Estrogen Deprivation and Myocardial Infarction: Role of Aerobic Exercise Training, Inflammation and Metabolomics.

In general, postmenopausal women present higher mortality, and worse prognosis after myocardial infarction (MI) compared to men, due to estrogen deficiency. After MI, cardiovascular alterations occur such as the autonomic imbalance and the pro-inflammatory cytokines increase. In this sense, therapies that aim to minimize deleterious effects caused by myocardial ischemia are important. Aerobic training has been proposed as a promising intervention in the prevention of cardiovascular diseases. On the other hand, some studies have attempted to identify potential biomarkers for cardiovascular diseases or specifically for MI. For this purpose, metabolomics has been used as a tool in the discovery of cardiovascular biomarkers. Therefore, the objective of this work is to discuss the changes involved in ovariectomy, myocardial infarction, and aerobic training, with emphasis on inflammation and metabolism. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

INTRODUCTION

Despite technological advances, cardiovascular diseases (CVDs) continue to be the leading cause of death in the world, surpassing even the number of cancer deaths and respiratory conditions [1, 2].

Generally in women, CVDs tend to appear later when compared to men due to the protective effect of ovarian hormones, such as estrogen [3]. Menopause is characterized by the drastic reduction of estrogen levels, culminating in changes in body composition, increased oxidative stress, central accumulation of fat and compromised vasodilation. These effects may increase the risk of CVDs, such as hypertension and atherosclerosis, which may result in myocardial infarction (MI) [4].

The prevention of CVDs is possible, in order to control the risk factors for these diseases [2]. The improvement of physical capacity and cardiorespiratory fitness has been pointed out as possible prevention [5].

In this sense, studies have already shown the efficacy of aerobic training (AT) in cardiovascular protection. However, the mechanisms involved have not yet been elucidated [6-8].

In this sense, the aim of this work is to discuss the changes involved in estrogen deprivation, MI, and AT, with emphasis on inflammation and metabolism.

MENOPAUSE AND CARDIOVASCULAR RISK

In recent decades, CVDs remain among the leading causes of death worldwide. Recent research has shown an increase in CVD incidence and mortality in women <55 years, as well as in postmenopausal women [1].

Menopause is an impairment that includes loss of ovaries reproductive function and menstruation absence (amenorrhea), either occurring spontaneously with advancing age or secondary to other conditions, such as medication or surgery. In this sense, a significant number of women enter menopause early (<45 years) or prematurely (<40 years), due to hysterectomy with or without ovariectomy, chemotherapy, radiotherapy or surgeries [9, 10].

Hormonal changes that begin during the menopausal transition affect many biological systems [11]. Studies have provided evidence that early menopause can negatively impact neurological health. For example, the Mayo Clinic Cohort Study of Aging Oophorectomy revealed that early surgical induction of menopause increased the risk of ischemic stroke, Parkinson's disease, doubled the risk of dementia, increased risk of depression and anxiety as well as the risk of mortality due to neurological disorders increased fivefold [9, 12-19]. Interestingly, these damaging effects increase when the age at the onset of menopause decreases. Similarly, The Nurses Health Study found that premenopausal oophorectomy was associated with significantly increased risks for cognitive impairment, dementia, depression, anxiety, stroke, Parkinson's disease, CVDs - such as coronary artery disease (CAD) - fractures and mortality [20-22].

In the past, estrogen was thought of as just a sex hormone; however, over time it has been shown that this hormone plays an important role in the regulation of behavioral and physiological events beyond the reproductive system. Estrogen has shown, for example, neuroprotective and neurogenesis effects in vivo and in vitro after ischemic stroke in animals [23]. Also, a drop in ovarian estrogen production can often cause debilitating physical symptoms, including heat waves and sweating, changes in sleep, urogenital atrophy, sexual dysfunction, changes in the central nervous system (CNS), mood changes and metabolic changes that predispose CVDs and diabetes [3, 11]. In particular, it has been shown that moderate to severe heatwaves and sleep problems are related to increased sympathetic nerve activity, based on the increase in LF / HF (low frequency / high frequency bands of heart rate variability) [24]. Also, estrogens are potent vasoactive hormones that promote vascular remodeling and elasticity, as well as regulate vasodilation and local inflammatory activity [3].

The reduction of circulating concentrations of estradiol in the climacteric period (transition from reproductive to non-reproductive life) promotes changes in the adipose tissue metabolism resulting in central accumulation of fat [25]. Postmenopausal estrogen deficiency leads to the activation of the renin-angiotensin system, supra-regulation of endothelin (a potent vasoconstrictor that increases sodium reabsorption in the kidney) and nitric oxide (NO)-mediated vasodilation impairment, thus increasing blood pressure (BP). Oxidative stress, increased by endothelins and angiotensin II, also results in increased BP and may contribute even more to an atherosclerotic process (Fig. ) [26].

Some studies have shown that estrogen may have an antioxidant and antiatherogenic effect [27], affect cholesterol metabolism and disposition, increase plasma levels of high-density lipoprotein [28] and protect coronary arteries against myointimal proliferation in premenopausal women [29]. Other studies have demonstrated the beneficial influence of ovarian hormones on cardiovascular autonomic control; estrogen seems to be able to increase vagal influence in heart and to reduce cardiovascular sympathetic discharge [30-33].

As a result, studies on hormone deficiency in postmenopausal women have revealed additional autonomic damage, such as reductions in heart rate variability and baroreflex sensitivity [30, 34-36]. These changes appear to be directly related to the increase in cardiac sympathetic activity combined with the reduction in vagal influence [24, 37]. In addition, it has been shown that ovarian hormones also appear to influence the cardiac contractile response, suggesting a possible direct suppressive effect of ovarian hormones on the expression of cardiac β-adrenergic receptors in young rats submitted to ovariectomy [38,39], as well as in postmenopausal women [40]. In the latter case, the responses were altered with hormone replacement therapy. Changes resulting from estrogen deficiency may be responsible for elevated BP at rest and exaggerated pressure responses to exercise and mental stress in postmenopausal women [37]. Finally, ovarian hormone deprivation decreases the expression of oxytocin in oxytocinergic neurons of the paraventricular nucleus of the hypothalamus, culminating in baroreflex dysfunction and autonomic dysregulation [41].

Shortly after menopause, in addition to increased BP, women also have subclinical vascular disease, which can be observed by the increase in the carotid and femoral artery intima-media thickness, elevation of coronary calcium score and decline in endothelial function with increase in oxidative stress, arterial stiffness, as well as impairment of flow-mediated vasodilation [42-44]. The risk of stroke doubles during the first decade after menopause and exceeds that of men at higher ages [45]. These vascular events, however, tend to have a more severe prognosis in women, since within five years after the first MI, 18% of women and 8% of men aged 45-64 develop HF [46].

The gold standard in the preclinical field to evaluate the effects of ovarian hormones in animal models is the ovariectomy, or surgical removal of the ovaries, often abbreviated as OVX. A disadvantage for the OVX model in the context of translational research is that most women retain all of their reproductive tracts during the menopause transition. However, removal of the ovaries prior to the onset of reproductive senescence allows researchers to control the impact of particular hormones and the main elements of reproduction processes without aging as a confounding factor, making it possible to mimic the condition of menopause and to explore new avenues of intervention associated with already known health risks [47].

Studies have used a model of ovarian hormone deprivation in the investigations of cardiovascular, autonomic and inflammatory alterations in rodents, in the presence or not of associated comorbidities (such as hypertension, diabetes, and metabolic syndrome) [48-52] as well as the influence of physical training on these parameters. Thus, findings show that OVX may have an impact on body weight, triglyceride concentration, insulin sensitivity, aerobic exercise capacity, baroreflex dysfunction, and inflammation. AT in animal models has shown to be effective in mitigating these effects, reducing oxidative stress, lipoperoxidation and mortality, increasing NO bioavailability and antioxidant defenses in cardiac and renal tissues, improving the hemodynamic state at rest, reflex control of the circulation and the anti-inflammatory response with the increase of the interleukin-10 (IL-10) in the cardiac tissue [48-51].

Estrogen replacement therapy failed to decrease cardiovascular events in randomized clinical trials, such as the Heart and Estrogen/progestin Replacement Study (HERS) [53], the Estrogen Replacement and Atherosclerosis [54], the Women's Angiographic Vitamin and Estrogen (WAVE) [55] the Papworth HRT Atherosclerosis (PHASE) study [56] and the Women's Health Initiative (WHI) study [57] that provided the initiation of estrogen replacement therapy in elderly women after menopause and already established CAD. Thus, interventions to detect, prevent and mitigate the clinical and pathological consequences of ovarian hormone deprivation have been seen as new and important strategies in the prevention of CVDs in this population. Again, AT seems to be an important factor, since physically active women demonstrate higher levels of heart rate variability and baroreflex sensitivity compared to their sedentary pairs and better inflammatory profile [34, 58].

MYOCARDIAL INFARCTION

The clinical consequences of CVDs usually occur later in women than in men, so CAD usually manifests ten years later and MI with sudden death 20 years later [46]. The reason for the relative protection of women against the development of atherosclerosis before menopause is poorly understood. This protective effect may be related to natural estrogen levels before menopause [59]. The protection conferred by sex hormones may be important, since women with hormone disorders develop atherosclerosis and MI earlier compared to healthy women. Polycystic ovary syndrome, for example, maybe associated with early onset of multiple risk factors, such as abdominal obesity, dyslipidemia, and diabetes mellitus [60, 61]. Ovarian hormones have been also associated with a less atherogenic lipid profile and a healthier fat distribution. However, these differences are attenuated after menopause and may increase the risk of MI [61].

The role of estrogen and its receptor (ER) in cardioprotection is corroborated by the fact that even men with ERα (ESR1) mutation have early CAD and, in animal models of cardiac ischemia, ERα activation reduces myocardial infarction size, cardiomyocyte apoptosis, inflammation and oxidative stress, induces vasodilation and increases neovascularization [62, 63].

MI is defined as myocardial cell death as a consequence of prolonged ischemia [64]. It usually results from the conversion of an atherosclerotic plaque into an atherothrombotic lesion in the coronary arteries. The alteration of this plaque may lead to the formation of overlapping thrombi resulting from exposure to subepithelial collagen, platelet aggregation, and fibrin deposition, resulting in coronary tree obstruction and consequently in MI [65]. Therefore, MI is a dynamic process that does not occur instantly but progressively and evolves over a few hours. Complete necrosis of myocardial cells takes 2 to 4 hours, or more [64].

After coronary occlusion, there is a complex and interrelated sequence of events called: post-infarction left ventricular remodeling (LVR). This remodeling describes the compensatory responses of the cardiovascular system when confronted with contractile function acute loss of the myocytes supplied by this artery [66]. In this sense, the myocytes may present areas of dyssynchrony, dyskinesia, hypokinesia, and akinesia. On the other hand, the non-infarcted myocardium presents hyperkinesia as a result of acute compensatory mechanisms, such as activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and Frank-Starling mechanism [64, 67-69]. Ventricular remodeling process is characterized by the left ventricle (LV) dilation, ventricular wall structure rearrangement, and increase of the remaining muscle mass [66]. LVR may continue for weeks or months until the tensile forces are counterbalanced by the tensile strength of the collagen scar [67]. At the biochemical level, there is a fast decrease in aerobic metabolism, leading to the production of high energy phosphates and degradation products, such as H+ ions and lactic acid. In addition, when ischemia is severe, loss of myocardial contractility occurs in 60 seconds, leading to early HF. Even so, damage caused by MI (necrosis) is irreversible only when ischemia is intense and prolonged for at least 20 minutes [65].

These compensatory mechanisms have a finite capacity to sustain cardiac function and are initially beneficial, maintaining cardiac output and perfusion to vital organs. However, when they are perpetuated, they become deleterious, when the remaining contractile tissue fails to maintain hemodynamics under normal conditions, the individual has a dilated and malfunctioning ventricle that eventually progresses to HF [76-72]. Neurohormonal activation increased sympathetic activity, and decreased parasympathetic activity, as well as the alteration in their respective receptors, which are characteristic of HF, may impair cardiac structure and function, promote changes in cardiorespiratory reflex control and baroreflex dysfunction and reduce the total heart rate variation [71, 73-78].

It is possible to evaluate myocardial lesion with necrosis through markers such as the MB (cardiac muscle) fraction of creatine kinase (CKMB), which is increased. Cardiac troponins I and T are contractile apparatus components of myocardial cells expressed usually in the heart, so the elevation of these biomarkers in the blood reflects a possibility of myocardial necrosis. In addition, normal turnover of myocardial cells, apoptosis, cellular release of troponin degradation products, increased cell wall permeability, and the formation of membranous blisters are possible structural protein release factors [64]. Necrosis completes around 6 hours, or 12 hours when there is an arterial collateral system stimulated [65].

For reasons that are still unknown, acute mortality in the first days after MI is higher in younger women than in men of the same age [79]. A cardiac rupture in acute MI has been reported more often in women than in men in studies in the United States, Europe, and Japan. These studies suggest that women die less frequently from arrhythmia, but more often from cardiac rupture [80-84]. In some, but not all studies, a higher in-hospital mortality rate after MI was observed in females, calculated based on age differences and associated comorbidities [85]. Thus, studies aimed at elucidating mechanisms associated with higher mortality and worse prognosis in women after a cardiac event are important, as well as the use of therapies that can prevent the most exacerbated consequences of MI in females associated with ovarian hormone deprivation.

In order to understand the effects of MI on the cardiovascular system and the autonomic nervous system in experimental models, occlusion of coronary artery branches has been used, showing both damages caused exclusively by MI and damage related to other risk factors such as hypertension, hyperglycemia, and diabetes [73, 86-96].

In this sense, these studies evaluated different therapeutic approaches in the management of MI deleterious effects and in the mortality index, such as mesenchymal and bone marrow stem cell therapy [88, 96] the inhibition of acetylcholinesterase by pyridostigmine bromide [77, 97] and AT, suggesting that it may attenuate dysfunctions related to baroreflex sensitivity and pulse interval variability, as well as the mortality induced by an ischemic event [75, 76, 77, 95, 98-100]. In addition, AT was shown to be important for the improvement of autonomic control, resting hemodynamic status and circulation reflex control, as well as the reduction of proinflammatory cytokines in animals submitted to IM [73, 99].

OVARIECYOMY, MYOCARDIAL INFARCTION AND METABOLOMICS

The heart needs to maintain adequate cardiac output to meet the needs of the body both in rest and effort [101]. Therefore, it is an organ that has a high energy demand and must produce a great quantity of ATP in order to keep it functioning [102]. Approximately 60-70% of the ATP hydrolysis increases the contractile shortening, and the remaining 30 to 40% is mainly used for the Ca2+ -ATPase pump and other ion pumps [103]. Most of these ATPs come from mitochondrial oxidative phosphorylation and the other part of glycolysis. In this way, the heart can use different substrates to produce energy, among them, fatty acids, carbohydrates, ketones, and amino acids. These substrates produce Acetyl-CoA that will participate in the tricarboxylic acid cycle (or Krebs cycle). In this cycle, reduced equivalents will be produced that will later enter the electron transport chain and together with the oxygen will produce ATP [102].

The healthy heart has some metabolic flexibility so that it can alternate between the fatty acids and carbohydrates oxidation depending on the workload and the supply of energy substrates. In this sense, the heart can produce the amount of energy required to sustain cardiac contractility against a variety of conditions [102].

For metabolites analysis (small endogenous molecules that are present in a single biological sample) on a large scale, the metabolomics is used [104]. This methodology has been widely applied as a new diagnostic tool in clinical and biomedical studies. The metabolic analysis has been used to understand the pathophysiological processes involved in the progression of the disease, as well as the search for new diagnostic or prognostic biomarkers of many comorbidities [105].

The non-target metabolomics is the unbiased analysis of all the metabolites presents within a biological system, under a given set of conditions. This process includes a selection of biological samples, pretreatment of the sample, the configuration of the analytical conditions, data acquisition, data analysis by chemometrics, database search and biological interpretation. Thus, this method provides a holistic approach in the field of biomedical research, in order to improve the diagnosis of the disease and to understand the mechanisms involved in the pathology [106].

In this sense, several studies have attempted to identify, through metabolomic analysis, potential biomarkers for CVDs [107, 108]. In particular, clinical studies of metabolic changes in the plasma of infarcted individuals suggest potential biomarkers of MI, such as phytosphingosine, sphinganine, acetylcarnitine, adenine, and inosine [109-112]. However, circulating biomarkers can be easily influenced by many tissues, affecting their specificity. A study evaluated the metabolic profile of cardiac tissue - left ventricle - in the infarcted and non-infarcted area of ​​rats [113]. The authors demonstrated that most of the fatty acids and intermediate metabolites of the tricarboxylic acid cycle are significantly decreased, the lactate and phosphate are elevated in the ischemic myocardium, which implies the greater decomposition and less synthesis of ATP and mitochondrial dysfunction after MI.

Also, plasma levels of each lipid class (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, lysophosphatidylcholine, lysophosphatidylcholine, sphingomyelin, ceramide, triacylglycerol, diacylglycerol, and cholesterol ester, except for free fatty acids) in animals with a greater ischemic event were significantly elevated when compared to normal animals [114].

A study that compared the metabolic profile of ovariectomized rats and sham rats showed OVX-specific variables, including arachidonic acid, eicosapentaenoic acid, ergocalciferol, and cholecalciferol [117]. In addition, ovarian hormone deprivation induces increased levels of cholesterol, glycerol, glucose, arachidonic acid, glutamic acid, glycine, and cystine. These effects suggest that OVX implies changes in the glucose metabolism, energy metabolism, lipid metabolism, and amino acid metabolism [118]. In this sense, another study showed that early estrogen replacement after OVX may prevent oxidative stress and metabolic alterations [119]. However, studies that determine the metabolic profile of cardiac tissue of rats submitted to ovarian hormone deprivation and myocardial ischemia are scarce and deserve attention, since future biomarkers can be determined by such conditions.

CHOLINERGIC ANTI-INFLAMMATORY REFLEX

The immune system's main function is to defend the body against invading agents, thus triggering an involuntary inflammatory response in order to prevent pathogenic action. However, when the inflammatory response is insufficient, the individual may become immunodeficient and may develop infection or diseases such as cancer. On the other hand, an excessive inflammatory response can lead to morbidity and mortality in diseases such as rheumatoid arthritis, atherosclerosis, cerebral ischemia, and myocardial ischemia. In this way, the inflammatory response may cause more damage than the initial stimulus. However, homeostasis is restored when inflammation is limited by anti-inflammatory response [118]. Chronic systemic inflammation is one of the causes of metabolic syndrome in menopause [119]. In ovariectomized rats, AT inhibits visceral macrophage infiltration and attenuates inflammatory cytokines production [120].

Some studies show that there is a neural pathway that, through a reflex, modulates the inflammatory response [118]. It can be said that the immune system and nervous system are not independent so that both produce cytokines and neurotransmitters that bind to receptors involved in physiological functions [121]. In this sense, immunity is mediated by interactions between immune cells and immunocompetent cell products [122]. Although many studies have demonstrated the action of the sympathetic nervous system, recent studies have shown the anti-inflammatory potential of the parasympathetic nervous system through the vagus nerve [123-125]. Therefore, different studies have shown that the electrical and pharmacological stimulation of the vagus nerve restricts the release of cytokines, using the cholinergic receptor to mediate the anti-inflammatory action of acetylcholine in immune cells [113, 124, 125].

Anti-inflammatory reflex is composed of afferent and efferent signals transmitted by the vagus nerve in response to agents derived from infections (cytokines, PAMPs, DAMPs) [122]. The action of pathogens culminates in the cytokines production that signals the bulb through the vagal afferent pathway [126]. Signs of the efferent vagus nerve are then transmitted through the celiac ganglia, where the vagus nerve ends. Soon after, the signals are sent to the spleen via the splenic nerve [125]. Activation of adrenergic neurons occurs in the spleen, resulting in the release of norepinephrine in 
T cells that can release acetylcholine. Acetylcholine crosses the marginal zone and enters the red pulp where interaction occurs with the nicotinic subunit of the alpha 7 receptor (α7 nAChR) present in macrophages. The α7 nAChR transduction signal suppresses the synthesis and release of inflammatory agents (TNF, IL-1, IL-18, HMGB1, and other cytokines). In this way, the inhibition of the inflammatory reflex can also be done through the pharmacological activation of the splenic neurons with the use of cholinergic agonists [122, 127-129]. α7 nAChR is negatively controlled by the gene expression of CHRNA7 which mediates the ability of the vagus nerve to regulate the inflammatory response to lesions and infections and positively by CHRFAM7A which is elevated in human leukocytes and increases the inflammatory response [130].

Another mechanism of action α7 nAChR occurs through ligand-receptor interaction in cells expressing cytokines, so that, after binding to acetylcholine, α7 nAChR transmits cholinergic anti-inflammatory signals into the cytoplasm, activating Janus kinase 2 (JAK2) [126, 131, 132]. Phosphorylation of JAK2 subsequently triggers the phosphorylation of signal transducer and activator of transcription 3 (STAT3), promoting its dimerization. The phosphorylated STAT3 is translocated from the cytoplasm to the nucleus and competes with the nuclear factor kB (NF-kB). These alterations decrease the production of tumor necrosis factor alpha (TNF-α) and other proinflammatory cytokines, such as high mobility group 1 (HMGB1) proteins, macrophages inflammatory protein 2 (MIP-2) and interleukin 6 (IL-6). Also, the anti-inflammatory action of α7nAChR agonists or vagus nerve stimulation is associated with down-regulation of CD14 expression and toll-4 receptor (TLR4) in immune system cells [133]. Thus, increasing the bioavailability of acetylcholine in order to prevent the translocation of NF-κB as well as the expression of CD14 and TLR4 in response to endotoxins, injury, ischemia, and other stimuli may be essential for the reduction of pro-inflammatory cytokines [131, 132].

It is known that vagus nerve may play a key role in controlling inflammation through the cholinergic anti-inflammatory pathway, which is mediated by α7 nAChR in macrophages. However, intracellular mechanisms are not yet fully elucidated. In this way, other studies have sought to understand such mechanisms [124, 134, 135]. In their study, Sun (2013) has shown that micro-RNA 124, for example, modulates LPS-induced cytokine production (through STAT3) by decreasing IL-6 production and TNF-α release, an important mediator of cholinergic anti-inflammatory action [135]. Another study showed that vagal nerve stimulation regulated the expression of PPARγ (peroxisome proliferator-activated receptor gamma) that plays an important role in the anti-inflammatory response in the Central Nervous System, reducing the extent of ischemic infarction, suppressing both the expression of cytokines pro-inflammatory effects on immune cell activation. In this way, PPARγ may be involved in the process by which the vagal stimulation modulates the neuroinflammatory response in ischemia [136]. Finally, although many studies show the participation of the Autonomic Nervous System in the anti-inflammatory response, further studies are needed to understand the molecular mechanisms behind this reflex.

OVARIECTOMY, MYOCARDIAL INFARCTION AND ANTI-INFLAMMATORY REFLEX DAMAGE

It is already established that ovariectomy induces negative changes in autonomic control and inflammation, thus contributing to cardiovascular risk and MI [49, 50]. Several molecular and cellular processes appear to be particularly important for pathologic ventricular remodeling after MI. The communication between fibroblasts, myocytes, and endothelial cells, as well as the extracellular matrix, is critical for alterations in the composition and function of the heart during normal development and pathological condition. Thus, the production of inflammatory cytokines such as IL-6 and TNF-α by activated fibroblasts, monocytes/macrophages and cardiomyocytes after an ischemic event has been demonstrated as an important link in the direct and indirect interaction between these cell types, culminating in a robust pathological cardiac remodeling [137, 138].

In cardiac hypertrophy, both the excessive increase of cardiac myocytes (CMs) and progressive fibrosis occur simultaneously. Thus, communication between different cell types through inflammatory mediators in the interstitium of the heart leads to the formation of an important immunoregulatory network that can lead to disordered hypertrophy, cardiac fibrosis and, consequently, HF [138]. Therefore, interventions that aim to reduce proinflammatory cytokine production by different heart cellular components may lead to cardiac remodeling closer to a physiological one, attenuating the loss of cardiac function after MI [139].

The maintenance of inflammatory status after MI has many lines of investigation, and there is no consensus. The chronic autonomic imbalance that favors the increase of the activity of the sympathetic nervous system and, especially, the reduction of the parasympathetic has been pointed out as a potentially involved mechanism [140-144]. Thus, it is possible to suggest that the reduction of the parasympathetic regulation after the ischemic event could negatively affect the anti-inflammatory reflex, reducing the action of the cholinergic pathway [144]. However, although some suggestions in the literature corroborate this information [145-147], there is still no robust evidence supporting a cause-and-effect relationship. Thus, it is possible that preventing and attenuating the autonomic dysfunction triggered by MI (mainly the reduction of cardiac vagal activity), it could lead to a less intense inflammatory response, to the point of reducing structural and functional impairment cardiac.

AEROBIC TRAINING

Several studies have shown the benefits of a healthy lifestyle, such as improvements in the cardiovascular system, metabolic profile, autonomic control, inflammation, as well as functional benefits, thus suggesting BP as important non-pharmacological conduct in the prevention and treatment of CVD risk factors [148-153]. Also, AT is effective in reducing body weight, increasing insulin sensitivity and glycemic control, preventing obesity and diabetes mellitus, as well as alleviating anxiety and stress [154].

There is a large literature that reports the effects of physical activity and BP on the reduction of CVDs mortality, especially about their action on traditional risk factors [155-157]. Thus, studies show that regular AT improves cardiovascular health, reduces the risk of heart disease, cerebrovascular diseases and various chronic conditions such as hypertension, accelerated biological aging, sarcopenia, liver disease, osteoporosis, some type of cancer (such as colon and breast cancer) and rheumatoid arthritis, in addition to preventing motor disorders and oxidative imbalance arising from cerebral ischemia [154, 158, 159].

In addition, AT has been used as an important approach in the prevention of cardiovascular comorbidities associated with ovarian hormone deprivation [160]. Benefits include inhibition of oxidative stress in the myocardium, avoidance of hypertension, glucose intolerance, dyslipidemia, and heart disease [160, 161]. In ovariectomized rats, AT also increases hippocampal estrogen levels [162] and improves autonomic control [49, 50].

Trained menopausal women have decreased arterial stiffness. This effect can be explained by the increase of nitric oxide synthase and increased NO release [119]. Exercise can also alleviate menopausal symptoms [158], and improve quality of life [159]. Moreover, AT can increase anti-inflammatory response after menopause reducing the risk of CVD [119]. Vieira-Potter et al. (2015) suggest that improvement of mitochondrial function and reduction of inflammation due to exercise may improve immuno-metabolism of adipose tissue [163].

For healthy adults (18-65 years), the American Heart Association recommends AT of moderate intensity, with a minimum of 30 minutes per day and five days per week, or AT of vigorous intensity, for a minimum of 20 minutes per day and three days per week for prevention and maintenance of health [164]. Mora et al. (2007) evaluated several factors such as lipids, inflammatory biomarkers, level of physical activity, weight, blood pressure and glycemia of 27,055 healthy women, showing that the risk of CVD decreased linearly with higher levels of activity [165]. Of these women, those who had reported levels of physical activity with energy expenditure greater than 1,500 calories per week, had a 40-60% reduction in the relative risk of coronary artery 
disease.

AT is also important in improving vascular alterations, including endothelial dysfunction, remodeling and arterial stiffness, present in type 2 diabetes, obesity, hypertension and metabolic syndrome (Fig. ) [166]. Another study has shown that AT concomitant with high fructose intake prevented metabolic, hemodynamic and diastolic dysfunction from developing metabolic syndrome [167].

In this sense, AT seems to have a preventive effect against these types of attacks, so that researchers have sought to identify the possible cardioprotective mechanisms of exercise to ischemia and reperfusion. Among these mechanisms, we can mention the alteration of coronary endothelial and vascular smooth muscle cell phenotype, the increase in the myogenic activity of the coronary arteries, the increase of angiogenesis and the decrease of arterial thickness [168, 169]. Another study suggested that elevation of heat shock proteins such as HSP-72 may increase cardioprotection against and ischemia and apoptosis [170]. The increased activity of myocardial cyclooxygenase (COX-2) seems to be related to late-phase ischemic preconditioning, thus having a protective effect. However, AT does not induce the increase of its expression [170]. A recent study showed that the combination of 17β-estradiol and AT had a positive protective effect on ovariectomy-induced cardiac apoptosis. This result suggests an important therapeutic approach in cardiac protection in bilaterally oophorectomized or menopausal women [171].

Antioxidant protection is also important in preventing risk factors. Elevation of exercise-induced manganese superoxide dismutase (MnSOD) activity decreases the risk of arrhythmias [172]. Also, physical exercise plays an anti-inflammatory role, triggering protection against cardiovascular diseases and type 2 diabetes, decreasing TNF-α [173, 174].

Regarding the prevention of comorbidities associated with MI, some studies have used the physical exercise model performed before the ischemic event. However, the number of studies is still scarce, and the results are contradictory [99, 100, 175-179]. Dayan et al. (2005) showed that 3 weeks of swimming before the induction of acute myocardial infarction significantly decreased ventricular remodeling and improved LV function in Sprague Dawley rats [175]. The first swimming session lasted from 20 to 30 minutes and was gradually increased by 30 minutes each session to 90 minutes on the 4th day, and was maintained until the end of the training period (5 days/week). Freimann et al. (2005) showed that 8 weeks of swimming increased arterial density and manifested the adaptation of genes related to stress and energy metabolism that may contribute to improving cardiac function during cardiac remodeling in Sprague Dawley rats submitted to ischemia surgery followed by 4 weeks of detraining [179]. The rats were subjected to a daily swimming session six days a week for seven weeks. The first session was held in 15 minutes and the duration increased by 15 minutes each session, reaching 90 min on the sixth day and maintained until the end of the training. However, Veiga et al. (2011 and 2012) pointed out that 8 weeks of swimming do not attenuate changes in systolic and diastolic functions following myocardial infarction induced by left coronary artery occlusion, suggesting that cardioprotection cannot be provided by physical training in this experimental model with female rats [176, 178]. Training initially consisted of a 10-minute swimming session, increasing the time by 10 minutes per day until 60 minutes on the sixth day. The training was maintained for a total period of eight weeks, five days a week, 60 min/day.

Already in an experimental treadmill model, Bozi et al. (2013) showed that 8 weeks of AT attenuated cardiac dysfunction and structural deterioration promoted by myocardial infarction in Wistar rats so that such benefits were associated with morphological and contractile properties of preserved cardiomyocytes [177]. The running velocity, treadmill inclination, and session duration were progressively increased throughout the protocol, and up to the 6th week, the rats were continuously running for 60 min at 18 m / min with a slope of 10 °, these measures were maintained until the end of the protocol. Rodrigues et al. (2014) showed that the AT before an ischemic event is effective in altering the aerobic capacity, morphology and left the ventricular function in rats submitted to MI [99]. In addition, these cardioprotective effects were associated with attenuated cardiac autonomic dysfunction seen in trained rats. The AT was performed on a treadmill, in low to moderate intensity (maximum running speed of 50% -70%) for 1 hour a day, 5 days a week for 8 weeks, with a gradual increase of speed from 0.3 to 1, 2 km/h. Finally, a recent study with Wistar rats showed that before MI, AT prevented additional losses in aerobic capacity, left the ventricular function, baroreflex sensitivity and cardiovascular autonomic control (attenuating sympathetic tone increase and reduction of parasympathetic tone) after ischemia. The AT was performed on a treadmill in low to moderate intensity (50 to 70% of maximum running speed) for one hour a day, five days a week, for eight weeks. Based on maximum treadmill exercise tests, training velocities ranged from 0.3 to 1.5 km / h during the eight weeks of training [100].

There is already a great deal of evidence about AT as a tool in the treatment of patients with established CAD. Thus, a meta-analysis based on 48 randomized controlled trials (8940 patients) showed that, compared to usual care, cardiac rehabilitation programs based on aerobic exercise were associated with a reduction in all causes of mortality, total cholesterol and triglyceride levels, and systolic blood pressure. There were no significant differences in infarct rates and nonfatal myocardial revascularization, in high and low-density lipoprotein cholesterol levels and diastolic pressure. Health-related quality of life improved to similar levels both with cardiac rehabilitation and with usual care [180]. Another meta-analysis, based on 34 studies, pointed out that exercise, even for a short period (1 to 3 months), reduces reinfarction rates and all causes of CVDs mortality. In addition, it had favorable effects on cardiovascular risk factors, including smoking, blood pressure, body weight, and lipid profile. It is worth remembering that the overall benefits observed by the practice persisted beyond the period of active intervention after MI [181].

Thus, exercise is a physiological stressor that can have multiple beneficial effects on the cardiovascular system. Therefore, a better understanding of the molecular mechanisms related to such benefits is predictable. The evidence collected suggests that TA, if adequately prescribed and supervised, is a very important tool in the prevention of CVDs, especially CAD and HF [182, 183]. However, cardiac rehabilitation is still underutilized; only one-third of patients with CAD receive any form of intervention [182]. Also, inadequate levels of physical activity are said to be a major health risk in the 21st century [183].

A study of rats submitted to the deprivation of ovarian and infarcted hormones showed that eight weeks of AT were able to improve hemodynamic state at rest and reflex control of the circulation, probably due to an increase in the vagal component. This suggests a homeostatic role for AT in reducing the autonomic impairment of myocardial infarction in postmenopausal women [73]. In another study, Almeida et al. (2015) found improvement in the cardiac function associated, among other factors, to the attenuation of the cardiac remodeling, the decrease in the expression of reactive oxygen species and the increase in antioxidant defenses [184]. Trained infarcted rats showed a reduction in expression of both type 1 angiotensin II receptor and Gp91phox (a subunit of NADPH oxidase generating superoxide anions) when compared to untrained infarcted rats. Also, these rats presented increased catalase antioxidant enzyme, which contributes to the reduction of oxidative stress. There was also a decrease in the production of collagen, an important fact in cardiac function since its increase impairs the force of ventricular contraction.

Thus, AT seems to be an important therapeutic target in the prevention and treatment of MI, especially with regard to the reduction of the chronic inflammatory response and autonomic remodeling and the improve of vagal activity to the heart, thus reducing cardiac work, the risk of fatal arrhythmias and the risk of HF, as well as increasing the survival of the affected individuals [73, 184]. However, there are still gaps in the knowledge of the cardioprotective mechanisms to MI, associated with AT in rats submitted to ovarian hormone deprivation.

CONCLUSION

Menopause induces various cardiometabolic and inflammatory changes in women, such as increased blood pressure, autonomic imbalance, change in adipose tissue metabolism, increase of pro-inflammatory cytokines and oxidative stress, which can culminate in CAD. However, several studies have shown that AT has a cardioprotective effect and is able to minimize these deleterious effects.