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Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice.
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.
Afiliación
  • Stöckigt F; Department of Cardiology, University Hospital Bonn, Bonn, Germany.
  • Eichhorn L; Department of Cardiology, Krankenhaus Porz, Urbacher Weg, Cologne, Germany.
  • Beiert T; Department of Anesthesiology, University Hospital Bonn, Bonn, Germany.
  • Knappe V; Department of Cardiology, University Hospital Bonn, Bonn, Germany.
  • Radecke T; Department of Cardiology, University Hospital Bonn, Bonn, Germany.
  • Steinmetz M; Department of Cardiology, University Hospital Essen, Hufelandstraße, Essen, Germany.
  • Nickenig G; Department of Cardiology, University Hospital Essen, Hufelandstraße, Essen, Germany.
  • Peeva V; Department of Cardiology, University Hospital Bonn, Bonn, Germany.
  • Kudin AP; Institute of Experimental Epileptology and Cognition Research, Bonn, Germany.
  • Kunz WS; Department of Epileptology, University Hospital of Bonn, Bonn, Germany.
  • Berwanger C; Institute of Experimental Epileptology and Cognition Research, Bonn, Germany.
  • Kamm L; Department of Epileptology, University Hospital of Bonn, Bonn, Germany.
  • Schultheis D; Institute of Experimental Epileptology and Cognition Research, Bonn, Germany.
  • Schlötzer-Schrehardt U; Department of Epileptology, University Hospital of Bonn, Bonn, Germany.
  • Clemen CS; Institute of Aerospace Medicine, German Aerospace Center (DLR), Linder Höhe, Cologne, Germany.
  • Schröder R; Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage, Erlangen, Germany.
  • Schrickel JW; Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage, Erlangen, Germany.
PLoS One ; 15(3): e0228913, 2020.
Article en En | MEDLINE | ID: mdl-32126091
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sustitución de Aminoácidos / Desmina / Bloqueo Atrioventricular / Cardiomiopatías Límite: Animals / Female / Humans / Male Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sustitución de Aminoácidos / Desmina / Bloqueo Atrioventricular / Cardiomiopatías Límite: Animals / Female / Humans / Male Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos