Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice

• Published in: PloS one Vol. 15; no. 3; p. e0228913
• Main Authors: Stöckigt, Florian, Eichhorn, Lars, Beiert, Thomas, Knappe, Vincent, Radecke, Tobias, Steinmetz, Martin, Nickenig, Georg, Peeva, Viktoriya, Kudin, Alexei P, Kunz, Wolfram S, Berwanger, Carolin, Kamm, Lisa, Schultheis, Dorothea, Schlötzer-Schrehardt, Ursula, Clemen, Christoph S, Schröder, Rolf, Schrickel, Jan W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03-03-2020; Public Library of Science (PLoS)
• Subjects: Analysis; Arrhythmia; Biology and Life Sciences; Echocardiography; Genes; Heart failure; Hypertension; Medicine and Health Sciences; Myocardial diseases; Research and Analysis Methods; Tachycardia; Germany; Missouri
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0228913

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.
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%, WT-TAC: 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.
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.