In normal cardiac myocytes, oxidation and antioxidation are in a state of balance. A moderate amount of ROS and reactive nitrogen species (RNS) act as redox signaling mediators and play an important role in the physiological functions of cells. However, if the generation of ROS and RNS exceeds the scavenging capacity of the cellular antioxidant system, it can cause damage to cells and tissues, leading to oxidative stress.

As a high-oxygen-consuming organ, heart relies primarily on fatty acid β-oxidation for energy supply under physiological conditions. In severe hypoxic conditions of the myocardium, the energy metabolism of cardiac myocytes shifts from fatty acid β-oxidation to glycolysis to maintain cellular vitality. When the myocardium is hypoxic, mitochondrial oxidative phosphorylation is impaired, leading to reduced ATP production, increased intracellular Ca²⁺ in the mitochondria and decreased antioxidant enzyme activity. If myocardial blood perfusion is not restored in time, it enters an irreversible damage phase characterized by diffuse mitochondrial swelling, cell membrane damage and significant glycogen consumption. However, when ischemic myocardium is reperfused with blood, accumulated fatty acids are fully oxidized, inhibiting the oxidation of glucose. Additionally, a large influx of oxygen into the cells leads to a burst increase in ROS through single-electron reduction reactions, which in turn triggers oxidative stress (17,18). The burst increase in ROS can react with biological macromolecules such as lipids, proteins, nucleic acids, disrupting their structure and function (19). ROS can also cause Na⁺ efflux and Ca²⁺ influx by reversing the Na⁺/Ca²⁺ exchanger, affecting L-type calcium channels, enhancing the activity of ryanodine receptor 2 and inhibiting the activity of sarcoplasmic reticulum Ca²⁺-adenosine triphosphate, thereby promoting intracellular Ca²⁺ overload (20). The increased concentration of ROS and Ca²⁺ can induce the persistent opening of the mitochondrial permeability transition pore (mPTP), increasing mitochondrial membrane permeability, allowing a large number of non-selective molecules and other substances to enter the mitochondria and causing their rupture, ultimately leading to irreversible death of cardiac myocytes, which plays a key role in MIRI (21).

In 1972, Shen (22) observed the accumulation of intracellular Ca²⁺ after brief occlusion and reperfusion of the coronary arteries in dogs and for the first time proposed the concept of calcium overload. Oxidative stress leads to cellular membrane damage, which in turn triggers calcium overload; mitochondrial dysfunction can induce calcium overload within the mitochondria, thereby disrupting the calcium homeostasis within the cell (23). Therefore, calcium overload is considered an intermediate link in the mechanism of MIRI. Ca²⁺ is an intracellular secondary messenger involved in maintaining cellular physiological functions. After a period of hypoxia in cardiac myocytes, anaerobic metabolism within the cell may lead to the accumulation of H⁺, a decrease in intracellular pH and an increase in intracellular Na⁺ levels through the Na⁺/H⁺ exchange (24). Reperfusion rapidly restores extracellular pH, leading to a significant difference in pH between the inside and outside of the cell, causing Na⁺ to flow inward through the Na⁺/H⁺ exchange. Excessive intracellular Na⁺ triggers the reversal of the Na⁺/Ca²⁺ exchanger, resulting in intracellular calcium overload (25).

Although the process of MIRI actually occurs in a sterile environment, the activation of innate and adaptive immune responses leads to the production of a large number of inflammatory cells and can also cause inflammatory reactions in other organs (26,27). Romson (28) found that the reduction in myocardial infarct size in dogs after depleting leukocytes with anti-leukocyte serum was as effective as using a free radical scavenger, indicating that leukocyte infiltration is involved in the process of MIRI and plays a certain role. On the other hand, during I/R, there is damage to the cell membrane, an increase in cell membrane-related degradation products and some of these degradation products have a strong inflammatory chemotactic effect, attracting a large number of leukocytes into the tissue or adsorbing onto the vascular endothelium, resulting in a significant increase in leukocytes in the microcirculation. During the process of ischemia-reperfusion, some protein precursors are activated within the vascular endothelial cells, leading to the release of various intercellular adhesion molecules, causing a massive infiltration of neutrophils. The massive infiltration of neutrophils plugs some capillaries and, when blood perfusion is restored, some or even all of the ischemic tissue still does not receive blood perfusion, which is the main reason for the no-reflow phenomenon in tissues after ischemia-reperfusion. Additionally, polymorphonuclear neutrophils (PMN) are an important source of oxygen free radicals during myocardial ischemia-reperfusion, which can cause peroxidative damage to myocardial cells (29). At the same time, the activation of PMNs can also cause an increase in intracellular Ca²⁺ concentration in myocardial cells and the related enzymes produced promote the degradation of membrane phospholipids, ultimately leading to myocardial cell damage.

Based on previous discussion, increased ROS production plays a key role in the development of MIRI. In the early phase after I/R injury, ROS production is markedly lower in the hearts of exercised mice compared with sedentary mice (47). Mechanistically, exercise induced the endothelial nitric oxidase synthase/NO and protein S-nitrosylation pathway in the mitochondria, leading to reduced mitochondrial ROS production and mPTP activation and thus, conveying cardioprotection against I/R injury (47). On the other hand, MG53, also known as TRIM72, is highly expressed in striated muscle and it has been proved that rhMG53 could preserve mitochondria integrity following oxidative stress, similar to plasma membrane repair, by binding to mitochondrial-specific lipid, cardiolipin for mitochondrial membrane repair using lipid rafts, reducing mitochondrial ROS accumulation and mitophagy (48). Further research needs to discover more particular target involved in exercise-induced protection against MIRI.

Promoting mitochondrial biogenesis, maintaining the balance of mitochondrial fission and fusion in the myocardium, enhancing mitochondrial autophagy activity and regulating energy metabolic disorders play a crucial role in improving mitochondrial quality control impairments in the myocardium following MIRI. mtDNA damage is one of the significant causes of mitochondrial biogenesis impairment in myocardial cells after MIRI. Tao et al (49) found that swimming training can adaptively increase mtDNA replication and transcription, activate the PGC-1α signaling pathway, enhance mitochondrial biogenesis, improve the energy metabolism of myocardial cells and alleviate acute myocardial injury. Similarly, Budiono et al (50) also discovered that compared with the MIRI model group mice, running exercise effectively improved mtDNA replication and transcription in rats, upregulated the expression of silent regulatory protein 3 and PCG-1α and other genes related to mitochondrial biogenesis. In the plasma of healthy athletes, it has also been found that exercise increases mtDNA replication and transcription as well as the activity of the mitochondrial respiratory chain (51).

Another study demonstrated that 8 weeks of aerobic exercise can reduce the size of myocardial infarction and Drp1 levels in rats, thereby inducing the regulation of mitochondrial fission to achieve protection for the heart (52). Similarly, Mishra et al (53) also found in their research that aerobic training can induce a decrease in Bax and Drp1 protein levels in rats and inhibit the activation of caspase-3, thereby improving mitochondrial function and protecting the heart after MIRI. Furthermore, Jiang et al (54) discovered in their study that acute myocardial ischemia leads to adverse mitochondrial network dynamics (high fission and low fusion) and lower mitochondrial respiration levels. Aerobic interval training can promote the expression of mitochondrial fusion proteins such as optic atrophy 1, inhibit the expression of Drp1, improve mitochondrial energy metabolism and promote myocardial remodeling.

Apoptosis of cardiomyocytes following MIRI can be inhibited through exercise (46) and numerous studies have confirmed the role of various types of exercise in suppressing mitochondrial-mediated cell apoptosis after MIRI. Zhang et al (55) found that 8 weeks of aerobic exercise provided protection for the myocardium against ischemia-reperfusion injury, partly by inhibiting myocardial cell apoptosis; Lai et al (56), in their study on swimming exercise, discovered that swimming could reduce the levels of tumor necrosis factor α, inhibit the activation of caspase-3 and enhance the expression of Bcl-2 protein, thereby reducing the number of apoptotic cells in the myocardium and proposed that swimming exercise could serve as an effective method to prevent myocardial injury; additionally, Gao et al (57) identified a lncRNA in the myocardium of mice after swimming training named cardiac physiological hypertrophy-associated regulator (CPhar) and DEAD-Box Helicase 17 (DDX17) is the binding partner of CPhar in regulating CPhar downstream factor activating transcription factor (ATF)7 by sequestering CCAAT/enhancer binding protein beta (C/EBPβ). The expression of ATF7 is negatively regulated by CPhar in the exercised heart. The upregulation of Cphar expression following exercise can reduce the transcriptional activity of the ATF7 and promote the expression of proliferation markers in cardiomyocyte hypertrophy, prevent OGD/R-induced cardiomyocyte apoptosis and improve myocardial injury. However, there is a lack of research on the differential effects of various exercise methods on improving myocardial cell apoptosis in MIRI; and there is also a lack of comparative horizontal research on the dose-response relationship between aerobic exercise and its improving effects on myocardial cell apoptosis. Another study found that the inhibitory effect of resistance exercise on cell apoptosis after MIRI is poor, with no statistical significance in changing the size of infarction and cell apoptosis compared with the control group (58). It is certain that exercise improves MIRI by altering myocardial cell apoptosis and further research is needed in the future regarding the type, intensity and timing of exercise.

Although the process of myocardial ischemia and reperfusion occurs in a sterile environment, there is still infiltration of inflammatory cells in the early stages of MIRI, mainly macrophages, monocytes and neutrophils, which originate from hematopoietic stem and progenitor cells (HSPC) (59,60). Voluntary exercise in mice reduces leptin production in adipose tissue, enhances the quiescence-promoting hematopoietic niche factors in leptin receptor-positive stromal bone marrow cells and decreases hematopoietic activity in mice, without hindering emergency hematopoiesis, thereby reducing the generation of inflammatory white blood cells and providing protection against myocardial damage (61). Another study shows that after running exercise, the upregulation of myonectin in mice leads to the inhibition of the inflammatory response of cultured macrophages to lipopolysaccharide through the S1P/cAMP/Akt-dependent signaling pathway and blocking the S1P-dependent pathway could reverse the infarct size in mice after I/R (62).

Current exercise-based CR programs for patients with MI and post-revascularization patients include aerobic exercise, resistance training and high-intensity interval training (HIIT). This section reviews the current status of these three exercise modalities.

Aerobic exercise remains the cornerstone and essential component of CR. Patients with CHD or MI often exhibit significant reductions in peak oxygen uptake (VO_2peak) (73,74), which is measured during maximal cardiopulmonary exercise testing (CPET) and can be summarized by the Fick Equation (75): VO 2 peak = CO x ( a-vO 2 diff )

Under CPET, VO_2peak reflects the functional reserve of the heart (cardiac output, CO) and skeletal muscles (arteriovenous oxygen difference, a-vO2diff) in meeting metabolic demands under severe physical stress. The decline in VO_2peak is attributed to multiple factors, including reduced sympathetic and parasympathetic tone, leading to blunted heart rate elevation during exercise (76). Impaired left ventricular function during exercise, results in inadequate oxygenated blood delivery to skeletal muscles (77,78). Adverse skeletal muscle adaptations, include decreased muscle mass (79,80), poor capillary-to-myofiber perfusion matching, reduced oxidative capacity (77), diminished a-vO_2diff and impaired adenosine triphosphate (ATP) synthesis (81).

Patients with lower VO_2peak typically present with more risk factors, including advanced age, delayed post-exercise heart rate recovery (indicative of autonomic dysfunction), elevated cardiac stress biomarkers (for example, N-terminal pro-B-type natriuretic peptide), systemic inflammation (for example, hs-CRP), higher non-fasting glucose levels, severe atherosclerosis and lower hemoglobin/hematocrit levels (82). These individuals also face higher risks of mortality and disability.

In 1995, Vanhees et al (83) demonstrated that a 1% improvement in VO_2peak through exercise-based CR in patients with CHD was associated with a 2% reduction in 5-year mortality. Evidence suggests that a sustained VO_2peak improvement of ≥3.5 ml·kg⁻¹·min⁻¹ over one year reduces mortality by 25% (84). Exercise-based CR can increase VO_2peak by 5.4 ml·kg⁻¹·min⁻¹ (95%CI: 4.2-6.6 ml·kg⁻¹·min⁻¹) (85), indicating that long-term adherence to prescribed exercise regimens improves survival and quality of life (QoL). The results of a randomized controlled trial involving 69 patients with coronary artery disease (CAD) conducted by Gonçalves et al (86) showed that compared with the control group, patients who underwent 6-week moderate-intensity continuous training (MICT) had a 9% increase in VO_2peak, significant increases in the peak torque of knee extensors and flexors and in addition, significant decreases in waist circumference, body fat percentage and abdominal fat percentage. This is of great significance for reducing cardiovascular risks. However, another study reports no statistically significant differences in VO_2peak between supervised exercise groups and controls after 8 weeks of CR in patients with CHD (87). These discrepancies may stem from limited sample sizes or variations in exercise intensity protocols, necessitating further validation of findings.

Existing evidence suggests that HIIT is non-inferior to, or even superior to, MICT-based aerobic exercise prescriptions in improving VO_2peak (88). Dun et al (89) reviewed randomized controlled trials (2013-2018) comparing HIIT and MICT in elderly patients with CHD. Their findings indicate that both MICT and HIIT improve VO_2peak, respiratory efficiency (that is, VE/VCO₂ slope), oxygen uptake efficiency slope, QoL, HR recovery and submaximal HR during cardiopulmonary exercise testing. Keteyian et al (88) observed that both long-interval HIIT and MICT increased resting HR, systolic blood pressure and VO_2peak in elderly patients with CHD, with greater improvements in the HIIT group. These results align with those of Kim et al (90), who demonstrated that 6 weeks of HIIT led to larger increases in post-rehabilitation VO_2peak and HR recovery compared with MICT in patients with cardiovascular disease (CVD) undergoing CR.

Two critical factors for HIIT in CR settings are intensity and interval design. For patients with CVD, HIIT is defined as 'near-maximal' effort, typically performed at intensities ≥80% of peak HR (commonly 85-95% of peak HR) or below VO_2peak (89). While such intensity may resemble daily activity challenges for decompensated patients, defining exercise intensity based on VO_2peak or peak HR faces limitations. First of all, tests to determine VO_2peak or peak HR are frequently terminated prematurely due to patient-related factors such as hypertension, anxiety, or episodes of muscle weakness, compromising measurement accuracy (91,92). Second, for patients with left main coronary stenosis or moderate-to-severe aortic stenosis, even after therapeutic interventions, submaximal VO_2peak testing remains risky (91,92). Third, Post-revascularization patients with CHD often continue heart rate-modulating medications (for example, β-blockers), which attenuate HR responses at rest and during exercise, potentially lowering recorded HR and VO_2peak during stress testing (93).

To address these limitations, researchers propose hybrid subjective-objective intensity monitoring. Commonly used subjective assessments include: Borg Rating of Perceived Exertion (RPE) (6-20 scale) and Dyspnea on Exertion (0-10 scale) (94-96).

Specifically, the protocol prescribes high-intensity intervals at an exercise intensity between 85 and 95% peak HR and RPE between 15 and 17 (Borg) and low-intensity intervals at 50 to 75% peak HR and RPE between12 and 14 (Borg). Interval duration and alternation patterns of high and low intensity are customized based on these parameters to optimize efficacy and safety (89).

The duration and ratio of high-intensity and low-intensity intervals are key parameters that differentiate HIIT from MICT and contribute to the HIIT-enhanced physiologic response and health benefits (97,98). Long-interval HIIT is the most widely used protocol for older patients with CHD and this may include four sets of high-intensity intervals, each lasting 4 min interspersed with three sets of low-intensity intervals, each lasting 3 min (99-101). Medium-interval HIITs, such as 8×2 min high-intensity intervals interspersed with 7×2 min low-intensity intervals, have also been used, albeit to a lesser extent, in older patients with CHD (102). For older patients with HF with reduced ejection fraction (HFrEF, NYHA II-III), medium- and short-interval protocols have been used such as 10×1 min high-intensity intervals interspersed with 9×2 min low-intensity intervals (103-105). All three protocols are safe and contribute to significant improvements in VO_2peak and QoL (90,101,106).

The safety of HIIT for clinical populations is an important topic, especially for older patients with CVD in whom the potential for adverse events is increased (107). Notably, HIIT protocols for clinical populations are modified to involve lower relative intensities (typically 85-95% of peak HR) compared with athletic training regimens. Overall, adverse event rates during HIIT in patients with CVD are relatively low.

Rognmo et al (106) examined the risk of cardiovascular events during HIIT and MICT among 4,846 patients with CR with CVD (mean age; 58 years). These investigators report only one fatal cardiac arrest during MICT and two nonfatal cardiac arrests during HIIT. The SMARTEX-HF study (105) demonstrated no differences between the HIIT and MICT groups in terms of total number of serious adverse events during the 12-week intervention and follow-up period (from weeks 13-52) in older patients with HFrEF. However, it remains imperative to conduct pre-exercise risk assessments, identify relative and absolute contraindications to exercise initiation or continuation and incorporate special considerations for elderly patients with CVD who may present with aging-related comorbidities such as frailty, sarcopenia, balance impairments, cognitive decline and polypharmacy (108).

Resistance exercise provides superior stimulation for skeletal muscle hypertrophy and strength gains compared with aerobic exercise. In patients with CVD, iron deficiency (common in this population) exacerbates metabolic acidosis during activity and impairs skeletal muscle mitochondrial oxidative capacity, both of which contribute to myopathy (109). Mitochondrial dysfunction, frequently reported in CVD, is linked to myocyte dysfunction and reduced vitality (110). Concurrently, oxidative stress and systemic low-grade inflammation in patients with CHD disrupt protein turnover, further hindering immune responses (111). These pathophysiological processes synergize with disuse atrophy secondary to prolonged bed rest post-revascularization [particularly after coronary artery bypass grafting (CABG)], accelerating skeletal muscle functional decline (112). A review highlights a positive correlation between muscle atrophy, dynapenia (age-related muscle weakness) and increased CVD-related mortality risk, alongside substantial negative effects on QoL (113). Collectively, these findings underscore the growing recognition of resistance training's critical role in CVD management.

Aerobic exercise demonstrates superior efficacy in improving VO_2peak compared with resistance exercise alone (114,115). However, resistance exercise itself modestly enhances VO_2peak, prompting interest in whether combined training yields additive benefits. In addition, a study on patients scheduled to undergo CABG showed that resistance training targeting the major muscle groups of the upper and lower limbs using cuff weights/dumbbells before CABG resulted in significant improvements in the 6-min walk test (6MWT), New York Heart Association (NYHA) functional classification and clinical frailty scale. These findings not only confirm the benefits of resistance training for patients with CAD but also enrich the development of perioperative rehabilitation training strategies for CABG, which is undoubtedly beneficial for improving patient prognosis (116).

A meta-analysis of 23 studies in patients with CHD revealed that combined training outperforms aerobic-only regimens in improving VO_2peak, muscle strength and peak work capacity. Notably, resistance exercise alone showed no significant difference from combined training in VO_2peak or strength gains, but the quality of evidence was low and very low and should therefore be interpreted with caution (117). On the other hand, assessments of flow-mediated dilation revealed that both resistance exercise and combined training improved vascular endothelial function (118).

In terms of QoL, combined training demonstrated superior efficacy over aerobic-only regimens in enhancing the emotional component of QoL among patients with CHD (119). A critical factor underlying these observed QoL improvements in resistance exercise participants appears to be increased self-efficacy, defined as the patient's perceived capacity to perform daily activities (120,121). This effect is particularly pronounced in women, who reported greater post-intervention gains in self-efficacy for stair climbing, weight lifting and walking following combined training compared with aerobic-only programs (122).