schuiringa, F.S.A.M. (2015) Genetic Cardiomyopathy; How do different Disease-causing Mutations influence Type of Cell Death and Fibrosis Pattern of the Myocardium. thesis, Medicine.

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Abstract

OBJECTIVES The aim of this study is to identify myocardial remodeling parameters (type of cell death and fibrosis pattern) in apex biopsies of patients with end stage genetic cardiomyopathy and compare these between causative mutation groups. BACKGROUND Cell death and fibrosis lead to cardiac dysfunction in genetic cardiomyopathy. Over a hundred disease-causing genes have been identified. Currently, classification and treatment of genetic cardiomyopathy are based on morphology and function of the heart instead of genetics. We hypothesize that different mutations have distinct pathomechanisms leading to myocardial remodeling. Analysis of complete heart slices showed a clear correlation between mutation groups (nine groups of genes that are responsible for a specific mechanism in the cell, e.g. the nuclear envelope) and the parameters fibrosis and cell death: autophagy was upregulated in the group calcium pump and desmin filament network. The groups sarcomeric and nuclear envelope revealed mainly endocardial fibrosis. Outer myocardial fibrosis was more distinct in calcium pump and desmin filament network. Before explantation, only biopsies can be studied. Unraveling histological characteristics of several mutation groups in apex biopsies can provide guidance in genetic testing, which will positively effect time and costs, and gives insight in the different pathomechanisms; essential knowledge for the development of targeted drugs. METHODS 38 apex biopsies of patients with end stage genetic cardiomyopathy were analyzed. Patients were classified according to their mutation in the functional groups: sarcomeric, desmin filament network, calcium pump, nuclear envelope, other and double mutation. Apoptosis, oncosis and autophagy were detected with immunostaining of active caspase 3, C4d and P62, respectively. Digital fibrosis quantification was performed on Masson’s trichrome stained slides with an in-house developed MATLAB script (http://sourceforge.net/projects/fibroqua nt/). The amount of fibrosis was quantified for the total slice and for the three myocardial layers separate (endocardial, inner myocardium and outer myocardium). RESULTS No significant results were found concerning apoptosis and oncosis rates. Calcium pump [8.48% ± 1.46] and desmin filament network [58.00, N=1] showed a trend towards upregulation of autophagy compared to controls [1.20% ± 0.59], although not significant. The total amount of fibrosis was significantly elevated compared to control [3.00% ± 0.37] in calcium pump [67.28 ± 12.09]. However, all groups showed elevation of total fibrosis compared to the controls. Endocardial fibrosis was significantly higher in sarcomeric [34.14% ± 5.89], calcium pump [67.28% ± 12.09] and nuclear envelope [38.28; 6.25], compared to control. Concerning outer myocardial fibrosis, the group calcium pump [44.38% ± 10.14] showed a significant elevation compared to control [2.32% ± 0.23]. Desmin filament network (N=1) revealed outer myocardial fibrosis of 62.00%. CONCLUSION We objectified myocardial remodeling characteristics that can be assigned to specific mutation groups. The data of the apex biopsies concerning cell death and fibrosis are in line with the findings in complete heart plaques. This suggests that a prediction can be made about a patients’ mutation based on histology: fibrosis pattern and P62 (autophagy) of the apex. Unraveling the effect of a mutation on the myocardium is important in order to understand the pathomechanism. Furthermore, a prediction of the possible mutation can facilitate genetic testing.

Item Type:	Thesis (Thesis)
Supervisor name:	Second'supervisors and Vink, drs. A. and Klooster, Z.J. van der and Department of Pathology, Heart Transplantation research grou and University Medical Centre Utrecht (UMCU) Utrecht, the Nether
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:48
Last Modified:	25 Jun 2020 10:48
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/887

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