**3. Characteristics of cardiac remodeling: effects of exercise training**

The myocardium is primarily composed of myocytes, vessels, and interstitial collagen matrix. Changes in the composition of these compartments reflect the process of cardiac remodeling that is closely associated with cardiac dysfunction [41]. Cardiac hypertrophy is more often related to these events, and according to the type of hypertrophy (physiological or pathological), different models of it are observed, with their signaling pathways.

Cardiac remodeling can be defined as the set of cardiac molecular, cellular, and interstitial modifications that will be clinically displayed by changes in cavity diameter, mass (hypertrophy or atrophy), geometry (evidenced by wall thickness and heart shape), in response to a given stimulus, which may be aggression, such as areas with fibrosis and scarring observed in infarction [42] or even by adaptation, which is a physiological process, such as enlargement of the ventricular cavity of long-distance runners (eg marathon runners) [43–45]. The sequence of pathological events begins with aggressions to the cardiac tissue that maybe through reduction of myocyte changes in the energy system, pressure overload, and volume overload, among other factors. From one or a combination of these episodes, remodeling is a cascade of genetic, biochemical, molecular, cellular, and structural changes that most often culminate in ventricular dysfunction resulting in heart failure [46–48].

Myocytes perform the contractile function of the myocardium, and their preservation is fundamental since most of them are not capable of multiplication. Myocyte reduction can occur by three mechanisms: autophagy, apoptosis, and necrosis. New evidence indicates that for the latter, there is a confluence of mechanisms, and their close relationship is called necroptosis [49]. Autophagy, on the other hand, maybe adaptive or deleterious, depending on the context of protein balance. Fibrosis, observed in acute post-myocardial infarction situations, is a response to myocyte death since, after cardiac signaling for the removal of dead myocytes, cardiac fibroblasts secrete proteins such as collagen I to form a scar and prevent rupture of the myocardium cardiac wall. This condition, considered as remodeling, continues in response to ventricular wall stress, so we have another event called myocyte hypertrophy. This effect leads to increases in final systolic and diastolic volume and reduction in ejection fraction [50].

Energy metabolism and oxidative stress are factors potentially responsible for cardiac remodeling. The imbalance between oxygen supply and consumption, including decreased free fatty acids and increased glucose utilization, may contribute to lower energy availability for ATPase proteins, favoring the generation of reactive oxygen species (ROS), resulting in all the consequences of oxidative stress [51–53]. Lipid peroxidation, DNA damage, fibroblast proliferation, metalloproteinase activation, apoptosis stimulation, changes in proteins responsible for calcium transit, and activation of signaling pathways for hypertrophy are conditions involved in oxidative stress which is implied in the oxidative stress cardiac remodeling process due to cellular signaling and imbalances in homeostasis. In short, ROS directly influence contractile function from the modification of central proteins to the excitation-contraction. Continuous pressure overload promotes the addition of sarcomeres in parallel, that is, it promotes the increase in ventricular wall thickness, called concentric hypertrophy, which can be observed in advanced systemic arterial hypertension and aortic valve stenosis. On the other hand, volume overload (e.g., valve insufficiency) results in serial sarcomere increase, called eccentric hypertrophy [54], present in cases of acute myocardial infarction [55].

Regarding the pathological processes of concentric hypertrophy, muscle thickening hinders capillary filling in the deepest regions of the myocardium, specifically the subendocardium, which impairs the maintenance of blood flow. About eccentric hypertrophy, the increase in mass occurs with a predominance of increased intracavitary dimensions with less expression of myocardial thickening, causing cardiac fiber disarrangement and alteration in the angle between them, with loss of spiral architecture of the myocardial fibers, associated with a contractile deficit of the ventricle [55]. There is a blood damping in the cardiac chambers, decreasing the irrigation of peripheral tissues [56].

Regarding the process of physiological hypertrophy, both eccentric and concentric, the stimuli are similar to the process presented in serious pathologies (e.g., pressure and volume overload). However, what define the ventricular geometry

**75**

cardiac puzzle.

**4. Conclusions**

*Exercise Training and Cardiac Remodeling DOI: http://dx.doi.org/10.5772/intechopen.89311*

attenuate the deleterious effects of aging [61, 62].

pattern presented during remodeling are the characteristics inherent to the stimulus received, in which, in physiological cases, there are no functional damages to the cardiovascular system. Even more, adaptations from exercise can be beneficial in improving heart function. Hence, the physiological adaptations occur from physical exercise, for example, depending on the type of exercise (e.g., running and strength training) of volume, intensity, and frequency. Regarding the benefits of regular aerobic exercise practice, there is a higher blood volume ejection due to increased ejection force or higher ventricular filling, thus reducing the resting heart rate. Diverse molecular pathways are associated with exercise-induced cardiac remodeling. However, the gene pathway (IGF-1) is well characterized and evidenced in the literature [57], due to the increase in cardiomyocytes in response to aerobic exercise [58]. However, cardiac remodeling in response to aerobic training is dependent to PI3K pathway activation and AKT phosphorylation [59]. Interestingly, short-term, aerobic training (4 weeks) can reprogram cardiac remodeling through AKT activity [60]. Additionally, in both animal and human models, exercise can

The role of miRNAs is of fundamental importance in the cardiac remodeling process [55, 63] mainly associated with exercise training [64, 65], due to their participation in left ventricular hypertrophy in aerobic exercise. Also, HIIT protocols show miRNA expression in cardiac hypertrophy [55]. Thus, exercise is an essential factor in identifying miRNA signatures associated with cardiac remodeling. MiRNA-29 targets the collagen gene, which increases with the induction of physical exercise, reducing collagen I and III, resulting in better ventricular function [66]. Also, miRNA-29 reduces collagen fibrosis and attenuates the deleterious effects of cardiovascular disease [67]. Therefore, although miRNAs and genes are closely related to the cardiac remodeling process, other factors are also important, such as proteomics and metabolomics. So many pieces still need to be fitted into this

Regardless of the type of stimulus imposed by exercise, the key point to ensuring positive myocardial adaptations is in the balance of training manipulation variables (frequency, intensity, and volume) as well as the nature of the modality chosen. Considering the intensity variable, which is widely investigated, it is clear that while low-intensity aerobic exercise improves cardiac remodeling in adult rats by reducing the size of the left atrium and the left ventricular (LV) posterior wall thickness, high-intensity aerobic exercise presents inverse responses, with increased left ventricular mass and LV posterior wall thickness. Dynamic exercise (running), which requires a continuous increase in cardiac function and contractility, differs from powerlifting which requires high blood pressure and a greater need for oxygen perfusion to skeletal muscles. This explains the ability of the circulatory system to

The responses related to the type of exercise are diverse, as they are interpreted from different experimental and clinical designs. Still, it is critical to search for research to assess the chronic effects of exercise, especially at the molecular level to find strategies for the prevention and treatment of cardiovascular disease. Perspectives point to the integration of studies involving immune response in the brain and heart in order to contribute to the understanding and longitudinal followup of several modalities, including the determination of the threshold of optimal internal and external stimulus loads to avoid cardiac toxicity, which leads to pathological cardiac remodeling, also considering the screening of individuals at risk.

differentiate exercise types according to different hematological stresses.

#### *Exercise Training and Cardiac Remodeling DOI: http://dx.doi.org/10.5772/intechopen.89311*

*Sports, Health and Exercise Medicine*

in heart failure [46–48].

volume and reduction in ejection fraction [50].

phy [54], present in cases of acute myocardial infarction [55].

irrigation of peripheral tissues [56].

diameter, mass (hypertrophy or atrophy), geometry (evidenced by wall thickness and heart shape), in response to a given stimulus, which may be aggression, such as areas with fibrosis and scarring observed in infarction [42] or even by adaptation, which is a physiological process, such as enlargement of the ventricular cavity of long-distance runners (eg marathon runners) [43–45]. The sequence of pathological events begins with aggressions to the cardiac tissue that maybe through reduction of myocyte changes in the energy system, pressure overload, and volume overload, among other factors. From one or a combination of these episodes, remodeling is a cascade of genetic, biochemical, molecular, cellular, and structural changes that most often culminate in ventricular dysfunction resulting

Myocytes perform the contractile function of the myocardium, and their preservation is fundamental since most of them are not capable of multiplication. Myocyte reduction can occur by three mechanisms: autophagy, apoptosis, and necrosis. New evidence indicates that for the latter, there is a confluence of mechanisms, and their close relationship is called necroptosis [49]. Autophagy, on the other hand, maybe adaptive or deleterious, depending on the context of protein balance. Fibrosis, observed in acute post-myocardial infarction situations, is a response to myocyte death since, after cardiac signaling for the removal of dead myocytes, cardiac fibroblasts secrete proteins such as collagen I to form a scar and prevent rupture of the myocardium cardiac wall. This condition, considered as remodeling, continues in response to ventricular wall stress, so we have another event called myocyte hypertrophy. This effect leads to increases in final systolic and diastolic

Energy metabolism and oxidative stress are factors potentially responsible for cardiac remodeling. The imbalance between oxygen supply and consumption, including decreased free fatty acids and increased glucose utilization, may contribute to lower energy availability for ATPase proteins, favoring the generation of reactive oxygen species (ROS), resulting in all the consequences of oxidative stress [51–53]. Lipid peroxidation, DNA damage, fibroblast proliferation, metalloproteinase activation, apoptosis stimulation, changes in proteins responsible for calcium transit, and activation of signaling pathways for hypertrophy are conditions involved in oxidative stress which is implied in the oxidative stress cardiac remodeling process due to cellular signaling and imbalances in homeostasis. In short, ROS directly influence contractile function from the modification of central proteins to the excitation-contraction. Continuous pressure overload promotes the addition of sarcomeres in parallel, that is, it promotes the increase in ventricular wall thickness, called concentric hypertrophy, which can be observed in advanced systemic arterial hypertension and aortic valve stenosis. On the other hand, volume overload (e.g., valve insufficiency) results in serial sarcomere increase, called eccentric hypertro-

Regarding the pathological processes of concentric hypertrophy, muscle thickening hinders capillary filling in the deepest regions of the myocardium, specifically the subendocardium, which impairs the maintenance of blood flow. About eccentric hypertrophy, the increase in mass occurs with a predominance of increased intracavitary dimensions with less expression of myocardial thickening, causing cardiac fiber disarrangement and alteration in the angle between them, with loss of spiral architecture of the myocardial fibers, associated with a contractile deficit of the ventricle [55]. There is a blood damping in the cardiac chambers, decreasing the

Regarding the process of physiological hypertrophy, both eccentric and concentric, the stimuli are similar to the process presented in serious pathologies (e.g., pressure and volume overload). However, what define the ventricular geometry

**74**

pattern presented during remodeling are the characteristics inherent to the stimulus received, in which, in physiological cases, there are no functional damages to the cardiovascular system. Even more, adaptations from exercise can be beneficial in improving heart function. Hence, the physiological adaptations occur from physical exercise, for example, depending on the type of exercise (e.g., running and strength training) of volume, intensity, and frequency. Regarding the benefits of regular aerobic exercise practice, there is a higher blood volume ejection due to increased ejection force or higher ventricular filling, thus reducing the resting heart rate.

Diverse molecular pathways are associated with exercise-induced cardiac remodeling. However, the gene pathway (IGF-1) is well characterized and evidenced in the literature [57], due to the increase in cardiomyocytes in response to aerobic exercise [58]. However, cardiac remodeling in response to aerobic training is dependent to PI3K pathway activation and AKT phosphorylation [59]. Interestingly, short-term, aerobic training (4 weeks) can reprogram cardiac remodeling through AKT activity [60]. Additionally, in both animal and human models, exercise can attenuate the deleterious effects of aging [61, 62].

The role of miRNAs is of fundamental importance in the cardiac remodeling process [55, 63] mainly associated with exercise training [64, 65], due to their participation in left ventricular hypertrophy in aerobic exercise. Also, HIIT protocols show miRNA expression in cardiac hypertrophy [55]. Thus, exercise is an essential factor in identifying miRNA signatures associated with cardiac remodeling. MiRNA-29 targets the collagen gene, which increases with the induction of physical exercise, reducing collagen I and III, resulting in better ventricular function [66]. Also, miRNA-29 reduces collagen fibrosis and attenuates the deleterious effects of cardiovascular disease [67]. Therefore, although miRNAs and genes are closely related to the cardiac remodeling process, other factors are also important, such as proteomics and metabolomics. So many pieces still need to be fitted into this cardiac puzzle.
