The effect of progressive aerobic continuous training on angiotensin-1, angiotensin-2 and angiotensin-converting enzyme type 2 in patients with heart failure

Background: Chronic hypertension causes structural and functional changes in the heart, ultimately leading to heart failure (HF), which further increases mortality and morbidit. HF is a complex clinical syndrome caused by various structural or functional abnormalities of the heart that impair the filling capacity of the ventricles. The findings of various trials have shown the association between long-term hypertension and HF. The association between hypertension and heart failure with preserved ejection fraction (H:FpEF) is well known, with left ventricular hypertrophy, arterial stiffness, and renal failure possibly contributing to this syndrome. 90% or more of patients with HFpEF in contemporary trials have a history of hypertension. Furthermore, many patients with HFpEF remain hypertensive, and concomitant treatment is one of the few recommended treatments for people with this heart failure phenotype. Recent evidence suggests that not only do many HFpEF patients remain hypertensive, but a significant proportion may have high blood pressure that is difficult to control, despite the use of multiple antihypertensive drugs. In fact, resistant hypertension appears to be as common in patients with HFpEF as in those with hypertension, affecting 10–20% of patients. Use of three antihypertensive drugs in different classes, including an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), a calcium channel blocker, and a diuretic, although there are differences between US and European guidelines. The Ang-(1-7)/ACE2/Mas axis is now considered a major mechanism that balances the vasoconstrictor effects of the classical RAS, which includes renin, ACE, Ang-2 and its receptors AT1 and AT2. Therefore, examining the enzymes of this axis can provide us with useful information in interventional research. Sports training programs are one of the basic elements in cardiac rehabilitation in patients with HF. In this regard, Tucker et al. reported in a meta-analysis of studies registered from 2007 to 2017 that moderate-intensity continuous exercise was an effective treatment for left ventricular remodeling in patients with HF who had clinically stable ejection fraction reduction. and improving performance in these patients; However, a research specifically aimed at determining the effect of increasing aerobic endurance training on variables related to blood pressure, especially the levels of Ang-1 and Ang-2 enzymes, as well as angiotensin-converting enzyme-2 (ACE-2) as one of the regulating enzymes Blood pressure was not done, which shows the necessity of the present research. According to the above, the aim of this study was to determine the effect of progressive aerobic continuous training on Ang-1, Ang-2 enzymes and ACE-2 in patients with heart failure. Materials and Methods:  In the present semi-experimental study, 20 men with heart failure referred to the Cardiac Rehabilitation Center of Imam Khomeini Hospital in Ahvaz were selected by snowball sampling method. Randomly were divided into 2 groups of 10 people including progressive aerobic continuous training group (mean age: 47.5 ± 7.84; body mass index: 29.27 ± 1.99) and control group (mean age: 48.8 ± 8.03; body mass index 26.93 ± 2.14). The training intervention consisted of eight weeks of training in three sessions per week. The training program included increasing continuous aerobic exercise with 40-85% of the subjects' reserve heart rate; No training intervention was performed in the control group. Blood variables were measured in fasting 48 hours before and 48 hours after the intervention period. To measure height and weight, the SECA scale and scale made in Germany were used. The blood samples of the patients were taken fasting and after blood pressure test. Enzyme-linked immunosorbent assay (ELISA) technique and Hangzhou Eastbiopharm kits were used to measure Ang I, Ang II and ACE-2 proteins. Dependent t-test and analysis of covariance were used for statistical analysis of the obtained data. Statistical analysis was performed using SPSS software version 26 and a significance level of P <0.05 was considered. Results: The results of analysis of covariance test showed that after the intervention period of progressive aerobic continuous training, there were a significant increase in the level of Ang-1 (P < 0.001) and a significant decrease in the levels of Ang-2 (P < 0.001) and ACE-2 (P < 0.001). P > 0) in the training group compared to the control group. Conclusion: The results of the current research showed that after the intervention period, progressive aerobic continuous training caused a significant decrease in the levels of Ang-2 and a significant increase in the levels of Ang-1 and ACE-2. The renin-angiotensin system (RAS) plays an important role in cardiovascular physiology by regulating blood pressure and electrolyte balance. RAS is mainly regulated by both angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme type 2 (ACE2). The classic ACE enzyme converts Ang I to Ang-2. In previous studies, it has been reported that ACE and Ang-2 levels increase in high blood pressure and increased afterload on the heart. Therefore, participating in aerobic activities in order to rehabilitate the heart can reduce the afterload on the heart and reduce blood pressure and Ang-2. Considering that exercise improves the sensitivity of baroreceptors, reduces stress and anxiety of Post HF patients, and reduces sympathetic activity. Considering the Ang-(1-7)/ACE2/Mas axis as a mechanism that balances the vasoconstrictor effects of the classical RAS, which includes renin, ACE, Ang-2 and its receptors AT1 and AT2; It seems that in Post HF patients, the reduction of ACE-2 to ACE ratio (ACE-2/ACE) is a more important factor that can moderate high blood pressure and heart complications caused by high blood pressure levels in HF patients; In our previous research, a significant decrease in systolic blood pressure and resting heart rate was observed in the exercise group compared to the control group; This improvement can be attributed to chronic cardiovascular adaptation to continuous aerobic exercise, including the increase of ACE2 and the decrease of Ang-2 compared to Ang-. According to the results of the present research, it can be said that rehabilitation exercises based on progressive aerobic continuous training through increasing ACE2 can modulate the renin-angiotensin system and reduce Ang-2 compared to Ang-1, and through the Ang-(1-7)/ ACE2/Mas can modulate blood pressure and reduce cardiovascular complications in patients with HF. It is likely that aerobic exercise regulates the local (cardiac) RAS to switch the ACE-Ang II-AT1R axis to the ACE2-Ang(1-7)-Mas receptor axis, And this setting inhibits cardiac regeneration in HF. which can probably justify the improvement of blood pressure and cardiovascular function in patients with HF.