Endothelial function is disturbed in a hypertensive diabetic animal model of HFpEF: Moderate continuous vs. high intensity interval training

Schmederer, Zelia; Rolim, Natale; Bowen, T. Scott; Linke, Axel; Wisløff, Ulrik; Adams, Volker

doi:10.1016/j.ijcard.2018.08.087

Cited by 33 publications

(28 citation statements)

References 48 publications

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“…As previous studies have shown, the ZSF1‐obese animals developed signs of HFpEF [elevated E/e′, elevated left ventricular end‐diastolic pressure (LVEDP), and preserved LVEF] at age of 20 weeks 17–20 . In addition, these animals show exercise intolerance, 20,21 reduced skeletal muscle contractility, 21 and impaired endothelial function 22 …”

Section: Introductionmentioning

confidence: 72%

“…Regarding the co‐morbidities triggering HFpEF like obesity, diabetes mellitus, hypertension, and hyperlipidaemia, it is well accepted that they are also associated with an increased risk to develop atherosclerosis/endothelial dysfunction and aortic stenosis (AS) 23,24 . The development of endothelial dysfunction in HFpEF is well accepted, 25,26 and recently, our group reported endothelial dysfunction also in ZSF1‐obese rats 22 . With respect to the association between HFpEF and AS, not much is known so far.…”

Section: Introductionmentioning

confidence: 95%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 95%

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

et al. 2020

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“…64 Recent evidence from animal models of HF have shown that high-intensity interval training can attenuate endothelial dysfunction in both female and male rats, which seems to act via mechanisms specifically lowering oxidative stress in males and increasing endothelial nitric oxide synthase expression in females. 75,76 Whether these molecular benefits are paralleled in male and female patients with HF remains unclear. Furthermore, sex-specific substrate utilization could play a key role in the exercise response in women and may fill the above-mentioned gap in the literature with regards to the effectiveness of exercise-based CR.…”

Section: Future Targets and Open Questions In Translational Cr Researchmentioning

confidence: 99%

“…75,162,163 More recently this line of research included a more clinically relevant animal model, in the way that HFpEF develops due to the onset of multiple comorbidities that mirror a metabolic syndrome. 76,164–166 Another problem with appropriate animal models may be that most models develop over a short time period, whereas in humans several years or decades sometimes pass before a clear phenotype is established.…”

Section: Challenges and Opportunities In Translational Cr Research Mementioning

confidence: 99%

Towards a personalised approach in exercise-based cardiovascular rehabilitation: How can translational research help? A ‘call to action’ from the Section on Secondary Prevention and Cardiac Rehabilitation of the European Association of Preventive Cardiology

Gevaert

Adams

Bahls

et al. 2019

Eur J Prev Cardiolog

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The benefit of regular physical activity and exercise training for the prevention of cardiovascular and metabolic diseases is undisputed. Many molecular mechanisms mediating exercise effects have been deciphered. Personalised exercise prescription can help patients in achieving their individual greatest benefit from an exercise-based cardiovascular rehabilitation programme. Yet, we still struggle to provide truly personalised exercise prescriptions to our patients. In this position paper, we address novel basic and translational research concepts that can help us understand the principles underlying the inter-individual differences in the response to exercise, and identify early on who would most likely benefit from which exercise intervention. This includes hereditary, non-hereditary and sex-specific concepts. Recent insights have helped us to take on a more holistic view, integrating exercise-mediated molecular mechanisms with those influenced by metabolism and immunity. Unfortunately, while the outline is recognisable, many details are still lacking to turn the understanding of a concept into a roadmap ready to be used in clinical routine. This position paper therefore also investigates perspectives on how the advent of ‘big data’ and the use of animal models could help unravel inter-individual responses to exercise parameters and thus influence hypothesis-building for translational research in exercise-based cardiovascular rehabilitation.

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“…19 The limited number of authentic HFpEF animal models poses a major limitation for the investigation of its pathophysiology and potential therapies for HFpEF. Available rodent models of HFpEF, including the ageing accelerate mouse, 20 the Dahl salt-sensitive (DSS) rat, 19,21 the Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF-1) rat, 22,23 the db/db mouse, 24 and the transverse aortic constriction (TAC) surgery/deoxycorticosterone acetate (TAC/ DOCA) mouse 25 have been described. However, which one is most suitable in terms of comparability with SM alterations in HFpEF patients remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Muscular changes in animal models of heart failure with preserved ejection fraction: what comes closest to the patient?

et al. 2020

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Aims Heart failure with preserved ejection fraction (HFpEF) is associated with reduced exercise capacity elicited by skeletal muscle (SM) alterations. Up to now, no clear medical treatment advice for HFpEF is available. Identification of the ideal animal model mimicking the human condition is a critical step in developing and testing treatment strategies. Several HFpEF animals have been described, but the most suitable in terms of comparability with SM alterations in HFpEF patients is unclear. The aim of the present study was to investigate molecular changes in SM of three different animal models and to compare them with alterations of muscle biopsies obtained from human HFpEF patients. Methods and results Skeletal muscle tissue was obtained from HFpEF and control patients and from three different animal models including the respective controls-ZSF1 rat, Dahl salt-sensitive rat, and transverse aortic constriction surgery/deoxycorticosterone mouse. The development of HFpEF was verified by echocardiography. Protein expression and enzyme activity of selected markers were assessed in SM tissue homogenates. Protein expression between SM tissue obtained from HFpEF patients and the ZSF1 rats revealed similarities for protein markers involved in muscle atrophy (MuRF1 expression, protein ubiquitinylation, and LC3) and mitochondrial metabolism (succinate dehydrogenase and malate dehydrogenase activity, porin expression). The other two animal models exhibited far less similarities to the human samples. Conclusions None of the three tested animal models mimics the condition in HFpEF patients completely, but among the animal models tested, the ZSF1 rat (ZSF1-lean vs. ZSF1-obese) shows the highest overlap to the human condition. Therefore, when studying therapeutic interventions to treat HFpEF and especially alterations in the SM, we suggest that the ZSF1 rat is a suitable model.

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Endothelial function is disturbed in a hypertensive diabetic animal model of HFpEF: Moderate continuous vs. high intensity interval training

Cited by 33 publications

References 48 publications

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

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

Towards a personalised approach in exercise-based cardiovascular rehabilitation: How can translational research help? A ‘call to action’ from the Section on Secondary Prevention and Cardiac Rehabilitation of the European Association of Preventive Cardiology

Muscular changes in animal models of heart failure with preserved ejection fraction: what comes closest to the patient?

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