Introduction
Myocardial injury represents a severe comorbidity of SARS-CoV-2 infection, particularly when infection-triggered coronary occlusion precipitates acute coronary syndromes (ACS).1,2 As a critical cardiovascular manifestation, ACS substantially contributes to elevated mortality rates in affected populations.1,2 Emerging evidence has demonstrated that impaired ventilatory efficiency is a characteristic functional impairment in COVID-19 survivors developing ACS, highlighting persistent cardiopulmonary sequelae post-infection.3 However, the mechanisms by which viral infection triggers non-infectious ACS remain controversial. This mini-review aimed to highlight the potential association between long COVID and ACS while exploring the therapeutic potential of phytochemical compounds in alleviating SARS-CoV-2-related long-term symptoms in ACS patients.
Acute infection with SARS-CoV-2 triggers ACS
Acute infections, especially viral ones, may worsen ACS by triggering widespread inflammation that destabilizes plaques and impairs endothelial function.
In addition to the well-established view that ischemia in ACS is an aseptic inflammation process, acute infections by pathogens, including viruses and bacteria, are suggested to accelerate the pathological progression of ACS. Substantial elevations in serum inflammatory biomarkers—including acute-phase reactants (C-reactive protein and procalcitonin), neutrophil-derived enzymes (myeloperoxidase), and circulating leukocyte subsets (macrophages, T lymphocytes, and neutrophils)—are characteristically observed during ACS pathogenesis, with significantly higher levels than those detected in stable coronary artery disease patients.4,5
The inflammatory activity is not limited to the culprit lesion in the coronary artery but extends across the entire coronary tree, indicating that this is a systemic inflammation. Growing evidence suggests that acute infection-induced inflammatory responses may directly influence atherosclerotic plaque stability, coronary arterial integrity, and peri-adventitial adipose tissue through cellular mediators and their molecular effectors, including cytokine networks, proteolytic enzymes, coagulation cascade components, oxidative metabolites, and vascular tone regulators.5 These targeted inflammatory mechanisms potentiate endothelial dysfunction through vasa vasorum leakage, compromise fibrous cap integrity via necrotic core expansion, and propagate platelet-rich thrombus formation through coordinated P-selectin/GPIIb-IIIa interactions, collectively implicating sterile inflammation as a critical driver of both ACS initiation and progression.6
SARS-CoV-2 virus infection accelerates ACS through the angiotensin-converting enzyme (ACE) 2 receptor
SARS-CoV-2 induces heart damage via ACE2, causing inflammation, endothelial dysfunction, and clot formation that trigger myocardial injury and atherosclerosis through cytokine storms, plaque rupture, clotting changes, and oxygen supply issues, all of which increase the risk of ACS.
The acute SARS-CoV-2 infection led to a global pandemic, with acute myocardial injury (AMI) being prominently associated with comorbidities, alongside acute pulmonary injury.7 AMI is pathologically defined by substantial elevations in high-sensitivity cardiac troponin and/or brain natriuretic peptide, biomarkers that reflect myocardial stress from ischemic insults (e.g., plaque rupture-induced coronary occlusion) or non-ischemic etiologies such as ACS, decompensated heart failure, inflammatory cardiomyopathies, and arrhythmogenic myocardial remodeling.8
For ischemic heart disease, elevated troponin levels can be driven not only by direct coronary artery occlusion but also by indirect myocardial injury, such as the cardiovascular inflammation process, which may accelerate ischemic myocardial injury.9 Notably, the latter occurs during acute SARS-CoV-2 infection, when internalization of the SARS-CoV-2 virus requires the ACE2 receptor for transport.10,11
The extensive ACE2 expression in cardiovascular tissues predisposes them to SARS-CoV-2 infection, driving endothelial dysfunction and vascular inflammation. This cascade promotes thrombotic events, systemic inflammatory responses, and hypoxia, while adrenergic overactivation exacerbates myocardial stress during cytokine storm progression.12–14 These effects may contribute to triggering ACS and accelerating atherosclerosis. The mechanisms are as follows (Fig. 1):
Firstly, Elevated troponin levels correlate with inflammatory markers such as D-dimer (coagulation), ferritin (acute-phase response), interleukin (IL)-6 (cytokine activity), and lactate dehydrogenase (tissue injury), suggesting systemic immune dysregulation involving cytokine storms and reactive phagocytic/lymphocytic responses, rather than direct myocardial damage, during SARS-CoV-2 infection.15–17
Secondly, marked inflammatory responses and hemodynamic instability predispose to atherosclerotic plaque rupture through mechanisms involving platelet activation/aggregation, ultimately precipitating acute coronary occlusion.18,19
Moreover, the inflammatory response impairs coronary endothelial function and hemostatic balance, increasing thrombin activity while reducing plasminogen activity,19 thus accelerating fibrin degradation products and D-dimer, leading to a pro-atherogenic and thrombogenic bias.20,21
Last but not least, the myocardial oxygen supply-demand imbalance due to hypoxia and tachycardia caused by systemic cytokine storms and pulmonary injury,22 probably becomes a synergistic factor that works with endothelial inflammation, vascular edema, and disseminated intravascular coagulation, ultimately exacerbating microvascular dysfunction, occlusion, or coronary spasm in myocardial tissue.23–25
Thus, it is deduced that myocardial injury in patients with SARS-CoV-2 infection could be due to inflammation-induced direct endothelial and vascular injury, plaque rupture with platelet activation and aggregation, microthrombi formation, microvascular dysfunction and occlusion, or coronary spasm.
Myocardial protective drugs can regulate the ACE2 receptor in SARS-CoV-2 virus infection
COVID-19, though primarily a respiratory illness, also affects the heart, raising questions about the use of ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) due to their effects on ACE2. Meanwhile, melatonin shows promise in protecting the heart by improving blood vessel function and stabilizing plaques, potentially reducing ACS risk.
COVID-19 patients predominantly present with fever and cough, more frequently in adults than in children, along with dyspnea and myalgia, among other clinical features.26 As SARS-CoV-2 virus entry into cells is ACE2-dependent, and ACEI and ARB are widely used in cardiovascular disorders, the rationale for the use of ACEI or ARB needs to be considered.27,28 So far, there are conflicting data on whether these drugs increase or have minimal effects on ACE2 levels, which still require further investigation.
Nevertheless, reports on melatonin suggest a potential protective role against myocardial injury in SARS-CoV-2 infection. The oxygen supply-demand imbalance caused by infection-stimulated hemodynamic activation, hypoxemia, and inflammation-induced plaque instability with coronary hypoperfusion leads to ischemic heart damage. Melatonin could enhance the bioavailability of nitric oxide and improve coronary endothelial function, alleviating plaque instability by inhibiting intra-plaque inflammation. Thus, it exerts a myocardial protective function, potentially mitigating ACS risk and even myocardial ischemia-reperfusion injury.29 Notably, this does not imply that melatonin is a specific medication targeting acute inflammation in AMI, but it inspires exploration of novel therapeutic approaches for alleviating ACS injury in patients with acute inflammation, such as those with SARS-CoV-2 infection.
Herb benefits both long COVID and myocardial diseases
The COVID-19 pandemic has accelerated research into traditional Chinese medicine and herbal therapies, highlighting their dual antiviral and cardioprotective benefits. These agents work through multiple mechanisms—blocking viral entry, suppressing replication, and reducing inflammation—potentially lowering ACS risk in COVID-19 patients.
Since the first novel coronavirus pneumonia case in 2019, COVID-19 has become a worldwide infectious disease. Following the outbreak, long COVID became a common symptom in most populations. In China, more than 85% of patients received traditional Chinese herbal medicine therapy.30 Treatment with Chinese herbal medicine has been shown to relieve patients’ symptoms.31
Accordingly, the most commonly used herb for patients is licorice. While the antiviral mechanisms of glycyrrhizin remain incompletely characterized, emerging evidence suggests its interaction with multiple signaling pathways—including protein kinase C, casein kinase II, AP-1, p38 MAPK, and NF-κB—modulates DNA repair mechanisms and transcriptional regulation.32–34 Glycyrrhiza species exert cardioprotective effects via coordinated mechanisms, including attenuation of oxidative damage through Nrf2/ARE pathway activation, upregulation of endogenous antioxidant defenses, restoration of cardiac functional parameters, and preservation of myocardial structural integrity.35 Moreover, glycyrrhizic acid and its bioactive metabolite glycyrrhetinic acid suppress inducible nitric oxide synthase expression in activated macrophages, reducing nitric oxide synthesis—a critical driver of oxidative and inflammatory cascades in acute lung injury pathogenesis. Agastache rugosa, Forsythia suspensa, Atractylodes macrocephala, and Scutellaria baicalensis are also widely used in the mild and moderate stages of COVID-19.36 In clinical treatment, licorice is used in many traditional Chinese medicine prescriptions, such as QingFeiPaiDu decoction,37 ShuFengJieDu granules,38 JinHuaQingGan granules, and LianHua QingWen capsules.39
LianHua QingWen granules, a classic traditional Chinese medicine formula,40,41 have been approved to treat fever, fatigue, and other symptoms caused by mild COVID-19. Regarding the effect of herbs in the composition of LianHua QingWen granules, Chen et al.42 show that several anti-plague components from lotus play a potential role in inhibiting COVID-19 by significantly affecting the binding between ACE2 and S protein, which is a critical mechanism for preventing viral infection. Pan et al.43 showed that puerarin and quercetin may also combat COVID-19 through a similar mechanism by affecting the interaction between S protein and ACE2.
Astragalus membranaceus has a variety of pharmacological activities, including anti-virus, anti-inflammatory, and immune system regulation. It is rich in Astragalus polysaccharides, which have antiviral effects.44,45 Honeysuckle is also an effective anti-inflammatory Chinese herbal medicine, which is used for a variety of viral infections,46 such as hepatitis B virus,47 dengue virus,48 and intestinal and respiratory viruses, etc. These two herbs have been used since ancient China. Yeh et al.49 showed that honeysuckle-Astragalus preparation can not only improve the expression of a group of COVID-19-related miRNAs but also inhibit the expression of IL-6 and TNF-α, key inflammatory factors in cytokine storms, indicating that it has a certain inhibitory effect on cytokine storms. Furthermore, this preparation can inhibit the binding of COVID-19 protein to the ACE2 receptor, thus playing an antiviral role. In clinical practice, many Chinese patent medicines are in use, including Astragalus membranaceus or honeysuckle, such as Fuling Paidu decoction and Jinhua Qinggan capsules,50 which can be used to treat patients at various stages.51,52
Herb-derived medicine is also under investigation for the treatment of SARS-CoV-2 virus infection. These compounds or phytomedicines include Coronil,53 Cuphea ignea,54 Reynoutria Rhizomes,55 Cordycepin,56–58 Glycyrrhizic Acid,59–61 Perilla frutescens,62,63 Cyperus rotundus Linn,64 Thymoquinone,65–67 and others. The underlying mechanisms for the antiviral effects involve preventing the replication of the virus (e.g., Reynoutria Rhizomes),55 exhibiting inhibitory potential against the COVID-19 polymerase enzyme (RdRp) (e.g., Cordycepin),68 effectively killing the SARS-CoV-2 virus by targeting key protein structures of the virus or through immune synergy with other antiviral drugs (e.g., Glycyrrhizic Acid),59 blocking viral RNA and protein synthesis (e.g., Perilla frutescens leaf extract),62 inhibiting SARS-CoV-2 virus proteases to reduce viral replication, and antagonizing angiotensin-converting enzyme 2 receptors (e.g., Thymoquinone).69 Thus, these studies provide promising candidates for treating SARS-CoV-2 virus-induced ACS and, therefore, diminishing ACS injury (Table 1 and Fig. 2).32,40–45,49,50,54,57,63-69
Table 1Mechanism of traditional Chinese medicine in the modulation of COVID-19 and myocardial diseases
| Name | Composition | Pharmacological action | Drug target/related signal | Mechanism of action | Myocardial protection | Study type (sample size) | Population characteristics | Key findings (odds/hazard ratio) | Reference |
|---|
| Honeysuckle Astragalus preparation | Astragalus membranaceus, Honeysuckle | Anti-virus, anti-inflammatory, regulating the immune system | IL-6, TNF-a | Suppressing cytokine storm, inhibiting the binding of COVID-19 protein and ACE2 receptor | Yes65,66 | Review (one study); Preclinical (animal study); Pharmaceutical Analysis (two studies); Multiple Databases Analysis (one study) | N/A | N/A | 40–45 |
| Licorice | Glycyrrhizic Acid | Anti-inflammatory, antioxidant, antitumor | Protein kinase C, casein kinase, AP-1, MAPK-p38 and NF-κB, iNOS | Targeting important protein structures of the virus or immune synergy effect with other antivirus drugs, Inhibition of acute lung injury | Yes67 | Review (two studies) | N/A | N/A | 32,54 |
| Nigella sativa | Thymoquinone | Antioxidant, anti-inflammatory, antiviral, antimicrobial, immunomodulatory, and anticoagulant | Cell surface heat shock protein (HSPA5), ACE2 receptor, IL-2, IL-4, IL-5, II-6, IL-12, IL-13 | Inhibiting virus proteases to diminish viral replication and as antagonism to angiotensin-converting ACE2 receptors | Yes68 | Review (one study) | N/A | N/A | 64 |
| Cuphea ignea | – | Antiulcerogenic, antitumor, antioxidant and antihypertensive | – | Inhibiting virus growth | No | Pharmaceutical Analysis (one study) | N/A | N/A | 49 |
| Reynoutria Rhizomes | – | Antioxidant, antitumor, anti-inflammatory, and antiviral | – | Preventing the replication of the virus, inhibiting virus growth | No | Pharmaceutical Analysis (one study) | N/A | N/A | 50 |
| Cordycepin | – | Anti-inflammatory, antiviral, antibacterial, etc. | – | Inhibiting RdRp | Yes69 | Molecular Dynamic simulation(one study) | N/A | N/A | 63 |
| Perilla | Perilla frutescens leaf extract | Leaves are used to tonify stomach function, discharge heat, and improve healthy qi, and seeds decrease qi, resolve phlegm, relieve cough and asthma, and alleviate constipation | CXCL10, IL-6, TNF-α, IFN-γ, MCP1 | Blocking viral RNA and protein synthesis, inhibiting proinflammatory factor expression | Unknown | Drug Extraction(one study) | N/A | N/A | 57 |
Non-herbal medicine benefits both long COVID and myocardial diseases
The S proteins of SARS-CoV-1 and CoV-2 share 76% overall sequence identity, yet the receptor-binding domain of the latter has 10–20 times higher affinity for the human ACE2 receptor protein.70 After the receptor-binding domain binds ACE2, two heptad repeat domains, HR1 and HR2, interact to form a six-helical bundle, bringing the viral and host membranes close to one another, resulting in fusion. Using a recently solved crystal structure of the HR1 and HR2 domains of the SARS-CoV-2 S protein, lipidated peptide fusion inhibitors have been designed to inhibit pseudovirus infection of cells, with IC50 values in the single-digit nanomolar range.71 Due to its broad-spectrum anti-coronavirus activity, EK1C4 can be used for the treatment and prevention of infection not only by SARS-CoV-2 but also by other HCoVs. However, its fundamental limitation is the substantial development costs. Anakinra is the first recombinant IL-1 receptor antagonist that binds to both IL-1α and IL-1β receptors and has received approval from the U.S. Food and Drug Administration (FDA) for treating rheumatoid arthritis. In survival analysis, the development of any thromboembolic event, pulmonary thromboembolism, and ACS was higher in the SoC group compared to the Anakinra group. The survival rate was also lower in the SoC group than in the Anakinra group for patients who experienced thromboembolic events and ACS.72 However, its effectiveness in patients already suffering from respiratory failure has shown controversial results, and it is not recommended.73
Nanotechnology-based herbal medicine may benefit both SARS-CoV-2 virus infection and ACS by targeting the ACE2 receptor
Nanotechnology has revolutionized the COVID-19 response, enabling mRNA vaccine development and offering targeted therapies. Lipid nanoparticles have driven vaccine success, while nanoceria and silver nanoparticles show promise in fighting the virus and its complications through ACE2 modulation.
The U.S. FDA has granted Emergency Use Authorization for two mRNA vaccine candidates: Pfizer-BioNTech’s BNT162b2 and Moderna’s mRNA-1273.74 Emerging studies demonstrate that comprehensive targeting of conserved immunodominant epitopes across the full-length spike glycoprotein in SARS-CoV-2 variants, while harnessing the anti-inflammatory potential of regulatory T cells, provides critical insights for developing pan-coronavirus vaccines with broad-spectrum efficacy.75,76 The unprecedented efficacy of mRNA vaccines (BNT162b2 and mRNA-1273) has marked a turning point in pandemic containment. Nanoparticle platforms have proven instrumental in vaccine development, with lipid-based vectors shielding labile mRNA from ribonucleases while facilitating endosomal escape for cytosolic delivery. Phase III trials demonstrated 95% efficacy rates—a breakthrough stemming from innovative lipid nanoparticle delivery systems that optimize antigen presentation and enhance immunogenicity.77
Nanoceria (NC) is a rare-earth nano drug with catalase and superoxide dismutase mimic activity. In clinical studies, there is evidence that nanoceria can pass through TGF-β signaling pathways, potentially inhibiting the progression of fibrosis.78 NC may effectively inhibit fibrosis and reduce collagen deposition.79 Targeted transport of NC to the lungs may effectively alleviate acute respiratory distress syndrome.80
Targeted transportation may achieve better results. Silver nanoparticles (AgNPs) have also become one of the drugs that can inhibit SARS-CoV-2 virus infection due to their strong antiviral effect. AgNPs can attach to the virus genome to prevent viral replication and new virus release.81 AgNPs are likely to inhibit severe inflammatory responses, cytokine storms, and pulmonary fibrosis in COVID-19.82 More interestingly, reports have shown that cationic nanoparticles can directly bind ACE2, decrease its activity, and down-regulate its expression level in lung tissue, resulting in the deregulation of the renin-angiotensin system.83 Binding to ACE2 by multivalent attachment of ligands to nanocarriers incorporating antiviral therapeutics could increase receptor avidity and impart specificity to these nanovectors for host cells in the pulmonary tract. These findings suggest that nanoparticle-carrying herbal medicine may exert both cardioprotective effects in ACS and anti-inflammatory effects in SARS-CoV-2 virus infection by targeting the ACE2 receptor.
Nanotechnology plays a role in COVID-19 detection,84 diagnosis, treatment, and other stages.85 Nanobodies demonstrate therapeutic potential for COVID-19 by attenuating pulmonary hyperinflammation through targeted viral neutralization and immunomodulatory mechanisms.86 Nanodrugs have higher safety and biocompatibility and can provide more accurate drug targeting.87 However, nanoparticles also have limitations due to their toxicity. Nanoparticles have low solubility and degradability, so they can persist in cells for a long time and are not easily degraded.88 Furthermore, there is still a lack of a clear clearance mechanism.89 Therefore, the application of nanotechnology still needs to be further explored.
Future directions
Current research progress in phytomedicine has established critical directions for addressing SARS-CoV-2-associated cardiovascular complications, requiring systematic advancement across five key areas. First, large-scale, multicenter, randomized controlled trials should be prioritized to evaluate dose-response relationships of standardized phytochemical formulations (e.g., glycyrrhizic acid, astragaloside IV). These trials should be supported by longitudinal follow-up databases with a minimum three-year monitoring period to assess sustained efficacy and safety. Mechanistically, advanced structural biology techniques such as cryo-electron microscopy are needed to elucidate molecular interactions between bioactive plant compounds and ACE2 receptors. Concurrently, innovations in nanotechnology must address organ-targeting limitations through pharmacokinetic modeling to optimize nanoparticle delivery efficiency and biodegradability, alongside standardized toxicity assessments. Clinically, interdisciplinary frameworks should validate the synergistic effects between phytomedicine and conventional cardiovascular therapies across diverse ethnic populations, utilizing unified cardiovascular endpoints for efficacy evaluation. Furthermore, international consortia should integrate multi-omics platforms and leverage global COVID-19 cardiovascular sequelae registries to identify biomarkers predictive of phytotherapy responsiveness. These coordinated efforts will bridge gaps between preclinical research and clinical translation, ultimately informing evidence-based integrative cardiovascular care strategies.
Conclusions
Current research on SARS-CoV-2-associated ACS and herbal/nanotechnology therapies faces limitations, including reliance on observational data, unclear ACE2 mechanisms, and insufficient long-term safety evidence. Potential biases, such as overemphasis on positive results, may skew conclusions. SARS-CoV-2 triggers ACS through inflammation-induced myocardial injury, requiring therapies that target both cardiovascular damage and virus-driven inflammation. Promising approaches include ACE2-modulating drugs, traditional Chinese medicine, and nanotechnology, which stabilize plaques, protect endothelial function, and enable targeted delivery. However, challenges like nanoparticle toxicity must be addressed. A comprehensive, multi-modal strategy is essential for improving SARS-CoV-2-associated ACS outcomes. Compared to conventional therapeutic regimens, Chinese patent medicines demonstrate superior safety profiles characterized by a reduced incidence of adverse effects and lower treatment costs.
Declarations
Funding
This study was supported by the Zhuhai Social Development Field Science and Technology Plan-Key Project (No. 2320004000286, to RYY) and the Basic and Applied Basic Research of Guangzhou City-University Joint Funding Project (No. 202201020382, to RYY).
Conflict of interest
The authors declare that there is no conflict of interest in the authorship and publication of this contribution.
Authors’ contributions
Contributed to study concept and design (QL, RYY, YD), drafting of the manuscript (XJ, YRL, HS,QZ), critical revision (YYL, ZZ), and finalization of the manuscript (QL). All authors read and approved the final manuscript (PZL, CPL).