Low‐intensity aerobic exercise improves cardiac remodelling of adult spontaneously hypertensive rats

Abstract We evaluated the influence of aerobic training on cardiac remodeling in untreated spontaneously hypertensive rats (SHR). Four experimental groups were used: sedentary (W‐SED, n=27) and trained (WEX, n=31) normotensive Wistar rats, and sedentary (SHR‐SED, n=27) and exercised (SHR‐EX, n=32) hypertensive rats. At 13 months old, trained groups underwent treadmill exercise five days a week for four months. Statistical analysis: ANOVA or Kruskal‐Wallis. Exercised groups had higher physical capacity. Hypertensive groups presented left ventricular (LV) concentric hypertrophy with impaired function. Left atrium diameter, LV posterior wall thickness and relative thickness, and isovolumetric relaxation time were lower in SHR‐EX than SHR‐SED. Interstitial collagen fraction and Type I‐Type III collagen ratio were higher in SHR‐SED than W‐SED. In SHR‐EX these parameters had intermediate values between W‐EX and SHRSED with no differences between either group. Myocardial matrix metalloproteinase‐2 activity, evaluated by zymography, was higher in SHR‐SED than W‐SED and SHR‐EX. TIMP‐2 was higher in hypertensive than normotensive groups. In conclusion, low intensity aerobic exercise reduces left atrium dimension and LV posterior wall thickness, and improves functional capacity, diastolic function, and metalloproteinase‐2 activity in adult SHR.


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Interstitial collagen fraction and Type I-Type III collagen ratio were higher in SHR-SED than W-SED. In SHR-EX these parameters had intermediate values between W-EX and SHRSED with no differences between either group. Myocardial matrix metalloproteinase-2 activity, evaluated by zymography, was higher in SHR-SED than W-SED and SHR-EX. TIMP-2 was higher in hypertensive than normotensive groups. In conclusion, low intensity aerobic exercise reduces left atrium dimension and LV posterior wall thickness, and improves functional capacity, diastolic function, and metalloproteinase-2 activity in adult SHR.

K E Y W O R D S
arterial hypertension, metalloproteinase, myocardial fibrosis, TIMP development on cardiac remodelling in adult SHR. As the effects of physical exercise on extracellular matrix changes during cardiac remodelling have been poorly addressed, our focus was on myocardial collagen tissue.

| ME THODS
The study protocol was approved by Botucatu Medical School Ethics Committee. Twelve-month-old male rats were divided into four groups: sedentary Wistar (W-SED, n = 27); exercised Wistar (W-EX, n = 31); sedentary SHR (SHR-SED, n = 27); and exercised SHR (SHR-EX, n = 32). Training protocol was started at 13 months of age and maintained for 16 weeks. We performed echocardiogram and assessed maximum functional capacity and blood pressure in non-anesthetized rats before and at the end of the exercise.
Maximum exercise capacity was assessed on a graded treadmill as previously described. 8 Exercise protocol consisted of 45 min/day treadmill running 5 days/week. 9 The average treadmill velocity was 17 m/min.

| Histology
Myocyte diameters were measured as the shortest distance between borders drawn across the nucleus. 12 Sirius Red F3BA-stained slides were used to quantify interstitial collagen fraction. 13

| Statistical analysis
Results are expressed as mean and standard deviation or median and percentiles. Variables were compared by analysis of variance (ANOVA) for a 2 × 2 factorial design followed by Tukey's test or Dunn's test. Statistical significance: P < 0.05.

| RE SULTS
Blood pressure was higher in hypertensive groups than their respective controls and unchanged by exercise. Exercise increased functional capacity in exercised groups compared with sedentary rats ( Figure S1).
Echocardiographic data are shown in Tables S1 and S2.
Hypertensive groups presented higher LV diastolic diameter-tobody weight ratio, left atrium diameter (LA)-to-body weight ratio, LV mass index, LV posterior wall thickness, relative wall thickness, Tei index, and isovolumetric relaxation time (IVRT), and lower posterior wall shortening velocity than their controls. SHR-EX had lower LV posterior wall thickness, LA, relative wall thickness, and IVRT than SHR-SED. Exercise did not change systolic function.
Atrial weight was lower in SHR-EX than SHR-SED. Myocyte diameter was statistically larger in hypertensive groups than their

| D ISCUSS I ON
We applied a low-intensity aerobic exercise protocol, previously shown to improve cardiac remodelling in ageing SHR. 7 Final exercise test showed that the protocol was efficient in improving physical capacity. The fact that exercise did not change blood pressure is in accordance with previous studies in aged SHR 2,7 and suggests that uncontrolled long-term hypertension is not modulated by physical exercise.
Echocardiogram performed prior to exercise (data not shown) ensured a uniform assignment of rats between groups. As expected, a decrease in structural parameters observed in SHR-EX was combined with improved diastolic function, characterized by a lower isovolumetric relaxation time in SHR-EX than SHR-SED.
Myocardial collagen fibres form a network regulating force transmission during myocyte shortening and resistance to pathological deformation. 15   conclude that the intensity of physical training has a direct influence on adaptations occurring in cardiac geometry and function of untreated hypertensive rats. and UNESP.

CO N FLI C T O F I NTE R E S T
Authors report no conflict of interest.

AUTH O R S CO NTR I B UTI O N
LUP and KO contributed to study design, manuscript writing, and fundraising; RLD, MJG, ARRL, MDMC, FCD, DRAR, BFP, TMMC, and MPO contributed to data collection. All authors have approved the final manuscript.

DATA AVA I L A B I L I T Y
All data generated or analysed during this study are included in this published article.