الفهرس 
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Abstract
This study was designed to evaluate the long-term effects of aerobic exercise and intermittent fasting on basal cardiac functions as well as the in vitro cardiac responses to beta adrenergic stimulation in experimentally induced thyrotoxic rats and to shed light on the possible effects of ghrelin hormone in such conditions.
The study was performed on 82 adult male Wister albino rats, allocated into 6 groups:
Non-exercised control group (n = 14): which received an intraperitoneal (i.p) injection of the solvent for L-thyroxine, once per day, 5 days/week.
Exercised control group (n = 12): which was subjected to swimming exercise for 60 min/ day, 5 days/week for 8 weeks (Ribiero et al., 2012). During the last 4 weeks of the study, rats in this group received an i.p. injection of the solvent for L-thyroxine, once/day, 5 days/week.
L-thyroxine induced thyrotoxic group (n = 15): During the last 4 weeks of the study, rats in this group started receiving an i.p. injection of L-thyroxine in a dose of 100 μg/kg B.W. once/day, 5 days/week (Pakdel et al., 2018).
L-thyroxine induced thyrotoxic group pre-treated with exercise (n = 12): rats of this group were subjected to swimming exercise for 60 min/ day, 5 days/week for the initial 4 weeks of the study. During the last 4 weeks of the study, the rats were abstained from the exercise regimen, but received an i.p. injection of L-thyroxine in a dose of 100 μg/kg B.W. once/day, 5 days/week.
L-thyroxine induced thyrotoxic group pre and co-treated with exercise (n = 13): Rats in this group were subjected to swimming exercise for 60 min/ day, 5 days/week for the initial 4 weeks of the study, then for the later 4 weeks, the rats continued swimming exercise while receiving an i.p. injection of L-thyroxine in a dose of 100 μg/kg B.W. once/day, 5 days/week.
L-thyroxine induced thyrotoxic group co-treated with intermittent fasting (IF) (n = 16): like the previous 5 groups, rats had free access to food of bread and milk as well as water ad libitum during the initial 4 weeks of the study, while, at the final 4 weeks, rats of this group were subjected to alternative day fasting regimen (Castello et al., 2010) while receiving an i.p. injection of L-thyroxine in a dose of 100 μg/kg B.W. once/day, 5 days/week.
All rats of all groups were subjected to
- Measurement of initial and final body weights, body mass indices.
- Measurement of arterial blood pressure.
- Biochemical assay of serum T3, T4, TSH, MDA, GPX, TNF α, BAX, BCL2, and active ghrelin hormone levels.
- Electrocardiographic recording.
- In vitro study of isolated hearts using Langendorff’s preparation.
- Measurement of cardiac weights
- Histopathological examination of rat left ventricles.
Our findings revealed that, four weeks’ treatment with levothyroxine in a dose of 100 μg/kg BW was sufficient to induce thyrotoxicosis evidenced by significant elevation in free serum T3, T4 together with the subsequent decrease in TSH. Exercised control group depressed TSH due to improved hypothalamic-pituitary axis sensitivity to thyroid hormones.
Regarding the lines of treatment, exercise pre- as well as pre and co-treatment and the co-treated with IF decreased T3, T4 and increased TSH compared to thyrotoxic group although they didn’t reach the control levels. T4 was lowest in the thyrotoxic group pre- and co-treated with exercise among different treated groups. reflecting that exercise couldn’t protect against thyrotoxicosis when used as a pre-treatment but can partially relief the condition when synchronizes the thyrotoxic condition.
Concerning body weight and body mass index, the thyrotoxic group showed significant reduction in BWG% compared to the non-exercised control group due to increased basal metabolic rate and beta adrenergic effects, in addition to the oxidative, inflammatory and apoptotic stresses encountered in this group.
Exercise-treated groups, especially the exercise pre and co treated group showed significantly lowered FBW, BWG %, FBMI and BMIG % compared to the thyrotoxic group and the non-exercised control group, due to synergistic effects of thyrotoxicosis and exercise in decreasing body weights parameters. Likewise, IF treated thyrotoxic group showed significantly decreased FBW, BWG %, FBMI and BMIG % compared to the thyrotoxic group and the non-exercised control group due to accelerated fat utilization and lipid oxidation. However, loss of weight in the IF treated group was not as marked as the exercise treated groups due to the adipogenic and anti-apoptotic effects of ghrelin being highest in this group among different studied groups.
Moreover, we found that thyrotoxic group was associated with significant elevation in all BP values compared to both control groups due to enhanced sympathetic activity and beta1 adrenergic sensitivity evidenced by the associated tachycardia and short PR interval in ECG. All treatment regimens were not able to reduce blood pressure values and remained significantly high compared to control groups. However, the IF treated group showed significantly lower BP values than exercise treated groups possibly due to high ghrelin.
Additionally, in the current work, the thyrotoxic group increased absolute left ventricle and whole heart weights compared to the control group together with low QRS voltage. This reflected the occurrence of pathological hypertrophy which was supported by the histological findings and could result from the associated inflammation, oxidative stress, and apoptosis.
Exercise treatment reduced absolute cardiac weights compared to the thyrotoxic group, as exercise counteracted apoptosis and inflammation. But the increase in relative cardiac weights in the exercised groups was parallel to the reduction in final body weight. Fasting was able to normalize left ventricle and whole heart weights which may be related to the antioxidant and antiapoptotic ghrelin properties.
ECG records revealed significant tachycardia and short PR interval in the thyrotoxic rats owing to direct effect of thyroid hormone on SA node activity and cardiac gap junctions. Long QT interval denoted increased risk of arrythmia. Low QRS voltage reflected thyrotoxic cardiomyopathy.
On the other hand, ECG recordings of the thyrotoxic group pre-treated with exercise remained non-significantly changed compared to the thyrotoxic group. Preserved tachycardia, short PR interval and the long QTc indicated the lack of exercise pre-treatment cardio protection against the thyrotoxic arrhythmogenic effects.
Meanwhile, the thyrotoxic group pre- and co-treated with exercise and the thyrotoxic group co-treated with IF conferred decreased HR compared to the thyrotoxic rats, owing to high ghrelin level, as it can enhance vagal tone. The thyrotoxic group pre- and co-treated with exercise shortened QT interval compared to thyrotoxic group which indicates cardio protection against arrythmia.
The in vitro recording of heart rate matched with the in vivo ECG findings. The thyrotoxic group was characterized by significant basal tachycardia along with decreased maximal responses to ISO infusion and delta changes compared to the control group, denoting reduced chronotropic reserve. This could be related to the initial tachycardia and thyrotoxicosis-induced cardiomyopathy.
The thyrotoxic group pre-treated with exercise didn’t reduce basal tachycardia compared to the thyrotoxic group, while the thyrotoxic group pre and co-treated with exercise decreased basal tachycardia compared to thyrotoxic group becoming non-significant from the control group. The HR maximal responses to ISO infusion were also significantly decreased in the thyrotoxic group pre- and co-treated with exercise compared to the thyrotoxic group which indicated lowered susceptibility to tachyarrhythmias upon sympathetic stimulation. Meanwhile, decreased delta changes of HR in thyrotoxic hearts as well as exercise treated groups compared to the controls indicated disability of our different exercise protocols to increase chronotropic cardiac reserve that was lowered in thyrotoxicosis and to optimize it towards normal.
On the other hand, IF decreased basal tachycardia and increased delta changes compared to the thyrotoxic group. So, IF normalized chronotropic behavior and maintained chronotropic reserve.
Concerning the cardiac inotropic state, thyrotoxicosis reduced basal, maximal responses and delta changes of PT/LV together with prolongation of values of TPT and reduction in their delta changes, reflecting the deteriorated systolic function. This state can be related to coronary insufficiency (decreased MFR/LV). Also, the decrease of ghrelin known for its anti-inflammatory and anti-oxidative properties aggravated the condition. Basal HRT was short, and its delta change was non-significant from the control. Therefore, to our point of view, thyrotoxicosis led to systolic rather than diastolic dysfunctions.
There were non-significant changes of PT, PT/LV, TPT, and HRT baseline and maximal responses to ISO infusion, in the exercise pre-treated thyrotoxic rats compared to untreated thyrotoxic rats. Failure of exercise protection against systolic dysfunction induced by thyrotoxicosis indicated that the effects of exercise were transient and the positive inotropism of exercise decays as the exercise regimen stops before the induction of thyrotoxicosis.
As shown in the current work, the thyrotoxic rats pre- and co- treated by exercise exhibited significant increases in the PT and PT/LV baseline and maximal response values compared to the untreated thyrotoxic rats and approached the control group values. Therefore, one of the interesting findings of this thesis is the likely ameliorating effect of exercise specially when applies as pre and co therapy rather than a pre-treatment only.
Likewise, the thyrotoxic group co-treated with IF was able to increase basal values and maximal responses of PT/LV compared to the thyrotoxic group and approached the control group values which indicated improved systolic functions. An additional ameliorating effect of IF was increasing HRT delta changes which reflected an improved diastolic function in this group compared to exercise treated groups. This might be attributed to the markedly high ghrelin level and its subsequent increase of MFR as well as decrease of oxidative and inflammatory stresses.
Accordingly, it is concluded that thyrotoxicosis deteriorated the chronotropic, inotropic and lusitropic responses of hearts to β-adrenergic stimulation. The thyrotoxic cardiomyopathy was systolic rather than diastolic. The decrease of ghrelin known for its anti-inflammatory and anti-oxidative properties aggravated the condition.
The thyrotoxic group pre-treated with exercise couldn’t exert cardioprotective effects owing to the transient effect of exercise which decays as exercise stops.
The thyrotoxic group pre- and co-treated with exercise lowered susceptibility to tachyarrhythmias upon sympathetic stimulation. However, there was disability of our different exercise protocols to increase chronotropic cardiac reserve that was lowered in thyrotoxicosis. Moreover, there were likely ameliorating effect of exercise specially when applied as pre and co therapy, on the inotropic state, rather than a pre-treatment only.
IF normalized chronotropic behavior of the hearts and maintained chronotropic reserve. IF also improved diastolic function compared to exercise treated groups. This might be attributed to the markedly high ghrelin level. This miraculous peptide exerted cardio-protection from thyrotoxic hazards as cardiac hypertrophy and fibrosis, left ventricular remodeling, cardiomyopathy, and diastolic dysfunction, in particular, due to its anti-inflammatory, antioxidant and antiapoptotic effects.
RECOMMENDATIONS
We recommend that thyrotoxic patients follow intermittent fasting regimen as a respectable line of treatment. Exercise is better to be continued during thyrotoxicosis to obtain considerable beneficial effects. However, further studies are recommended to elucidate the recommended exercise loads in terms of duration and intensity on different thyrotoxic disorders.
We also recommend studying a combined effects of exercise along with IF on thyrotoxic hearts.