Exercise training has no effect on the development of aortic valve stenosis in mice

Introduction:

Severe and symptomatic aortic valve stenosis (AS) has a high mortality of 50 % in the course of 2 years. Physical exercise reduces cardiovascular morbidity and mortality in population-based studies. Nevertheless, it is unclear, if exercise has a protective effect on the development of aortic valve stenosis. Therefore, we investigated the development of aortic valve stenosis in a AS mice model performing a treadmill-based training program.

Method:

After the measurement of baseline parameters mice were assigned to two groups: 1. AS-training: treadmill-based exercise training and wire injury induced AS (n=14) and 2. AS-control: inactive mice with wire injury induced AS (n=9). The treadmill-based exercise training was performed according to established protocols and was made up of 60 minutes at a speed of 15 m/min with 2-minute breaks every 15 minutes. Therefore, mice were acclimatised to a treadmill and trained from 3 weeks before AS induction onwards. The inactive mice were sedentary in their cages. AS in mice was induced via a wire injury model as previously described. Body parameters were measured weekly. Echocardiography was obtained at the start of the experiment, before wire injury and every two weeks over 6 weeks after surgery. All animal experiments were performed according to "Principles of laboratory animal care", institutional guidelines and the German animal protection law. Hearts were analysed histologically by staining (HE, von Kossa, Pico-Sirius-Red and CD68).

Results:

The treadmill training mediated several effects. Trained mice showed less body weight gain (body weight in g (week 0): AS-training 25.3, AS-control 25.3; (week 3) AS-training 26.5 (+1,2), AS-control 27.6 (+2.3); (week 9) AS-training 26.4 (+1.1), AS-control 28.4 (+3.1), p< 0.05). After the first three weeks the increase of the left ventricular posterior wall thickness was greater in trained mice (LVPW-s in mm (week 0): AS-training 1,14 vs AS-control 1,16; (week 3) AS-training 1,34 vs AS-control 1,26, p>0.05).

Six weeks after wire injury, mice developed significant AS, as illustrated by increased peak blood flow velocity and peak pressure gradient over the aortic valve. There were however no significant differences between the trained and the control group (peak velocity in mm/s (week 9): AS-training 2398, AS-control 2368, p=ns; Pmax in mmHg (week 9): AS-training 24, AS-control 23, p=ns). Moreover, echocardiographic imaging showed no difference of absolute values regarding left ventricular ejection fraction, LV dimensions, stroke volume or fractional shortening. In a multiple variable analysis there was merely a correlation between the peak velocity and body weight due to training. Histologically, the aortic valve cusp tissue area was similarly enlarged in both treatment groups (AS-training: 178,281 μm2 vs AS-control 198,851 μm2; p=ns). Interestingly, Sirius-Red staining showed more fibrosis in inactive mice (percent of area: AS-training 26 vs AS-control 44; p<0.05).

Conclusion:

Although population-based data suggests that physical exercise reduces cardiovascular morbidity and mortality, AS development is similar in trained (AS-training) and sedentary mice (AS-control). Interestingly, enhanced fibrosis could be detected in inactive mice. This study has several limitations such as the duration of the experiment and the young age of mice. Further studies have to be executed in order to evaluate a more long-term effect of exercise in this model of AS.