Copyright © 2004, European Society of Cardiology
Different therapeutic responses to treadmill exercise of heart failure due to ischemia and infarction in rats
First Department of Internal Medicine, Fukushima Medical University, Hikarigaoka 1, Fukushima, 960-1295, Japan
* Corresponding author. Tel.: +81 24 548 2111x2300; fax: +81 24 548 1821. Email address: maruyama{at}fmu.ac.jp
Received 6 April 2004; revised 27 October 2004; accepted 28 October 2004
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionAcknowledgmentsReferences |
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Objective: The effects of exercise, a therapeutic tool in ischemic heart disease (IHD), may differ in ischemic and infarcted hearts.
Methods and results: To assess this, we created coronary stenosis (CS), which reduced coronary flow reserve (CFR), or coronary occlusion to induce myocardial infarction (MI) in rats, and subjected them to treadmill exercise for either 5 (5-min Ex) or 15 min/day (15-min Ex) for 12 weeks. Left ventricular (LV) diameters were increased and ejection fractions decreased by echocardiography, and myocardial nitric oxide (NO) activity, measured by the in vitro MVO2 method, was reduced in both CS and MI rats compared with the sham. In CS rats, myocardial wall thickening fractions were not affected at 5 min of exercise, whereas they were reduced at 15 min of exercise, suggesting exercise-induced ischemia. Despite no changes in CS severity, the 5-min Ex increased CFR, ameliorated myocardial NO activity, attenuated left ventricular (LV) dysfunction and remodeling, reduced serum brain natriuretic peptide (BNP) levels, and improved survival, whereas the 15-min Ex aggravated LV dysfunction and remodeling. In contrast, neither of the exercise protocols improved these parameters in MI rats.
Conclusions: Therapeutic responses to exercise differed in ischemic and infarcted hearts, partly via circulatory modulation downstream of the epicardial CS in relation to exercise-induced ischemia. When employing exercise for IHD, the causes of IHD, as well as the exercise protocols, need to be considered to achieve optimal effects.
KEYWORDS Ischemia; Heart failure; Nitric oxide; Remodeling
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionAcknowledgmentsReferences |
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Exercise therapy improves coronary endothelial function and myocardial perfusion in heart failure due to ischemic heart disease (IHD; [1,2]). On the other hand, the benefits of exercise therapy on left ventricular (LV) dysfunction and remodeling due to IHD may not be optimal because of adverse or nonsignificant effects [3–7]. In addition, it remains to be determined whether exercise therapy improves the prognosis of patients with IHD [8,9]. The lack of agreement about the effects of exercise may partly be due to differences in the severity of ischemic myocardial damage and in the exercise protocols. Actually, the patients in previous reports [1–8] had prior myocardial infarctions (MIs), but most of them also had coronary stenosis (CS), showing that infarcted and ischemic myocardium coexisted in the same patients with IHD. Since ischemic but viable myocardium and infarcted nonviable myocardium may have different responses to some kinds of pharmaceuticals [10,11], therapeutic responses to exercise may also differ in these subtypes of IHD. However, the effects of exercise in different kinds of IHD have not been compared thoroughly.
In IHD, the improvement of myocardial perfusion by exercise may be due to the development of collateral circulation [12] and the improvement of coronary microvascular vasodilation [1] rather than to significant modification of the severity of epicardial coronary artery stenosis. Coronary vasodilatory function related to nitric oxide (NO) was reported to be impaired at the arteriole level of the excised coronary artery in chronic myocardial ischemia and to have been ameliorated by exercise therapy [13,14]. With respect to such improvement of microvascular vasodilation by exercise, it was reported that there is amelioration of endothelial NO synthase expression in the coronary microvasculature via an increased shear stress in the vascular wall [15,16]. Therefore, we hypothesized that these mechanisms involving NO may result in attenuation of myocardial cell loss and fibrosis. It would be of interest to assess how different exercise protocols, with and without inducible ischemia, affect the coronary circulation, myocardial NO activity in the coronary microvasculature, LV function and remodeling, and prognosis in ischemic heart failure of different origins.
In the present study, we postulated that viable ischemic and infarcted myocardium may have different responses to exercises with respect to LV function and remodeling and mortality through the modulation of coronary circulation, especially the downstream of epicardial coronary artery stenosis. We assessed this in rat models of coronary stenosis and permanent coronary occlusion. In rats with coronary stenosis, myocardial damage changes slowly from reversible to irreversible, and LV dysfunction and remodeling develop progressively with time after creating coronary stenosis [11], thus mimicking the features of ischemic cardiomyopathy [17]. We examined whether and how different daily treadmill exercises prevent ischemia- or infarction-related gradual worsening of hemodynamics, LV function and remodeling, and also myocardial perfusion and functional activity of myocardial NO in these two rat heart failure models.
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2. Methods |
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The investigation conformed to the Guideline on Animal Experiments of Fukushima Medical University, the Japanese Government Animal Protection and Management Law (NO.115), and the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institute of Health (NIH Publication No. 85-23, revised 1996).
2.1. Animal models and treadmill exercise
Adult male Sprague–Dawley rats (290–310 g; n=405) were used for the experiments shown in Fig. 1. When they were 10 weeks old, under general anesthesia with sodium pentobarbital 45 mg/kg, stenosis at the left coronary artery was created in 201 rats, as reported previously [11], with modifications of the site of stenosis and the severity by using a 325-µm diameter thread instead of 275 µm. After the chest was opened under artificial ventilation, the proximal portion of the left coronary artery, 1–2 mm below its origin from the aorta, was occluded with the thread using the surgical strings (NescosutureTM, HV1306YG75-DC1; Aswell, Osaka, Japan), followed by thread removal. Transient coronary occlusion and recanalization were confirmed by the elevation of ECG ST segment exceeding the R wave amplitude and its reversal, respectively. Rats with persistent ST elevation on electrocardiograms after thread removal or with fatal ventricular arrhythmia (n=26) were excluded from the study.
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As another model of IHD, myocardial infarction (MI; n=152) was created by tight ligation at a site of the left coronary artery, equivalent to that of the coronary stenosis procedure (the post-MI groups). We confirmed persistent ST elevation in this group. Seven rats died during surgery. In a preliminary study in rats with acute coronary occlusion (n=10), the risk area was delineated by 1% Evans blue infusion for 1 min at 100 mm Hg into the left ventricle. The risk area (%), assessed by ratios of myocardial weights, was 49.4 ± 4.9% of the total left ventricle.
The survivors (n=372, including 52 sham rats; Fig. 1) were returned to their cages and allowed free access to food and water. The 245 final survivors, except for 37 rats used for hemodynamic measurements during exercise, as described below, were sacrificed 12 weeks later. As shown in Fig. 1 and the Table 1, the rats were divided randomly into seven treatment groups, consisting of sham, coronary stenosis or occlusion, and short, long, or no exercise.
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2.2. Daily treadmill exercise
A rodent treadmill machine was custom-made for us by Okazaki Sangyo (Tokyo, Japan). Daily plain walking exercise was performed for 5 (short) or 15 min (long) once a day, 5 days a week, starting at 11 m/min on the 4th day after surgery and then at 28 m/min on the 5th and subsequent days for 12 weeks according to a previous report [15], with the modifications that plane walking was used in our study. At the first treadmill exercise on the 4th day after surgery, some rats were puzzled by the operating machine. However, rats began to walk and run well on the 5th day since their bodies and tails collided with the plastic wall of the machine behind them when the machine was operating. Rats in the sham and the two no-exercise groups were put on the treadmill machine for 15 min/day, but the machine was not operating.
2.3. Hemodynamics in awake animals
Peak systolic blood pressure (SBP) and heart rate (HR) in awake rats were measured by the tail cuff method before and 4, 8, and 12 weeks after creating coronary stenosis or occlusion.
2.4. Echocardiography
Echocardiographic assessment of LV function and remodeling was performed blindly before and 4, 8, and 12 weeks after creating coronary stenosis or occlusion. In anesthetized rats, B and M mode echo recordings at the middle portion of the left ventricle were obtained using SONOS 100 (HP) with a 10 MHz probe. LV end-diastolic and end-systolic diameters (LVEDD and LVESD, respectively) were measured, and LV ejection fraction [LVEF=(end-diastolic volume–end-systolic volume)/end-diastolic volume] was obtained by the Pombo method [11].
2.5. Hemodynamics at exercise following coronary stenosis or occlusion
In randomly selected rats (n=15, 15, and 7 in the sham, coronary stenosis, and post-MI groups, respectively), a polyethylene tube filled with heparin was inserted into the right external carotid artery and was fixed with ties when cardiac surgery was performed. This method, not involving the common and internal carotid arteries, allowed us to not cause stroke in these rats. In this series of experiments, treadmill exercise (15 min/day) was also started on the 4th day. Hemodynamics was measured on the 6th day. At the time of exercise, the tube was connected to a pressure transducer and a polygraph, and HR and SBP were monitored continuously during each exercise period. In addition, before and 15 min after starting exercise, blood (0.3 mL) was sampled through the tube for measuring lactate level by the peroxidase electrode method. In the subgroups (n=8 of 15 each in the sham and coronary stenosed rats described above), the myocardial wall thickening fraction (end-systolic thickening–end-diastolic thickening/end-diastolic thickening; ratio) in the risk area at resting state and after up to 15 min of exercise was measured by the pulsed Doppler technique utilizing a single epicardial transducer [18], to assess exercise-induced ischemia. Following open-chest sham surgery or creation of coronary stenosis under general anesthesia, a 2-mm-diameter single Doppler transducer probe (DMT202C, Matec Instrument, North Borough, MA, USA), which was connected on line to the wall-thickening-tracking module applicable to rodents (20 MHz; WT-20, Matec Instrument), was attached by suturing on the epicardial surface of the middle portion of the LV anterior wall within the risk area, and then, the chest was closed. The sampling point was set at a depth of 1 mm below the probe in the endocardial layer of the risk area, which was confirmed by the display of WT-20. On the 6th day after surgery, at resting state and during 15 min of exercise, the changes in wall thickness were recorded serially on WT-20. They were not measured in post-MI rats because of thin walls in the risk areas. Finally, after the experiments, these rats were sacrificed by an overdose of pentobarbital.
2.6. Cardiac catheterization in the anesthetized, resting state before sacrifice
Body weights were measured, and cardiac catheterization was performed in anesthetized rats. Before they were sacrificed 12 weeks after creating coronary stenosis or occlusion, LV end-diastolic pressure (LVEDP), peak systolic pressure (LVSP) and ± maximal LVdP/dt were measured. Blood samples were obtained without starvation; serum levels of norepinephrine were measured by HPLC, and rat brain natriuretic peptide (BNP)-32, with an ELISA kit (S-1192, Peninsula Lab., LA, San Carlos, CA, USA), according to the manufacturer's procedure.
2.7. Colored microspheres
Twelve weeks after coronary stenosis, occlusion, or sham operations, myocardial blood flow (MBF: mL/min/g) and coronary flow reserve (CFR: mL/min/g; maximal MBF by infusing 10 mg/kg/min dipyridamole for 10-min basal MBF) in the risk area were measured by the colored microsphere method reported previously ([11]; Fig. 1). For this purpose, polyethylene catheters were inserted into the left ventricle and the right femoral artery, and during flow measurements, HR by limb lead ECG, and LVSP and EDP by a catheter were also monitored. During 60-s continuous blood drawing, at 2 mL/min as the reference sampling from the femoral artery, about 50 x 104 microspheres (E-Z TRACTM Ultraspheres,TM no. 015-010/V and Y, 15.1-µm diameter, Interactive Medical Technologies, Irvine, CA, USA) were injected as a bolus through a catheter into the left ventricle at the basal state and during dipyridamole infusion. The risk area was delineated by reoccluding the coronary artery and then infusing Evans blue as mentioned above.
Although 0.5 mL of arterial blood was sampled from the catheter for BNP-32 measurement, as mentioned above (n=7 each group), before the microsphere study, this procedure did not alter LVSP, EDP, and HR (data not shown).
2.8. Functional activity of NO in myocardium at risk
After cardiac catheterization (Fig. 1 and Table 1), approximately 30 mg of myocardial specimens from the endocardial side within the risk area in the coronary stenosis model was removed quickly. In contrast, in the post-MI group, the specimens were taken from the marginal zone of the underperfused areas. Epicardium and endocardium were removed from the specimens, and they were bathed at 37 °C for 2 h in Krebs' solution bubbled with a mixture of 20% O2, 3% CO2, and 77% N2. After equilibrium, O2 uptake by myocardial specimens was measured polarographically, according to the method of Xie et al. [19], with minor modifications. First, in vitro MVO2 in each myocardial specimen was measured for 5 min after the specimen was placed in the buffer and was calculated as a rate of decrease in the in vitro MVO2 (% changes of the in vitro MVO2 from baseline values). Then, in vitro MVO2 was measured after adding 0.1 mmol/L bradykinin (BK) to assess BK receptor-mediated NO production by coronary eNOS, or 0.1 mmol/L sodium nitroprusside (SNP) instead of 0.1 mmol/L S-nitroso-N-acetylpenicillamine (SNAP; [19]) to assess the maximal effect of an excessive of NO donor. Finally, nonspecific changes of in vitro MVO2 after KCN administration were subtracted from the in vitro MVO2 obtained at each step. In a preliminary study, we confirmed that the significant decrease in in vitro MVO2 caused by BK was reversed by pretreatment with 0.1 mmol/L NG-nitro-L-arginine, indicating an essential role for NO in these effects of BK. We also confirmed that SNP and SNAP (0.1 mmol/L each) had similar effects in decreasing in vitro MVO2 in sham, coronary stenosis, and occlusion rats.
2.9. Histopathology
After echocardiography at 12 weeks, the heart weight was measured. The severity of coronary stenosis, excluding the three coronary occlusion groups, and myocardial fibrosis in all seven groups were assessed. The severity of coronary stenosis assessed by cross-sectional area (CSA) changes was determined as described previously [11]. Namely, after the cardiac catheterization, rats were sacrificed and fixed with 10% neutral buffered formalin perfused at a pressure of 100 mm Hg. In 5-µm-thick paraffin-embedded sections stained with elastica Van Gieson, CSAs of left coronary arterial inner lumen were measured by the point-counting method of Weibel [20] by light microscopy at x 400 magnification. CSA at the stenotic site (assumed by the minimal CSA) divided by the reference CSA measured in 50 sections proximal to the sections of the stenotic area multiplied by 100 was considered the degree (%) of stenosis.
Paraffin-embedded sections of myocardial slices (5 µm thick) were stained with elastica Masson and H&E. The LV-free wall was divided into five radial segments, and in the central three segments (the part of the risk areas that has the most severe myocardial damage within the risk areas), myocardial fibrosis [fibrosis area/areas of three segments: (%)] was calculated using the point-counting method [20].
2.10. Data analysis
Data are presented as means ± S.E. Statistical analysis was performed by the two-way analysis of variance. If F test results were <0.05, Bonfferoni's post hoc test was performed. Among the multiple intergroup comparisons, to avoid complicated presentation, the data were compared with the three reference groups (sham, coronary stenosis, and post-MI without exercise; Table 1). A value of p<0.05 was considered significant.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionAcknowledgmentsReferences |
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3.1. Survivals
In the 5-min exercise coronary stenosis group, the 4-day to 12-week survival rate was higher than in the coronary stenosis group without exercise (96% versus 76%, p=0.02; Fig. 1 and Table 1). The survival rate did not differ significantly between the post-MI groups (no exercise, 5-min exercise, and 15-min exercise: 69%, 76%, and 74%, respectively), although the sample numbers were not large.
3.2. SBP and HR in awake rats
HR in awake rats before and 4 to 12 weeks after the surgery was similar among the groups, whereas SBP decreased at 12 weeks in the 15-min exercise coronary stenosis group and in all three post-MI groups compared with the sham (only the data from before and at 12 weeks after surgery are shown in Fig. 2).
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3.3. Body weight and coronary stenosis severity
Body weights 12 weeks after the surgery did not differ significantly among the seven groups, ranging from 352 ± 32 to 380 ± 13 g. Coronary stenosis severity was similar among the three groups, regardless of the exercise protocols (Table 1).
3.4. Hemodynamics at exercise
During exercise, SBP did not change significantly in the sham, coronary stenosis, and post-MI groups, but HR increased at 5 and 15 min of exercise (p<0.01 each) (Fig. 3). In the sham, coronary stenosis, and post-MI groups, compared with the values at a resting state, circulating lactic acid levels at 15 min of exercise tended to increase from 3.6 ± 0.9, 3.1 ± 1.3, and 3.5 ± 0.7 mmol/L (baseline) to 6.1 ± 1.3, 4.9 ± 0.7, and 5.9 ± 0.9 mmol/L, respectively (NS).
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The wall thickening fraction at the resting state was lower (p<0.01) in the coronary stenosis group than in the sham (Fig. 3). The value increased at 5 and 15 min of exercise in the sham, whereas it increased (p<0.01) at 5 min but not at 15 min of exercise of the coronary stenosis group.
3.5. Echocardiography
Compared with the sham, both the coronary stenosis and post-MI groups without exercise had increased LVEDD and LVESD and decreased LVEF (Fig. 4). The changes of LVEDD, LVESD, and LVEF caused by coronary occlusion were greater (p<0.01 each) than those caused by coronary stenosis at 4 to 12 weeks (asterisks on these statistics are not shown in Fig. 4).
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Compared with the no-exercise group, LVEDD and LVESD were decreased and LVEF was increased in the 5-min exercise group with coronary stenosis, whereas LVEDD and LVESD were increased and LVEF was decreased in the 15-min exercise group (Fig. 4, left panel). On the other hand, neither the 5- nor the 15-min exercise post-MI groups had modified LVEDD, LVESD, and LVEF (Fig. 4, right panel).
Representative M mode echo recordings of the left ventricle in each group are shown in Fig. 1.
3.6. Cardiac catheterization data
The coronary stenosis and occlusion groups without exercise had increased LVEDP, decreased ± LVdP/dT, and increased heart weight, compared with the sham (Table 1). With coronary stenosis, these changes were ameliorated in the 5-min exercise group, whereas they were aggravated in the 15-min exercise group. On the other hand, both exercise groups with MI did not show any modification of these variables.
3.7. Myocardial blood flow and coronary flow reserve
Dipyridamole infusion caused 13 ± 4 and 0.5 ± 0.1 mm Hg reductions of LVSP and LVEDP, respectively, and 27 ± 3 bpm increases in HR in the sham, three coronary, stenosis, and three post-MI groups (NS among the groups). Compared with the sham, the coronary stenosis group without exercise had decreased CFR, and MBF and CFR were decreased in the 15-min exercise group (Fig. 5). Compared with the no-exercise group, CFR increased only in the 5-min exercise group. In the three post-MI groups, MBF and CFR were low (p<0.01 each versus sham and corresponding coronary stenosis groups), and there were no differences between the groups (Fig. 5).
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3.8. In vitro MVO2
As shown in Fig. 6, SNP similarly and significantly decreased in vitro MVO2 in both the coronary stenosis and post-MI groups. In contrast, the responses to BK differed among the groups. In the sham, BK submaximally (NS versus SNP) decreased in vitro MVO2, whereas the decrease caused by BK in the coronary stenosis group without exercise was less than that of the sham. This blunted response to BK was ameliorated in the 5-min exercise but not in the 15-min exercise group with coronary stenosis. The response of in vitro MVO2 to BK remained blunted in both the 5- and 15-min exercise post-MI groups.
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3.9. Serum parameters
Serum data are shown in the Table 1. Compared with the sham, serum norepinephrine and BNP-32 levels increased in the coronary stenosis and post-MI groups. These increases were attenuated in the 5-min exercise group with coronary stenosis, while the levels remained high in both the 5- and 15-min exercise post-MI groups.
3.10. Histopathology
Compared with the sham, myocardial fibrosis (%) in the risk area was greater in the coronary stenosis and post-MI groups without exercise (Table 1). It was decreased in the 5-min exercise group but rather increased in the 15-min exercise group with coronary stenosis. In the post-MI group, myocardial fibrosis without exercise was greater than in the coronary stenosis group without exercise and was similar among the no-exercise and the 5- and 15-min exercise groups.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionAcknowledgmentsReferences |
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4.1. The effects of exercise and their clinical implications
The results of the present study can be summarized as follows. First, the effects of daily exercise on coronary stenosis induced LV dysfunction and remodeling, and survivals differed between rats given different durations of exercise. Second, the effects of daily exercise differed between coronary stenosis- and MI-induced LV dysfunction and remodeling. Namely, neither the shorter nor the longer durations of exercise modified LV dysfunction and remodeling and survivals in post-MI rats, in contrast to the significant beneficial changes caused by the shorter exercise duration in various variables, including the ones mentioned above, i.e., myocardial perfusion, functional activity of myocardial NO at risk, circulating norepinephrine, and BNP levels in rats with coronary stenosis. Myocardial wall thickening fraction, however, decreased significantly during the 15-min exercise, suggesting that our exercise intensity was critical for gradually evoking ischemia in our coronary stenosis model. Such longer exercise-induced ischemia may have augmented coronary-stenosis-induced LV dysfunction and remodeling. Thus, daily exercise has different effects on the subtypes of IHD in rats, at least partly in association with the modulation of coronary circulation downstream of epicardial stenosis. Our results suggest that, when employing exercise therapy for HF due to IHD, the causes of LV dysfunction, as well as the exercise protocol, including the duration of exercise, need to be considered to achieve optimal therapeutic effects.
4.2. Methodological considerations
The present study has several limitations. First, our exercise protocols in rats are from an educated guess rather than firmly based on selected targets. In addition, although we estimated exercise intensity by its duration and by measuring SBP, HR, lactate production, and myocardial wall thickening fraction during exercise, we did not assess oxygen consumption during exercise. Second, in our coronary stenosis and post-MI groups, the survival rates varied between 72% (5-min exercise post-MI group) and 96% (5-min exercise coronary stenosis group). We cannot rule out the possibility that rats that dropped out might have biased the morphological and histological results in these groups. In addition, the survival rates were not always parallel with the degrees of LV dysfunction and remodeling in two coronary stenosis (except the 5-min exercise) and the three post-MI groups. The determinant(s) of the survival rates with exercises needs to be clarified in a future study. Third, we started exercise on the 4th day after the surgery. Multiple protocols will be required to identify the optimal time for starting effective exercise. Fourth, coronary flow measurement by microspheres in the anesthetized state is not the same as that in the awake state. Furthermore, although coronary circulation is regulated by many factors, we did not investigate the mechanisms of myocardial flow changes, such as those mediated by coronary resistance or collateral circulation. Fifth, the effects of exercise may depend on the grade of coronary stenosis, but we used only one kind of coronary stenosis. Sixth, it remains to be determined how exercise affects other aspects of heart biology, such as myocardial proliferation, matrix metalloproteinase activities, and calcium kinetics, which affect LV dysfunction and remodeling. Seventh, we did not assess microrheology and platelet function, which may have contributed to the effect of exercise [1]. Eighth, the present data were obtained using rats, in which collateral development following myocardial ischemia seems to be poor, and other various responses associated with exercise following myocardial ischemia might also be different in rats and humans. Therefore, direct application of these findings to clinical settings must be done carefully.
4.3. Exercise and coronary circulation downstream of epicardial stenosis
The shorter exercise duration, but not the longer one, improved LV function in rats with coronary stenosis. Among the possible mechanisms responsible for these diverse effects, CFR and myocardial NO seem to be involved. Since epicardial coronary stenosis severity was not modified by either exercise protocol, and microvascular vasodilatation caused by NO action is partly involved in increased flow [13,21], it is plausible that the modification of coronary circulation downstream of the epicardial stenosis by the shorter duration exercise, probably due to an increase in shear stress, contributed further to the increase in CFR assessed by dipyridamole. In contrast, the longer duration exercise did not ameliorate impairment of myocardial NO activity and rather aggravated LV dysfunction and remodeling in rats with coronary stenosis. Moreover, the longer exercise duration remarkably increased myocardial fibrosis in the risk area, mimicking that which occurred in the post-MI rats (Table 1). If the duration of exercise is long, myocardial ischemic damage is severe due to limited CFR. This leads to the impairment of coronary circulation via coronary microvascular dysfunction, to myocardial hibernation, and finally, to irreversible damage. This may be supported by the results that basal MBF in the 15-min exercise coronary stenosis group, but not in the 5-min exercise group, was lower than that of the sham, and that cardiac dysfunction, shown by enlarged LV volume and decreased LVEF, gradually became evident in the 15-min exercise group, suggesting progression of myocardial hibernation in this group. These issues need to be investigated in future studies of how repeated ischemia induced by exercise aggravates myocardial perfusion and function in the long term in our models.
In the post-MI groups, neither MBF and CFR nor myocardial NO activity in the risk area was modified by exercise. We assume that a loss of flow-dependent vascular shear stress from epicardial permanent coronary occlusion might be one of the reasons why exercise had no effect in this model.
4.4. Exercise intensities and duration
The exercises up to 15 min tended to increase the level of circulating lactate, but not significantly, suggesting that the exercises were not anaerobic. In general, much longer durations of exercise than ours have been used in animals [12,15,16] and humans [9]. Hence, the apparent lack of an antiremodeling effect from our longer exercise in post-MI rats does not necessarily exclude the possible benefit of exercise therapy from a still longer or more intense exercise protocol. In addition, it is highly likely that optimal exercise for infarcted myocardium is not the same as that for the protection of ischemic but viable myocardium. Thus, exercise therapy must be designed carefully, taking into account the subtype of IHD.
4.5. Stenosis severity
The question may arise as to why an approximately 60% in the grade of coronary stenosis caused such significant CFR reduction, LV dysfunction, and remodeling in our model. In our study, rats without coronary stenosis had approximately 5 mL/min of MBF, which seems to be higher than in humans. Quite high HR in rats may have affected this basal high MBF, and it would be expected that a relatively high flow rate easily leads to the evocation of a reduction of CFR, even in the presence of moderate coronary stenosis. In fact, there is evidence for myocardial ischemia with this degree of coronary stenosis.
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Acknowledgments |
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This study was supported by a grant-in-aid for Scientific Research from the Japanese Ministry of Education, Science, and Culture (No. 11670696).
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Notes |
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Time for primary review 34 days
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