Back to Search
Start Over
Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2019 Mar 15; Vol. 115 (4), pp. 788-799. - Publication Year :
- 2019
-
Abstract
- Aims: The ability of the right ventricle (RV) to adapt to increased afterload is the major determinant of survival in patients with pulmonary hypertension (PH). In this study, we explored the effect of genetic background on RV adaptation and survival in a rat model of severe pulmonary arterial hypertension (PAH).<br />Methods and Results: PH was induced by a single injection of SU5416 (SU) in age-matched Sprague Dawley (SD) or Fischer rats, followed by a 3-week exposure to chronic hypoxia (SUHx). SD and Fischer rats exhibited similar elevations in RV systolic pressure, number of occlusive pulmonary vascular lesions, and RV hypertrophy (RV/LV+S) in response to SUHx. However, no Fischer rats survived beyond 7 weeks compared with complete survival for SD rats. This high early mortality of Fischer rats was associated with significantly greater RV dilatation and reduced ejection fraction, cardiac output, and exercise capacity at 4 weeks post-SU. Moreover, microarray analysis revealed that over 300 genes were uniquely regulated in the RV in the severe PAH model in the Fischer compared with SD rats, mainly related to angiogenesis and vascular homoeostasis, fatty acid metabolism, and innate immunity. A focused polymerase chain reaction array confirmed down-regulation of angiogenic genes in the Fischer compared with SD RV. Furthermore, Fischer rats demonstrated significantly lower RV capillary density compared with SD rats in response to SUHx.<br />Conclusion: Fischer rats are prone to develop RV failure in response to increased afterload. Moreover, the high mortality in the SUHx model of severe PAH was caused by a failure of RV adaptation associated with lack of adequate microvascular angiogenesis, together with metabolic and immunological responses in the hypertrophied RV.<br /> (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Subjects :
- Adaptation, Physiological
Animals
Disease Models, Animal
Exercise Tolerance
Gene Expression Regulation
Heart Failure genetics
Heart Failure metabolism
Heart Failure physiopathology
Hypertension, Pulmonary genetics
Hypertension, Pulmonary metabolism
Hypertension, Pulmonary physiopathology
Hypertrophy, Right Ventricular genetics
Hypertrophy, Right Ventricular metabolism
Hypertrophy, Right Ventricular physiopathology
Male
Myocytes, Cardiac metabolism
Neovascularization, Physiologic
Rats, Inbred F344
Rats, Sprague-Dawley
Severity of Illness Index
Signal Transduction
Species Specificity
Transcriptome
Ventricular Dysfunction, Right genetics
Ventricular Dysfunction, Right metabolism
Ventricular Dysfunction, Right physiopathology
Heart Failure etiology
Hypertension, Pulmonary complications
Hypertrophy, Right Ventricular etiology
Ventricular Dysfunction, Right etiology
Ventricular Function, Right
Ventricular Remodeling
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 115
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 30357319
- Full Text :
- https://doi.org/10.1093/cvr/cvy258