Summary
Background
Eccentric exercise training has been shown to improve muscle force strength without excessive cardiovascular stress. Such an exercise modality deserves to be tested in pulmonary arterial hypertension.
Aim
We aimed to assess the effects of an eccentric training modality on cardiac function and survival in an experimental monocrotaline-induced model of pulmonary arterial hypertension with right ventricular dysfunction.
Methods
Forty rats were randomly assigned to one of four groups: 40 mg/kg monocrotaline-injected sedentary rats; 40 mg/kg monocrotaline-injected eccentric-trained rats; sedentary control rats; or eccentric-trained control rats. Eccentric exercise training consisted of downhill running on a treadmill with a −15° slope for 30 minutes, 5 days a week for 4 weeks. Training tolerance was assessed by echocardiography, right ventricle catheterization and the rats’ maximal eccentric speed.
Results
Survival in monocrotaline-injected eccentric-trained rats was not different from that in monocrotaline-injected sedentary rats. Monocrotaline-injected eccentric-trained rats tolerated this training modality well, and haemodynamic status did not deteriorate further compared with monocrotaline-injected sedentary rats. The eccentric maximal speed decline was less pronounced in trained compared with sedentary pulmonary arterial hypertension rats.
Conclusions
Eccentric exercise training had no detrimental effects on right heart pressure, cardiac function and survival in rats with stable monocrotaline-induced pulmonary hypertension.
Résumé
Contexte
Un entraînement de type excentrique permet d’améliorer la force musculaire sans stimulation cardiovasculaire excessive. De ce fait, cette modalité d’exercice mérite d’être testée en cas d’hypertension artérielle pulmonaire.
Objectif
Nous avons étudié les effets d’un entraînement de type excentrique sur la survie et la fonction cardiaque d’un modèle d’hypertension artérielle pulmonaire avec dysfonction ventriculaire droite.
Méthodes
Au total, 40 rats ont été randomisés dans quatre groupes : 40 mg/kg monocrotaline-sédentaire, 40 mg/kg monocrotaline-excentrique, témoin-sédentaire, témoin-excentrique. Les rats ont été entraînés pendant 30 min, 5 jours sur sept, pendant quatre semaines. Ils couraient sur un tapis incliné à –15° (course en descente). L’effet de l’entraînement a été évalué par l’échocardiographie, le cathétérisme cardiaque droit et la vitesse maximale de course.
Résultats
La survie des rats monocrotaline-excentriques et monocrotaline-sédentaires ne différait pas. L’évolution des paramètres hémodynamiques des rats monocrotaline-excentriques a été similaire à celle des rats monocrotaline-sédentaires. La dégradation de la vitesse maximale de course a été moins marquée dans le groupe monocrotaline entraîné que dans le groupe des rats sédentaires.
Conclusion
L’entraînement de type excentrique n’a pas d’effet délétère sur la fonction cardiaque droite, la pression ventriculaire droite et la survie de rats ayant une hypertension artérielle pulmonaire peu évolutive induite par la monocrotaline.
Background
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodelling, which results in an increase in vascular resistance and, progressively, in right ventricular (RV) hypertrophy. Eventually, RV dysfunction and subsequent failure lead to incapacity of the heart to maintain cardiac output, exercise intolerance, poor quality of life and premature death . Advances in pharmaceutical therapies have facilitated improvements in haemodynamics, exercise capacity and patient survival . However, exertional dyspnoea is often persistent, despite adequate treatment, and results in difficulty in performing day-to-day activities. As peripheral muscular deconditioning is involved in functional limitation in PAH, and may in part explain dyspnoea , cardiopulmonary rehabilitation has been recently proposed for these patients. Historically, PAH patients have been discouraged from performing intense exercise because of the risk of sudden cardiac death or deterioration of RV function. However, a few prospective studies in stable treated patients have suggested that exercise training can be performed without a negative impact on cardiac function or any major adverse events . In the last 2015 European Society of Cardiology/ERS guidelines for the diagnosis and treatment of pulmonary hypertension , exercise training was recommended by the experts as adjunctive therapy. It is important to diversify training modalities, in order to improve PAH patients’ adherence to physical exercise and to adapt physical activity to patients with low cardiovascular reserve.
Eccentric exercise is classically used to improve muscle strength and power in healthy subjects and patients. In addition, eccentric exercise muscle contraction has the advantages of low metabolic cost and then low cardioventilatory solicitation . For a given level of oxygen consumption (VO 2 ), eccentric exercise contractions generate higher muscular forces than concentric contractions, and substantial neural adaptations. As a result, for a given level of VO 2 , eccentric exercise training can result in greater increases in muscle strength than concentric training, which in turn translate into an increase in skeletal muscle size and strength . It has been shown that it is possible to increase the size and strength of skeletal muscle with eccentric exercise training at a training intensity that is insufficient to have any structural or functional impact on muscles when trained in a concentric manner . Therefore, patients whose low cardiovascular reserve prevents the maintenance of sufficient training intensity using concentric modalities may still be able to improve muscle strength using eccentric exercise training modalities.
Concentric contractions are characterized by muscle fibres shortening (the quadriceps contracts concentrically in order to climb hills or stairs, or to cycle), and eccentric exercise contractions are characterized by muscle fibres lengthening (the quadriceps contracts eccentrically in order to go down hills or stairs, or when braking). Interestingly, a muscle can store energy during a brief stretch. The post-stretch energy release allows a reduction in the metabolic energy expenditure of eccentric exercise contractions . In this paper, we use the term “eccentric exercise”, but we agree that the use of “negative work”, (as proposed by Padulo et al. ), related to work induced by lowering or decelerating, may be more appropriate. Indeed, for a given movement, some muscles are in eccentric exercise mode, whereas antagonists contract concentrically to allow movement precision. In animals, eccentric exercise has been based mainly on downhill running or an isokinetic test device .
Eccentric exercise training could be proposed for PAH patients on the condition that it has no deleterious cardiac effect. In this experiment, our main purpose was to assess the effects of eccentric exercise training (downhill running) on haemodynamic and cardiac remodelling variables and survival in an experimental monocrotaline-injected model of PAH. We selected a rat model of “stable” PAH for which concentric training has been shown to be beneficial . The exercise training consisted of 30-minute sessions of downhill running, at 50% of each rat’s maximal running speed (V max ), for 5 days per week.
Methods
Experimental model
Experiments were performed on 40 adult male Wistar rats (Centre d’Élevage Dépré, Saint Dulchard, France) weighing 224 ± 8 g. PAH was induced by a single subcutaneous injection (40 mg/kg body weight) of monocrotaline (Sigma Medical, St Louis, MO, USA), to mimic stable PAH . Control rats were injected with the same volume of saline solution. Animals were housed in a neutral temperature environment (22 ± 2 °C) on a 12-hour light-dark cycle, and received food and water ad libitum. Rats were weighed twice a week. Procedures were conducted in accordance with the US National Institutes of Health guidelines, and were approved by the Ethics Committee of the University of Strasbourg (Reference number: AL/02/13/07/09).
Experimental design
Animals were randomly assigned to one of two study groups: a monocrotaline-injected group and a control group. In the 2 weeks following injection, all rats were made familiar with the treadmill (Panlab S.L., Barcelona, Spain), and ran for 5 minutes, three times a week, at a constant speed of 15 cm/s, with no slope. Mild electric stimulation was used to encourage the rats to run. After those 2 weeks, all animals performed a maximal incremental running test on the treadmill with a −15° slope, the speed being increased by 10 cm/s every 90 seconds to maximum tolerance. A rat was considered to be exhausted when the animal accepted the electric stimulus of the treadmill three consecutive times. The animals were then randomly allocated to an eccentric exercise training group (monocrotaline-injected eccentric-trained [MTecc], n = 13 rats; or eccentric-trained control [CLecc], n = 7 rats) or a sedentary group (monocrotaline-injected sedentary [MTsed], n = 13 rats; or sedentary control [CLsed], n = 7 rats) ( Fig. 1 ). The eccentric exercise training consisted of downhill running with the treadmill set at a −15° slope for 33 minutes, 5 days a week for 4 weeks (3 minutes of warm-up at a constant speed of 15 cm/s, and 30 minutes at a constant speed of 50% of the V max reached by each rat). We showed in our laboratory that for eccentric exercise, 50% of the V max corresponds to about 65% of maximal VO 2 (unpublished data). The maximal eccentric exercise incremental test was repeated after a 2-week training period, and at the end of the training programme. Training speed was adapted after the second maximal test for each rat, to keep with the 50% V max goal. The sedentary rats (CLsed and MTsed) performed the three maximal exercise tests, and ran on the downhill treadmill for 5 minutes, three times a week, at 15 cm/s, with the same downhill slope (−15°), for 4 weeks.
Haemodynamic evaluation
Echocardiography
Echocardiography (Agilent Technologies, Andover, MA, USA; equipped with a 12 MHz linear transducer) was performed every 2 weeks after injection, on anaesthetized but spontaneously breathing rats in a supine position. Anaesthesia was induced by inhaled isoflurane at 3.5% (Aerrane™; Baxter S. A. S., Maurepas, France) in an induction chamber, and maintained at 2% using a facemask. The average duration of anaesthesia was 15–20 minutes. Three consecutive measures of all variables were performed online, and then averaged. Measured variables for RV remodelling and function were: RV end-diastolic diameter (RV EDD); RV free wall thickness; right ventricle/left ventricle (RV/LV) ratio; and tricuspid annular plane systolic excursion (TAPSE; used as an index of systolic RV function). Pulsed-wave Doppler pulmonary outflow was recorded in the short-axis parasternal view, and the pulmonary artery acceleration time (PAAT; in ms) was measured. Cardiac output (mL/min) was calculated as TVI Ao × HR × S Ao , where TVI Ao is the time-velocity integral of the pulsed-wave Doppler aortic outflow, HR is the heart rate and S Ao is the aortic surface (calculated as π × [D 2 /4]; D is the aortic diameter just below the aortic valve in the parasternal view). Stroke volume was the ratio between cardiac output and heart rate.
RV catheterization of closed-chest rats
At the end of the study protocol (24 hours after the previous training session), closed-chest catheterization was performed under general anaesthesia, but in spontaneously breathing animals, as previously described . RV pressures were recorded by using a fully filled catheter connected to a pressure transducer and physiological recorder (ML 818 PowerLab 15T; ADInstruments, Oxford, UK). RV systolic pressure was assumed to be equal to pulmonary arterial systolic pressure.
Autopsy
After RV catheterization, anaesthesia was maintained with isoflurane 2.5%, and both ventricles and the lung were isolated and weighed. The ratio of RV weight to LV plus septum weight (RV/[LV + septum]) was used as an index of RV hypertrophy and PAH severity. The lung was weighed immediately after sacrifice to obtain wet lung mass. We dried the lung for 60 minutes at 120 °C on a heater plate. After 24 hours at an ambient temperature and humidity, the lung was weighed.
Statistical analysis
Data are expressed as mean ± standard error of the mean. Data were analysed using two-way (effects of monocrotaline injection and training were studied) or three-way (monocrotaline administration, training and time effects were studied) analysis of variance followed by a Neuman-Keuls post-hoc test. These analyses were performed on the rats that completed all measurements (echocardiography, exercise test). A Kaplan-Meier analysis and log-rank test were used to evaluate and compare survival in the four groups. Values of P < 0.05 were considered as significant.
Results
Survival at 6 weeks
In the monocrotaline-injected group, 11/13 MTsed rats and 10/13 MTecc rats were alive at the end of the study (non-significant difference). Four rats died during the fourth week after injection (MTsed group, n = 2; MTecc group, n = 2), and one died during the fifth week (MTecc group). All of the control animals survived ( Fig. 2 ).
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