Physical exercise and endothelial dysfunction

Ghisi, Gabriela Lima de Melo; Durieux, Adriana; Pinho, Ricardo; Benetti, Magnus

doi:10.1590/S0066-782X2010001500025

Abstracts

The role of the endothelium was considered mainly as a selective barrier for the diffusion of macromolecules from the lumen of blood vessels to the interstitial space. During the last 20 years, many other functions have been defined for the endothelium, such as the regulation of the vagal tonus, the promotion and inhibition of neovascular growth and the modulation of inflammation, of platelet aggregation and coagulation. This finding is considered one of the most important concepts in modern vascular biology. Currently, atherosclerosis is the prototype of the disease characterized in all its phases by an endothelial dysfunction, defined as an insufficient offer of nitric oxide (NO), which predisposes the endothelium to oxidative stress, inflammation, erosion and vasoconstriction. In this sense, several experimental studies have demonstrated that physical exercise is capable of restoring and improving the endothelial function. The impact of exercise on the endothelium has been broadly discussed. Considering its vasodilating effect and the risk factors, the possibility of treating coronary artery disease and its outcomes without the inclusion of physical exercise became unconceivable. However, the literature is still controversial regarding the intensity of physical effort that is necessary to cause significant protective alterations in endothelial functions. Moreover, the association between intense physical exercises and increased oxygen consumption, with a consequent increase in free radical formation, is also discussed.

Exercise; endothelium; endothelium, vascular; coronary artery disease

Considerava-se que o papel do endotélio era, sobretudo, de barreira seletiva para a difusão de macromoléculas da luz dos vasos sanguíneos para o espaço intersticial. Durante os últimos 20 anos, foram definidas muitas outras funções para o endotélio, como a regulação do tônus vagal, a promoção e inibição do crescimento neovascular e a modulação da inflamação, da agregação plaquetária e da coagulação. Esse achado é considerado um dos mais importantes conceitos da biologia vascular moderna. Atualmente, a aterosclerose é o protótipo da doença caracterizada em todas as suas fases por uma disfunção endotelial, que é definida como uma oferta insuficiente de óxido nítrico (ON), o qual dispõe o endotélio a estresse oxidativo, inflamação, erosão e vasoconstrição. Nesse sentido, numerosos estudos experimentais têm demonstrado que o exercício físico é capaz de restaurar e melhorar a função endotelial. O impacto do exercício no endotélio vem sendo amplamente discutido. Diante de seu efeito vasodilatador e sobre os fatores de risco, tornou-se insustentável a hipótese de tratamento da doença arterial coronariana e de seus desfechos sem a inclusão do exercício físico. Entretanto, a literatura ainda é controversa quanto à intensidade de esforço necessária para provocar alterações protetoras significativas na função endotelial. Ainda, a relação entre exercícios intensos e aumento no consumo de oxigênio, com consequente aumento na formação de radicais livres, também é discutida.

Exercício; endotélio; endotélio vascular; doença de artéria coronariana

Se consideraba que el papel del endotelio era, sobre todo, de barrera selectiva para la difusión de macromoléculas de la luz de los vasos sanguíneos al espacio intersticial. Durante los últimos 20 años, fueron definidas muchas otras funciones para el endotelio, como la regulación del tono vagal, la promoción e inhibición del crecimiento neovascular y la modulación de la inflamación, de la agregación plaquetaria y de la coagulación. Ese hallazgo es considerado uno de los más importantes conceptos de la biología vascular moderna. Actualmente, la aterosclerosis es el prototipo de la enfermedad caracterizada en todas sus fases por una disfunción endotelial, que es definida como una oferta insuficiente de óxido nítrico (ON), el cual expone al endotelio a estrés oxidativo, inflamación, erosión y vasoconstricción. En ese sentido, numerosos estudios experimentales han demostrado que el ejercicio físico es capaz de restaurar y mejorar la función endotelial. El impacto del ejercicio en el endotelio viene siendo ampliamente discutido. Delante de su efecto vasodilatador y sobre los factores de riesgo, se volvió insostenible la hipótesis de tratamiento de la enfermedad arterial coronaria y de sus desenlaces sin la inclusión del ejercicio físico. Entre tanto, la literatura aun es controvertida en cuanto a la intensidad de esfuerzo necesaria para provocar alteraciones protectoras significativas en la función endotelial. Aun la relación entre ejercicios intensos y aumento en el consumo de oxígeno, con consecuente aumento en la formación de radicales libres, también es discutida.

Ejercicio; Endotelio; Endotelio Vascular; Enfermedad de Arteria Coronaria

CLINICAL UPDATE

^IUniversidade do Estado de Santa Catarina - UDESC, Florianópolis, SC - Brazil

^IIUniversidade do Extremo Sul Catarinense - UNESC, Criciúma, SC - Brazil

Mailing address

ABSTRACT

The role of the endothelium was considered mainly as a selective barrier for the diffusion of macromolecules from the lumen of blood vessels to the interstitial space. During the last 20 years, many other functions have been defined for the endothelium, such as the regulation of the vagal tonus, the promotion and inhibition of neovascular growth and the modulation of inflammation, of platelet aggregation and coagulation. This finding is considered one of the most important concepts in modern vascular biology. Currently, atherosclerosis is the prototype of the disease characterized in all its phases by an endothelial dysfunction, defined as an insufficient offer of nitric oxide (NO), which predisposes the endothelium to oxidative stress, inflammation, erosion and vasoconstriction. In this sense, several experimental studies have demonstrated that physical exercise is capable of restoring and improving the endothelial function. The impact of exercise on the endothelium has been broadly discussed. Considering its vasodilating effect and the risk factors, the possibility of treating coronary artery disease and its outcomes without the inclusion of physical exercise became unconceivable. However, the literature is still controversial regarding the intensity of physical effort that is necessary to cause significant protective alterations in endothelial functions. Moreover, the association between intense physical exercises and increased oxygen consumption, with a consequent increase in free radical formation, is also discussed.

Keywords: Exercise; endothelium; endothelium, vascular; coronary artery disease.

Introduction

The mechanisms involved in endothelial function control are multifactorial and, most of the times, can be altered due to the association of a pathological process¹. Several studies have demonstrated the association between abnormal endothelial function and cardiovascular diseases, considering endothelial dysfunction as the triggering factor of the atherogenesis process^2-4.

Among several functions, the vascular endothelium is responsible for the synthesis of vasoconstrictor and vasodilating factors, with nitric oxide (NO) being one of the most important endothelium-derived relaxation factors^1,5,6. NO also has many antiatherogenic properties, which include monocyte, leukocyte and platelet adhesion inhibition, antioxidative properties and inhibition of smooth muscle cell proliferation. The decrease in the bioavailability of NO - endothelial dysfunction - seems to be present in the cardiovascular diseases⁷.

Moderate exercises are known as stimulators of NO release; considering this fact, the regular physical exercise can be considered as a protective factor against cardiovascular diseases^8,9.

As the o vascular endothelium is constantly exposed to several chemical and mechanical stresses, the endothelial cells have a variety of defenses; however, the development of several diseases associated with the cardiovascular system can overcome these defenses, causing structural damage and subsequent function failure. The complexity and importance of the vascular endothelium in the disease suggest that multiple processes are involved with the endothelial adaptations to exercise training¹⁰.

Studies have demonstrated that the vascular endothelium-mediated vasodilation is initially reduced in the atherosclerosis process, even before the morphological angiographic alterations occur^3,11.

This vasodilation progressively decreases as the atherosclerosis severity increases and also due to the associated risk factors, such as hypertension, dyslipidemia and sedentary life style^7,12-14.

Evidence supports the protective effect of exercise on the decrease of oxidative stress, which has a direct impact on the use of exercise practice as treatment of cardiovascular diseasesproporcionas^1,5,15. This review tries to associate physical exercise and endothelial function, not only under normal physiological patterns, but also related to cardiovascular diseases.

The evascular endothelium

The cells that constitute the intimal layer of the blood and lymphatic vascular systems, typically epithelial concerning its structure, position and function, develop from the mesoderm and are called endothelial cells. The membrane that is constituted by these cells is called the endotheliums^10,16.

The vascular endothelium is considered an active and dynamic tissue. This actual "organ" controls important functions, such as the regulation of vascular tonus, fluidification, coagulation, maintenance of blood circulation, as well as inflammatory responses. Therefore, the endothelium represents an interface between the circulation elements and the several systems in the body¹⁰.

In the 80s, the first evidence appeared that the endothelial cells release nitric oxide (NO) through the action of several enzymes that regulate the arterial tonus. Moreover, studies demonstrated that the NO inhibits platelet and leukocyte action and modulates smooth muscle cell proliferation in the medial layer of the arteries. These actions are altered when there is a decrease in the synthesis of NO^4,10. Thus, the NO is one of the most important endothelium-derived factors^7,13. NO is synthesized from L-arginine by the nitric oxide synthase (NOS) enzyme. Three isoforms of NOS have been identified: the neural, the inducible and the endothelial isoforms. The so-called constitutive forms (neural and endothelial NOS) produce the NO that participates in neural transmission, as neurotransmitter and neuromodulator, in endothelium-mediated vasodilation and also have platelet antiaggregation action. On the other hand, the inducible isoforms produces large amounts of NO, which are important in the cytotoxicity process against invading microorganisms and tumor cells¹⁷. The basal NO production seems to be the main protector of immune, nervous and cardiovascular stimulation¹⁸.

Physiologically, the force that the blood exercises on the arterial walls (shear stress) is a stimulus for the release of vasorelaxation factors produced by the vascular endothelium, such as NO. This fact is more evident in the arteries in which the amount of NO produced is higher than in the veins. Thus, when there is an increase in shear stress, the release of NO is accelerated. In coronary circulation, this stress force also has an important role in the adaptation of the coronary flow that can increase several times during the exercises^6,19,20.

The damage to the vascular endothelium caused by risk factors such as dyslipidemia and systemic arterial hypertension causes the progressive loss of these physiological protective functions, characterizing the endothelial dysfunction^1,4,5,19,21. Figure 1 shows this association²².

Endothelial dysfunction

Since the 1970s on, the understanding of the genesis and progression of atherosclerosis has progressively increased. In 1973, Ross and Glomaser²³ suggested that the coronary atherosclerosis started with an injury to the arterial wall leading to the denudation of the endothelium or desquamation of the arterial endothelial lining. This hypothesis was supported by recent evidence that indicated that even the classic fatty streaks - the first lesion common in childhood - are inflammatory lesions consisting of monocyte-derived macrophages and T lymphocytes²⁴.

The vascular endothelium, when affected by risk factors, progressively loses its physiological protective function and starts to be a source of elements that participate in the progression of atherosclerosis. This damage - endothelial activation - alters the vasodilating response, reducing the antithrombotic activity, causing structural alterations and, obviously, causing vascular damages^12-14,24.

The endothelial dysfunction is considered a characteristic feature of patients with atherosclerosis of the coronary arteries, which influences the start and progression of this disease and its adverse events²⁵. Physiologically, the vascular endothelium produces biological substances - such as NO, prostacyclin and bradykinin - which contribute to maintain the vascular tonus with predominance of vasodilation, with the objective of regulating the blood flow and maintain a non-adherent endothelial surface²⁶.

The growing knowledge that the lumen diameter of the coronaries of the epicardium, resistance vessels and major peripheral arteries is highly dynamic in response to flow-mediated factors (NO and endothelium-1) has caused an advance in the understanding of atherosclerosis^27,28. In a study with acetylcholine (Ach) infusion, which causes a vasodilating response that depends on the endothelial NO release, Ludmer et al²⁷ observed a paradoxical vasoconstriction of atherosclerotic segments of coronary arteries in response to this infusion²⁸. According to the authors, the study of the flow-mediated vasodilation is a good indicator of endothelial functions^27,29,30.

Among the factors that cause damage to the vascular endothelium, the reactive oxygen species (ROS), and more specifically the free radicals (FR), are considered one of the main factors that impair the endothelial function and trigger atherogenesis,^14,25.

Currently, it is believed that the main mechanism by which the oxidative stress alters the endothelial function is the inactivation of NO by free radicals such as superoxide anion (O₂^·-) and oxidated LDL. These FR deactivate the endothelial receptors for acetylcholine, serotonin, thrombin, bradykinin and other mediators, decreasing the stimulation of NOS in the endothelial cells and consequent decrease in the NO production, impairing smooth muscle cell relaxation and predisposing to the formation of atheroma plaques^13,31,32.

Moreover, the production of ROS can react with the NO molecule and produce the peroxynitrite anion (ONOO^-) and nitrogen dioxide (NO₂), which can increase the inflammatory injury in vascular cells, decreasing the availability of NO for cells and favoring the thromboembolic processes^31,33.

The association between endothelial function and coronary artery disease (CAD) was confirmed by Al Suwaidi et al³⁴, who demonstrated the predictive value of the endothelial dysfunction and atherosclerosis progression, regardless of the traditional risk factors. A total of 157 patients with coronary disease were followed for a period of 2.3 years, divided in three groups: (normal endothelial function, moderate dysfunction and severe dysfunction). The results showed a higher number of cardiovascular events in the group with severe endothelial dysfunction, whereas there were no events in the other groups. This association was observed in other studies^30,35-38.

Rozanski et al³⁹ compared the peripheral blood flow response in 57 coronary patients and 50 apparently healthy individuals, submitted to physical exercise on an ergometric treadmill. The results showed that, among the healthy individuals, 76% showed vasodilation throughout the exercise, whereas 35% of the individuals with CAD showed progressive vasoconstriction.

Regarding the treatment of the endothelial dysfunction, there are currently several interventions that can attenuate this dysfunction in humans¹. Studies have demonstrated a significant increase in the endothelial function when the plasma lipid levels are treated with a therapy that promotes their decrease⁴⁰. One study demonstrated the increase in endothelial function in patients with type II diabetes with a 3-day treatment based on cerivastatin⁴¹. Another study showed an increase in the endothelial function in patients that decreased LDL and underwent antioxidant therapy with vitamin C⁴². Furthermore, important studies have shown that interventions including angiotensin-converting enzyme inhibitors (ACEI), HMG-CoA reductase inhibitors, folic acid supplementation in hyperhomocysteinemic patients and, currently, angiotensin II receptor blockers, attenuate endothelial dysfunction in patients with CAD^43,44.

Among the interventions, the aerobic physical exercise is shown to be the most important tool to maintain and/or recover the endothelial function⁹.

Physical exercise and the vascular endothelium

Since the 1908s, studies have demonstrated that the physical exercise can modify the control of vascular resistance and the neural control of coronary circulation⁴⁵. Di Carlo et al⁴⁶ observed in animals that the physical training results in an increase in the coronary artery resistance, sensitive to alpha and beta adrenergic agents and adenosine. When the alpha-adrenergic agents are blocked, the adenosine promotes an important vasodilation, in addition to decreasing the concentration of phenylephrine, which is an important coronary vasoconstrictor.

The association between physical exercise and CAD prevention has been extensively discussed and the results of several studies have shown the impact of physical exercise on the treatment of this disease^47-50. The classic studies of Oldridge et al⁵¹ and of O'Conner et al⁵² confirmed an important decrease of 20% to 25% in the mortality due to cardiovascular diseases in patients submitted to cardiac rehabilitation. Moreover, in another study carried out with more than 3,000 apparently healthy men and women in the USA, the association between the regulatory effect of physical activity on inflammation and the decrease in the risk of cardiovascular events was confirmed⁵³.

Regarding the molecular mechanisms, the physical training is associated with significant physiological adaptations involving the skeletal and cardiac musculature, the circulating blood volume and several metabolic modifications. Studies have shown that the exercise also leads to a significant increase in endothelial NOS, which almost always results in an increase in the amount of NO. Moreover, the exercise induces the release of extracellular superoxide-dismutase, which can also contribute to improve the amount of NO. It is known that the NO does not produce only vasodilation, but also inhibits platelet aggregation and has antioxidant, antiproliferative and antiapoptotic properties. These effects suggest that the increase in the NO production and exercise rate can also decrease the progression of vascular diseases^{1,4,6,8-10,54}.

Therefore, the physical training can prevent endothelial dysfunction by maintaining the availability of NO consequent to the prevention of oxidative stress. This evidence suggests that the physical exercise can prevent or attenuate the decline in endothelium-dependent vasodilation⁵⁵.

The beneficial effects of the regular practice of exercises on cardiovascular diseases are especially associated with the higher production of vasodilating agents derived from the vascular endothelium, with the consequent decrease in peripheral vascular resistance, decreasing the levels of LDL-cholesterol and inhibiting platelet aggregation⁵⁴.

Study results have demonstrated that the physical training results in significant improvement in myocardial perfusion⁵⁶ (Figure 2)²². Among the components involved in this coronary circulation improvement are: endothelial functionf.sm^9,20,57; the velocity of production and oxidation of NO^6,58; microcirculation^9,20,57,59; the regression of atherosclerotic lesions^3,60,61; the neoformation of collateral vessels^3,60,61; the decrease in blood viscosity¹⁸ and the increase in the diastolic perfusion time⁵⁹.

Although it has been defined that the physical exercise results in these benefits in patients with coronary diseases, the processes by which these benefits are established are yet to be clarified. Studies have suggested that the mechanism by which the physical exercise reduces the progression of atherosclerosis and the risk of recurrent events is related to the improvement in muscle tonus and endothelial function^62-71.

Haskell et al⁶⁴, using quantitative angiography, compared the vascular coronary reactivity in long-distance runners and sedentary individuals. Initially, they did not find any significant differences between the groups regarding the basal diameter of epicardial coronary arteries; however, when sublingual nitroglycerin was used, the coronary arteries of the runners were 200% more reactive to vasodilation when compared to the group of sedentary individuals.

In two clinical trials carried out by Hambrecht et al^65,66, with patients with congestive heart failure (CHF), a significant improvement in myocardial perfusion was observed, In the first study⁶⁵, 20 patients underwent physical training for six months. In the experimental group, the peripheral blood flow increased significantly in response to acetylcholine versus no change in the control group. There was also an increase in peak oxygen uptake, which was correlated with the increase in endothelium-dependent changes in the peripheral flow. The results were similar in the second study⁶⁶⁷.

Higashi et al⁶³ studied the blood flow in the forearm of 17 patients with mild hypertension that participated in a regular program of physical exercises and a control group. After 12 weeks, the blood flow response in the forearm of the physical training group was significantly increased when compared to the control group. There was also an increase in the Ach-stimulated NO release. This study demonstrated an improvement in the endothelium-dependent vasodilation mediated by the increase in endothelial NO²⁴.

DeSouza et al⁶⁸, in a study with 68 sedentary men and endurance runners, aged 22-35 years and 50-67 years, did not find an age-related decrease in the blood flow of the forearm in response to Ach in the endurance runners. Also in this study, 13 middle-aged sedentary men were submitted to a 12-week running and walking program (5-6 days a week, 40-45 minutes per session and 70%-75% of maximal HR). It was observed that the increase in the blood flow of the forearm (mediated by the acetylcholine) was significant (30%) for similar levels of young individuals, middle-aged adults and elderly individuals that were endurance runners.

It is accepted that the vascular inflammation, vascular oxidative stress and aging are important factors associated with cardiovascular diseases³. Yung et al²¹ embrought evidence of the protective role of exercise in different populations - metabolic syndrome, diabetes, aging, hypertension, menopause, stroke - focused on the coronary artery disease. The authors believe that there is no doubt about the benefits that regular physical exercises can bring to patients with cardiovascular diseases - by decreasing the degree of endothelial dysfunction - and to young and healthy individuals - by preventing the development of cardiovascular disorders by maintaining a normal endothelial function.

Other studies have demonstrated that the physical training can prevent age-related endothelial dysfunction by repairing the availability of NO consequent to the prevention of oxidative stress⁵⁵. This clinical and epidemiological evidence suggests that the physical exercise can prevent or attenuate the decline in the age-related endothelium-dependent vasodilation and reestablish the levels in sedentary adults and elderly individuals.

A study carried out by Hambretch et al⁶¹ demonstrated, by angiography, that the high-intensity aerobic physical exercise improved the endothelial function and the coronary circulation associated to non-stenotic coronary atherosclerosis and that its probable cause was the recruitment of collateral vessels and possible blood flow increase in the ischemic areas of the myocardium. In this study, the patients were submitted to an exercise program for 4 weeks, 6 times a week, for 10 minutes, with an intensity of 80% of maximal HR. The results showed a decrease of 54% in the paradoxical vasodilation of the coronary arteries in response to the infusion of Ach in the exercise group, when compared to the control group. The physical exercise also resulted in a significant improvement in the coronary flow reserve and flow-dependent coronary vasodilation and no changes in the control group.

This study was the first to demonstrate an improvement in the endothelial function with high-intensity aerobic physical exercises in the coronary arteries of patients with CAD and documented endothelial dysfunction.

In a study employing an animal model, Johnson and Parker⁷¹ investigated a group of pigs submitted to training, with induced coronary occlusion of the pulmonary arteries. The findings showed that the arteries demonstrated improvement in the maximal relaxation for Ach. Moreover, the inhibition of NO synthesis significantly decreased the Ach-induced relaxation, with a significant improvement in the exercise group outcome. It was concluded that the physical exercise improves the endothelium-dependent vasorelaxation in pulmonary arteries by increasing the NO release and by a decreased production of a prostanoid constrictor.

Link et al⁷⁰ investigated the systemic effect of physical training on the lower limbs, on the endothelial function of the radial artery in 22 men with CHF. After 4 weeks, the exercise group showed a significant increase in the internal diameter of the radial artery in response to Ach infusion, when compared to the control group. The authors concluded that the increase in endothelium-dependent vasodilation was associated with changes in the functional workload capacity.

Vona et al⁷² carried out a study with 54 patients post-recent acute myocardial infarction (AMI), divided in two groups: untrained and trained with moderate workload. After a three-month follow-up, the results showed that the physical training improved the vasodilation of the vascular endothelium of the individuals that underwent training and that this response was associated with a significant increase in exercise tolerance. Moreover, the study showed that the benefits on the endothelial function disappeared one month after training withdrawal.

Allen et al⁷ demonstrated an association between regional endothelial function (BAR) and plasma NO availability following a physiological stress - a physical test of symptomatic tolerance. Individuals with risk factors for cardiovascular diseases or with established disease demonstrated a lack of response to this physiological stress in both markers. Conversely, the healthy young individuals showed a significant increase in NO with exercise and in BAR. Moreover, the physical training in the patients at risk seems to increase both responses, as the responses in the risk group start to get close to those in the healthy group, suggesting that the endothelial function might be restored. The results also suggest that the amount of plasma NO is related to the endothelial function, to the cardiovascular diseases and responds favorably to physical training.

Johnson et al⁷³ presented a study in which the short-term exercise associated with the increase in the pulmonary blood flow was correlated with the improvement in the endothelium-dependent vasodilating response in the pulmonary arteries of animals, divided in training group (low intensity) and sedentary group. The effectiveness of the training was demonstrated by comparing the body weight-heart ratio and evaluating the musculoskeletal oxidative capacity. After one week of experiment, the results showed significant improvement in the body weight-heart ratio and in the endothelium-dependent maximal relaxation in the training group. As for the endothelium-independent response, there were no significant differences. The data indicated that this short-term exercise protocol results in the increase of the protein expression of NOS and improves the pulmonary artery relaxation mediated by acetylcholine.

Roberts et al⁷⁴ submitted obese children to daily physical activity and a low-fat, high-fiber diet and observed that after these changes in habits, there was a decrease in the production of ROS; increase in the production of NO; improvement in lipid levels; decrease in the endothelial activation and adherence; decrease in the inflammation and platelet destabilization. These responses occur rapidly in young individuals and, according to the authors, the changes must be started before 20 years of age.

A study carried out by Lippincott et al⁷⁵, analyzing individuals who had sedentary professions, observed that 15 to 20 minutes a day of daily exercises at the workplace for 3 months improved endothelial function. Moreover, there was an improvement in blood pressure and LDL-c and total cholesterol levels, which contributed to the decrease in the risk of cardiovascular events.

What still seems to be unclear are the effects of different exercise intensities on endothelial fucntion²¹. A study carried out by Farsidfar et al⁷⁶ ouevaluated the anaerobic threshold and the peak oxygen uptake in the flow-mediated dilation by acute exercise in patients with stable CAD. The vasoreactivity was increased with elevated levels of exercise; however, it decreased significantly at the peak thresholds. Other studies also concluded that moderate levels of exercise (close to the anaerobic threshold) can be considered therapeutic and preventive for coronary patients^76,77.

The physical exercise and the oxidative stress have been the object of many researches aimed at analyzing their association and as the cause of several vascular diseases^{25,26,50,76-78}. Performing acute vigorous exercise constitutes a physiological stress to the body due to the great energy demand, which causes heat release and intense modifications in the muscular and systemic chemical environment, followed by concomitant increase in the production of free radicals¹. The regular exposure to exercise - physical training - promotes a set of morphological and functional adaptations that increase the body's capacity to respond to the exercise stress¹.

According to Goto et al⁶ it is essential to understand the biochemical paradox observed in this situation, not only to correlate stress and exercise, but also to associate them to the treatment of cardiovascular diseases.

Conclusion and future considerations

Atherosclerosis is no longer studied as a disease of lipids, but is now seen as a dynamic and progressive process, resulting from endothelial dysfunction and inflammation. The study of the pathogenesis of this process is crucial, as well as the understanding of the cellular and molecular mechanisms to better create preventive interventions. The scientific evidence suggests that the alteration in the endothelial function occurs well before the clinical manifestations and vascular alterations and that its clinical assessment can be used as a predictor of cardiovascular events.

For a long time, it remained unclear how the physical exercise could improve the myocardial perfusion in coronary patients. Currently, the theories of atherosclerosis regression and formation of collateral circulation have been more broadly discussed. Although it is believed that there is a possibility of lesion regression as a result of large amounts of aerobic exercise, it is unlikely that this will result in a significant improvement in myocardial perfusion, observed much before that.

The new possibilities for coronary endothelial function investigation in vivo and in vitro have increasingly demonstrated the impact of aerobic exercise on endothelial dysfunction and, consequently, on the coronary disease. As described before, the endothelial dysfunction has been well documented as an initial phenomenon of atherosclerosisu^1,14,21,47, as it seems to precede structural changes and clinical manifestations of CAD. The focus of detection of endothelial dysfunction in many studies is criticized by researchers⁸⁰, who believe that efforts should be made to its treatment, not to its causes.

Regardless of that, further studies are recommended so that all mechanism involved in the association between exercise and vascular endothelium can be better understood, including which intensity of aerobic exercise is the ideal one to attain the indicated changes, including other questions. We believe it is imperative to rule out the hypothesis that endothelial dysfunction is an indicator of plaque instability or an independent prognostic marker, so that physical exercises can de definitively added to the treatment strategy.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any post-graduation program.

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