ZSF1 rat as animal model for HFpEF: Development of reduced diastolic function and skeletal muscle dysfunction

Abstract

Aims: The prevalence of heart failure with preserved ejection fraction (HFpEF) is still increasing, and so far, no pharmaceutical treatment has proven to be effective. A key obstacle for testing new pharmaceutical substances is the availability of suitable animal models for HFpEF, which realistically reflect the clinical picture. The aim of the present study was to characterize the development of HFpEF and skeletal muscle (SM) dysfunction in ZSF1 rats over time.

Methods and results: Echocardiography and functional analyses of the SM were performed in 6-, 10-, 15-, 20-, and 32-week-old ZSF1-lean and ZSF1-obese. Furthermore, myocardial and SM tissue was collected for molecular and histological analyses. HFpEF markers were evident as early as 10 weeks of age. Diastolic dysfunction, confirmed by a significant increase in E/e', was detectable at 10 weeks. Increased left ventricular mRNA expression of collagen and BNP was detected in ZSF1-obese animals as early as 15 and 20 weeks, respectively. The loss of muscle force was measurable in the extensor digitorum longus starting at 15 weeks, whereas the soleus muscle function was impaired at Week 32. In addition, at Week 20, markers for aortic valve sclerosis were increased.

Conclusions: Our measurements confirmed the appearance of HFpEF in ZSF1-obese rats as early as 10 weeks of age, most likely as a result of the pre-existing co-morbidities. In addition, SM function was reduced after the manifestation of HFpEF. In conclusion, the ZSF1 rat may serve as a suitable animal model to study pharmaceutical strategies for the treatment of HFpEF.

Keywords: Diastolic dysfunction; Heart failure with preserved ejection fraction; Skeletal muscle; ZSF1 rat.

FIGURE 1

Body weight (A), heart weight (B), tibia length (C), and wet weight of the TA (D), EDL (E), and soleus (F) muscle was determined in ZSF1‐lean (square, solid line) and ZSF1‐obese (triangle, dashed line) at different ages. Values are shown as mean ± SEM. ** P < 0.01, *** P < 0.001 vs. ZSF1‐lean. TA, tibialis anterior; EDL, extensor digitorum longus.

FIGURE 2

LVAW;d (A), LVEDD (B), LV mass (C), E/e′ (D), mean arterial pressure (E), and left ventricular ejection fraction (LVEF) (F) were assessed in ZSF1‐lean (square, solid line) and ZSF1‐obese (triangle, dashed line) at different ages by echocardiography and invasive haemodynamic measurements. Values are shown as mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. ZSF1‐lean. LVAW;d, thickness of the left ventricular anterior wall; LVEDD, left ventricular end‐diastolic diameter; LV, left ventricular.

FIGURE 3

Soleus absolute force generation of ZSF1‐lean (square, solid line) and ZSF1‐obese (triangle, dashed line) rats at 6 (A), 10 (B), 15 (C), 20 (D), and 32 (E) weeks of age. The % difference in maximal absolute force between ZSF1‐lean and obese animals was calculated for the different age groups. Values are shown as mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. ZSF1‐lean.

FIGURE 4

Soleus‐specific muscle force generation of ZSF1‐lean (square, solid line) and ZSF1‐obese (triangle, dashed line) rats at 6 (A), 10 (B), 15 (C), 20 (D), and 32 (E) weeks of age. The % difference in maximal absolute force between ZSF1‐lean and obese animals was calculated for the different age groups. Values are shown as mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. ZSF1‐lean.

FIGURE 5

Aortic valve function in lean (square, solid line) and obese (triangles, dashed line) ZSF1 rats. (A) Mean aortic valve peak velocity (m/s), (B) mean aortic valve peak pressure gradient (mmHg), and (C) aortic valve opening area (mm²) in 6‐, 10‐, 15‐, 20‐, and 32‐week‐old animals. Representative pulsed‐wave Doppler recordings of ZSF1‐lean (D) and ZSF1‐obese (E) are depicted. Values are shown as mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. ZSF1‐lean.

FIGURE 6

mRNA expression in the left ventricle of BNP (A), collagen 1A1 (B), collagen 1A2 (C), and collagen 3A1 (D) was quantified in ZSF1‐lean (black bars) and ZSF1‐obese (grey bars) rats at different ages. Expression values are expressed as x‐fold change vs. ZSF1‐lean animals and shown as mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. ZSF1‐lean.