Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice
Stöckigt F, Eichhorn L, Beiert T, Knappe V, Radecke T, Steinmetz M, Nickenig G, Peeva V, Kudin AP, Kunz WS, Berwanger C, Kamm L, Schultheis D, Schlötzer-Schrehardt U, Clemen CS, Schröder R, Schrickel JW (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 15
Article Number: e0228913
Journal Issue: 3
DOI: 10.1371/journal.pone.0228913
Abstract
Background Mutations in the human desmin gene (DES) cause autosomal-dominant and -recessive cardiomyopathies, leading to heart failure, arrhythmias, and AV blocks. We analyzed the effects of vascular pressure overload in a patient-mimicking p.R349P desmin knock-in mouse model that harbors the orthologue of the frequent human DES missense mutation p. R350P. Methods and results Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT) littermates. Echocardiography demonstrated reduced left ventricular ejection fraction in HET-TAC (WT-sham: 69.5 ± 2.9%, HET-sham: 64.5 ± 4.7%, WTTAC: 63.5 ± 4.9%, HET-TAC: 55.7 ± 5.4%; p<0.01). Cardiac output was significantly reduced in HET-TAC (WT sham: 13088 ± 2385 μl/min, HET sham: 10391 ± 1349μl/min, WT-TAC: 8097 ± 1903μl/min, HET-TAC: 5793 ± 2517μl/min; p<0.01). Incidence and duration of AV blocks as well as the probability to induce ventricular tachycardias was highest in HET-TAC. We observed reduced mtDNA copy numbers in HET-TAC (WT-sham: 12546 ± 406, HET-sham: 13526 ± 781, WT-TAC: 11155 ± 3315, HET-TAC: 8649 ± 1582; p = 0.025), but no mtDNA deletions. The activity of respiratory chain complexes I and IV showed the greatest reductions in HET-TAC. Conclusion Pressure overload in HET mice aggravated the clinical phenotype of cardiomyopathy and resulted in mitochondrial dysfunction. Preventive avoidance of pressure overload/arterial hypertension in desminopathy patients might represent a crucial therapeutic measure.
Authors with CRIS profile
Involved external institutions
Universitätsklinikum Bonn
Germany (DE)
Universitätsklinikum Essen
Germany (DE)
Institute of Experimental Epileptology and Cognition Research
Germany (DE)
Deutsches Zentrum für Luft- und Raumfahrt e.V. (DLR) / German Aerospace Center
Germany (DE)
Germany (DE)
Universitätsklinikum Essen
Germany (DE)
Institute of Experimental Epileptology and Cognition Research
Germany (DE)
Deutsches Zentrum für Luft- und Raumfahrt e.V. (DLR) / German Aerospace Center
Germany (DE)
How to cite
APA:
Stöckigt, F., Eichhorn, L., Beiert, T., Knappe, V., Radecke, T., Steinmetz, M.,... Schrickel, J.W. (2020). Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice. PLoS ONE, 15(3). https://doi.org/10.1371/journal.pone.0228913
MLA:
Stöckigt, Florian, et al. "Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice." PLoS ONE 15.3 (2020).
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