Experimental evidence for the influence of pregnancy history on HFpEF development later in life
R Magaye, B H Wang, M Kiyar, G J Niu, S Bailey, R Nuon, J Thomas, H Kiriazis, A Dogra, K Grigolon, D Donner, D M KayeAbstract
Background
Women with heart failure with preserved ejection fraction (HFpEF) account for over half of all HFpEF related hospitalisations, and the prevalence increases further with increasing age and renal disease. There are several potential gender-specific contributors in women, including aging related hormonal disruptions and the potential influence of prior pregnancy and related complications on changes in cardiovascular structure. There is limited mechanistic research as to how prior pregnancy may act as priming process for the development of HFpEF later in life (post menopause).
Purpose
The study aimed to investigate whether mice with prior pregnancy responded differentially to HFpEF drivers during exposure in the post-estrous phase of life (ie “post menopause”).
Methods
14-month-old female C57bl/6J mice who had multiple pregnancies (MP) and age matched mice with no prior pregnancies (NP) were used. Both groups were fed 60% high fat diet (HFD) for 12 weeks and received angiotensin II (Ang II: 0.85 mg/kg/day) infusion via osmatic minipump from week 6 to 12. We compared blood pressure, morphometric parameters, and cardiac function, alongside histological and molecular changes to determine the differences in response at end point.
Results
At the end point, 17-month-old MP mice receiving HFD + Ang II had significantly greater increase in body weight (p<0.05) and systolic blood pressure (p<0.001) compared to NP mice receiving HFD + Ang II. The MP mice on HFD + Ang II also had higher kidney weights (p<0.01), which were accompanied by higher levels of collagen deposition (p<0.001), increased mRNA levels of Col3a1, Col1a1, and Tnfa (p<0.01) compared to NP mice on HFD + Ang II. In the heart, the MP mice receiving HFD+ Ang II had significantly higher mRNA expression levels of hypertrophic markers; Myh7 (p<0.0001) and Nppa (p<0.05), together with significantly higher heart weights (p<0.05). Both groups had significant increase in collagen deposition (p<0.01) and expression levels of Col3a1 and Col1a1 mRNA in the heart (p<0.0001) compared to their respective control groups.
Conclusion
In the presence of obesity and elevated blood pressures, having a history of multiple pregnancies can drive progression to HFpEF by exacerbating kidney injury later in life.ESC Figure