Endothelial function is disturbed in a hypertensive diabetic animal model of HFpEF: Moderate continuous vs. high intensity interval training
Introduction
Heart failure (HF) is the most frequent cause of hospitalization in patients above 65 years with increasing incidence. Approximately 50% of the HF patients have a preserved ventricular ejection fraction (HFpEF) [1], which is associated with several comorbidities such as arterial hypertension, diabetes, obesity and renal dysfunction. Classic treatment regimens that have proven effective in HF patients with reduced ejection fraction (HFrEF) have failed to improve survival in HFpEF [[2], [3], [4], [5]]. However, exercise training (ET) might be an alternative treatment option, since several studies [[6], [7], [8], [9], [10]] and meta-analyses [[11], [12], [13]] in HFpEF reported beneficial effects on exercise intolerance, which is the main symptom associated with this disease. Further, findings from a small pilot study in HFpEF patients also suggested that high-intensity interval training (HIIT) exerts greater benefits than moderate-intensity continuous exercise training (MCT) [14]. In contrast to HFrEF (reviewed in [15]), however, the mechanisms responsible for the benefits of ET in HFpEF remain largely unclear.
Some years ago, Paulus and Tschöpe [16] presented a new paradigm for the development of HFpEF where coronary microvascular inflammation-triggered endothelial dysfunction initiated a cascade leading to eventual fibrosis and stiffening of the cardiomyocytes. Hence, endothelial dysfunction might play a crucial role in the pathogenesis as well as the outcome of HFpEF, making it a potential target for prevention and treatment of HFpEF. Yet in HFpEF patients data with respect to endothelial dysfunction remains controversial, with some [[17], [18], [19], [20]] but not others [21,22] reporting impaired endothelial function when compared to controls. This controversy is further complicated in that a gold-standard experimental model of HFpEF is still missing to directly confirm patient findings and, of the few models developed only a limited number have investigated endothelial function [23,24]. Using a nutritive hypertensive rat model of HFpEF, we recently demonstrated that HIIT prevented the development of endothelial dysfunction in the setting of primary prevention [23]. However, no data are yet available in HFpEF investigating either the impact of ET on endothelial function in the setting of secondary prevention or on the effects of different training modalities.
The present study, therefore, used a genetic hypertensive, diabetic-related rat model (ZSF1 lean and obese rats) characterized by cardiorenal metabolic syndrome. The ZSF1 model was developed by crossing rat strains with two separate leptin receptor mutations (fa and facp), the lean female ZDF rat (+/fa) and the lean male SHHF rat (+/facp), derived from the obese spontaneously hypertensive rat carrying the corpulent facp gene) [25]. After the ZSF1 obese rats developed signs of HFpEF we assessed 1) the degree of endothelial dysfunction developed; and 2) the efficacy of various exercise training regimes (HIIT or MCT) to reverse endothelial dysfunction. We hypothesized that the development of HFpEF would be associated with endothelial dysfunction triggered by a cascade of molecular alterations, which would be rescued by both exercise training regimes.
Section snippets
Animals and study design
Male ZSF1 lean (control, n = 19) and ZSF1 obese (n = 47) rats were included into the study, as previously published [26,27]. At the age of 20 weeks the development of HFpEF was confirmed by echocardiography/invasive hemodynamic measurements and tissue material from a subset of animals were collected (control n = 8; ZSF1 obese n = 12). The remaining control rats (control, n = 11) were kept sedentary for another 8 weeks whereas the remaining ZSF1 obese animals were randomized into the following
Animal characteristics
20 weeks of age: As shown in Table 1 (see supplement) the ZSF1 obese animals exhibited signs of HFpEF when compared to control rats. This was documented by a significant increase in E/E´ and LVEDP, whereas VO2peak was significantly reduced. Despite a significant increase in body weight, LVEF was still preserved in both groups (above 60%) with no difference in systolic blood pressure.
28 weeks of age: LVEDP and E/E´ were still significantly increased in the ZSF1 obese animals when compared to
Discussion
The key findings emerging from the present study can be summarized as follows: 1) endothelial dysfunction was present in the aorta of HFpEF animals and this was associated with numerous molecular alterations including reduced expression and activation (phosphorylation) of eNOS, an increase in expression of NADPH oxidase and nitrotyrosine modifications and activation of JNK, reduced coverage of the vessel wall by endothelial cells, and a reduced collagen I/III ratio; 2) ET, independent of the
Conclusions
Our data provide additional evidence that endothelial function (endothelial-dependent and endothelial-independent) is impaired in HFpEF, which was associated with a reduced expression of eNOS (NO production), an elevated activation of JNK and expression of the NADPH oxidase subunit gp91phox (oxidative stress reducing NO bioavailability) and a reduction in endothelial cell coverage and collagen I/III ratio (vascular stiffness impeding endothelial-independent vasodilation). ET, initiated after
Sources of funding
Support for this study was provided by the European Commission, Framework Program 7, grant number: EU 602405-2. The authors are supported by grants from the K.G. Jebsen Foundation (UW, NR) Norwegian Research Council (UW), and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology (UW) and the Medical Faculty of the University Leipzig (ZS).
Disclosures
No conflicts of interest, financial or otherwise, are declared by the author(s).
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