A Novel Approach to Modeling Acute Cardiac Decompensation and Recovery in Rats
Creators: name: Thiele, Arne
name: Hendrik, Bartolomaeus
name: Anandakumar, Harithaa
name: Nicola, Wilck
Publisher: name: Zenodo
Year: 2024

description: Project Abstract

Background: Acute decompensations of heart failure (HF) frequently cause further structural and functional cardiac damage despite clinical recompensation, thus leading to increased mortality. Rodent models that reflect the development of HF and the occurrence of decompensations may allow for testing of novel therapies. However, few such rodent models reflecting acute decompensation of pre-existing HF are available. Here, we aimed to establish a novel rat model of HF, which combines two established protocols to achieve both the development of cardiac dysfunction and the ability to add a second stimulus to induce cardiac decompensation.

Methods: To induce HF, 10-week-old male Sprague-Dawley (SD) rats were challenged with chronic volume overload induced by a medium-sized infrarenal aortocaval fistula (ACF). After three weeks, rats received subcutaneous deoxycorticosterone acetate (DOCA) pellets (100mg) and 1% NaCl in the drinking water to induce decompensation. The cessation of DOCA-release after 21 days allowed for the subsequent investigation of a two-week recovery phase, after which the study was terminated. Weight-matched and sham-operated SD rats without DOCA/salt served as controls. Longitudinal examinations were performed prior to ACF surgery, before/after DOCA/salt, and after recovery, each comprising blood collection and echocardiography. Further investigations included histological and gene expression analyses of harvested tissue and plasma proteomics.

Results: ACF establishment resulted in increased left ventricular (LV) mass, LV wall thickness and LV diameter as well as elevated levels of plasma brain natriuretic peptide (BNP) with preserved systolic and diastolic function. The DOCA/salt stimulus induced cardiac decompensation, indicated by reduced ejection fraction and fractional shortening, increased E/e’ as well as markedly increased LV mass, LV wall thickness, LV diameter and plasma BNP. After cessation of the DOCA/salt stimulus, several echocardiographic parameters partially recovered. Histological and gene expression analyses revealed ongoing pathological cardiac hypertrophy and fibrosis after partial echocardiographic recovery. Increased lung, liver and spleen weight also pointed to significant organ congestion in ACF+DOCA/salt rats. Lastly, longitudinal targeted plasma proteome analysis revealed 33 proteins with a dysregulated pattern in ACF+DOCA/salt, including known markers from patient studies (e.g. Vegfd, Tnfrsf11b, Tgfb1).

Conclusion: We present a novel HF rat model that enables the precise induction of cardiac decompensation with subsequent recompensation. We observed a partial recovery of cardiac performance after decompensation with persistent structural defects to the heart. Dysregulation and partial recovery were likewise mirrored in the plasma proteome. We propose the use of this model to study novel therapeutic approaches to treat decompensated HF and its long-term consequences.

 

Project StructureThe zenodo repository contains a zipped folder (`shunt_zenodo.zip`), which opens up to the following structure: 

➜  arne_shunt tree .
.
├── arne_shunt.Rproj
├── data
│   ├── 230330_Arne Thiele_Olink_samples_adapted Anja.xlsx
│   └── Mouse Exploratory_Thiele_NPX.xlsx
├── filtered_significant_analytes.csv
├── plots
│   ├── dist_boxPLots.pdf
│   ├── meanCenteredPCA.pdf
│   ├── modelDiagnostics.pdf
│   ├── model_vis_plots_sig_under_0.05.pdf
│   ├── pca_plots.pdf
│   ├── pca_plots_shunt.pdf
│   ├── single_combined_pca_shunt.pdf
│   └── venn.pdf
├── scripts
│   ├── olink_plots.R
    └── play.R


4 directories, 15 files



the raw data is present under the `data` folder

the script used to analyse the data is the `olink_plots.R` file present within the `scripts` folder

all the QC, analysis plots, model diagnostics and visualisation can be found within the `plots` folder. 

the pacakges used can be found within the script