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Moderate exercise training does not worsen left ventricle remodeling and function in untreated severe hypertensive rats

¹Laboratoire de Physiopathologie de la Paroi Artérielle, Université François Rabelais, UFR Médecine, Tours; and ²Laboratoire Interuniversitaire de Biologie de l'Activité Physique et Sportive, Université Clermont-Ferrand, France

Submitted 24 April 2007 ; accepted in final form 20 November 2007

	ABSTRACT

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Exercise training and hypertension induced cardiac hypertrophy but modulate differently left ventricle (LV) function. This study set out to evaluate cardiac adaptations induced by moderate exercise training in normotensive and untreated severe hypertensive rats. Four groups of animals were studied: normotensive (Ctl) and severe hypertensive (HT) Wistar rats were assigned to be sedentary (Sed) or perform a moderate exercise training (Ex) over a 10-wk period. Severe hypertension was induced in rat by a two-kidney, one-clip model. At the end of the training period, hemodynamic parameters and LV morphology and function were assessed using catheterism and conventional pulsed Doppler echocardiography. LV histology was performed to study fibrosis infiltrations. Severe hypertension increased systolic blood pressure to 202 ± 9 mmHg and induced pathological hypertrophy (LV hypertrophy index was 0.34 ± 0.02 vs. 0.44 ± 0.02 in Ctl-Sed and HT-Sed groups, respectively) with LV relaxation alteration (early-to-atrial wave ratio = 2.02 ± 0.11 vs. 1.63 ± 0.12). Blood pressure was not altered by exercise training, but arterial stiffness was reduced in trained hypertensive rats (pulse pressure was 75 ± 7 vs. 62 ± 3 mmHg in HT-Sed and HT-Ex groups, respectively). Exercise training induced eccentric hypertrophy in both Ex groups by increasing LV cavity without alteration of LV systolic function. However, LV hypertrophy index was significantly decreased in normotensive rats only (0.34 ± 0.02 vs. 0.30 ± 0.02 in Ctl-Sed and Ctl-Ex groups, respectively). Moreover, exercise training improved LV passive filling in Ctl-Ex rats but not in Ht-Ex rats. In this study, exercise training did not reduce blood pressure and induced an additional physiological hypertrophy in untreated HT rats, which was slightly blunted when compared with Ctl rats. However, cardiac function was not worsened by exercise training.

renal hypertension; cardiac function

In another way, hypertension also induces LV hypertrophy (21, 28). However, hypertension leads to pathological hypertrophy named "concentric hypertrophy," characterized by LV diameter reduction and increase in wall thickness and LV mass index, and it could induce ventricular dysfunction associated with heart failure (21), particularly in the case of severe hypertension [characterized by a systolic blood pressure (SBP) of at least 180 mmHg and/or a diastolic BP (DBP) of at least 110 mmHg]. Physical exercise is recommended for low to moderate hypertension. Indeed, a slight decrease in BP (7, 11, 17) and an increase in vessel compliance (10) were reported after exercise training in hypertensive animals. Moreover, several studies reported a decrease of LV hypertrophy following an exercise training protocol in hypertensive subjects (13, 30).

Nevertheless, information about the effects of exercise training on cardiac morphology and function in the case of untreated severe hypertension is lacking in human and animal models. Kokkinos et al. reported a reduced BP and LV hypertrophy with regular exercise in treated severe hypertensive African-Americans (13). Moreno et al. reported that physical exercise could correct systolic dysfunction in hypertensive rats (19). In addition, no animal studies have focused on LV diastolic function alterations induced by exercise training in severe hypertensive rats.

This study was undertaken to evaluate the effect of a moderate exercise training protocol on cardiac morphology and LV function in normotensive and untreated severe hypertensive rats. Considering the convenient effects of exercise training on cardiac morphology and function as well as results of a previously published work on vascular effect of exercise training in untreated severe hypertensive rats (1), we hypothesized first that moderate exercise training could correct LV concentric hypertrophy and second that exercise training could correct diastolic dysfunction existing in untreated severe hypertensive rats.

	MATERIALS AND METHODS

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Animals.   The investigations were carried out in agreement with the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH Publications No. 85-23, revised 1996) and with the approval of the ethics committee Comité Régional d'Ethique pour l'Experimentation Animale (region Centre, France).

Thirty-eight adult male Wistar rats (10-wk-old, weighing 325 ± 25 g, Harlan) were randomized in hypertensive group (HT) and normotensive control group (Ctl). Then, Ctl and HT groups were respectively divided in two experimental protocols. The first was housed for 10 wk and were sedentary: Ctl-Sed (n = 10) and HT-Sed (n = 9) groups. The second was housed for 10 wk and performed a 10-wk moderate exercise training protocol: Ctl-Ex (n = 8) and HT-Ex (n = 11) groups. Animals were fed ad libitum with free access to tap water in a room with a 12:12-h light-dark cycle and a temperature maintained at 21°C.

Severe hypertension model.   A two-kidney, one-clip unilateral renovascular hypertension model (Goldblatt hypertension) was performed in HT group by constricting the left renal artery. Briefly, animals were anesthetized by intraperitoneal (IP) injection of ketamine (100 mg/kg) and chloropromazine (5 mg/kg). After a laparotomy, the left renal artery was isolated and was partially constricted using a 3-mm-long, 1-mm-wide U-shaped silver clip with an internal gap of 0.25 mm. In rats assigned to Ctl group, surgical intervention was performed, but the left renal artery was unclipped. Experimentations started after a 3-wk surgical recovery period. To evaluate the degree of hypertension, we compared results of BP measurements and cardiac tissue weighing within the two Ctl groups; results are presented in Tables 1 and 2.

Maximal running speed of each group was estimated from an incremental exercise test performed before, after 5 wk, and at the end of the exercise-training protocol or sedentary period. Incremental exercise test was spent in the following way. The test was started by a 5-min warm-up to a 7.5 m/min running speed. Next, running speed was increased by 1.5 m/min every 2 min. When animals reached 85–90% of their suspected maximal running speed, running speed was increased by 0.5 m/min every minute. Maximal running speed achieved was considered as the maximal exercise capacity and served as reference to normalize subsequent training sessions.

Transthoracic echocardiography measurements.   Left cardiac morphology and function were evaluated using a noninvasive transthoracic echocardiography method. This method has been shown to be suitable for pathophysiological cardiac studies performed in mammals and to provide in vivo index of local adaptation of the myocardium (4, 15). Transthoracic echocardiographic determinations were performed in the lateral decubitus position using a commercially available echocardiograph (Esaote Biomedica with a 6- to 15-MHz transducer). Echocardiography was performed in anesthetized animals with ketamine (100 mg/kg IP) and xylazine (7.5 mg/kg IP) and consisted of two-dimensional mode, time-motion (TM) mode, and blood flow measurements in pulsed Doppler mode. TM mode measurements were obtained according to the recommendations of the American Society of Echocardiography in the parasternal long-axis view. The parameters measured were diastolic septal wall thickness, diastolic posterior wall thickness of the LV, and end-diastolic and end-systolic diameter of the LV and systolic aorta diameter. From TM mode measurements, LV hypertrophy index was calculated as [(diastolic septal wall thickness + diastolic posterior wall thickness)/2]/(end-diastolic diameter/2), and LV shortening fraction was calculated as (end-diastolic diameter – end-systolic diameter)/end-diastolic diameter x 100. Stroke volume was obtained as the product of the aortic root area and integral of aortic blood velocity and time. LV end-diastolic area was measured in the apical four-chamber view. LV inflow and aorta outflow measurements were performed in the apical four- and five-chamber view using pulsed Doppler mode. End systolic wall stress was measured by the method described by Reichek et al. (24). End-systolic wall stress (10³ dyn/mm²) equals (0.334 x LV end-systolic pressure x LV end-systolic diameter)/LV end-systolic posterior wall thickness (1 + LV end-systolic posterior wall thickness/LV end-systolic diameter). From mitral inflow, we measured the early (E) and atrial (A) waves peak velocities and the E-to-A peak velocities ratio. Aortic peak velocity was also recorded.

All data were measured on digital recordings by one experimenter. Intra-animal and intraobserver variability were tested on 10 animals to ensure correct measurement before experimentation.

Hemodynamic measurements.   Two days after completion of the exercise-training protocol (or sedentary confinement), BP was measured using arterial catheterism. Rats were anesthetized with ketamine (100 mg/kg IP) and xylazine (7.5 mg/kg IP). Briefly, the right carotid artery was cannulated with a polyethylene catheter filled with heparinized saline solution (0.9%) and connected to a Baxter uniflow gauge pressure transducer. Hemodynamic signals were collected on a strip-chart recorder (Hewlett Packard 78342A, Palo Alto, CA). Mean arterial BP (MAP) was calculated as (SBP + DBP x 2)/3, and pulse pressure as SBP – DBP. Later, the catheter was advanced into the LV, and the maximal rates of increase and fall in LV pressure (+dP/dt and –dP/dt) were determined as indexes of global cardiac contractility and relaxation.

Histological analysis and tissue weighing.   After hemodynamic measurements, the animal thorax was opened, and the heart was rapidly excised and place in a cold (4°C) physiological saline solution. The heart was dried out with a thin paper towel and weighed (Sartorius BP 160 P, Göttingen, Germany). Then, atria, large vessels, and surrounding epicardial fat were carefully removed. RV and LV including septum (LV + S) were weighed separately. LV + S-to-heart mass ratio was calculated as an index of LV hypertrophy. Paraffin embedded LVs were cut in thin slices (4 µm) and observed in optical microscopy after HES coloration (hematoxylin, eosin, safran). Masson coloration allowed evaluation of the interstitial fibrosis infiltration.

Statistical analysis.   Results are presented as means ± SE. Each variable was compared between the four groups using a two-way ANOVA (group x exercise-training status). When an overall difference was found, a post hoc test of Holm Sidak was done (Sigmastat 3.0.1, Systat Software). A P value of <0.05 was set as the criterion for significance in all comparisons.

	RESULTS

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Body weight and tissue weighing.   Body weight and tissue weighing parameters are presented in Table 1. Renovascular hypertension induced loss of weight in both sedentary and trained HT rats compared with their Ctl counterpart. Total heart and LV + S weights (expressed in mg/100 g body wt) as well as LV + S-to-heart ratio were significantly greater in HT rats compared with Ctl. Exercise training induced an increase of the two first cited parameters in both Ctl and HT rats without modification of the LV + S-to-heart ratio. Concerning RV, although ANOVA analysis showed significant group and training main effects, post hoc analysis showed that exercise training only induced a significant increase of RV weight in HT-Ex rats compared with their sedentary counterpart.

LV histology.   Microscopic optical observation (Fig. 1) did not reveal any LV alterations in both Ctl-Sed and Ctl-Ex rats. In HT rats, typical aspects of cardiomyocyte hypertrophy were observed as well as fibrosis area. Exercise training does not alter these fibrosis infiltrations in HT-Ex rats.

View larger version (78K): [in this window] [in a new window]   Fig. 1. Histological examination of myocardium in optical microscopy (hematoxylin, eosine, safran, and trichrome coloration). A: control sedentary (Ctl-Sed) rats. B: control exercise (Ctl-Ex) rats. C: hypertensive sedentary (HT-Sed) rats. D: hypertensive exercise (HT-Ex) rats. Top magnification = x20; bottom magnification = x40. Moderate exercise training in Ctl rats induced hypertrophy without fibrosis lesions (top). In HT rats, fibrosis infiltration (blue) appeared in large areas (top). Moderate exercise training did not increase this fibrosis extend. Coronary remodeling (arrows) occurred in HT-Ex and Ctl-Ex groups without any differences (bottom).

Maximal exercise capacity.   Maximal exercise capacity (expressed in m·min^–1·100 g body wt^–1) measured at weeks 1, 5, and 10 of the moderate exercise training or sedentary period are presented in Fig. 2. At the first week, maximal exercise capacity was similar within all four groups. Over the 10-wk period, maximal exercise capacity progressively decreased in both sedentary groups, increased in the two trained groups, and was significantly higher than in both sedentary groups at weeks 5 and 10. This increase was not significantly different within Ctl-Ex and HT-Ex groups.

View larger version (11K): [in this window] [in a new window]   Fig. 2. Evolution of the maximal exercise capacity during the 10-wk exercise training period or sedentary period (expressed in m·min–1·100 g body wt–1). , Ctl-Sed rats (n = 10); , Ctl-Ex rats (n = 8); , HT-Sed rats (n = 9); , HT-Ex rats (n = 11). Significantly different from sedentary rats (P < 0.05).

	DISCUSSION

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Using the two-kidney, one-clip model, we induced severe hypertension in the two HT groups as attested by BP measurements. Echocardiographic and tissue weighing data as well as hemodynamic measurements confirmed the development of a pathological LV hypertrophy with arterial stiffness in our HT rats. Theses results were consistent with numerous studies (5, 21, 22, 25). Furthermore, the decrease in weight gain was observed in the initial weeks of hypertension may be related to the negative sodium balance observed in a model of renovascular hypertension, as previously described (14).

Moderate exercise training effects on BP.   Moderate exercise training did not significantly alter BP even if a slight decrease (not significant) was observed in the HT-Ex group compared with HT-Sed. Some studies reported a significant decrease of SBP after exercise training in hypertensive animals (7, 17), but others (19, 27) did not report the same results. These divergent conclusions may reflect differences in intensity, duration, and type of exercise training protocol as well as hypertension model use. In our study, the lack of BP decrease after the exercise-training period could be attributed to the hypertension model we used; some authors did not observe BP reduction after exercise training in rat with renovascular hypertension (16, 19, 28). Nevertheless, the significant decrease of pulse pressure observed in HT-Ex rats compared with their sedentary counterparts seemed to indicate a reduction of arterial stiffness. In that case, moderate exercise training could contribute to an improvement of vascular compliance, as it was previously shown in trained rats (10, 12, 32).

Moderate exercise training effects on cardiac remodeling.   In Ctl rats, moderate exercise training induced cardiac hypertrophy characterized by an increase of total heart and ventricle weight. Echocardiography in two-dimensional and TM mode confirmed the LV cavity enlargement without significant change of wall thickness. Echocardiography also revealed a slight increase of RV chamber size and free-wall thickness. (Data are not shown because the shape of the RV induced technical limitations that do not allow a systematic accurate evaluation.) It led to a decrease of LV hypertrophy index in normotensive trained rats. All these data were in accordance with the development of a physiological hypertrophy (8, 23).

In HT rats, moderate exercise training increased existing LV cardiac hypertrophy as shown by the increase of the LV weight compared with HT-Sed rats. Nevertheless, this additional LV hypertrophy observed in HT-Ex rats did not worsen cardiac remodeling. Indeed, this hypertrophy was accompanied by an increase of total heart and ventricle weight without modification of LV + S-to-heart ratio. In addition, moderate exercise training increased the LV chamber size (LV area and diastolic diameter) as a result the lack of LV hypertrophy index modification. Nevertheless, the increase of LV internal diameter induced by exercise training was not significant, and values were smaller in HT-Ex rats compared with Ctl-Ex. In addition, LV hypertrophy index was unaltered by exercise training in HT rats, whereas it was decreased in Ctl. It appeared that severe hypertension could blunt the training effect normally observed in normotensive rats This smaller LV adaptation to exercise training observed in hypertensive rat may be secondary to collagen accumulation (2), which could restrict ventricular enlargement induced by exercise training. Indeed, our histological data showed fibrosis infiltration in HT rats that was not reversed by exercise training.

These results indicated that moderate exercise training induced an additional physiological hypertrophy in untreated severe hypertensive rats, although these adaptations were blunted compared with normotensive rats. Nevertheless, this cardiac remodeling did not worsen the existing pathological LV hypertrophy, which was consistent with some animal studies (2, 26, 28) but opposite to some human studies, which reported a reduced LV hypertrophy in treated hypertensive subjects or in the case of moderate hypertension (13, 30).

Exercise training effects on LV function.   Hypertension did not disturb systolic function as previously shown (22). Moderate exercise training did not alter systolic function in both Ctl and HT rats as previously described (13, 19). Indeed, neither +dP/dt measurements nor shortening fraction measured by pulsed Doppler echocardiography was significantly altered by moderate exercise training in both HT and Ctl rats. The better cardiac performance observed in Ex groups was characterized by the increase of stroke volume, the increase of end-systolic wall stress, as well as the decrease of aortic acceleration time and could be attributed to the LV chamber size enlargement-induced increase of cardiac preload.

Concerning LV diastolic function, data showed an impairment of LV diastolic function with severe hypertension as previously reported (9, 18). Indeed, peak E- and peak A-wave velocity were respectively decreased and increased in HT rats compared with Ctl. In addition, E-to-A-wave velocity ratio and isovolumetric relaxation time were respectively decreased and increased in hypertensive rats, which revealed an impairment of LV relaxation. Moderate exercise training improved LV passive filling in Ctl-Ex rats, as attested by an increase of peak E-to-A-wave velocity ratio and by a decrease of peak A-wave velocity compared with their sedentary counterpart. These results were in accordance with previous studies that showed a better cardiac performance in normotensive trained rats (6, 31). However, this diastolic LV filling enhancement due to exercise training in Ctl-Ex rats was not observed in HT-Ex rats. Indeed, ANOVA analysis showed a group x training interaction for peak A-wave velocity. Severe hypertension could blunt exercise training effects on diastolic function, as attested by the lack of modification for peak E-to-A-wave ratio. It seems to be in accordance with the study of Palmer et al. (20), who reported that run training provides protective benefits on cardiomyocyte diastolic Ca²⁺ regulation in normotensive rats and thus could enhance LV relaxation during diastole but not in trained rats with renal hypertension. On the other hand, Burgess et al. (2) showed a reduced maximal rate of fall of LV pressure (–dP/dt) concomitant with an accumulation of collagen in LV of hypertensive rats compared with trained normotensive rats. Our histological data confirmed the presence of fibrosis area in hypertensive remodeled LV. If –dP/dt values were smaller in HT rats compared with Ctl rats, the differences were not significant. Finally, exercise training did not alter this collagen accumulation or –dP/dt values in hypertensive rats. It could explain the lack of LV diastolic function alteration like observed in normotensive trained rats.

In conclusion, the results of the present study demonstrate that moderate exercise training effects on cardiac remodeling and function normally observed in normotensive rats were blunted in untreated severe hypertensive rats. Nevertheless, moderate exercise training performed in untreated severe hypertensive animals induced the development of an additional LV hypertrophy that did not worsen LV remodeling and function and particularly diastolic function. Anyway, further human studies are needed for this to be recommended in patients with severe hypertensive cardiomyopathy.

	FOOTNOTES

 

Address for reprint requests and other correspondence: P. Bonnet, Laboratoire de Physiopathologie de la Paroi Artérielle, EA 3852, UFR Médecine, Université François Rabelais, 10 Boulevard Tonnellé, 37032 Tours Cedex 1, France (e-mail: bonnet{at}med.univ-tours.fr)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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This Article Abstract Full Text (PDF) Free All Versions of this Article: 104/2/321    most recent 00442.2007v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Boissiere, J. Articles by Bonnet, P. Search for Related Content PubMed PubMed Citation Articles by Boissiere, J. Articles by Bonnet, P.