Abstract
Background: Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor to heart failure, but its importance in RV failure has been challenged. This study aims to assess whether myocardial fibrosis drives the transition from compensated to decompensated volume load-induced RV dysfunction. Methods: Wistar rats were subjected to aorto-caval shunt (ACS, n = 23) or sham (control, n = 15) surgery, and sacrificed after 1 month, 3 months, or 6 months. Echocardiography, RV pressure-volume analysis, assessment of gene expression and cardiac histology were performed. Results: At 6 months, 6/8 ACS-rats (75%) showed clinical signs of RV failure (pleural effusion, ascites and/or liver edema), whereas at 1 month and 3 months, no signs of RV failure had developed yet. Cardiac output has increased two- to threefold and biventricular dilatation occurred, while LV ejection fraction gradually decreased. At 1 month and 3 months, RV end-systolic elastance (Ees) remained unaltered, but at 6 months, RV Ees had decreased substantially. In the RV, no oxidative stress, inflammation, pro-fibrotic signaling (TGFβ1 and pSMAD2/3), or fibrosis were present at any time point. Conclusions: In the ACS rat model, long-term volume load was initially well tolerated at 1 month and 3 months, but induced overt clinical signs of end-stage RV failure at 6 months. However, no myocardial fibrosis or increased pro-fibrotic signaling had developed. These findings indicate that myocardial fibrosis is not involved in the transition from compensated to decompensated RV dysfunction in this model.
| Original language | English |
|---|---|
| Article number | 557514 |
| Journal | Frontiers in Physiology |
| Volume | 12 |
| DOIs | |
| Publication status | Published - 26 Feb 2021 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank Annemieke Smit-van Oosten, Michel Weij, and Daryll Eichhorn for performing the ACS surgery and excellent technical assistance with the animal experiments. We thank Silke Oberdorf-Maass for technical assistance in the laboratory. We also thank Kirsten Lodder for her excellent laboratory analyses and contribution to finalizing the revisions. Funding. We acknowledge the financial support from the Sebald Fund, Stichting Hartekind, the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences Grant 2012-08 and 2018-2023 awarded to the Phaedra consortium (http://www.phaedraresearch.nl). We also acknowledge the support for KK by the Dutch Lung Foundation (grant number: 5.2.17. 198J0).
Publisher Copyright:
© Copyright © 2021 Hagdorn, Kurakula, Koop, Bossers, Mavrogiannis, van Leusden, van der Feen, de Boer, Goumans and Berger.
