1. INTRODUCTION

Cardiovascular disease is a leading cause of death worldwide.1–4 Acute myocardial infarction (AMI) occurs when a plaque in a coronary artery ruptures or erodes, causing a blood clot that blocks the artery, leading to reduced blood flow to myocardial cells. This is believed to be a dangerous situation that may lead to death.5–7 Swift detection and medical intervention are vital to restore blood flow and minimize damage. Troponin and creatine kinase are current biomarkers for AMI diagnosis, whereas percutaneous coronary intervention (PCI) is the common approach, alongside drug therapies.2–4,8–16 The AMI-related in-hospital mortality rate has decreased remarkably, but overall improvement in patient outcomes still requires further effort.10,17 Novel biomarkers are being explored with the aim of achieving earlier and more accurate diagnosis of AMI.11,18,19 Hypothermia therapy is considered to have potential benefits in reducing reperfusion injury by reducing the energy demand of myocardial cells.20–24 Supersaturated oxygen (SSO2) therapy shows potential for improving oxygenation and minimize infarction size.25–29 Inflammation targeting methods after AMI have promising results in animal trials, and a randomized controlled trial (RCT) the Colchicine cardiovascular outcomes trial (the COLCOT trial) has demonstrated the beneficial effects of colchicine.30–37 Targeting angiogenesis, using stem cells, biomaterials, and gene therapy, holds promise for regenerating myocardial tissue.38 Stem cell therapy enables the regeneration of necrotic myocardial tissue by using stem cells. Two primary categories are pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), and adult stem cells, including mesenchymal stem cells (MSCs), skeletal muscle myoblast cardiac stem cells (SkMCs), and bone marrow cells (BMCs).8 In this article, we review the novel techniques of approaching AMI in advance and new methods to treat myocardial infarction (MI) mentioned above.

2. EPIDEMIOLOGY AND DEMOGRAPHICS OF AMI

In the past two decades, outcomes regarding AMI have progressed significantly in the United States, including 30-day mortality after AMI (20.0%-12.4%), 30-day all-cause rate of readmissions (21.0%-15.3%), and 1-year recurrent AMI (7.1%-5.1%),17 and this trend of improvement was also reported in Taiwan, with a lower post-AMI in-hospital mortality (6.5% in 2011 vs 9.1% in 1997).39,40 The key factors may be attributed to the adoption of the troponin test to shorten the time of diagnosis and the development of PCI for early revascularization.40 Therefore, further efforts and strategies to reduce total ischemic time are paramount issues in the future.41

3. NEW SERUM BIOMARKERS FOR THE DIAGNOSIS OF AMI

To improve the prognosis of AMI patients, the main issues of novel biomarkers are their accuracy and speed.42 In addition to myocardial necrosis, other processes involved in AMI have been studied (Table 1), allowing for new biomarker approaches in AMI.18

Table 1 - Novel blood biomarkers for the diagnosis of acute myocardial infarction Mechanism Biomarkers Myocyte necrosis H-FABP, IMA, cMyC Neurohormonal activation BNP, NT-proBNP, copeptin, MR-proADM Inflammation CRP, IL-6, PCT, MMPs, IL-1β, IL-37, angiopoietin-like protein 2 Plaque destabilization and myocyte rupture MPO, CD40, lipoprotein A, apolipoproteins A and B, endocan, platelet-related markers Peptide, protein, and enzyme released GDF-15, Gal-3, sST2 Circulating ribonucleic acids miRNAs, circular RNAs, lncRNAs

BNP = B-type natriuretic peptide; CD40 = cluster of differentiation 40 protein; cMyC = cardiac myosin–binding protein C; CRP = C-reactive protein; Gal-3 = galectin-3; GDF-15 = growth differentiation factor 15; H-FABP = heart-type fatty acid–binding protein; IL-1β = interleukin-1β; IL-37 = interleukin-37; IL-6 = interleukin-6; IMA = ischemia-modified albumin; lncRNAs = long noncoding RNAs; miRNAs = microRNAs; MMPs = matrix metalloproteinases; MPO = myeloperoxidase; MR-proADM = mid-regional proadrenomedullin; NT-proBNP = N-terminal pro B-type natriuretic peptide; PCT = procalcitonin; sST2 = soluble suppression of tumorigenicity factor 2.

3.1. Biomarkers of myocyte necrosis

Biomarkers of myocyte necrosis, such as heart-type fatty acid–binding protein (H-FABP), ischemia-modified albumin, and sarcomeric cardiac myosin–binding protein C (cMyC), have been proposed in recent studies, with cMyC deemed promising.43–45

3.2. Biomarkers of neurohormone activation

Biomarkers of neurohormonal activation, including B-type natriuretic peptide, the N-terminal fragment of its precursor (NT-proBNP), copeptin, and mid-regional proadrenomedullin (MR-proADM), have been demonstrated.46–49

3.3. Biomarkers of inflammation

Biomarkers of inflammation, including C-reactive protein, interleukin-6 (IL-6), procalcitonin (PCT), matrix metalloproteinases (MMPs), interleukin-1β (IL-1β), interleukin-37 (IL-37), and angiopoietin-like protein 2, which are challenged due to its nonspecificity and required further studies before drawing a clear conclusion.50–54

3.4. Biomarkers of plaque destabilization and myocyte rupture

Plaque destabilization and myocyte rupture may produce myeloperoxidase (MPO), cluster of differentiation 40 protein (CD40), lipid markers (lipoprotein A, apolipoproteins A and B), endothelial cells (endocan), and platelets (mean platelet volume, mean platelet volume-to-platelet count ratio, beta-thromboglobulin, and platelet miR-126), which can be valuable; however, more studies are needed.55–57

3.5. Peptide, protein, and enzyme released

In addition to the biomarkers associated with myocardial necrosis and related processes, novel peptides, proteins, and enzyme candidates have emerged. For example, growth differentiation factor 15 (GDF-15), galectin-3 (Gal-3), and soluble suppression of tumorigenicity factor 2 (sST2) are promising new AMI biomarkers.58–60

3.6. Circulating ribonucleic acids

Moreover, circulating ribonucleic acids (RNAs) in AMI have been widely studied recently, including noncoding RNAs such as microRNAs (miRNAs), circular RNAs, and long noncoding RNAs (lncRNAs).61,62

Future large sample-size clinical trials are needed to ensure the efficacy of the new biomarkers under study, and the multibiomarker-based approach to AMI remains promising (Table 2).18

Table 2 - Selected studies of new serum biomarkers for the diagnosis of AMI Study Design Patient characteristics Objectives Endpoints Results Tousoulis et al56 Cohort 596 patients with 310 patients (201 patients with stable CAD, 109 patients with AMI) with CAD and 286 healthy controls To study the association between sCD40L and coronary artery disease Serum concentrations of sCD40L in different groups Patients with AMI got higher levels of sCD40L compared to both CAD (p < 0.01) and controls (p < 0.01). Besides, CAD also had higher levels of sCD40L compared to controls (p < 0.01) Kelly et al52 Cohort 997 patients with AMI Aim to study the association between procalcitonin and major adverse cardiac events, LV function and remodeling after AMI Major adverse cardiac events, LV function and volume Procalcitonin was related to major adverse cardiac events on univariable and multivariable analysis. Weak but statistically significant association with LV function and remodeling were also observed Ray et al48 Cohort 451 patients with history of CAD and absent of cTn at admission To investigate the additional value of copeptin to conventional cTn for ruling out AMI on patients with acute chest pain The NPV of the combined measurement of copeptin and cTnI The combination of copeptin and cTnI enables clinicians to rule-out AMI presenting, with an NPV of 98% Cheng et al61 Meta-analysis 19 studies were included with 8 discussed miR-499 as a diagnostic biomarker of MI, 7 studies investigated miR-1, 4 studies evaluated miR-133a, 6 papers studied miR-208b, and 5 studies discussed another 9 types of miRNA To evaluate the diagnostic performance of circulating miRNAs as biomarkers of MI Sensitivity, specificity, and AUC for various miRNAs (miR-499, miR-1, miR-133a, miR-208b) as diagnostic markers of MI Particularly miR-499 and miR-133a, showed high-sensitivity and specificity for detecting myocardial infarction. The sensitivity and specificity for total miRNAs were 0.78 and 0.82, respectively, while for miR-499, miR-1, miR-133a, and miR-208b, they were 0.88 and 0.87, 0.63 and 0.76, 0.89 and 0.87, and 0.78 and 0.88, respectively Zhang et al58 Meta-analysis 8 cohorts, including 8903 participants with ACS To investigate the potential of GDF-15, a member of the TGF-β superfamily, as a predictive cytokine for the prognosis of ACS Risk of mortality and recurrent MI in patients with ACS High plasma GDF-15 levels were found to be associated with an increased risk of mortality and recurrent MI in patients with ACS Lisowska et al59 Cohort 333 patients including 233 patients with MI and 100 patients with stable CAD and 100 healthy controls To determine if Gal-3 can act as an independent risk factor of CAD occurrence and its advancement Gal-3 concentrations, mortality rate, cardiovascular risk Gal-3 may be an independent risk factor of CAD occurrence and independent prognostic factors of increased risk of all-cause mortality in patients post-MI Fanola et al51 RCT 4939 moderate to high risk patients within 30 d of hospitalization with an ACS Aim to study the prognostic implications of IL-6 after ACS Adverse cardiovascular events and cardiovascular death For every SD increase in IL-6, 10% higher risk of adverse cardiovascular events were noted (adjusted HR = 1.10; 95% CI, 1.01-1.19) and a 22% higher risk of cardiovascular death or heart failure were also noted. (adjusted HR = 1.22; 95% CI, 1.11-1.34) Schernthaner et al60 Case-control 194 patients, including 118 AMI patients and 76 controls with excluded CAD To study the role of novel biomarkers such as sST2, GDF-15, suPAR, H-FABP, and plasma fetuin A, representing different pathobiological pathways in patients with AMI Serum levels of sST2, GDF-15, suPAR, H-FABP, and plasma fetuin A The study found that compared to controls, patients with STEMI and NSTEMI had higher levels of sST2, GDF-15, suPAR, H-FABP, and lower plasma fetuin A levels Falkentoft et al49 Cohort 1122 patients admitted to the hospital with chest pain of <12 h duration and ST-segment elevation To examine the prognostic value of MR-proADM at admission in patients with STEMI Short- and long-term mortality and hospital admission for heart failure Doubling MR-proADM level was associated with an increased risk of 30-d mortality (HR = 2.67; 95% CI, 1.01-7.11; p = 0.049), long-term mortality (HR = 3.23; 95% CI, 1.97-5.29; p < 0.0001), and heart failure (HR = 2.71; 95% CI, 1.32-5.58; p = 0.007) Lahdentausta et al53 Cohort 669 patients with 343 patients included 108 unstable angina pectoris and 235 AMI patients and 326 controls without previous CAD To evaluate the association between MMP-9 and the MMP-9/TIMP-1 ratio and ACS Major adverse cardiac events MMP-9 and the MMP-9/TIMP-1 ratio were related to ACS (OR = 5.81; 95% CI, 2.65-12.76, 4.96, and 2.37-10.38). Besides, high serum level of MMP-9 activation potential is related to poor cardiovascular outcome Omran et al55 Cohort 150 patients admitted to the emergency department with chest pain and suspected AMI The aim of the study was to investigate the role of MPO as a biomarker for early diagnosis of AMI in patients admitted with chest pain Diagnostic accuracy, including sensitivity, specificity, PPV, NPV The study found that MPO levels were significantly higher in patients with AMI compared to those with non-AMI chest pain. MPO also had high-sensitivity (94.5%) and specificity (56%) for the diagnosis of AMI in 0 to 6 h the first onset of the symptoms, with a PPV of 82.5% and an NPV of 82.4% Kaier et al45 Cohort 776 patients with persisting chest discomfort, acute dyspnea without known pulmonary disease or suspected AMI Whether the novel biomarker, cMyC, can help early diagnosis of AMI Discrimination power, diagnostic performance Discrimination power of cMyC was better than that of high-sensitivity cTnT. At a previously published rule-out threshold (10 ng/L), cMyC achieves 100% sensitivity and NPV in patients after 2 h of AMI-related symptoms

ACS = acute coronary syndrome; AMI = acute myocardial infarction; AUC = area under the curve; CAD = coronary artery disease; cMyC = cardiac myosin–binding protein c; cTn = cardiac troponin; cTnI = cardiac troponin I; cTnT = cardiac troponin T; Gal-3 = galectin-3; GDF-15 = growth differentiation factor 15; H-FABP = heart-type fatty acid–binding protein; HR = hazard ratio; IL-6 = interleukin-6; LV = left ventricle; MI = myocardial infarction; miR-1 = micro ribonucleic acid 1; miR-133a = micro ribonucleic acid 133a; miR-208b = micro ribonucleic acid 208b; miR-499 = micro ribonucleic acid 499; miRNA = micro ribonucleic acid; MMP-9 = matrix metallopeptidase 9; MPO = myeloperoxidase; MR-proADM = mid-regional proadrenomedullin; NPV = negative predictive value; NSTEMI = non-ST-segment elevation myocardial infarction; OR = odds ratio; PPV = positive predictive value; RCT = randomized controlled trial; sCD40L = soluble cluster of differentiation 40 protein ligand; sST2 = soluble suppression of tumorigenesis 2; STEMI = ST-segment elevation myocardial infarction; suPAR = soluble urokinase plasminogen activator receptor; TGF-β = transforming growth factor β; TIMP-1 = metallopeptidase inhibitor-1.

4. HYPOTHERMIA THERAPY FOR AMI

There are four main types of reperfusion injury: myocardial stunning, reperfusion-induced arrhythmias, the no-reflow phenomenon, and lethal myocardial reperfusion injury.20 Hypothermia therapy is believed to be beneficial to reperfusion injury by reducing the energy demand of myocardial cells.21,22 It has a multifaceted impact on various signaling pathways involved in myocardial ischemia and reperfusion injury.21,24 This distinguishes it from single-target approaches, such as pharmacological interventions, and makes it a promising treatment strategy.21,24

4.1. Myocardial stunning

Myocardial stunning is a transient status in which myocardial cells are unable to fully regain contractility immediately after reperfusion from AMI.63 This condition may increase the risk of cardiogenic shock.63 Temperature significantly influences myocardial contractility.21 Mild hypothermia therapy (32°C-35°C) is reported to better preserve myocardial contractility after reperfusion, whereas severe hypothermia therapy (20°C-28°C) has shown pessimistic results.64–66

4.2. Reperfusion-induced arrhythmias

After reperfusion, electrical changes can occur in the myocardium, including the development of ventricular arrhythmias.67 It is believed to be an expression of myocardial reperfusion injury and is negatively correlated with infarction size.68

Studies have revealed that more arrhythmias, including ventricle tachycardia and atrial fibrillation, were noted in both systemic mild and severe hypothermia therapy compared to normal cardial temperature.23,69,70 However, in regional mild hypothermia, studies have shown positive results regarding the impact of hypothermia therapy on sustaining ventricular tachycardia.71,72 Further studies are needed to draw a clear conclusion.

4.3. No-reflow phenomenon

The no-reflow phenomenon observed after reperfusion is hypothesized to be caused by interstitial edema and obstructive swelling of endothelial cells, leading to compression of the microvasculature.21 Regarding the no-reflow phenomenon in hypothermia therapy, it was successfully proven that hypothermia therapy minimizes the damage of the no-reflow phenomenon by limiting edema in animal studies, but the available human data remains limited.23,73,74

4.4. Lethal myocardial reperfusion injury

During ischemia, a lack of oxygen and nutrients leads to reduced cellular metabolism and lactate accumulation. However, when blood flow is suddenly restored, a series of complex pathological processes, including oxidative stress, inflammation, calcium overload, mitochondrial dysfunction, and activation of cell death pathways, can occur, leading to the exacerbation of myocardial injury. This phenomenon, which represents paradoxical harm, is called lethal myocardial reperfusion injury.20,75,76 With regard to lethal myocardial reperfusion injury, many animal studies have proven that hypothermia therapy reduces lethal myocardial reperfusion injury; however, in RCTs involving patients with AMI, such results remain unclear.21,73,77,78

Although further clinical studies are needed to confirm the safety and efficacy of hypothermia therapy, this method remains a potential therapy for myocardial reperfusion injury because of its multitarget effects.21 Furthermore, new strategies, such as selective hypothermia therapy, will be a major consideration in future.21,24

5. SSO2 THERAPY FOR AMI

Microvascular obstruction (MVO), caused by releasing debris downstream and endothelial swelling owing to ischemia after PCI reperfusion, can lead to the “low or no-reflow” phenomenon and significantly affect the infarct size of AMI.25 SSO2 is an approach that utilizes catheter to enhance regional coronary blood oxygen pressure to an extremely high levels following PCI in patients with AMI, aiming to elevate oxygen levels in endothelial cells and myocardial tissue through the transportation of plasma.25,26

The AMI with hyperoxemia therapy I (AMIHOT-I) trial, an RCT involving 269 patients, found no significant difference in the infarct size between the groups in the overall cohort. However, subgroup analysis revealed that patients with anterior infarcts who received treatment with SSO2 within 6 hours of symptom onset had a smaller infarct size than the control group. Additionally, these patients exhibited improved regional wall motion. Furthermore, the area under the ST-segment deviation time curve over 3 hours decreased in the SSO2-treated group.28

The AMIHOT II study, based on the AMIHOT-I study, an RCT involving 301 patients, revealed that in patients with anterior ST-segment elevation myocardial infarction (STEMI) who underwent PCI within 6 hours of symptom onset, the infusion of SSO2 into the infarct territory of the left anterior descending artery led to a significant reduction in infarct size. This reduction in infarct size was accompanied by noninferior rates of major adverse cardiovascular events (MACEs) at 30 days compared to standard treatment.29

The intracoronary hyperoxemic SSO2 therapy (IC-HOT) study, an RCT involving 100 patients, showed that infusion of SSO2 following primary PCI in patients with anterior STEMI was associated with improved 1-year clinical outcomes. Specifically, patients who received SSO2 therapy demonstrated lower rates of death, new-onset heart failure (HF), or HF hospitalization than those who received standard treatment.27

The Food and Drug Administration has also approved SSO2 as an adjunct therapy for the reperfusion of STEMI.25

6. FUTURE THERAPEUTIC APPROACHES TO TARGET INFLAMMATION OF INJURED MYOCARDIAL CELLS

After AMI, to decrease the proinflammatory response and to enhance the following anti-inflammatory reparative response are believed to limiting MI size and preventing adverse left ventricle (LV) remodeling.79 Therefore, several methods, such as corticosteroids and nonsteroidal anti-inflammatory drugs, complement cascade inhibition, neutrophils inhibition, P-selectin antibody, and therapeutic targeting of inflammatory cytokines (IL-1β, IL-6), are targeting proinflammatory response after AMI.80–86 Many of these studies failed to reveal optimistic outcomes in clinical trials87; however, new methods are emerging to target post-AMI inflammation (Table 3). Multitargeted therapies that combine anti-inflammatory agents with mitochondrial and endothelial protective therapies are a promising approach.88

Table 3 - Novel therapeutic approaches to target inflammation of injured myocardial cells Category Target Outcome Evidence Antibody Toll like receptor 2 or 4 Decreased myocardial infarction size Animals trials Drug NLRP3 inflammasome Decreased myocardial infarction size Animals trials RNAse 1 eRNA Decreased myocardial infarction size Animals trials Colchicine Tubulin and microtubule Decreased ischemic cardiovascular events RCT trials Decreased inflammatory markers

eRNA = enhancer RNA; NLPR3 = nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3; RCT = randomized controlled trial; RNAse 1 = ribonuclease 1.

6.1. Anti–toll-like receptor 2 or 4 antibodies

The use of anti–toll-like receptor 2 or 4 antibodies at the time of reperfusion may decrease the release of several inflammatory mediators and lead to reduced MI size in animal models.30,36 However, associated clinical trials are still underway.31

6.2. Nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3 inflammasome inhibitor

In animal trials, pharmacological inhibition of the nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome, a component activating the inflammatory process, minimized MI size when administered within 60 minutes of reperfusion initiation; however, further clinical investigations are required.32,33

6.3. Ribonuclease 1

Small experimental animal studies have shown that using ribonuclease 1 (RNase1) to break down extracellular RNA (eRNA) after AMI may decrease infarction size, but more clinical trials to support these results are still need.34,35

6.4. Colchicine

Colchicine, a widely used potent anti-inflammatory medication, inhibits tubulin polymerization, and microtubule formation. The beneficial effects of colchicine in post-MI patients have been demonstrated in an RCT.37 Specifically, colchicine has been shown to reduce ischemic cardiovascular events and lead to a decrease in inflammatory markers such as high-sensitivity C-reactive protein and white cell counts.37 These findings suggest that colchicine exerts anti-inflammatory effects in post-MI patients.37 However, larger trials are needed to assess individual end points such as benefits of reducing MI sizes, subgroups analyses and the risks related to colchicine use.37

Although more clinical studies are needed to demonstrate the efficacy and safety of these novel methods, they remain promising strategies to reduce infarction size and prevent adverse LV remodeling when AMI occurs (Table 4).87

Table 4 - Selected studies of novel therapeutic approaches to target inflammation of injured myocardial cells Study Design Participants characteristics Objectives Endpoints Results Arslan et al30 RCT animal trial 38 female pigs To evaluate the therapeutic efficacy of humanized anti-TLR2 antibody, OPD-305 for ischemia/reperfusion injury Cardiac function, geometry, infarction size, and cTnI levels Administration of OPN-305 before reperfusion significantly reduced infarct size (45% reduction, p = 0.041). Pigs treated with OPN-305 also showed a significant preservation of systolic function Toldo et al33 Cohort animal trial CD-1 male mice To assess the effects of NLRP3 inhibition in the inflammatory response to myocardial ischemia/reperfusion injury Infarction size in 1, 3, and 24 h Inhibition of the NLRP3 inflammasome within 1 h of reperfusion reduced the inflammatory response to myocardial ischemia/reperfusion injury and limited myocardial damage Cabrera-Fuentes et al34 Cohort animal trial Wistar rats 10 to 12 wk old and weighing 225 to 300 g To investigate the role of eRNA and TNF-α in cardiac ischemia/reperfusion injury and to evaluate the potential therapeutic effect of RNase1 Levels of eRNA and TNF-α in plasma and cardiac tissue, cardiac function, infarct size, and apoptosis The study found that ischemia/reperfusion injury increased the levels of eRNA and TNF-α in plasma and cardiac tissue, leading to increased apoptosis, larger infarct size, and impaired cardiac function. Treatment with RNase1 prevented the harmful interaction between eRNA and TNF-α and attenuated cardiac injury, resulting in reduced apoptosis, smaller infarct size, and improved cardiac function Stieger et al35 Cohort animal trial Male C57BL/6J mice aged 10 to 12 wk To investigate the role of eRNA in myocardial infarction and to evaluate the therapeutic potential of targeting eRNA using RNase1 Myocardial edema formation, infarct size, and survival rate Treatment with RNase1 significantly reduced edema formation and infarct size and improved survival rate in mice with myocardial infarction compared to control treatment Tardif et al37 RCT 4745 patients who had a myocardial infarction within 30 d before enrollment with 2366 in colchicine group and 2379 in placebo group To assess the efficacy and safety of low-dose colchicine in reducing cardiovascular events and inflammation after myocardial infarction Ischemic cardiovascular events, such as recurrent myocardial infarction, stroke, or cardiovascular death The study demonstrated that treatment with low-dose colchicine significantly reduced the risk of ischemic cardiovascular events in patients after myocardial infarction. Additionally, colchicine treatment led to a reduction in inflammatory markers, suggesting its anti-inflammatory effects

cTnI = cardiac troponin I; eRNA = extracellular RNA; NLRP 3 = nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3; RCT = randomized controlled trial; TLR2 = toll like receptor 2; RNase1 = ribonuclease 1; TNF-α = tumor necrosis factor-α.

7. TARGETING ANGIOGENESIS IN MI

Angiogenesis, which forms new vessels based on former vasculature, can effectively decrease the size of cardiac tissue necrosis and promote myocardial cell regeneration by restoring blood supply after infarction.38 There are several strategies to induce angiogenesis in MI.

7.1. Mesenchymal stem cells

MSCs are stromal cells with self-renewal ability and the capacity to differentiate into multiple cell types.89 They can be derived from various tissues, including the umbilical cord, endometrial polyps, bone marrow, and other stem cell sources.89 MSCs have been widely researched in recent years, because of their powerful applications and ease of collection.90

7.2. Engineered exosomes with particles

Engineered exosomes with particles that have many effects, including anti-inflammatory, anti-apoptotic, anti-cardiac remodeling, and stimulation of angiogenesis, remain the mainstream exosome modality.91

7.3. Natural and artificial biomaterials

Both natural and artificial biomaterials, such as collagen, fibrinogen, and polypyrrole-coated biospring, have the advantages of degradability and easy access and were assessed for repairing infarcted myocardial cells in recent years.92

7.4. Biological factors

Biological factors, such as stromal cell–derived factor-1 (SDF-1) and Annexin V, play a role in infarcted myocardial cell repair and have gained popularity in recent years.93

7.5. Gene therapy

Gene therapy using genetic engineering technology may help repair infarcted myocardial cells by constructing angiogenic fusion plasmids or producing angiogenic gene–modified cells.94,95

To target angiogenesis in MI, it is necessary to understand the therapeutic mechanisms, and more studies and clinical trials are required.38

8. STEM CELL THERAPY

Because the necrotic myocardial tissue of MI cannot be repaired using traditional treatments, the use of stem cells has gained attention.8 Two kinds of stem cells are mainly used: pluripotent stem cells, which include ESC and iPSC, and adult stem cells, which contain MSCs, SkMCs, and BMC.8

8.1. Pluripotent stem cells

ESCs use is still limited due to possible inappropriate differentiation and aggressive immune response.96–99 Using iPSCs may avoid immune rejection because they are collected from patient somatic cells, but the efficiency of differentiation is very low.