The Effects Of Combined Pre-MI And Post-MI Exercise On The Left Ventricular Remodeling And Cardiac Function Of Rats After Myocardial Infarction

Lifestyle interventions including exercise training have been shown to be a feasible option to the prevention and treatment of cardiovascular diseases. Many Studies have showed that the prior exercise was beneficial to the left ventricular remodeling after myocardial infarction (MI) in rats. However, it is controversial whether exercise after MI is beneficial to the left ventricular remodeling and prognosis or not. We propose a hypothesis that combined pre-MI and post-MI exercises can improve both the left ventricular remodeling and prognosis in rats. Firstly, we shall study the effects of prior different intensities exercise on infarct region, function and angiogenesis of left ventricle (LV) in post-MI rats. Secondly, MI will be created in Sprague–Dawley rats after treadmill exercise for 5 weeks, then the rats will undergo non-exercise or a 8-weeks of treadmill exercise at 4 weeks after MI . In addition, sham-operated group and non-exercise group will be established at the same time respectively. The effects of pre-MI exercise, post-MI exercise, combined pre-MI and post-MI exercise on the left ventricular remodeling and mortality will be investigated. The results showed that combined pre-MI and post-MI exercise obtain more beneficial effects on the left ventricular remodeling and prognosis than pre-MI exercise, or post-MI exercise alone. The study will provide the scientific evidences for the design of clinical trials and the optimized protocol of MI rehabilitation, and will have important significance to the prevention and therapy for MI.Part I: Differential Effects of Prior Different Intensities Exercise on Infarct Region, Function and Angiogenesis of Left Ventricle in Post-Myocardial Infarction Rats at the Acute PhaseIntroduction: We investigated the effects of prior different intensities exercise on infarct region, function and angiogenesis of left ventricle (LV) in post-MI rats, and examined the expression of VEGF proteins in left ventricle and plasma.Methods: Male Sprague–Dawley rats were randomly assigned to six groups. The exercise-trained rats were familiarized with running on a treadmill before the formal experiment. Thereafter, the exercised rats underwent a daily 60-min treadmill exercise, 5d/wk, for 6 wk. Different treadmill speeds were carried out in the high intensity exercise group (HIE-MI group, 30 m/min), moderate intensity exercise groups (MIE-Sh and MIE-MI groups, 21 m/min), low intensity exercise group (LIE-MI group, 12 m/min), respectively, whereas the untrained rats (Sed-Sh and Sed-MI groups) remained sedentary. At 6 wk, 24 h after the last treadmill exercise or the corresponding sedentary protocol, all rats underwent either acute MI (LIE-MI, MIE-MI, HIE-MI and Sed-MI groups) or sham MI operation (MIE-Sh and Sed-Sh groups). Then, all rats were sacrificed at 7d after recovery. Echocardiographic and hemodynamic measurements were performed at the end of the experimental protocol, and hearts were sampled for histological and molecular analysis. The infarct regions were analyzed by using Masson's trichrome staining; intramyocardial microvessels were detected by using Factor VIII-related antigen staining; and cardiac VEGF protein levels were determined by Western blotting analysis; plasma VEGF concentrations were examined by enzyme-linked immunosorbent assay.Results: Compared with Sed-Sh group, MIE-Sh group ameliorated left ventricular function and increased microvessels intensity, though the difference was not significant (P>0.05). Compared with Sed-MI group, MIE-MI and HIE-MI groups significantly reduced left ventricular infarct size, improved hemodynamic parameters, increased fractional shortening, scar thickness and microvessel density(P<0.05), but LIE-MI rats only had slight, not significant effect on these parameters. In addition, the hemodynamic parameters and microvessel density in HIE-MI rats were significantly better than those in MIE-MI rats (P<0.05). Interestingly, Compared with Sed-MI group, the hearts and plasma of exercised rats displayed higher levels of VEGF protein in MIE-MI and HIE-MI groups(P<0.05). However, there was no significant difference between MIE-MI and HIE-MI groups.Conclusion: Moderate intensity exercise before acute MI improved LV function, reduced scar size, increased scar thickness and microvessel density in post-MI rat. Additional higher intensity exercise could have little further effect. Low intensity exercise may be beneficial, but not sufficient to improve MI. Moderate and high intensity exercise upregulated the expression of VEGF protein, and contributed to the increased microvessels, which may partly benefit to the improved cardiac function after MI.Part II: The Effects of Combined Pre-MI and Post-MI Exercise Activing the VEGF Signaling Pathway on the Left Ventricular Remodeling and Dynamic Cardiac Function of Rats after Myocardial Infarction at the Chronic PhaseIntroduction: In this study, we investigated the effects of combined Pre-MI and Post-MI exercise on infarct region, angiogenesis and dynamic cardiac function of left ventricle in post-MI rats, and further examined the mRNA and proteins expression of VEGF and its receptors in left ventricle.Methods: Male Sprague–Dawley rats were randomly assigned to six groups. The exercise-trained rats (PreE-Sh, PreE-MI, ComE-MI groups) were familiarized with running on a treadmill before the formal experiment. Thereafter, the exercised rats underwent a daily 60-min treadmill exercise, 5d/wk, for 5 wk. whereas the untrained rats (Sed-Sh and Sed-MI groups) remained sedentary. At 5 wk, 24 h after the last treadmill exercise or the corresponding sedentary protocol, all rats underwent either acute MI (Sed-MI, PreE-MI, PostE-MI and ComE-MI groups) or sham MI operation (Sed-Sh and PreE-Sh groups). Then, PostE-MI and ComE-MI groups were familiarized with running on a treadmill at 4 wk after recovery. Thereafter, the exercised rats underwent a daily 60-min treadmill exercise, 5d/wk, for 8 wk. All of the rats were sacrificed at the end of the experimental protocol .Echocardiographic and hemodynamic measurements were performed before the end of the experimental protocol, and hearts were sampled for histological and molecular analysis. The infarct regions were analyzed by using Masson's trichrome staining; intramyocardial microvessels were detected by using Factor VIII-related antigen staining; the mRNA expressions of VEGF and its receptors in hearts were examingd by real time PCR; and cardiac protein levels of VEGF and its receptors were determined by Western blotting analysis.Results: Compared with Sed-Sh group, PreE-Sh group ameliorated left ventricular function and increased microvessels intensity, though the difference was not significant (P>0.05). Compared with Sed-MI group, PreE-MI and ComE-MI groups significantly reduced left ventricular infarct size, and increased scar thickness (P<0.05). PostE-MI and ComE-MI groups improved hemodynamic parameters, increased fractional shortening, and microvessel density (P<0.05), but PreE-MI rats only had slight, not significant effect on these parameters. In addition, the differences between PreE-MI and PostE-MI rats were not significant in hemodynamic parameters and significant in microvessel density (P<0.05). However, compared with PreE-MI and PostE-MI groups, these parameters were significantly improved in ComE-MI group. Compared with Sed-MI group, the exercised hearts displayed higher levels of VEGF, Flt 1, Flk1 mRNA(P<0.05), and also displayed higher levels of VEGF, Flt 1, Flk1 proteins in PostE-MI and ComE-MI groups(P<0.05). However, there was no significant difference between PostE-MI and ComE-MI groups (P>0.05).Conclusion: Pre-MI exercise reduced scar size, increased scar thickness, but did not significantly improved LV function and microvessel density. Post-MI exercise did not reduce scar size and increased scar thickness, but improved LV function and microvessel density. Combined exercise reduced scar size, increased scar thickness and microvessel density, also improved LV function. Post-MI exercise and Combined exercise upregulated the expression of VEGF and its receptors, and contributed to the increased microvessels, which may partly benefit to the improved the LV remodelling and cardiac function after MI.