| First Author | Stöckigt F | Year | 2020 |
| Journal | PLoS One | Volume | 15 |
| Issue | 3 | Pages | e0228913 |
| PubMed ID | 32126091 | Mgi Jnum | J:285984 |
| Mgi Id | MGI:6400057 | Doi | 10.1371/journal.pone.0228913 |
| Citation | Stockigt F, et al. (2020) Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice. PLoS One 15(3):e0228913 |
| abstractText | 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 mul/min, HET sham: 10391 +/- 1349mul/min, WT-TAC: 8097 +/- 1903mul/min, HET-TAC: 5793 +/- 2517mul/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. |
