PLoS ONE (Jan 2020)

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

  • Florian Stöckigt,
  • Lars Eichhorn,
  • Thomas Beiert,
  • Vincent Knappe,
  • Tobias Radecke,
  • Martin Steinmetz,
  • Georg Nickenig,
  • Viktoriya Peeva,
  • Alexei P Kudin,
  • Wolfram S Kunz,
  • Carolin Berwanger,
  • Lisa Kamm,
  • Dorothea Schultheis,
  • Ursula Schlötzer-Schrehardt,
  • Christoph S Clemen,
  • Rolf Schröder,
  • Jan W Schrickel

DOI
https://doi.org/10.1371/journal.pone.0228913
Journal volume & issue
Vol. 15, no. 3
p. e0228913

Abstract

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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%, 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. 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.