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-weekold 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.

Abnormal skeletal muscle blood flow, contractile mechanics and fibre morphology in a rat model of obese‐HFpEF

“…This allowed various sites in the muscle contractile process to be evaluated for dysfunction in HFpEF, including neuromuscular transmission and excitation-contraction coupling. Consistent with previous data where absolute maximal soleus force was reduced by ∼20% in HFpEF rats vs. controls (Bowen et al 2018;Schauer et al 2020), we observed that absolute twitch and maximal forces in both the soleus and EDL were lower in HFpEF rats. However, limb muscle weakness was closely associated with fibre atrophy as, after normalising for muscle mass, specific forces were not different between groups independent of whether the neural and blood supply remained intact.…”

“…As previously noted (Leite et al 2015;Franssen et al 2016;van Dijk et al 2016;Bowen et al 2017b;Schauer et al 2020), by 20 weeks of age obese-ZSF1 rats have developed typical metabolic signs associated with HFpEF including obesity (P < 0.001; Fig. 1A), hyperglycaemia (P < 0.001; Fig.…”

“…We also compared groups at a relatively early time point in the progression of HFpEF, which may limit translation of our findings to more advanced stages of the E. Espino-Gonzalez and others J Physiol 0.0 disease. In addition, our experiments were performed in male rats only such that it remains unclear whether similar findings would be observed in females, although a recent study confirmed that a similar time course in disease progression is observed in females (Schauer et al 2020). Further, while differences in physical activity levels between groups were not measured and cannot be ruled out as having an influence on our experimental measures, it is well established that disuse alone fails to account for the skeletal muscle impairments developed during heart failure (Simonini et al 1996;Miller et al 2009).…”

“…Twenty-week-old male obese (n = 8) and lean (n = 8) diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats (Charles River Laboratories) were used in this study. While both lean and obese ZSF1 rats inherit the hypertension gene, only the obese ZSF1 rats inherit a mutation in the leptin receptor gene (Lepr fa Lepr cp /Crl) that drives weight gain and the metabolic impairments associated with typical signs of HFpEF developing as early as 10 weeks of age (Schauer et al 2020) and well established after 20 weeks (Leite et al 2015;Franssen et al 2016;van Dijk et al 2016;Bowen et al 2017b). Lean ZSF1 rats served as controls.…”

“…Furthermore, a knowledge gap still exists in relation to potential sites of skeletal muscle dysfunction in HFpEF that include the contribution of neuromuscular transmission vs. excitation-contraction failure and/or the impact on more physiologically relevant mechanical measures (i.e. shortening velocity and power), with previous studies performed using only in vitro isometric contractions under direct muscle stimulation (Bowen et al 2015(Bowen et al , 2017b(Bowen et al , 2018Schauer et al 2020).…”