Exercise training for myocardial ischemia reperfusion injury: Mechanism and clinical practice (Review)

Introduction

Coronary heart disease (CHD) remains a major cause of mortality and morbidity worldwide (1). The most common form of CHD is myocardial infraction (MI). MI remains a substantial impression on global health, affecting >7 million individuals worldwide each year. Concordantly, its economic impact is enormous. In 2010, >1.1 million US hospitalizations were a result of MI, with estimated direct costs of at least US$450 billion (2).

The most important therapy for patients suffered by acute myocardial infraction (AMI) remains reperfusion. Over the past few decades, advances in pharmacological, catheter-based and surgical reperfusion have improved outcomes for patients with AMI. However, the reperfusion could also lead to further myocardial injury and dysfunction which is known as myocardial ischemia reperfusion injury (MIRI). MIRI alters homeostatic processes and also influences left ventricular remodeling after ST-segment elevation myocardial infarction (STEMI), increasing the risk of arrhythmias and potentially leading to heart failure.

Exercise training can exert beneficial effects for cardiovascular health on multiple aspects, including reducing cardiovascular risk factors and cardiovascular events (3-4), promoting physiological cardiac hypertrophy (5-8) and inducing vascular (9-11), cardiometabolic (12,13) and systemic adaptations (14,15). On the other hand, the benefits to MI and MIRI of exercise training have been proved in recent years. The present review focused on these basic researches and clinical practices, summarized the current situation of exercise-based cardiac rehabilitation (CR), investigated the mechanisms of exercise improving MIRI and attempted develop novel therapeutic targets and strategies for CHD.

Pathological mechanisms of MIRI

In 1960, Jennings defined ischemia/reperfusion (I/R) injury as damage to the heart tissue caused by blood flow restored during restoration (16). A number of pathophysiological processes including ion accumulation, mitochondrial membrane damage, the formation of reactive oxygen species (ROS), disturbances in nitric oxide (NO) metabolism, endothelial dysfunction, platelet aggregation, immune activation, apoptosis and autophagy are developing in I/R injury (1) (Fig. 1).

Figure 1 Pathological mechanisms of MIRI. (A) Oxidative Stress; (B) Calcium Overload; (C) Energy Metabolism Disorder; (D) Inflammation; (E) Mitochondrial Dysfunction; (F) MQC Disorder. MIRI, myocardial ischemia reperfusion injury; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; IMS, intermembrane space; NADH, nicotinamide adenine dinucleotide, FADH2, flavine adenine dinucleotide, reduced; UQ, ubiquinone; Cyt c, cytochrome c; mPTP, mitochondrial permeability transition pore; ROS, reactive oxygen species; ADP, adenosine diphosphate; ATP, adenosine triphosphate; Na+, sodium ion; Ca2+, calcium ion; H+, hydrogen ion; NHE, sodium-hydrogen exchanger; NCX, sodium-calcium exchanger; TCA, tricarboxylic acid cycle; DAMPs, damage-associated molecular patterns; IL-1α, interleukin-1 α; mtDNA, mitochondrial DNA; TLR, Toll-like receptor; NF-κB, nuclear factor κ B.

Oxidative stress

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).

Calcium overload

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).

Inflammation

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.

Mitochondrial dysfunction

Increased mitochondrial oxidative stress

Mitochondria are key determinants of cell life and death. Under normal physiological conditions, mitochondria can promptly eliminate bio-oxidative damage caused by the accumulation of excessive ROS. Research has found that when blood flow is restored after ischemia, a large influx of oxygen can exacerbate the generation of ROS, damaging mitochondrial DNA (mtDNA), proteins, lipids and affecting the normal function of the electron transport chain (ETC) within the mitochondria, ultimately leading to mitochondrial dysfunction (30). Therefore, repairing mtDNA can enhance mitochondrial antioxidant function, reduce the area of myocardial infarction and improve cardiac function (31). Additionally, Chen et al (32) discovered that reversible blockade of the electron transport chain at complex I during ischemia can protect the ETC and reduce mitochondrial and cardiac damage.

Mitochondrial dysfunction induced hyperapoptosis

Apoptosis is an inevitable outcome following MIRI, with mitochondria playing a crucial role in myocardial cell apoptosis (33) and changes in mitochondrial membrane permeability being a primary factor (34). After MIRI, the mitochondrial membrane potential becomes unbalanced, inducing the opening of the mPTP. The sustained opening of mPTP leads to the release of cytochrome c from the mitochondria into the cytoplasm, where it forms an apoptosome with the apoptotic protease activating factor-1 (Apaf-1) and the procaspase-9, a precursor of cysteine protease 9. With the assistance of deoxyadenosine triphosphate, caspase-9 is activated, initiating the downstream caspase-3 apoptotic cascade, thereby activating the mitochondrial apoptosis pathway and further exacerbating MIRI (35). Therefore, timely clearance of damaged mitochondria and inhibition of mPTP opening are of significant importance for reducing apoptosis in reperfused myocardial cells and alleviating myocardial injury following reperfusion therapy (36).

Impaired mitochondrial quality control

Mitochondria can maintain the normal functioning of their physiological functions through self-repair mechanisms such as fusion/fission and mitophagy, which are collectively referred to as 'mitochondrial quality control'. Regulating the mitochondrial quality control system can correct mitochondrial metabolic disorders and reduce MIRI. Myocardial ischemia-reperfusion leads to a decrease in mitochondrial fusion proteins 1/2 (Mitofusin1/2, Mfn1/2) and during myocardial ischemia and the onset of reperfusion, inhibiting mitochondrial dysfunction and dynamic imbalance can protect the heart, effectively reducing infarct size and improving cardiac function (37). Bai et al (36) demonstrated that the administration of melatonin during reperfusion can alleviate A/R injury by inhibiting excessive mitochondrial autophagy through the SIRT3/SOD2 signaling pathway. Therefore, regulating the 'normalization' of mitochondrial autophagy levels in MIRI is of significant importance for the recovery of the disease course.

Disturbance in energy metabolism

When myocardial cells are deprived of oxygen and oxygenated hemoglobin is consumed to a certain extent, changes occur in energy metabolism, shifting from aerobic oxidation to glycolysis as the primary source of energy. The ATP produced by glycolysis gradually becomes the only source of energy to maintain the survival of myocardial cells (38). The enhancement of glycolysis leads to an increase in intracellular lactate levels. As ischemia prolongs, metabolic products such as lactate accumulate within the cells, causing acidosis. Relevant studies have found that after 10 min of ischemia, the intracellular pH value of myocardial cells can drop to 5.8-6.0 (39). Intracellular acidosis inhibits phosphofructokinase in the glycolytic process, suppressing the glycolytic pathway and exacerbating the body's energy supply deficiency. When ischemic tissue is reperfused, the inhibitory effect on the glycolytic pathway is reduced, leading to further acidosis. On the other hand, the structure and function of mitochondria are severely damaged by ischemia. Although aerobic reperfusion is restored, mitochondria cannot effectively perform aerobic oxidation to produce energy, resulting in a significant period after reperfusion where energy sources still mainly rely on glycolysis. Experiments have shown that the acceleration of glycolysis remains active even in the early stages of myocardial reperfusion and for several days afterward, indicating that glycolysis is an important source of energy for the heart during reperfusion (40). However, the ATP produced by glycolysis is far from meeting the needs of myocardial cells. Other studies have found that after myocardial ischemia-reperfusion, the metabolism of fatty acid oxidation is enhanced, which instead of promoting the recovery of cardiac function, delays it (41). An increase in fatty acid oxidation during ischemia-reperfusion inhibits glucose oxidation and phosphorylation. Although more ATP is produced, oxygen consumption also increases, which ultimately has a detrimental effect on myocardial cells, leading to increased damage (42). Additionally, reports have shown that myocardial energy metabolism disorders are prone to induce arrhythmias and cause electrophysiological changes in myocardial cells (43). It is evident that energy metabolism disorders are another significant factor causing I/R injury.

Molecular and cellular mechanisms underlying exercise benefits in MIRI

Numerous studies have provided evidence supporting that exercise training is an effective intervention which reduces MIRI (44-46). The protective effect of exercise against MIRI is shown to be closely related to exercise-enhanced myocardial antioxidant capacity, amelioration of mitochondrial dysfunction, apoptosis and inflammation caused by MIRI (Fig. 2).

Figure 2 The key mechanisms by which exercise ameliorates MIRI. (A) Exercise induced the eNOS/NO and protein S-NO pathway in the mitochondria, leading to reduced mitochondrial ROS production and mPTP activation and thus conveying cardioprotection against I/R injury. (B) AKT-mediated HKII-mitochondrial interaction due to exercise protects mitochondria by inhibiting mitochondrial apoptotic cascades and contributes to the increased cardioprotection against MIRI. (C) Exercise-induced CPhar elevation could prevent MIRI and cardiac dysfunction. Mechanically, CPhar can act as binding partner of DDX17 to inhibit the expression of downstream molecule ATF7 through sequestering C/EBPβ. (D) Voluntary exercise reduced leptin production in adipose tissue, enhanced the quiescence-promoting hematopoietic niche factors in leptin receptor-positive stromal bone marrow cells and decreased hematopoietic activity, reducing the generation of inflammatory white blood cells and providing protection against myocardial damage. MIRI, myocardial ischemia reperfusion injury; eNOS, endothelial nitric oxidase synthases; NO, nitric oxide; S-NO, S-nitrosylation; ROS, reactive oxygen species; mPTP, mitochondrial permeability transition pore; I/R, ischemia/reperfusion; AKT, protein kinase B; HKII, Hexokinase II; CPhar, Cardiac Physiological Hypertrophy-Associated Regulator; ATF7, activating transcription factor 7; Ca2+, calcium ion; TCA, tricarboxylic acid cycle; VDAC, voltage dependent anion channel; DRP, dynamin-related protein; BAX, BCL2-Associated X; P, phosphorylation; DDX17, DEAD-Box Helicase 17; C/EBPβ, CCAAT/enhancer binding protein beta; CXCL12, C-X-C Motif Chemokine Ligand 12; CVD, cardiovascular disease.

Exercise reduce myocardial oxidative stress caused by MIRI

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.

Exercise ameliorate mitochondrial dysfunction

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.

Exercise mitigates apoptosis in cardiomyocytes

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.

Exercise reduces inflammation

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).

Exercise in clinical practice for myocardial infarction and myocardial I/R injury

The role of exercise in improving symptoms and prognosis in cardiac patients has long been documented (63). However, until the 1930s-1940s, patients with MI or angina were largely advised to avoid physical exertion to prevent cardiac rupture and hypoxemia (64,65). In 1952, Levine and Lown (66) reported that armchair exercises were safe and beneficial for hospitalized patients with MI during recovery. Wenger (67) later introduced a progressive physical activity protocol initiated in intensive care units. Despite early criticism over safety concerns, Hellerstein and Ford's (68) expansion of CR to outpatient settings marked a significant milestone in the field.

To date, growing evidence supports the benefits of exercise in improving cardiac function and prognosis following CHD or MI reperfusion therapy. A meta-analysis encompassing 10 randomized controlled trials with 1,274 patients demonstrated that combining exercise with percutaneous coronary intervention (PCI) was associated with reduced risks of cardiac death, MI, coronary angioplasty, angina and restenosis compared with PCI alone (69). The exercise group also showed significant improvements in left ventricular ejection fraction over the non-exercise group. Furthermore, exercise rehabilitation reduces levels of high-sensitivity C-reactive protein (hs-CRP) and inflammatory cytokines (for example, TNF-α and IL-6) in post-PCI patients with CHD (70). Rehabilitation exercise enhances autonomic nervous function, increases maximal oxygen uptake capacity in muscles, reduces myocardial oxidative stress, prevents abnormal degradation of extracellular matrix collagen and fibrosis and improves ventricular remodeling and cardiac pumping function (71,72). Through these mechanisms, exercise markedly improves cardiac function and reduces the incidence of major adverse cardiac events in PCI-treated patients with CHD. These findings have greatly advanced the implementation and adoption of exercise-based CR in clinical practice.

Types of exercises

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

Aerobic exercise remains the cornerstone and essential component of CR. Patients with CHD or MI often exhibit significant reductions in peak oxygen uptake (VO2peak) (73,74), which is measured during maximal cardiopulmonary exercise testing (CPET) and can be summarized by the Fick Equation (75):

Under CPET, VO2peak 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 VO2peak 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-vO2diff and impaired adenosine triphosphate (ATP) synthesis (81).

Patients with lower VO2peak 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 VO2peak through exercise-based CR in patients with CHD was associated with a 2% reduction in 5-year mortality. Evidence suggests that a sustained VO2peak improvement of ≥3.5 ml·kg−¹·min−¹ over one year reduces mortality by 25% (84). Exercise-based CR can increase VO2peak 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 VO2peak, 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 VO2peak 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.

HIIT

Existing evidence suggests that HIIT is non-inferior to, or even superior to, MICT-based aerobic exercise prescriptions in improving VO2peak (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 VO2peak, 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 VO2peak 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 VO2peak 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 VO2peak (89). While such intensity may resemble daily activity challenges for decompensated patients, defining exercise intensity based on VO2peak or peak HR faces limitations. First of all, tests to determine VO2peak 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 VO2peak 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 VO2peak 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 VO2peak 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

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 VO2peak compared with resistance exercise alone (114,115). However, resistance exercise itself modestly enhances VO2peak, 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 VO2peak, muscle strength and peak work capacity. Notably, resistance exercise alone showed no significant difference from combined training in VO2peak 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).

The current problems and probable solution

Low participation of CR

Although a number of researches have proved that all of the three types of exercise benefit patients with CHD and a 2020 report indicating increased enrollment in exercise-based CR programs among patients post-PCI and post-CABG, overall participation rates remain suboptimal (123). A retrospective analysis (124) demonstrated the efficacy of CR in reducing two-year mortality post-CABG; however, only 60% of eligible patients enrolled and a mere 12% completed all 36 prescribed sessions. The most pronounced gaps occur among women, elderly patients, ethnic minorities, socioeconomically disadvantaged individuals and those residing in regions with limited CR program access (123,125). Interventions such as automated referral systems and patient navigators have shown promise, boosting CR participation from 30-74% (126-128).

A sufficient number of CR-capable clinics and institutes is fundamental to the effective functioning of referral systems. However, current infrastructure falls short of meeting the annual influx of revascularization patients (124,129). Furthermore, medically frail individuals or those residing in geographically remote areas face potential risks (such as compromised safety during travel and diminished motivation) when attempting to access center-based CR programs (121).

Home-based CR and digital technologies in CR

To address these challenges, home-based CR has emerged as a critical future direction in CR delivery. Patients receive structured exercise prescriptions with real-time guidance via smartphones and wearable fitness trackers (for example, Fitbit and Garmin). Biometric data (for example, HR, activity duration and caloric expenditure) are securely shared with clinicians and CR specialists to refine therapeutic interventions (Fig. 3). Additionally, education relating to behavioral determinants and interventions can be implemented with app-based approaches, setting goals for patients to achieve while completing educational aspects of CR. Digital CR would also enable patients to design their own activity schedules. Several existing technologies could even upgrade the next iteration of CR. Smartwatch sensors already track heart rate, activity and oxygen saturation and electrocardiogram (ECG) data can be used by physicians to monitor remote CR. Smartwatch ECG technology could potentially provide monitoring during exercise, thereby adding data not collected currently in traditional CR (130).

Figure 3 Digital technologies in home-based CR. CR, cardiac rehabilitation; HIIT, high-intensity interval training; HR, heart rate; AI, artificial intelligence.

A recent observational study comparing home-based CR with center-based programs, which involved a diverse population in southern California, showed similar rates of attainment of secondary prevention targets and lower 12-month hospital readmission rates among groups of patients who participated in home-based programs (131). Another multicenter randomized controlled trial on home-based cardiac rehabilitation included 179 patients, including those with acute coronary syndrome and coronary revascularization. The results showed that the VO2peak of patients who participated in home-based CR at 6 months was markedly improved compared with the control group [1.6 (95%CI: 0.9-2.4) ml/kg−1/min−1 vs. +0.2 (95%CI: −0.4 to 0.8) ml/kg−1/min−1] (132). A Veterans Administration observational study comparing participation in a home-based program with no participation in CR showed that mortality was 36% lower among patients who chose home-based CR than among those who chose not to participate in CR. Initiation of CR also appears to be higher for home-based CR than for center-based programs (43 vs. 13%) (133). These research findings have confirmed the effectiveness of home-based cardiac rehabilitation. Future studies should probably place greater emphasis on the in-depth integration of artificial intelligence and home-based CR, develop and design algorithms and systems that can formulate rehabilitation strategies more accurately, efficiently and individually based on a large amount of clinical data. Undoubtedly, this will be a good thing for patients.

Prospective and conclusion

The present review synthesized current knowledge on the underlying mechanisms and clinical applications of exercise in mitigating MIRI. In summary, current research on the mechanisms involves multiple aspects and has demonstrated the efficacy of exercise in ameliorating MIRI. However, most studies focus on exercise preconditioning, where exercise is performed prior to establishing animal models of MI or MIRI. In contrast, studies that more closely align with clinical reality, that is, initiating exercise after establishing MIRI models, remain limited. Furthermore, CR programs typically incorporate mixed exercise modalities, including aerobic exercise, resistance training and HIIT. Previous research has predominantly emphasized aerobic exercises such as swimming and running, with fewer investigations exploring combinations with other exercise types. Lastly, advancements in technology have enabled the application of multi-omics approaches to investigate mechanisms from transcriptional, translational and metabolic perspectives. These methodologies are critical for elucidating how post-MIRI exercise reduces infarct size and improves ventricular remodeling. With increased participation from researchers and greater funding support, it is considered that the mechanisms underlying exercise-induced improvements in MIRI will be further revealed and comprehensively elucidated.

Robust clinical evidence supports the efficacy of CR in enhancing cardiac function and QoL for CHD patient's post-revascularization. However, the precise mechanisms by which exercise confers cardioprotection remain incompletely elucidated, which needs basic researches to reveal mechanisms. The integration between clinical practice and basic research must be strengthened. This requires the clinical translation of basic research findings, which remains a pivotal focus for future endeavors in advancing evidence-based CR.

Availability of data and materials

Not applicable.

Authors' contributions

JG was responsible for conceptualization, writing the original draft and visualization. LL, YD, SZ, ZZ were responsible for literature collection and curation. DL, JM were responsible for supervision, writing, reviewing and editing. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Funding

The present review was supported by a grant from the National Natural Science Foundation of China (grant no. 82372191).

References