*1.6 Cardiovascular System and Exercise*

The interplay between the cardiovascular system and exercise basically depends on the type of exercise (aerobic, resistance) performed, the exercise intensity and duration, and muscle mass involvement [27]. The most striking neurohormonal response to regular physical activity is improved cardiac parasympathetic regulation. It has been demonstrated that the heart rate values of very well-trained individuals can reach as low as 30–35 beats per minute [28].

Regular high-intensity exercise training may result in cardiac morphological adaptation, called athlete's heart—i.e., myocardial hypertrophy, which is more eccentric in patients who perform endurance training and more concentric in patients who perform resistance training [29]. It has been demonstrated that the mean left ventricular end-diastolic diameter in athletes increases compared with that in normal subjects, with typical values equal to 53.7 mm and 49.6 mm, respectively [30]. Morphological changes in the left ventricle after regular exercise have also been validated in patients with chronic heart failure. Hambrecht demonstrated reverse left ventricular remodeling with the slight improvement of the left ventricular ejection

fraction from 30% to 35% after aerobic training in patients with ischemic and dilated cardiomyopathy. It has been postulated that reverse remodeling is evoked by the peripheral effects of aerobic training—i.e., improved antioxidative protection in the skeletal muscle, enhanced parasympathetic tone, and improved vasodilation [31]. To date, aerobic training has also been found to improve left ventricular diastolic filling at rest and during exercise [32]. Increases in the cross-sectional area of the coronary arteries and in coronary collateral formation have been demonstrated in animal models due to the use of a regular training program [33]. A growing body of evidence indicates that regular endurance exercise reduces the risk of death during clinical ischemia-reperfusion injury due to it offering enhanced antioxidative protection [34]. Another postulated cardioprotective effect of regular exercise is the improved electrical stability of the heart, which has been demonstrated in animal models [35,36].

Hemodynamic adaptations to exercise include increases in stroke volume. The resting stroke volume of individuals who exercise regularly may reach 100 mL due to prolonged diastolic filling period. During submaximal exercises, stroke volume increases by 20–40 mL and may reach as high as 160 mL during maximal exertion [37]. The impacts of aerobic and resistance exercise on blood pressure have been the subject of debate in the past due to safety concerns. Exercise has been shown to reduce blood pressure in both normotensive and hypertensive individuals [38]. The beneficial effect of regular exercise on plasma glucose and triglycerides has been well established [39–45]. Table 3 shows the main effects of regular exercise on the cardiovascular, neurohumoral, and other systems.


**Table 3.** Effects of regular exercise.

### *1.7. Exercise-Induced Preconditioning*

### 1.7.1. Ischemia-Reperfusion Injury (IRI)

### Definition

Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide [46]. Reperfusion procedures that involve restoring the blood flow to the ischemic region as quickly as possible are the chief therapeutic goal of AMI [47]. The primary pathological cause of AMI is paradoxical cardiomyocyte dysfunction, known as ischemia-reperfusion injury (IRI) [48]. Ischemia-reperfusion injury (IRI) is defined as the paradoxical exacerbation of cellular dysfunction and death following the restoration of blood flow to previously ischemic tissues [49].

### Severity Levels of IR-Induced Cardiac Injury

The three different severity levels of IR-induced cardiac injury are proportional to the duration of ischemia. The lowest level of injury is cardiac arrhythmias followed by rapid reperfusion after one to five minutes of ischemia without impaired myocardial contractile performance or cardiac cell death. The second level of injury is five to 20 min of ischemia-reperfusion, termed as myocardial stunning, characterized by ventricular contraction deficits that last 24–72 h following the insult without cardiac cell death. The third and most severe IR injury level is myocardial cell death, which occurs when the duration of ischemia exceeds 20 min. During this IR injury level, cardiac myocytes are irreversibly damaged, and death occurs due to apoptosis and necrosis processes that take place within ventricular myocytes [48].

### 1.7.2. Ischemic Preconditioning

### Definition

Ischemic preconditioning refers to the protection of the ischemic myocardium by short periods of sublethal ischemia separated by short bursts of reperfusion delivered before the ischemic insult [50]. It provides the myocardium with a powerful means of protection against acute myocardial ischemia and makes it more resistant to a subsequent ischemic insult. In addition, reconditioning protects against postischemic contractile dysfunction and ischemia- and reperfusion-induced ventricular arrhythmias. Ischemic preconditioning has two phases of protection. The early phase develops within minutes of the initial ischemic insult and lasts 2 to 3 h. The late phase becomes apparent 12 to 24 h later and lasts 3 to 4 days [51].

### Experimental Models

Ischemic preconditioning has been demonstrated in several animal species, as well as in isolated human cardiomyocytes [50]. This term was introduced in 1986 by Murry et al., who investigated this phenomenon on an open-chest canine. An experimental dog group was exposed to four consecutive periods of ischemic episodes (5 min coronary occlusions interspersed with 5 min reperfusion periods) then subjected to a prolonged, more severe ischemic insult (a 40 min coronary occlusion followed by four days of reperfusion). The control dogs group underwent the 40 min occlusion with no prior exposure to ischemia. Surprisingly, the experimental dogs showed markedly reduced infarct size (75%) compared to the controls, and this effect was independent of differences in coronary collateral blood flow [52].

### Remote Ischemic Conditioning (RIC)

It has been well established that preconditioning protection does not require brief ischemia to be applied directly to the myocardium itself. Remote ischemic conditioning was originally observed as a laboratory curiosity in non-invasive cardioprotective therapy, wherein brief bouts of ischemia-reperfusion in one coronary vascular region reduced the infarct size resulting from the sustained occlusion and reperfusion of an adjacent coronary artery. Moreover, studies have shown that RIC is a systemic phenomenon and can be evoked from longer distances [53]. For example, local insult induced by ischemia-reperfusion in the extremities or other parenchymal organs can elicit protection in the heart (in which the infarct size is reduced).

RIC can be achieved by inflating a standard sphygmomanometer cuff placed on the upper arm above systolic pressure to restrict blood flow temporarily by utilizing four cycles of five minutes of cuff inflation interspersed by five minutes of complete cuff deflation. More recently, an automated RIC device was created with the intention of providing RIC to adult patients undergoing cardiothoracic surgery or procedures [54]. In addition, RIC is an essential mechanical intervention to induce cardio protection accompanying reperfusion in patients with AMI because this method is non-invasive and can be applied during coronary occlusion before primary PCI.

### 1.7.3. Exercise Promotes Preconditioning

It has been well established that exercise and elevated physical activity have beneficial effects in reducing CVD risk and providing protection from cardiovascular events. Exercise displays a strong correlation with decreased risk of myocardial infarction (MI) and limits the damage caused by ischemia and reperfusion if such an MI event occurs [48]. Like the ischemic preconditioning phenomenon, the protection provided by exercise appears to occur in a biphasic manner, with two separate phases of protection, beginning immediately after a single episode of exertion and continuing for multiple days. The first phase begins immediately following the acute exercise bout and quickly subsides within three hours of preconditioning. Then, after approximately 24 h, the second phase of protection begins, persisting for at least nine days and potentially extending to several weeks. This phase has been reported to be more robust than the first phase [55]. The mechanisms contributing to exercise-induced preconditioning include the activation of mitochondrial antioxidant enzyme superoxide dismutase (SOD2) in ventricular myocytes and the increased expression of mitochondrial potassium channels [48]. The mechanisms and underlying causes of the warm-up phenomenon were investigated by Tomal et al. in 1996 [50]. In this study, patients with coronary artery disease underwent two consecutive exercise tests (ET), followed by a third test two hours later. The rate–pressure product before the onset of ischemia decreased during the third ET (*p* < 0.005) by more than during the first and second ET. In addition, the time to both 1–5 mm ST-segment depression and anginal pain onset was higher during the second and third ET (*p* < 0.001, respectively). Thus, this study suggested that the warm-up angina phenomenon observed within minutes of a first ET results from adaptation to ischemia through improvements to myocardial perfusion or preconditioning, increasing both the time to ischemia and the ischemic threshold. In contrast, the warm-up angina phenomenon observed two hours after repeated ET results from a slower increase in cardiac workload, causing an increase in time to ischemia but not in the ischemic threshold.

Training below the level of the ischemia threshold will not place sufficient ischemic stress on the myocardium to induce exercise IPC. One study compared the effects of an 8-week interval training program carried out in two groups of patients with stable angina by assessing the influence of warm-up ischemia prior to training conducted either at or below the ischemic threshold. One group underwent pre-training exercise IPC and the other group did not. The exercise IPC group showed a statistically significant improvement in all post-training variables except for maximum ST depression (STD). The improved variables included maximal workload (28%), walking distance (24%), exercise duration (20%), and time to 1 mm STD (28%). Moreover, the beneficial effect of training in the exercise IPC group on both exercise-induced ischemia and physical capacity was sustained for up to 10 days and 1 month, respectively [56]. Thus, based on the results of Korzeniowska-Kubacka et al., the warm-up effect of exercise IPC may have a major beneficial effect and appears to be necessary for exercise training in cardiac rehabilitation. Thus, cardioprotective strategies that have been used in clinical studies for acute myocardial infarction entail early and late ischemic preconditioning evoked by brief episodes of coronary occlusion–reperfusion, postconditioning (cycles of re-occlusion–reperfusion are

delivered after an ischemic index event), the remote ischemic conditioning of a limb (using arm cuff inflation–deflation cycles), and pharmacological cardio protection (achieved by the intracoronary delivery of adenosine or nitrates and the intravenous delivery of beta-blocker or cyclosporine A just before or at early reperfusion).
