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

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

doi:10.1371/journal.pone.0228913

Abstract

BackgroundMutations 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 resultsTransverse 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.ConclusionPressure 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.

Highlights

The disease progression in genetically determined forms of cardiomyopathies might be aggravated by different etiological factors
In the present study we investigated the influence of pressure overload on cardiac function in a knock-in mouse model for human desminopathies, which encompass autosomal-dominant and very rare autosomal-recessive forms of cardiomyopathies and myopathies [1]
We found that the expression of mutant desmin protein can cause widespread mitochondrial pathology comprising morphological, enzymatic and genetic alterations in skeletal muscle tissue [16]. Further exploiting this desminopathy mouse model, we studied the impact of transverse aortic constriction (TAC)-induced pressure overload on cardiac function and mitochondrial properties

Summary

Introduction

The disease progression in genetically determined forms of cardiomyopathies might be aggravated by different etiological factors. In the present study we investigated the influence of pressure overload on cardiac function in a knock-in mouse model for human desminopathies, which encompass autosomal-dominant and very rare autosomal-recessive forms of cardiomyopathies and myopathies [1]. Cardiac involvement most often results in a dilated cardiomyopathy (DCM) phenotype. The estimated prevalence a desmin gen (DES) mutation in all DCM patients ranges between one and two percent [3]. 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.

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Conclusion