The role of high intensity interval training on endoplasmic reticulum stress in heart failure with preserved ejection fraction
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a condition that accounts for approximately 50 % of HF cases with the prevalence increased with advancing age. As of now, no effective treatment is available for HFpEF, which calls for continued efforts towards novel therapies. Despite many concerns about safety and effectiveness of exercise training in HF patients, results from clinical trials have suggested exercise training is safe, improves exercise capacity and health status in HF patients. In some cases, animal models may mimic the human condition closely. In HFpEF, Dahl salt-sensitive (SS) rat is an experimental model that have recently been reported to develop cardiac hypertrophy induced by pressure overload and progressing to diastolic dysfunction with normal left ventricular ejection fraction (LVEF). In order to better understand the mechanisms underlying processes behind HFpEF, we aimed in the present study, to investigate benefits of high intensity interval training intervention in order to prevent and/or delay the development of HFpEF in female Dahl SS rats, and search for the potential effect of this intensity of exercise training modulating unfolded protein response (UPR) in HFpEF.
Method and Results: Female Dahl SS rats were randomized into low-salt (LS, n = 20), high-salt (HS, n = 40) and high intensity interval training (HIT, n = 20)groups. HIT was performed three times per week, with four intervals of four minutes at 90 % VO2max, separated by three minutes at 60 % VO2max. Non-invasive blood pressure measured in different time points showed sustained hypertensive levels in HS rats, followed by cardiac remodeling and diastolic dysfunction with normal LVEF assessed by echocardiography. Maximum oxygen uptake (VO2max) was measured before the HS rats start the high-salt diet and at different time points to adjust the exercise training intensity. Although exercise training had no effect either reducing blood pressure levels or preventing pathological cardiac hypertrophy and diastolic dysfunction, exercise tolerance was improved in HS rats after HIT. Moreover, the expression of proteins involved in endoplasmic reticulum stress, such as GRP74, ATF6α, pIRE1, and CHOP, was measured using western blot, and showed no difference related to HFpEF condition, with no effect of HIT modulating UPR. Survival distribution was significantly reduced in HS compared to LS rats, and HIT did not prevent increased mortality in female Dahl SS rats fed a high-salt diet for 28 weeks.
Conclusions: Taken together, our data showed that high-salt diet induced cardiac hypertrophy in female Dahl SS rats with symptoms for HFpEF, and that ER stress was not associated with the development of the disease. We also showed that HIT did not reverse cardiac remodeling and hemodynamic overloading in HFpEF, with no modulation of the UPR.