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

ABSTRACT: 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.

SUBMITTER: Stockigt F

PROVIDER: S-EPMC7053759 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Stöckigt Florian F Eichhorn Lars L Beiert Thomas T Knappe Vincent V Radecke Tobias T Steinmetz Martin M Nickenig Georg G Peeva Viktoriya V Kudin Alexei P AP Kunz Wolfram S WS Berwanger Carolin C Kamm Lisa L Schultheis Dorothea D Schlötzer-Schrehardt Ursula U Clemen Christoph S CS Schröder Rolf R Schrickel Jan W JW

PloS one 20200303 3

<h4>Background</h4>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.<h4>Methods and results</h4>Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT ...[more]

PMID: 32126091

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Project description:Chronic pressure overload initiates a series of molecular alterations in the human heart that predate macroscopic organ-level remodeling and downstream heart failure (HF). We hypothesized that integrating easily accessible circulating mediators (proteome) with their expression in the heart (transcriptome) may prioritize targets for study in human pressure overload. Among individuals with severe aortic stenosis (AS)—a pressure overload state—we measured the circulating proteome (Olink) and examined associations with myocardial structure/function (N=519), cardiac MRI-based tissue fibrosis (N=145), and outcomes in AS (N=802). We constructed proteomic signatures of cardiac remodeling and tested their association with HF in the UK Biobank (N=36,668). For proteo-transcriptional integration, we examined a "remodeling proteome” prioritized by proteome-phenotype relations at the transcriptional level via single nuclear RNA-sequencing (snRNA-seq) in 20 human hearts (11 with AS at the time of surgical aortic valve replacement [AVR] and 9 donor hearts not used for transplantation). We identified three principal components of myocardial remodeling (across 12 echocardiographic measures in 503 patients with AS) loaded on cardiac morphology, systolic, and diastolic function traits. Proteins associated with these components (the “remodeling proteome”) specified both known and novel mediators of fibrosis, hypertrophy, and oxidative stress, several of which were associated with interstitial fibrosis by cardiac MRI. Proteomic signatures of remodeling were strongly linked to mortality (AS cohort and UK Biobank) and incident HF (UK Biobank). At a myocardial level, we observed broad differential expression of genes encoding the remodeling proteome between AS and donor hearts, featuring convergent fibrosis pathways (WNT9A, ITGA6, AGRN, CRIM1, SEMA4C, LAYN, PTX3, HMOX1) and metabolic-inflammatory signaling (ENPP2/ATX, TNF), among others. Differential expression of proteo-transcriptionally prioritized genes was prominent in fibroblasts, cardiomyocytes, and endothelial cells. Proteo-transcriptional prioritization in human pressure overload hearts identifies both known and novel targets that are mechanistically relevant to HF pathogenesis. Future integrative studies to index circulating biomarkers over time to myocardial tissue level is warranted to inform pathways of HF progression.

Dataset Information

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

Publications

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

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