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A translational mouse model of HFpEF

Session Rapid Fire 1 - Basic Science

Speaker Aad Withaar

Congress : Heart Failure 2019

  • Topic : basic science
  • Sub-topic : Basic Science - Cardiac Diseases:Heart Failure
  • Session type : Rapid Fire Abstracts
  • FP Number : 7

Authors : C Withaar (Groningen,NL), LMG Meems (Groningen,NL), C Gehlken (Groningen,NL), HHW Sillje (Groningen,NL), AA Voors (Groningen,NL), RA De Boer (Groningen,NL), CSP Lam (Groningen,NL)

Authors:
C Withaar1 , LMG Meems1 , C Gehlken1 , HHW Sillje1 , AA Voors1 , RA De Boer1 , CSP Lam1 , 1University Medical Center Groningen, Experimental Cardiology - Groningen - Netherlands (The) ,

Citation:

Background

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease with limited therapeutic options. Pathophysiology of HFpEF is complex as a large proportion of HFpEF patients have comorbidities such as obesity, diabetes and hypertension. Importance of heterogeneity and comorbidities is underscored in pre-clinical mouse models, that mostly are models with one (simple) perturbation. This mismatch in underlying pathophysiological mechanisms may contribute to the limited translational value and hinder the development of novel therapeutics. Therefore, in this study we present a heterogeneous HFpEF mouse model that closely mimics the human HFpEF phenotype.

Purpose

We aimed to design a HFpEF mouse model integrating four hallmarks of human HFpEF: aging, female sex, obesity and hypertension.

Methods

18-22 months old female C57BL/6J mice (n=10) were fed a control (CTRL) or high fat diet (HFD) for 12 weeks. During the last 4 weeks, hypertension was induced with angiotensin-II (Ang) infusion (1,25mg/kg/day) (CTRL+Ang or HFD+Ang). Prior to sacrifice, echocardiographic measurements were obtained and images were used for strain analysis. Using PCR, mRNA levels of collagen, atrial natriuretic peptide (ANP), and metallopeptidase inhibitor 1 (TIMP-1) and growth and inflammatory plasma markers were determined. Histological analysis of fibrosis was performed.

Results

HFD+Ang induced increased lung weights (CTRL 9.9 ± 0.5 vs. HFD+Ang 14.3±1.2 p<0.01) atrial weights(0.5±0.05 vs. 0.9±0.08 p<0.01) and increased body and fat weights. Echocardiography showed preserved ejection fraction with substantial cardiac hypertrophy in HFD and even more pronounced in HFD+Ang. Increased myocardial fibrosis was observed. mRNA levels of collagen, ANP and TIMP-1 were increased in CTRL+Ang and HFD+Ang. Plasma levels of growth factors and TIMP-1 were significantly elevated in HFD+Ang. Global longitudinal strain was impaired in HFD+Ang compared to CTRL (-21.4±1 vs. -14.1±0.6 p<0.01). During left ventricle diastolic early filling the reverse peak longitudinal strain rate is lower in the HFD+Ang compared to CTRL (10,7±0.8 vs. 7.5±0.7 p<0.01).

Conclusion

We for the first time showed that by using a multifactorial approach, we were able to closely mimic the human situation. Our mouse HFpEF model uniquely recapitulates the typical human HFpEF signature: impaired movement of the myocardial endocardium, collagen deposition, fibrosis and an increase in cardiac hypertrophy and lung congestion with a preserved ejection fraction. This model is currently available for testing potential novel treatment modalities for patients with HFpEF.

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